溃疡性结肠炎口服干预：整合抗氧化抗炎、肠道递送、黏膜屏障修复与微生态调节

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Ulcerative colitis (UC) involves immune dysregulation, barrier dysfunction, and dysbiosis, driving chronic inflammation and pain. Current treatments show limited efficacy and high toxicity. This study develops an engineered nanozyme, CO&MnOx@Hs (CMHs), synthesized via in-situ manganese oxide (MnOx) generation on halloysite nanotubes (Hs) with controlled encapsulation of the carbon monoxide (CO)-releasing molecule CORM-401 for gas therapy. CMHs selectively accumulate at inflamed UC sites, where MnOx scavenges reactive oxygen species (ROS) while CO exerts anti-inflammatory effects. These combined actions restore immune homeostasis, repair intestinal barrier, modulate gut microbiota, and alleviate inflammation-associated pain. In murine ulcerative colitis, CMHs outperform conventional treatments, demonstrating superior therapeutic efficacy. Mechanistic studies reveal that CMHs activate Nrf2/HO-1 for antioxidant effects while modulating PI3K-Akt and HIF-1α/LDHA pathways to promote M2 macrophage polarization and suppress NF-κB/TNF signaling. CMHs also fortify the intestinal barrier by mitigating bacterial invasion and ROS-induced damage while activating focal adhesion and ECM-receptor interaction. 16S ribosomal RNA sequencing further confirms CMHs' ability to remodel gut microbiota, reinforcing their immunomodulatory potential. Importantly, CMHs relieve chronic pain by reducing inflammation, inhibiting SP secretion and TACR1 expression, and suppressing TRPV1 channel activation and Ca2+ influx. These findings establish CMHs as a multi-targeted and highly effective therapeutic strategy for UC.

Background: Intestinal barrier dysfunction and persistent inflammatory response are key pathophysiologic features of ulcerative colitis (UC). High mobility group box‐1 protein (HMGB1), an important inflammatory mediator and immunomodulatory factor, has been shown to be involved in the pathogenesis of UC. However, the association between HMGB1 and intestinal barrier dysfunction is unclear.

Ulcerative colitis (UC) is a complicated and recurrent intestinal disease. Currently available drugs for UC treatment are scarce, therefore, novel therapeutic drugs for the UC are urgently to be developed. Gingerenone A (GA) is a phenolic compound known for its anti‐inflammatory effect, but its effect on UC remains unknown. Here, it is shown that GA protects mice against UC, which is closely associated with inhibiting intestinal mucosal inflammation and enhancing intestinal barrier integrity in vivo and in vitro. Of note, RNA sequencing analysis demonstrates an evident correlation with IL‐17 signaling pathway after GA treatment, and this effect is further corroborated by Western blot. Mechanistically, GA directly interacts with IL‐17RA protein through pull‐down, surface plasmon resonance analysis and molecular dynamics simulation. Importantly, lentivirus‐mediated IL‐17RA/Act1 knock‐down or GA co‐treatment with brodalumab/ixekizumab significantly impairs the protective effects of GA against DSS‐induced inflammation and barrier dysfunction, suggesting a critical role of IL‐17RA signaling for GA‐mediated protection against UC. Overall, these results indicate that GA is an effective agent against UC mainly through the direct binding of IL‐17RA to inhibit inflammatory signaling activation.

Macrophage polarization is closely associated with the pathogenesis of ulcerative colitis (UC). Quercetin, a flavonoid, has shown promise as a treatment for inflammatory diseases, but its specific mechanism of action remains unclear. This study investigates whether quercetin can regulate intestinal macrophage polarization and promote intestinal tissue repair via the cGAS-STING pathway for the treatment of UC. In vivo, mice with 3% DSS-induced UC were intraperitoneally injected with quercetin and RU.521 for 7 days, following which their general conditions and corresponding therapeutic effects were assessed. The impact of interferon-stimulated DNA (ISD) and quercetin on macrophage polarization and the cGAS-STING pathway was investigated using RAW264.7 cells and bone marrow-derived macrophages (BMDMs) in vitro. The results demonstrated that ISD induced M1 macrophage polarization and activated the cGAS-STING pathway in vitro, while quercetin reversed ISD’s inflammatory effects. In vivo, quercetin suppressed the cGAS-STING pathway in the intestinal macrophages of DSS-induced UC mice, which reduced M1 macrophage polarization, increased M2 polarization, and facilitated intestinal barrier repair in UC. Taken together, these findings provide new insights into the mechanisms via which quercetin could be used to treat UC.

Ulcerative colitis (UC) is a recurrent intestinal disease caused by a complex of factors, and there are serious adverse effects and tolerance problems associated with the current long-term use of therapeutic drugs. The development of natural food sources and multi-targeted drugs for the treatment of UC is imminent. Portulaca oleracea L. (PO), as a vegetable, has been shown in studies to have an anti-UC effects. However, the relationship between the abundant active ingredients contained in Portulaca oleracea L. and the improvement of intestinal barrier, gut microbiota and metabolites is unclear. In the present study, Portulaca oleracea L. which was found to be rich in phenolic acid-based active ingredients, were effective in alleviating dextran sulfate sodium (DSS)-induced body weight loss, disease activity index (DAI) score and colon length in mice. It also decreased C-reactive protein (CRP) and myeloperoxidase (MPO) responses, reduced the permeation of fluorescein isothiocyanate (FITC)-dextran, lipopolysaccharide (LPS) and evans blue (EB), and improved histopathological scores. Meanwhile, in vitro and in vivo validation revealed the protective effects of purslane on the intestinal barrier indicators ZO-1, Occludin and Claudin-1, and inhibited the expression of inflammation-associated iNOS and NLRP3 proteins through the NF-κB signaling pathway. In addition, purslane increased the diversity of the intestinal flora, enhancing the proportion of the genera Butyricoccus, Dorea and Bifidobacterium and decreasing the percentage of Bacteroides, Turicibacter and Parabacteroides. Serum metabolomics analysis showed that the imbalance of 39 metabolites was significantly reversed after PO deployment. Enrichment analysis showed that Pentose phosphate pathway and Pyruvate metabolism pathway were the key pathways of PO against UC. Overall, purslane effectively improved the intestinal barrier disruption and intestinal inflammation by inhibiting the NF-κB signaling pathway, and adjusted the disorder of gut microbiota and metabolites to exert anti-UC effects.

This study is to investigate the effect of SPS on the UC model. An animal model of UC induced by DSS was developed using C57BL/6 mice. The body weight was recorded every day, and the symptoms related to UC were detected. H&E staining, AB-PAS staining and PSR staining were used to evaluate the histopathological changes of the colon. Inflammation and mucosal barrier indicators were detected by qRT-PCR, and the 16 S rRNA sequence was used to detect the intestinal flora. SPS can significantly prevent and treat DSS-induced ulcerative colitis in animals. SPS significantly improved clinical symptoms, alleviated pathological damage, inhibited the infiltration of intestinal inflammatory cells. SPS treatment can protect goblet cells, enhance the expression of tight junction proteins and mucins, inhibit the expression of antimicrobial peptides, thereby improving intestinal barrier integrity. The prevention and treatment mechanism of SPS may be related to the inhibition of STAT3/NF-κB signaling pathway to regulate intestinal barrier function. In particular, SPS also significantly adjusted the structure of intestinal flora, significantly increasing the abundance of Akkermansia and Limosilactobacillus and inhibiting the abundance of Bacteroides. Overall, SPS has a significant therapeutic effect on ulcerative colitis mice, and is expected to play its value effectively in clinical treatment.

Ferroptosis, a recently discovered form of regulated cell death, has been implicated in the development of ulcerative colitis (UC). While Piezo1's role in inducing ferroptosis in chondrocytes and pulmonary endothelial cells is documented, its regulatory function in ferroptosis and intestinal epithelial cells in UC remains unclear. To address this, colonic tissue samples from patients with UC were examined, and specific intestinal epithelial Piezo1-deficient (Piezo1ΔIEC) mice were created to investigate Piezo1's role in UC pathogenesis. Elevated epithelial Piezo1 levels were observed in patients with UC, correlating with increased ferroptosis and tight junction (TJ) disruption. In dextran sulfate sodium (DSS)-induced colitis, Piezo1ΔIEC mice exhibited significantly reduced intestinal inflammation and improved gut barrier function compared to wild-type (WT) mice. Moreover, Piezo1 deficiency in colitis mice and lipopolysaccharide (LPS)-stimulated Caco-2 cells led to higher TJ protein levels, reduced lipid peroxidation, enhanced mitochondrial function, and altered expression of ferroptosis-associated proteins. Additionally, erastin, a ferroptosis activator, reversed the protective effect of Piezo1 silencing against LPS-induced ferroptosis in Caco-2 cells. Mechanistically, Piezo1 was found to regulate ferroptosis via the AMPK/mTOR signaling pathway. These findings highlight a novel role for Piezo1 deletion in mitigating ferroptosis in intestinal epithelial cells, suggesting Piezo1 as a potential therapeutic target for UC treatment.

We aimed to investigate the effect of a polysaccharide from Tremella aurantialba on ulcerative colitis (UC), which targets ferroptosis in epithelial cells. TA 2-1 (127 kDa) was isolated from T. aurantialba and consisted of Man, Xyl, GlcA, Glc, Fuc and Rha with a molar ratio of 59.2: 23.2: 13.9: 1.6: 1.7: 0.4, exhibited a 1, 3-Man structure with branch chains of T-Xylp, 1,3-Xylp, 1,4-GlcAp, and T-Manp at its O-2 position. TA 2-1 (100 mg/mL) inhibited the cell viability of ferroptosis (19.8 %) in RLS3-induced Caco2 cells and significantly ameliorated symptoms in the colons of mice with dextran sodium sulfate (DSS)-induced UC. TA 2-1 remarkably repaired the intestinal barrier by upregulating claudin-1 and zonula occludens-1 levels. Further analysis found TA 2-1 significantly suppressed lipid peroxidation by regulating ferroptosis-related proteins in UC mice, suggesting that its protective effects are partially mediated by inhibiting ferroptosis. Further analysis of the gut microbiota and fecal microbiota transplantation revealed TA 2-1 might relieve UC symptoms or inhibit ferroptosis by modulating the gut microbiota's composition or metabolites. Results suggest the protective effects of TA 2-1 on the intestinal barrier by inhibiting ferroptosis of epithelial cells, at least by regulating the gut microbiota, highlighting the potential of TA 2-1 in UC treatment.

Ulcerative colitis is a common type of inflammatory bowel disease that affects millions of individuals around the world. Traditional UC treatment has focused on suppressing immune responses rather than treating the underlying causes of UC, which include oxidative stress, inflammation, and microbiota dysbiosis. Diosmin (DIO), a naturally occurring flavonoid, possesses antioxidant and anti-inflammatory properties. This study aimed to assess the efficacy of DIO in treating dextran-sulfate sodium (DSS)-induced colitis, and to investigate some of its underlying mechanisms, with an emphasis on Akkermansia muciniphila abundance, inflammatory markers, and intestinal barrier function. C57BL/6 mice were given 4% (w/v) DSS to induce colitis. DSS-induced mice were administered DIO (100 and 200 mg/kg) or sulfasalazine orally for 7 days. Every day, the disease activity index (DAI) was determined by recording body weight, diarrhea, and bloody stool. Changes in fecal A. muciniphila abundance, colonic MUC1 and MUC2 expression, as well as oxidative stress and inflammatory markers were all assessed. Histopathological changes, colonic PIK3PR3 and ZO-1 levels, and immunohistochemical examinations of occludin and claudin-1, were investigated. DIO administration resulted in a dose-dependent decrease in DAI, as well as increase in A. muciniphila abundance and MUC2 expression while decreasing MUC1 expression. DIO also dramatically reduced colonic oxidative stress and inflammation by regulating the NF-κB and Nrf2 cascades, restored intestinal barrier integrity by inhibiting PIK3R3 and inducing ZO-1, and improved occludin/claudin-1 gene expression and immunostaining. This study provides the first evidence that DIO preserves intestinal barrier integrity and increases A. muciniphila abundance in DSS-induced colitis. However, more research is required to explore the impact of DIO on the overall composition and diversity of the gut microbiota. Likewise, it will be important to fully understand the molecular mechanisms by which A. muciniphila maintains intestinal barrier function and its potential use as an adjuvant in the treatment of UC.

Ulcerative colitis (UC) is a chronic and recurrent inflammatory bowel disease (IBD). There is a growing prevalence of UC, but current conventional drugs lack efficacy. Carthamin yellow (CY) is a flavonoid compound extracted from safflower that is widely used and has various pharmacological effects. In the present study, we established colitis models in mice via DSS and in Caco-2 cells via lipopolysaccharide (LPS). Our results showed that CY treatment attenuated the symptoms of colitis by decreasing colonic pathological damage and improving disease activity index (DAI) scores. Notably, we observed that CY treatment decreased the levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) by inhibiting the NLRP3/Caspase-1/IL-1β and MAPK/NF-κB signaling pathways. Moreover, we verified that treatment with CY obviously improved intestinal barrier function in both DSS-induced mice and LPS-stimulated Caco-2 cells. Ferroptosis-related markers were assessed. CY attenuated DSS-induced colitis by inhibiting ferroptosis, as assessed by Fe2+ accumulation, total antioxidant capacity (T-AOC), and reactive oxygen species (ROS), 4-hydroxynonenal (4-HNE), and glutathione (GSH) levels. Additionally, there was an increase in superoxide dismutase (SOD) and catalase (CAT) activity, as well as alterations in ferroptosis-related protein and gene expression (ACSL4, GPX4, SLC7A11, TfR1, and FTH1). Further analyses revealed that CY could inhibit ferroptosis via the Nrf2/GPX4 axis in both in vivo and RSL3-induced Caco-2 cell models. Importantly, the antiferroptotic and protective effects of CY were nullified by Nrf2 knockout in vivo and by the use of ML385 in vitro. In conclusion, the effects of CY on UC are strongly associated with the Nrf2 pathway. CY might be a potential candidate for the treatment of UC. Therefore, our results provide an important reference for investigating the mechanisms of flavonoid compounds involved in preventing inflammatory diseases.

Flavonoid natural products are emerging as a promising approach for treating Ulcerative Colitis (UC) due to their natural origin and minimal toxicity. This study investigates the effects of Neohesperidin (NEO), a natural flavonoid, on Dextran Sodium Sulfate (DSS)-induced UC in mice, focusing on the underlying molecular mechanisms. Early intervention with NEO (25 and 50 mg/kg) mitigated colon shortening, restored damaged barrier proteins, and significantly reduced the inflammatory cytokine levels. Moreover, NEO inhibited the MAPK/NF-κB signaling pathway and enhanced the levels of intestinal barrier proteins (Claudin-3 and ZO-1). Additionally, NEO increased beneficial intestinal probiotics (S24-7 and Lactobacillaceae) while reducing harmful bacteria (Erysipelotrichi, Enterobacteriaceae). Fecal microbial transplantation (FMT) results demonstrated that NEO (50 mg/kg) markedly improved UC symptoms. In conclusion, early NEO intervention may alleviate DSS-induced UC by inhibiting inflammatory responses, preserving intestinal barrier integrity and modulating gut microbiota.

Intestinal barrier dysfunction characterized by the functional loss of the intestinal epithelium's tight junction (TJ) barrier is a key factor in the pathogenesis of ulcerative colitis (UC). Although rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor, has shown promise in inducing clinical remission and mucosal healing in inflammatory bowel disease, its underlying mechanism remains elusive. Thus, this study investigated the role of the mTOR pathway in regulating the intestinal barrier. To investigate the molecular mechanism regulating the intestinal barrier, specific intestinal epithelial phenazine biosynthesis-like domain-containing protein (PBLD)-deficient (PBLDIEC-/-) mice and control wild-type (WT) mice were intraperitoneally injected with rapamycin or MHY1485. To determine the relevance of the findings for UC, we analyzed transcriptome data and single-cell expression profiles from public databases and intestinal mucosal tissues obtained from patients with active UC or colon cancer. We observed that mTOR activation in the intestinal epithelium of patients with active UC. Moreover, in vivo, rapamycin markedly increased the expressions of PBLD and TJ proteins and reduced intestinal inflammation in mice with dextran sulfate sodium-induced enteritis. However, the therapeutic efficacy of rapamycin was notably reduced in PBLDIEC-/- mice. In vitro, rapamycin influenced PBLD expression by modulating the nuclear transcription of transcription factor EB (TFEB). Angiomotin (AMOT) could directly bind to PBLD, and rapamycin could not effectively increase the expression of TJ proteins after the knockdown of PBLD or AMOT. In summary, the administration of rapamycin is a potential treatment for UC, and targeting the mTOR/PBLD/AMOT axis is a potential novel approach for UC treatment.

The objective of this study was to investigate whether pectin extracted from comfrey roots (CRPs) could alleviate ulcerative colitis (UC) induced by sodium dextran sulfate (DSS) in mice by improving the intestinal barrier. CRP was able to relieve symptoms associated with weight loss, diarrhea, and colon length in UC mice. CRP inhibited the excessive secretion of TNF-α and IL-6 and increased the level of IL-10 in the serum. After CRP treatment, the mRNA expression levels of ZO-1 and Muc2 increased. The colonic epithelial cells recovered well, and the mucous layer was relatively intact in the CRP group. CRP and 5-aminosalicylic acid (ASA) alleviated UC symptoms in mice by reducing the abundance of Oscillibacter, Alistipes, and Anaeroplasma and increasing the abundance of Lachnospiraceae_UCG-001 to regulate the intestinal microflora. The abundance of Rikenellaceae was positively correlated with the mRNA expression level of ZO-1, and the abundance of Monoglobus was positively correlated with the mRNA expression level of Muc2. These results suggested that CRP could repair the intestinal barrier and mitigate DSS-induced colon damage in mice, indicating that CRP may be a potential functional component in combating UC.

Ulcerative colitis (UC) is a global intestinal disease, and conventional therapeutic drugs often fail to meet the needs of patients. There is an urgent need to find efficient and affordable novel biological therapies. Saccharomyces boulardii has been widely used in food and pharmaceutical research due to its anti-inflammatory properties and gut health benefits. However, there is still a relatively limited comparison and evaluation of different forms of S. boulardii treatment for UC. This study aimed to compare the therapeutic effects of S. boulardii, heat-killed S. boulardii, and S. boulardii β-glucan on UC, to explore the potential of heat-killed S. boulardii as a new biological therapy. The results demonstrate that all three treatments were able to restore body weight, reduce the disease activity index (DAI), inhibit splenomegaly, shorten colon length, and alleviate histopathological damage to colonic epithelial tissues in DSS-induced colitis mice. The oral administration of S. boulardii, heat-killed S. boulardii, and S. boulardii β-glucan also increased the levels of tight junction proteins (Occludin and ZO-1), decreased the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the serum, and suppressed the expressions of TNF-α, IL-1β, and IL-6 mRNA in the colon. In particular, in terms of gut microbiota, S. boulardii, heat-killed S. boulardii, and S. boulardii β-glucan exhibited varying degrees of modulation on DSS-induced dysbiosis. Among them, heat-killed S. boulardii maximally restored the composition, structure, and functionality of the intestinal microbiota to normal levels. In conclusion, heat-killed S. boulardii showed greater advantages over S. boulardii and S. boulardii β-glucan in the treatment of intestinal diseases, and it holds promise as an effective novel biological therapy for UC. This study is of great importance in improving the quality of life for UC patients and reducing the burden of the disease.

Bacteroides fragilis (B. fragilis) is a Gram-negative, obligate anaerobic, commensal bacterium residing in the human gut and holds therapeutic potential for ulcerative colitis (UC). Previous studies have indicated that capsular polysaccharide A (PSA) of B. fragilis is a crucial component for its effectiveness, possessing various biological activities such as anti-inflammatory, anti-tumor, and immune-modulating effects. We previously isolated and characterized the B. fragilis strain ZY-312 from the feces of a healthy breastfed infant, and extracted its PSA, named TP2. In this study, we explored the impact of TP2 on colonic inflammation and delved into its potential mechanisms. Initially, we used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis in rats and found that TP2 treatment significantly ameliorated TNBS-induced weight loss, increased clinical scores, extensive ulcers, and intestinal epithelial damage in UC rats. Further analysis revealed that TP2 effectively restored the intestinal barrier integrity in UC rats by regulating the expression of Muc-2, tight junction proteins (ZO-1, occludin, claudin-1, and claudin-2), as well as apoptosis-related proteins Bcl-2, BAX, and Cleaved-Caspase-3. Additionally, TP2 suppressed the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL23, while promoting the secretion of anti-inflammatory cytokines IL-10 and IL-22, thereby inhibiting the occurrence of inflammation. TP2 also downregulated the phosphorylation levels of AKT and PI3K, effectively inhibiting the abnormal activation of the PI3K/AKT signaling pathway. More interestingly, 16S rRNA sequencing results showed that TP2 restored the ecological imbalance of the rat intestinal microbiota, with an increase in beneficial bacteria such as Lactobacillus and Limosilactobacillus observed in the treatment group. In conclusion, TP2 through the regulation of intestinal barrier-related cells and proteins, inhibition of apoptosis, modulation of inflammation-related cytokine levels, and control of abnormal activation of the PI3K/AKT signaling pathway, restores intestinal barrier integrity. Additionally, by reshaping the ecological imbalance of the gut microbiota, TP2 ultimately alleviates ulcerative colitis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE Globally, plant materials are widely used as an additional and alternative therapy for the treating of diverse diseases. Ulcerative colitis (UC) is a chronic, recurrent and nonspecific inflammation of the bowel, referred to as "modern intractable disease" according to the World Health Organization. With the continuous development of theoretical research in Traditional Chinese Medicine (TCM) and the advantages of TCM in terms of low side effects, TCM has shown great progress in the research of treating UC. AIM OF THIS REVIEW This review aimed to explore the correlation between intestinal microbiota and UC, summarize research advances in TCM for treating UC, and discuss the mechanism of action of TCM remedies in regulating intestinal microbiota and repairing damaged intestinal barrier, which will provide a theoretical basis for future studies to elucidate the mechanism of TCM remedies based on gut microbiota and provide novel ideas for the clinical treatment of UC. METHODS We have collected and collated relevant articles from different scientific databases in recent years on the use of TCM in treating UC in relation to intestinal microecology. Based on the available studies, the therapeutic effects of TCM are analysed and the correlation between the pathogenesis of UC and intestinal microecology is explored. RESULTS TCM is used to further protect the intestinal epithelium and tight junctions, regulate immunity and intestinal flora by regulating intestinal microecology, thereby achieving the effect of treating UC. Additionally, TCM remedies can effectively increase the abundance of beneficial bacteria that produce short-chain fatty acids, decrease the abundance of pathogenic bacteria, restore the balance of intestinal microbiota, and indirectly alleviate intestinal mucosal immune barrier dysfunction and promote the repair of damaged colorectal mucosa. CONCLUSION Intestinal microbiota is closely related to UC pathogenesis. The alleviation of intestinal dysbiosis can be a potential novel therapeutic strategy for UC. TCM remedies can exert protective and therapeutic effects on UC through various mechanisms. Although intestinal microbiota can aid in the identification of different TCM syndromes types, further studies are needed using modern medical technology. This will improve the clinical therapeutic efficacy of TCM remedies in UC and promote the application of precision medicine.

Oxidative stress and intestinal inflammation are main pathological features of ulcerative colitis (UC). Ferroptosis, characterized by iron accumulation and lipid peroxidation, is closely related to the pathologic process of UC. 16S rRNA sequencing for intestinal microbiota analysis and gas chromatography-mass spectrometry (GC-MS) for short-chain fatty acid (SCFA) contents clearly demonstrated lower amounts of butyrate-producing bacteria and butyrate in colitis mice. However, the precise mechanisms of sodium butyrate (NaB) in treating UC remain largely unclear. We found that ferroptosis occurred in colitis models, as evidenced by the inflammatory response, intracellular iron level, mitochondria ultrastructural observations and associated protein expression. NaB inhibited ferroptosis in colitis, significantly rescued weight loss and colon shortening in mice and reduced inflammatory lesions and mitochondrial damage. Furthermore, NaB improved intestinal barrier integrity and markedly suppressed the expression of pro-ferroptosis proteins. Conversely, the protein expression of anti-ferroptosis markers including nuclear factor erythroid-related Factor 2 (Nrf2) and glutathione peroxidase 4 (GPX4), was significantly upregulated with NaB treatment. Moreover, the knockdown of Nrf2 reversed the anti-colitis effect of NaB. Taken together, NaB exhibited a protective effect by ameliorating ferroptosis in experimental colitis through Nrf2/GPX4 signaling and improving intestinal barrier integrity, which provides a novel mechanism for NaB prevention of UC.

The mammalian gastrointestinal tract is continuously vulnerable to numerous bacteria and food additives as well as to environmental tox-ins that damage the epithelia of the gut [1]. Disturbance in intestinal

Ulcerative colitis (UC) is a chronic, non-specific inflammatory disease of the intestines with a significant increase in global incidence in recent years. Oxidative stress and inflammation are two hallmarks of UC pathogenesis. Anemoside B4 (AB4), a pentacyclic triterpenoid saponin, exhibits significant antioxidant and anti-inflammatory properties and shows potential for preventing UC. Here, an animal model induced by dextran sodium sulfate (DSS) was used to investigate the effect of AB4 on UC. The results demonstrated that AB4 significantly reduces intestinal oxidative stress and inflammation in UC mice, while also protecting intestinal barrier function. Furthermore, AB4 helps restore intestinal microbial balance primarily by modulating the abundance of Lactobacillus, which enhances the metabolism of short-chain fatty acids and upregulates the production of butyric acid (BA). Pseudogerm-free mice and fecal microbiota transplantation (FMT) demonstrated that AB4 significantly mitigated UC in a gut microbe-dependent manner. Both AB4 and BA markedly activate the aromatic hydrocarbon receptor (AhR). The intestinal organoid results suggest BA may activate the AhR to inhibit ROS production and activation of NLRP3 inflammasome, thereby protecting intestinal integrity. Administration of AhR antagonists abolished the protective effects, thus confirming the involvement of AhR in the underlying mechanism. Overall, these results indicate that AB4 is an effective agent against UC mainly by activating the AhR through gut microbial short-chain fatty acid metabolites to inhibit intestinal oxidative stress and inflammation.

Ulcerative colitis (UC) is defined as a chronic intestinal inflammation with an unknown cause. During its occurrence and development, oxidative stress and intestinal microbiota dysbiosis play important roles. Nevertheless, the treatment of UC continues to pose significant challenges due to the intricate nature of physiological barriers and the suboptimal targeting efficacy of traditional therapeutic strategies. To solve the dilemma facing UC treatment, in this study, we developed a metal-phenolic nanozyme, designated as DHM-Zn, which exhibits anti-inflammatory and antioxidant properties via metal coordination between dihydromyricetin (DHM) and Zn2+. Furthermore, we engineered yeast microcapsules (YM) encapsulating the metal-phenolic nanozymes (DZ@YM), leveraging the inherent biosafety and tolerability advantages offered by natural microorganisms. Following oral administration, the intestinal retention characteristics of YM facilitated the efficient aggregation of DHM-Zn nanozymes at the inflammation site, thereby extending their therapeutic efficacy. In addition to augmenting anti-inflammatory and antioxidant effects, DZ@YM contributed to the restoration of intestinal microbial balance by increasing the abundance of beneficial bacteria such as Parabacteroides and Muribaculaceae, while regulating potentially harmful bacteria like Clostridium-sensu-stricto and Escherichia-Shigella, thereby achieving a synergistic multi-pathway therapeutic approach. Collectively, with excellent biocompatibility, this novel therapeutic approach demonstrates extensive potential for clinical application in the treatment of UC and offers new directions and insights for UC therapy.

Ulcerative colitis (UC) is a long-term inflammatory bowel disease characterized by intense inflammation of the colorectal mucosa. Overproduction of reactive oxygen species exacerbates the progression of UC, which is linked to mitochondrial impairment and dysbiosis of the intestinal microbiota. CaGA nanozymes have demonstrated efficacy in the treatment of UC. The modulation of M1 and M2 polarization of macrophages by CaGA nanozymes has been demonstrated to be useful in reducing inflammation. Furthermore, CaGA nanozymes regulate the M1 and M2 polarization of macrophages, efficiently decreasing inflammation. The oral delivery of CaGA nanozymes resulted in their enrichment in inflamed areas of the colon and effectively reduced colonic damage in mice with DSS-induced colitis by improving the repair of the intestinal barrier. An investigation of 16S rDNA sequencing revealed that CaGA nanozymes regulate populations of both pathogenic and helpful bacteria and impact the progression of ulcerative colitis by influencing the tricarboxylic acid (TCA) cycle. Thus, CaGA nanozymes may be employed in the management of ulcerative colitis to control the intestinal milieu and improve the preservation of the intestinal barrier by decreasing the invasion of inflammatory cells and restoring mitochondrial activity. STATEMENT OF SIGNIFICANCE: CaGA nanozymes exhibit multifunctional enzymatic activity, effectively eliminating cellular RONS with robust antioxidant capacity. CaGA nanoenzymes promote macrophage M1 to M2 polarization and produce anti-inflammatory effects. CaGA nanozymes increase cell viability by restoring impaired mitochondrial function, reducing reactive oxygen species (ROS) production, and restoring the ability of mitochondria to produce ATP. CaGA nanozymes modulate intestinal flora diversity and composition, potentially influencing inflammatory pathways via aromatic compound metabolism. They participate in cellular energy and biosynthesis, regulating ulcerative colitis (UC)-related intestinal function through the tricarboxylic acid (TCA) and urea cycles. Calcium ions bind to GA nanomedicine and small particles are readily absorbed by inflammatory cells, preventing diarrhea from being rapidly excreted.

OBJECTIVE This study aimed to systematically evaluate the therapeutic effects of Psoralen (PSO) on ulcerative colitis (UC) and investigate its underlying mechanisms, with a particular focus on intestinal barrier function, gut microbiota, inflammation, oxidative stress, and ferroptosis. METHODS UC was induced in mice via 2.25 % dextran sulfate sodium (DSS). The therapeutic efficacy of PSO was assessed by monitoring body weight, disease activity index (DAI), colon length, and histopathological alterations. Intestinal barrier integrity was evaluated through tight junction protein expression and permeability assays. Changes in gut microbiota were analyzed by 16S rDNA sequencing. Inflammatory cytokines, oxidative stress markers, and ferroptosis-related proteins were quantified by ELISA and Western blot. RESULTS PSO significantly mitigated UC symptoms, demonstrated by reduced weight loss, decreased DAI scores, prolonged colon length, and improved histopathology. It reinforced intestinal barrier integrity by upregulating ZO-1, Claudin-1, and Occludin while reducing permeability. PSO modulated gut microbiota by promoting beneficial bacteria and inhibiting pathogenic species. Additionally, it suppressed the expression of IL-6, TNF-α, and IL-1β and inhibited the TLR4/MyD88/NF-κB and JAK2/STAT3 signaling pathways. PSO also alleviated oxidative stress, as evidenced by decreased ROS and MDA levels, and increased SOD and GSH. It inhibited ferroptosis by reducing Fe2+ accumulation and modulating ferroptosis-related proteins. CONCLUSION PSO exerts therapeutic effects on UC through a multi-target mechanism that enhances the intestinal barrier, modulates the gut microbiota, exerts anti-inflammatory actions, mitigates oxidative stress, and inhibits ferroptosis, highlighting its potential as a promising therapeutic candidate.

Inflammation and oxidative stress are important features of traumatic ulcerative colitis (UC). Turmeric has been used as a dietary and functional ingredient for its potent anti-inflammatory effects in UC therapy. However, its practical effectiveness is hindered by limited reactive oxygen species (ROS) elimination properties. To address this, we constructed a unique treatment agent by growing cerium oxide (CeO2) nanocrystals on the membranes of turmeric-derived nanovesicles (TNVs), named as TNV-Ce. The resulted TNV-Ce could suppress inflammation and exhibit exceptional ROS-scavenging activity, which was validated both in lipopolysaccharide-induced macrophages and dextran sulfate sodium salt-induced chronic colitis mouse model. Following oral administration, TNV-Ce significantly accumulated at inflamed sites, effectively eliminating ROS and inhibiting pro-inflammatory cytokines for synergistic action against UC.

Introduction Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease with limited therapeutic options. Baicalein, a phenolic flavonoid extracted from Scutellaria baicalensis, has been traditionally used in Chinese medicine for its potent anti-inflammatory, anti-tumor, and antiviral properties. This plant, known as Huang-Qin, is indigenous to East Asia and has been widely used to treat various conditions such as fever, respiratory diseases, and inflammation. Aim of the Study This study aimed to establish a C. elegans model of UC induced by dextran sodium sulfate (DSS) and to investigate the protective effects of baicalein on intestinal injury. Materials and Methods DSS was used to induce acute intestinal injury in C. elegans. N2 and mutant strains (daf-2 and daf-16) were exposed to DSS at concentrations of 5% (w/v), which identified as optimal for inducing intestinal inflammation. The effects of 25 μM, 50 μM, and 100 μM of baicalein on intestinal barrier function, oxidative stress markers, and relevant gene expression were evaluated, including genes related to epithelial barrier integrity (clc-2, mtm-6, etc.), oxidative stress, and the IIS and p38 MAPK pathways. Results Baicalein significantly improved physiological condition and intestinal permeability in worm treated with 5% DSS. It restored the expression of epithelial barrier genes and reduced oxidative stress, as indicated by decreased ROS, enhancing SOD activity, daf-16 nuclear translocation etc. Baicalein’s protective effects were associated with the activation of the p38 MAPK and IIS pathways. In daf-2 and daf-16 mutant strains, baicalein demonstrated partial dependence on the IIS pathway for its protective effects. Conclusion This study established a DSS-induced UC model in C. elegans and demonstrated that baicalein exerts protective effects on intestinal barrier integrity and oxidative stress, through the IIS and MAPK pathways. These findings support the use of C. elegans as a model for UC research and provide valuable insights into baicalein’s therapeutic potential for inflammatory bowel diseases.

Background: Curcumin (Cur) and tryptophan (Trp) both show promise for treating ulcerative colitis (UC) alone, but their combination has not been explored. This study investigated the therapeutic advantage of the combination (Cur–Trp) for DSS-induced ulcerative colitis in mice. Methods: We established a mouse model of ulcerative colitis induced by dextran sulfate sodium (DSS). The mice were treated with Cur, Trp, or Cur–Trp, and to evaluate the therapeutic effects, we assessed clinical signs such as body weight, disease activity index (DAI), and colon length. We also examined intestinal barrier function through indicators including histopathological changes, inflammatory factors, oxidative stress levels, mucin secretion, and tight junction protein expression. Additionally, we analyzed the composition of gut microbiota and the content of its metabolites like short-chain fatty acids (SCFAs). Results: The Cur–Trp group produced the most significant improvement, exceeding that of Cur or Trp group. This was evidenced by a significant recovery of this sign, including slower weight loss, reduced colon shortening, and de-creased disease activity index. Compared with the model group, the weight loss of mice in the Cur–Trp group was reduced from 17.15% to 9.73%, which was better than that in the cur group (11.33%) and the Trp group (11.59%). The DAI decreased from the model group (3.6) to the Cur–Trp group (2.4), while the DAI in the Cur group and the Trp group only decreased to 2.9 and 2.8, respectively. The colon length in the Cur–Trp group (6.52 cm) was larger than that in the cur group (6.31 cm), the Trp group (6.23 cm) and the model group (5.5 cm). The Cur–Trp intervention effectively restored intestinal barrier function, as shown by reducing colon tissue dam-age, modulating inflammatory factors, restoring oxidative balance, increasing mucin secretion, and upregulating tight junction protein expression. Further studies showed that the combination uniquely modulated the gut microbiome, increased the Firmicutes/Bacteroidetes (F/B) ratio, decreased the genus of pro-inflammatory bacteria, and in-creased beneficial bacteria, while increasing SCFA levels to alleviate DSS-induced ulcerative colitis. Conclusions: Cur–Trp has shown great potential in alleviating colitis and promoting intestinal barrier function, suggesting that the combination of Cur and Trp has the potential to be developed as a therapeutic functional food or dietary supplement for UC. However, more studies are needed to validate this finding. Future research should focus on elucidating the precise molecular mechanisms, optimizing dosage and clinical trials in chronic models and humans to provide more targeted treatment options.

BACKGROUND Nudix hydrolase 1 (NUDT1) plays a crucial role in tumours, where it helps limit cellular damage caused by reactive oxygen species. However, the exact function of NUDT1 in ulcerative colitis (UC) is not well understood. METHODS NUDT1 expression in the intestinal mucosal tissues of patients with UC was analysed using quantitative reverse transcription polymerase chain reaction. A public database was used to analyse the expression of selected signature genes of interest in patients with UC with different NUDT1 expression levels. TH588, a potent NUDT1 inhibitor, was used to treat intestinal epithelial cells (IECs) in mice. The functions of the IECs were assessed using quantitative reverse transcription polymerase chain reaction, flow cytometry, western blotting, and fluorescence microscopy. A mouse model of dextran sodium sulphate-induced colitis was established. RESULTS We examined NUDT1 expression and found that it was significantly elevated in the colon tissues of patients with UC. A colitis model was established in wild-type mice treated with TH588, which significantly reduced intestinal mucosal inflammation and induced notable alterations in faecal microbiota composition. Moreover, TH588 helped preserve intestinal mucosal barrier function. Inhibition of NUDT1 expression in IECs enhanced antioxidant activity by increasing Nrf2 expression and reducing ERK phosphorylation, which, in turn, stabilised tight junctions in IECs exposed to oxidative stress. CONCLUSIONS Our research emphasises the role of NUDT1 in modulating the intestinal microbiota and intestinal mucosal barrier in UC, indicating that targeting NUDT1 during intestinal mucosal inflammation could serve as a promising therapeutic strategy for UC.

Ulcerative colitis (UC) is a diffuse chronic inflammation in the superficial intestine. Excessive accumulation of reactive oxygen species (ROS) leads to the of the colorectal damage. As the anti-inflammation therapy needs to be last for at least 3–5 years, the drugs demand less toxicity. However, current treatments in the clinic are often accompanied by unavoidable adverse side effects. Hydrogen is a nontoxic antioxidant reagent with excellent permeability of biomembranes, which shows the potential in treating UC. A novel simply designed hydrogen storage particle, Magnesium Hydride (MgH2) particle with an outer shell of passivated Magnesium oxide (MgO), was constructed in the current study to enable the safe and controlled release of hydrogen. This studies demonstrated that magnesium hydride particle (MgH2@MgO) was effective in scavenging excessive ROS, relieving the inflammation, and reversing the progression of UC through inhibiting the NF-κB signaling pathway, which provided the experimental evidence for the clinical prevention and therapy of UC.

Inflammatory bowel disease (IBD) etiology is intricately linked to oxidative stress and inflammasome activation. Natural antioxidant nobiletin (NOB) contains excellent anti-inflammatory properties in alleviating intestinal injury. However, the insufficient water solubility and low bioavailability restrict its oral intervention for IBD. Herein, we constructed a highly efficient NOB-loaded yeast microcapsule (YM, NEFY) exhibiting marked therapeutic efficacy for dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) at a low oral dose of NOB (20 mg/kg). We utilized the metal polyphenol network (MPN) formed by self-assembly of epigallocatechin gallate (EGCG) and FeCl3 as the intermediate carrier to improve the encapsulation efficiency (EE) of NOB by 4.2 times. These microcapsules effectively alleviated the inflammatory reaction and oxidative stress of RAW264.7 macrophages induced by lipopolysaccharide (LPS). In vivo, NEFY with biocompatibility enabled the intestinal enrichment of NOB through controlled gastrointestinal release and macrophage targeting. In addition, NEFY could inhibit NLRP3 inflammasome and balance the macrophage polarization, which favors the complete intestinal mucosal barrier and recovery of colitis. Based on the oral targeted delivery platform of YM, this work proposes a novel strategy for developing and utilizing the natural flavone NOB to intervene in intestinal inflammation-related diseases.

Excessive oxidative stress and NLRP3 inflammasome activation are considered the main drivers of inflammatory bowel disease (IBD), and inhibition of inflammasomes ameliorates clinical symptoms and morphological manifestations of IBD. Herein, we examined the roles of NLRP3 activation in IBD and modulation of NLRP3 by sulforaphane (SFN), a compound with multiple pharmacological activities that is extracted from cruciferous plants. To simulate human IBD, we established a mouse colitis model by administering dextran sodium sulfate in the drinking water. SFN (25, 50 mg·kg-1·d-1, ig) or the positive control sulfasalazine (500 mg/kg, ig) was administered to colitis-affected mice for 7 days. Model mice displayed pathological alterations in colon tissue as well as classic symptoms of colitis beyond substantial tissue inflammation. Expression of NLRP3, ASC, and caspase-1 was significantly elevated in the colonic epithelium. The expression of NLRP3 inflammasomes led to activation of downstream proteins and increases in the cytokines IL-18 and IL-1β. SFN administration either fully or partially reversed these changes, thus restoring IL-18 and IL-1β, substantially inhibiting NLRP3 activation, and decreasing inflammation. SFN alleviated the inflammation induced by LPS and NLRP3 agonists in RAW264.7 cells by decreasing the levels of reactive oxygen species. In summary, our results revealed the pathological roles of oxidative stress and NLRP3 in colitis, and indicated that SFN might serve as a natural NLRP3 inhibitor, thereby providing a new strategy for alternative colitis treatment.

Ulcerative colitis (UC) is an idiopathic inflammatory disease. We intend to explore the mechanism of Rutin in the therapy of UC. Disease activity index (DAI) and hematoxylin-eosin staining were employed to assess therapeutic effect of Rutin on dextran sulfate sodium-stimulated mice. The proliferation was detected by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay. Oxidative stress (OS) was assessed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Inflammatory factors were detected using enzyme-linked immunosorbent assay and immunofluorescence staining. mRNA and protein expressions were detected by real-time quantitative polymerase chain reaction and immunoblotting assay. Rutin decreased DAI scores and ameliorated pathological damage in UC mice with decreased levels of inflammatory factors. Rutin recovered the inhibited proliferation of fetal human colon cells caused by lipopolysaccharide. Rutin inhibited OS by reducing ROS and MDA, while enhancing SOD activity in LPS-induced fetal human colon cells. Rutin inhibited NLRP3 inflammasome in UC mice and cell model. Silencing NLRP3 enhanced the inhibitory effect of Rutin on OS in lipopolysaccharide-induced fetal human colon cells. Conversely, NLRP3 overexpression reversed the restraining role of Rutin in OS. Rutin ameliorates UC by inhibiting inflammation and OS through suppressing NLRP3 inflammasome.

Ulcerative colitis (UC) poses a threat to human health. The present study attempts to unravel the efficacy and potential mechanisms of paeoniflorin (PF), a naturally sourced active ingredient, for the management of UC. By establishing a DSS (dextran sulphate sodium)-induced experimental rat model of UC, this study found that PF was effective in ameliorating UC symptoms, inhibiting oxidative stress, inflammation and apoptosis, and repairing colonic epithelial damage. In addition, metabolomics revealed that PF may alleviate UC by primarily improving linoleic acid metabolism. Mechanistically, PF inhibited the CDC42/JNK signaling pathway by targeting CDC42. In particular, HuProtTM20K proteomics, molecular docking and MST revealed that PF is a novel CDC42 inhibitor. In LPS-treated Caco-2 cells, PF similarly inhibited oxidative stress, inflammation, and apoptosis and down-regulated the CDC42/JNK signaling pathway. Overall, PF inhibits oxidative stress, inflammation and apoptosis and repairs colonic epithelial damage through modulation of serum metabolites and inhibition of the CDC42/JNK signaling pathway, leading to alleviation of UC.

Curcumin (CUR) is a natural polyphenol that holds promise for treating ulcerative colitis (UC), yet oral administration of CUR exhibits limited bioavailability and existing formulations for oral delivery of CUR often suffer from unsatisfactory loading capacity. This study presents hydroxyethyl starch-curcumin microspheres (HC-MSs) with excellent CUR loading capacity (54.52 %), and the HC-MSs can further encapsulate anti-inflammatory drugs dexamethasone (DEX) to obtain a combination formulation (DHC-MSs) with high DEX loading capacity (19.91 %), for combination therapy of UC. The microspheres were successfully engineered, retaining the anti-oxidative and anti-inflammatory activities of parental CUR and demonstrating excellent biocompatibility and controlled release properties, notably triggered by α-amylase, facilitating targeted drug delivery to inflamed sites. In a mouse UC model induced by dextran sulfate sodium, the microspheres effectively accumulated in inflamed colons and both HC-MSs and DHC-MSs exhibited superior therapeutic efficacy in alleviating UC symptoms compared to free DEX. Moreover, mechanistic exploration uncovered the multifaceted therapeutic mechanisms of these formulations, encompassing anti-inflammatory actions, mitigation of spleen enlargement, and modulation of gut microbiota composition. These findings underscore the potential of HC-MSs and DHC-MSs as promising formulations for UC, with implications for advancing treatment modalities for various inflammatory bowel disorders.

BACKGROUND Ulcerative colitis (UC) is a disease that is difficult to treat and has been associated with high rates of recurrence. Moreover, the current medications for UC induce serious side effects following prolonged use. Ganjiang Huangqin Huanglian Renshen Decoction (GJHQHLRSD), has been traditionally used to treat UC. However, its protective mechanisms have not been fully studied. PURPOSE In this study the mechanisms by which GJHQHLRSD treats UC was investigated. METHODS The GJHQHLRSD and GJHQHLRSD drug-containing serum (GJHQHLRSD-DS) were characterized using LC-MS/MS. The therapeutic effect of GJHQHLRSD on dextran sodium sulfate (DSS)-induced UC was explored by assessing various parameters including intestinal flora 16S rRNA, intestinal barrier function, oxidative stress (OS) response, inflammatory cytokines, colonic histopathological injury, colon length, disease activity index (DAI) and body weight. RESULTS Treatment with GJHQHLRSD increased body weight, ameliorated colon length shortening and edema, reduced the DAI score, improved the pathological injury, down-regulated the levels of IL-1β, IL-6, IL-8, TNF-α, LPS, LDH, TLR4, and NLRP3, and up-regulated the ZO-1 and Occludin levels in UC mice. It also decreased intestinal oxidative stress in UC mice and improved mitogenic activity by modulating mitochondrial ultrastructure as well as the expression level of PINK1, LC3-II/Ⅰ, Beclin-1, p62, and Parkin proteins. In addition, we found that the effects of GJHQHLRSD on UC mice were inhibited by 3-MA.GJHQHLRSD treatment reduced the imbalance of intestinal flora in UC mice, by regulating the inflammation and oxidative stress. CONCLUSION These findings suggested that GJHQHLRSD effectively attenuated inflammatory responses, inhibited the TLR4/NF-κB/NLRP3 signalling, oxidative stress, and modulated the gut microbiota, and alleviated the DSS-induced UC symptoms, making it a promising and innovative therapeutic option for the treatment of UC.

BACKGROUND Epimedium polysaccharide (EPS) is a bioactive compound derived from the traditional Chinese herb Epimedium brevicornum. The objective of this study was to investigate the protective effects of EPS on ulcerative colitis (UC) and to elucidate the underlying mechanisms involved. RESULTS The findings showed that EPS treatment mitigated UC symptoms, including weight loss, anal bleeding, elevated disease activity index (DAI), and colon shortening. Hematoxylin and eosin (H&E) and Alcian blue-periodic acid-Schiff (AB-PAS) staining demonstrated that EPS alleviated histopathological damage and improved the integrity of the colonic mucosa. Mechanistically, EPS was found to substantially decrease inflammation by inhibiting the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway and to alleviate oxidative stress through modulation of the Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (Keap1/Nrf2) pathway. Notably, EPS failed to exert protective effects against dextran sulfate sodium (DSS)-induced UC in Nrf2-knockout (Nrf2-/-) mice. Additionally, Western blotting and immunohistochemical analysis demonstrated that EPS facilitated autophagy via the adenosine monophosphate-dependent protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway. In vitro experiments revealed that EPS effectively suppressed lipopolysaccharide (LPS)-mediated cellular damage and oxidative stress by regulating Keap1/Nrf2 pathway. Transcriptomic analysis of LPS-treated Caco-2 cells following EPS treatment revealed a significant up-regulation of Nrf2 expression. CONCLUSION In conclusion, the findings of this study suggest that EPS exerts protective effects against DSS-induced UC through the inhibition of the TLR4/NF-κB signaling pathway, regulation of the Keap1/Nrf2 pathway, and promotion of autophagy via the AMPK/mTOR pathway. Consequently, EPS may represent a potential therapeutic target for the treatment of UC. © 2024 Society of Chemical Industry.

BACKGROUND Amauroderma rugosum (AR) is a medicinal mushroom commonly used to treat inflammation, gastric disorders, epilepsy, and cancers due to its remarkable anti-inflammatory and anti-oxidative properties. This study was designed to evaluate the pharmacological effects of AR and its underlying mechanism of action against ulcerative colitis (UC) in vitro and in vivo. METHODS A UC mouse model was established by administration of dextran sulfate sodium (DSS). AR extract was administered intragastrically to mice for 7 days. At the end of the experiment, histopathology, macrophage phenotype, oxidative stress, and inflammatory status were examined in vivo. Furthermore, RAW 264.7, THP-1, and Caco-2 cells were used to elucidate the mechanism of action of AR in vitro. RESULTS AR extract (0.5-2 mg/mL) significantly suppressed lipopolysaccharide (LPS) and interferon-gamma (IFN-γ)-induced M1 macrophage (pro-inflammatory) polarization in both RAW 264.7 and THP-1 cells. LPS-induced pro-inflammatory mediators (nitric oxide, TNF-α, IL-1β, MCP-1, and IL-6) were reduced by AR extract in a concentration-dependent manner. Similarly, AR extract downregulated MAPK signaling activity in LPS-stimulated RAW 264.7 cells. AR extract elicited a concentration-dependent increase in the mRNA expression of M2 (anti-inflammatory) phenotype markers (CD206, Arg-1, Fizz-1, and Ym-1) in RAW 264.7 cells. Moreover, AR extract suppressed DSS-induced ROS generation and mitochondrial dysfunction in Caco-2 cells. The in vivo experiment revealed that AR extract (200 mg/kg) increased colon length compared to the DSS-treated group. In addition, disease activity index, spleen ratio, body weight, oxidative stress, and colonic inflammation were markedly improved by AR treatment in DSS-induced UC mice. Finally, AR suppressed M1 and promoted M2 macrophage polarization in UC mice. CONCLUSION The AR extract protected against DSS-induced UC by regulating macrophage polarization and suppressing oxidative stress. These valuable findings suggest that adequate intake of AR can prevent and/or treat UC.

BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by intestinal barrier dysfunction, oxidative stress, and inflammation. Biochanin A (BCA) is a natural flavonoid found in various plants, known for its anti-inflammatory, antioxidant, and anticancer properties, while its therapeutic role in UC and potential mechanism remains unexplored. PURPOSE To explores the therapeutic potential of BCA in alleviating UC, focusing on its effects on ferroptosis and the JAK2/STAT3 signaling pathway. METHODS The BCA's therapeutic effects on Dextran sulfate sodium (DSS)-induced colitis model in C57BL/6J mice was investigated. Subsequently, a comprehensive range of techniques was performed to investigate the impact of BCA on intestinal barrier integrity, oxidative stress, inflammation. Besides, the RNA sequencing was performed to explore the potential mechanism. The role of ferroptosis inhibition in BCA's effects in vitro and in vivo was explored by co-treating with the ferroptosis activator Erastin. RESULTS Treatment of colitis mice with BCA significantly improved DAI scores and histopathological damage scores, reduced oxidative stress, enhanced intestinal barrier function, and suppress inflammatory responses. RNA sequencing result found that BCA could lead to the inhibition of ferroptosis in mice colon tissue. Moreover, erastin co-treatment negated BCA's effects in vitro and vivo. Mechanistically, BCA exerts these effects by suppressing the JAK2/STAT3 pathway, which plays a pivotal role in ferroptosis and inflammation. Molecular docking studies further confirm the direct binding of BCA to both GPX4 and STAT3. CONCLUSION These results establish BCA as a promising natural compound for UC treatment, offering a novel therapeutic strategy by specifically targeting ferroptosis and its associated molecular pathways, thereby addressing key gaps in current UC management and advancing potential clinical applications.

Ulcerative colitis (UC) is one of the most common and difficult-to-treat inflammatory diseases Currently, the standard of care includes immunological modulation and anti-inflammatory medication to alleviate symptoms; however, these treatments are associated with several side effects. As a result, developing novel, safe, and effective treatment strategies is crucial. The gut microbiota and its influence on the onset and progression of UC through their regulation of immunity, barrier integrity, and homeostasis, serves as a promising target for UC therapy. In this review, we explore the pathological changes that take place in UC along with the role of gut microbiota and its metabolites in disease progression and modulation. Additionally, we offer a thorough description of novel UC treatment approaches that focus on altering the gut microbiota and its metabolites. These protocols include FMT, probiotics, prebiotics, and micro/nanoparticles. The ultimate goal is to offer a theoretical basis for the advancement of innovative therapeutic strategies for UC.

The consumption of wampee has traditionally been utilized to alleviate gastrointestinal inflammation and associated disorders; however, its exact mechanism has remained unknown. The aim of this study was to elucidate the therapeutic efficacy and underlying mechanism of wampee polyphenol extract (WPE) in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). The findings revealed that WPE alleviated diverse symptoms of UC, regulated various inflammatory cytokines, and effectively protected the colon tissue structure and barrier integrity, thereby inhibiting LPS translocation. Moreover, WPE restored the richness and diversity of gut microbiota and optimized its structure at the phylum and genus levels, causing a notable improvement in short- chain fatty acid (SCFA) metabolism, particularly acetic acid, propionic acid, and butyric acid. Consequently, WPE was demonstrated to effectively suppress the LPS-induced TLR4-p38 MAPK/NF-κB signaling pathway by modulating gut microbiota and SCFA metabolism. These findings provided a theoretical basis for the use of wampee as a potential functional natural food for UC.

Akkermansia muciniphila (A. muciniphila) plays an important role in intestinal regulation, while it is presently unclear whether live or pasteurized A. muciniphila has different effects on the intestinal health. In the present study, live or pasteurized A. muciniphila was administered to dextran sulfate sodium (DSS)-induced ulcerative colitis mice to investigate its influences on the host intestinal health, gut microbiota, and metabolomic phenotype. The results showed that pasteurized A. muciniphila alleviated the symptoms of colitis in mice more efficiently by encouraging the proliferation of beneficial intestinal bacteria, increasing the production of short-chain fatty acids, and inhibiting intestinal inflammation. Moreover, pasteurized A. muciniphila increased the abundance of Parasutterella and Akkermansia and thus affected the metabolism of lipid and lipid-like molecules associated with lysophosphatidylcholines (LysoPCs). Notably, prophylactic supplementation of pasteurized A. muciniphila increased the relative abundance of the anti-inflammatory microbe Dubosiella, thereby activating intestinal sphingolipid metabolism to alleviate intestinal damage. In conclusion, pasteurized A. muciniphila showed a more effective amelioration of DSS-induced colitis by repairing the dysbiosis of gut microbiota and intestinal metabolism compared to live A. muciniphila, providing a potential strategy to explore the protective effect of A. muciniphila on host intestinal health.

Ulcerative colitis (UC) is an inflammatory bowel disease with increasing incidence in the world, especially in developing countries. Although knowledge of its pathogenesis has progressed over the last years, some details require clarification. Studies have highlighted the role of microbial dysbiosis and immune dysfunction as essential factors that may initiate the typical high-grade inflammatory outcome. In order to better understand the immunopathophysiological aspects of UC, experimental murine models are valuable tools. Some of the most commonly used chemicals to induce colitis are trinitrobenzene sulfonic acid, oxazolone and dextran sodium sulfate. These may also be used to investigate new ways of preventing or treating UC and therefore improving targeting in human studies. The use of functional foods or bioactive compounds from plants may constitute an innovative direction towards the future of alternative medicine. Considering the above, this review focused on updated information regarding the 1. gut microbiota and immunopathogenesis of UC; 2. the most utilized animal models of the disease and their relevance; and 3. experimental application of natural products, not yet tested in clinical trials.

Recent studies have shown that intestinal commensal bacteria-derived vesicles may have potential effects in alleviating ulcerative colitis (UC). Although Bifidobacterium longum is widely used to prevent colitis, the potential role of B. longum-derived extracellular vesicles has yet to be explored. Here, we extracted B. longum NSP001-derived extracellular vesicles (NEVs) and investigated the regulatory roles of NEVs in colitis. Our results demonstrated that NEVs alleviate UC by improving intestinal barrier, modulating immune cell differentiation, and promoting the production of SCFAs. NEVs’ improvement of inflammation in pseudo-germ-free mice implies that the anti-inflammatory effect of NEVs does not exclusively depend on the regulation of gut microbiota. In conclusion, we suggest that B. longum NSP001 improves UC through the secretion of NEVs. In addition, the study emphasizes the critical role of NEVs in maintaining host immune homeostasis via suppressing STAT3 pathway, thereby highlighting their potential as a novel postbiotic to alleviate UC.

Polygonatum cyrtonema polysaccharides (PCP) exhibit ameliorative effects on colitis. However, whether the protective effects of PCP depend on the gut microbiota and how PCP regulates intestinal immune responses to alleviate colitis remain unclear. Therefore, this study investigated the effect of PCP against colitis focusing on the regulation of intestinal immune response. The PCP structure was reclassified as fructan. PCP treatment significantly reduced the symptoms of colitis. PCP restored IgA, ZO-1, Occludin, and MUC2 expression to enhance intestinal barrier function. Oral PCP administration markedly inhibited excessive inflammation-mediated immune response by modulating inflammatory cytokines secretion and Th17/Tregs cell balance and restored gut microbial composition. Interestingly, PCP still had a significant ameliorating effect on intestinal inflammation in colitis mice with gut microbial depletion by antibiotics. In the Caco-2/RAW264.7 co-culture inflammation model, PCP treatment improved the intestinal epithelial barrier function by regulating the inflammatory immune response through signal transduction pathways. Overall, these findings suggested that the alleviating effects of PCP on colitis are independent of gut microbiota, and that PCP can directly modulate the inflammatory immune response and intestinal barrier function, which in turn regulates gut microbiota. These findings will provide new insights into the action mechanism of natural polysaccharides in relieving colitis.

Natural plant‐derived polysaccharides exhibit substantial potential for treating ulcerative colitis (UC) owing to their anti‐inflammatory and antioxidant properties and favorable safety profiles. However, their practical application faces several challenges, including structural instability in gastric acid, imprecise targeting of inflamed regions, and limited intestinal retention times. To address these limitations, pH‐responsive, colon‐targeting microspheres (pWGPAC MSs) are developed for delivering phosphorylated wild ginseng polysaccharides (pWGP) to alleviate UC. These pWGPAC MSs are fabricated by incorporating pWGP into calcium‐crosslinked alginate microspheres with subsequent chitosan surface modification to enhance mucosal adhesion. These pWGPAC MSs demonstrated exceptional stability under acidic conditions while enabling targeted release in the colon. In a mouse model of UC, the pWGPAC MSs effectively mitigated mucosal injury, attenuated inflammation, and restored intestinal barrier function. Further mechanistic investigations revealed that these pWGPAC MSs modulated the TLR4/MYD88 signaling pathway and promoted M2 macrophage polarization. Integrated microbiome and metabolome analyses demonstrated that these pWGPAC MSs regulated the gut microbiota composition and decreased pro‐inflammatory metabolite levels. In addition, these microspheres demonstrated promising safety profiles. Collectively, these findings establish pWGPAC MSs as a promising therapeutic strategy for the treatment of UC and provide a solid foundation for future clinical applications.

Ulcerative colitis (UC) is a chronic, non-specific inflammatory bowel disease characterized by inflammation and injury of the colonic mucosa, exhibiting an increasing global incidence. Although research into UC pathogenesis is ongoing, the precise mechanisms remain to be fully elucidated. Studies indicate that UC development results from a complex interplay of factors, including genetic predisposition, environmental exposures, gut microbial dysbiosis, and immune dysregulation. Specifically, UC pathogenesis involves aberrant immune responses triggered by interactions between the host and gut microbiota. A complex, dynamic relationship exists between the microbial community and the host immune system throughout UC pathogenesis. Accumulating evidence suggests that changes in microbiota composition significantly impact gut immunity. This review will examine the intricate balance between the gut microbiota and mucosal immunity in UC progression and discuss potential therapeutic applications, providing a reference for further clinical treatment of this patient population.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon. Recent research has highlighted the significant role of gut microbiota in the pathogenesis and treatment of UC. This review aims to provide a comprehensive overview of the current understanding of the relationship between gut microbiota and UC. We discuss the involvement of gut microbiota in the onset of UC, including the dysbiosis observed in patients and its potential mechanisms. Additionally, the role of extra-intestinal microbiota in UC pathogenesis is explored, which has been less studied but is gaining attention. The influence of gut microbiota on the efficacy of biological immunotherapy for UC is also examined, highlighting how microbial composition can influence treatment outcomes. Furthermore, we review microbiota transplantation, and their potential benefits in UC management. Finally, we consider the combined use of antibiotics and biological agents in UC treatment, discussing their synergistic effects and potential drawbacks. This review underscores the importance of gut microbiota in UC and suggests that targeting microbial communities could offer new avenues for effective treatment.

Polysaccharides from edible and medicinal plants are promising natural agents for intestinal health. In this study, a homogeneous polysaccharide (AMP) was isolated from Atractylodes macrocephala Koidz. Structural characterization revealed that AMP (Mw = 3.56 kDa) primarily consisted of fructose (92.4 %) and glucose (7.6 %), with β-D-fructofuranose and α-d-glucopyranose residues linked through →1)-β-D-Fruf-(2→, →1,6)-β-D-Fruf-(2→, and α-D-Glcp-(1 → glycosidic bonds. In vivo studies confirmed the efficacy of AMP against ulcerative colitis (UC) in a DSS-induced mouse model, as evidenced by a significant improvement in disease symptoms, including increased body weight, longer colon length, and elevated goblet cell counts, coupled with a reduction in the disease activity index and histological damage. Mechanistically, AMP attenuated inflammation by restoring intestinal barrier integrity and regulating the gut microbiota to maintain its homeostasis. These regulatory effects were further validated through fecal microbiota transplantation (FMT) and antibiotic intervention (Abx). Olink proteomics and western blotting demonstrated that the ameliorative effect of AMP on UC, mediated via the PI3K/Akt pathway, was entirely dependent on the homeostasis of the gut microbiota. Collectively, these findings position AMP as a promising functional food ingredient or natural therapeutic for UC, providing a scientific basis for the high-value exploitation of A. macrocephala.

ETHNOPHARMACOLOGICAL RELEVANCE Lizhong decoction (LZD), a Traditional Chinese Medicine formula, is widely utilized to treat gastrointestinal diseases, including ulcerative colitis in China for thousands of years. AIM OF THE STUDY To investigate whether the protective effect of LZD on ulcerative colitis is dependent on gut microbiota and T-cell immune homeostasis. MATERIAL AND METHODS The preventive effects of LZD on dextran sodium sulfate (DSS)-induced colitis mice were evaluated through the measurement of body weight, disease activity index, colon length and hematoxylin-eosin staining. Flow cytometry was used to detect the ratio of Th17/Treg cells. Pseudo sterile mice and fecal transplantation experiments were used to investigate whether the preventive effect of LZD was dependent on the gut microbiota. The alterations of gut microbiota were identified by the 16S rDNA sequencing. The content of intestinal short-chain fatty acids (SCFAs) was detected by LC-MS/MS analysis. The downstream signal pathways of SCFAs were detected by the immunoblotting. RESULTS LZD administration significantly alleviated weight loss and intestinal injury in DSS-induced colitis mice. LZD administration also promotes the balance of Th17/Treg cells. Moreover, LZD administration relies on gut microbiota to alleviate ulcerative colitis and regulate Th17/Treg cell balance. LZD administration significantly improves gut microbial composition in colitis mice, elevating the abundance of SCFAs producing bacterium such as lachnospiraceae_nk4a136_group and Akkermansia. LZD treatment further increases the abundance of SCFAs and promotes activation of free fatty acid activated receptor 2 (FFAR2). CONCLUSION LZD administration promotes Th17/Treg cell balance in a gut microbiota-SCFAs dependent manner, which in turn ameliorates ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory condition of the colon, closely linked to dysbiosis of gut microbiota and imbalances in bile acids. Lithocholic acid (LCA), a secondary bile acid, plays a crucial role in maintaining gut health; however, its specific therapeutic potential in UC remains to be fully elucidated. This study investigates the efficacy of LCA in alleviating UC and explores the underlying mechanisms, particularly focusing on the PXR/TLR4/NF-κB/NLRP3 signaling pathway and gut microbiota modulation. Using a dextran sulfate sodium (DSS)-induced colitis model, our findings demonstrate that LCA administration significantly alleviates colitis symptoms, evidenced by reduced disease activity index (DAI), increased colon length, improved intestinal barrier function, and decreased colonic inflammation. Mechanistically, LCA activates the pregnane X receptor (PXR), which inhibits TLR4-mediated NF-κB/NLRP3 inflammasome activation, leading to reduced colonic inflammation and lower levels of pro-inflammatory cytokines. Furthermore, LCA remodels gut microbiota by promoting beneficial bacterial growth, such as Akkermansiaceae, Lactobacillaceae and Muribaculaceae, while suppressing pathogenic and opportunistic pathogens, including Enterobacteriaceae and Bacteroidaceae. The gut microbiota-dependent effects of LCA were corroborated through antibiotic treatment and fecal microbiota transplantation (FMT) experiments. Notably, the absence of intestinal flora affected PXR expression and activity, modifying the aforementioned effects. Overall, our findings reveal that LCA ameliorates experimental colitis by regulating the PXR/TLR4/NF-κB/NLRP3 signaling cascade and modulating gut microbiota composition. This study underscores LCA’s potential as a targeted therapeutic strategy and a promising microbiota-focused approach for managing UC, offering new insights into the role of bile acids in intestinal health and disease management.

Ulcerative colitis (UC) is characterized by impaired gut barrier, dysregulated immune responses and pronounced gut dysbiosis. Euglena gracilis (EG), rich in β-1,3-glucan (EGP), exhibits immunomodulatory properties, yet its effects on colitis and EGP's role as a core bioactive component are unclear. The aim of this study was to investigate the protective effects of EGP against UC by targeting gut barrier, T-cell immunity and gut microbiota. Results indicated that EG and EGP effectively improved the body weight, colon growth and reduced disease activity index of the DSS-induced mice. Both treatments also significantly suppressed the level of TNF-α and IL-6, restored gut barrier by upregulating ZO-1 and balanced Th17/Treg cells ratio. Microbiota analysis revealed EG and EGP reshaped gut microbiota composition, with an increase in beneficial strains, particularly within the Bacteroidota phylum. Metabolomics linked these changes to enhanced amino acid metabolism. Bacteroides fragilis, a Bacteroidota member, displayed similar anti-colitis bioactivity. In vitro fermentation with fecal samples from UC patients confirmed EGP's role in reshaping gut microbiota, increasing beneficial families such as Clostridiaceae and Lactobacillaceae, while enhancing tryptophan metabolism with anti-inflammatory indoles. These findings identify EGP as the core active component of EG, highlighting its potential in UC prevention through microbiota modulation, gut barrier support and immune regulation.

Background/Objectives: Ulcerative colitis (UC) is a chronic and easily recurrent inflammatory bowel disease. The gut microbiota and plasma metabolites play pivotal roles in the development and progression of UC. Therefore, therapeutic strategies targeting the intestinal flora or plasma metabolites offer promising avenues for the treatment of UC. Luteolin (Lut), originating from a variety of vegetables and fruits, has attracted attention for its potent anti-inflammatory properties and potential to modulate intestinal flora. Methods: The therapeutic efficacy of Lut was evaluated in an established dextran sodium sulfate (DSS)-induced colitis mice model. The clinical symptoms were analyzed, and biological samples were collected for microscopic examination and the evaluation of the epithelial barrier function, microbiome, and metabolomics. Results: The findings revealed that Lut administration at a dose of 25 mg/kg significantly ameliorated systemic UC symptoms in mice, effectively reduced the systemic inflammatory response, and significantly repaired colonic barrier function. Furthermore, Lut supplementation mitigated gut microbiota dysbiosis in a UC murine model, increasing the abundance of Muribaculaceae, Rikenella, and Prevotellaceae while decreasing Escherichia_Shigella and Bacteroides levels. These alterations in gut microbiota also influenced plasma metabolism, significantly increasing phosphatidylcholine (PC), 6′-Deamino- 6′-hydroxyneomycin C, and gamma-L-glutamyl-butyrosine B levels and decreasing Motapizone and Arachidoyl-Ethanolamide (AEA) levels. Conclusions: This study reveals that Lut supplementation modulates intestinal inflammation by restoring the gut microbiota community structure, thereby altering the synthesis of inflammation-related metabolites. Lut is a potential nutritional supplement with anti-inflammatory properties and offers a novel alternative for UC intervention and mitigation. In addition, further studies are needed to ascertain whether specific microbial communities or metabolites can mediate the recovery from UC.

Ulcerative colitis (UC), a chronic inflammatory bowel disease driven by gut dysbiosis, immune dysregulation, and oxidative stress, lacks universally effective therapies. Fucoidan (FCD), a sulfated polysaccharide derived from brown algae, has emerged as a multifaceted therapeutic candidate due to its anti-inflammatory, antioxidant, and immunomodulatory properties. This review synthesizes FCD’s mechanisms in UC pathogenesis, emphasizing its suppression of NF-κB and MAPK signaling pathways to reduce proinflammatory cytokines (e.g., IL-6, TNF-α) and regulate TLR-mediated macrophage polarization. FCD enhances intestinal barrier integrity via upregulation of tight junction proteins (Claudin-1, ZO-1) and mucin MUC2 expression, while remodeling gut microbial ecology through enrichment of SCFAs-producing bacteria (e.g., Ruminococcaceae) and suppression of pathogens (Escherichia coli, Candida albicans). Preclinical studies highlight LMWF as a superior candidate, demonstrating enhanced bioavailability and efficacy in mitigating DSS-induced colitis. Despite its promise, challenges persist in structural heterogeneity (source- and extraction-dependent), scalable production of LMWF, and insufficient pharmacokinetic data. Emerging strategies—including nanoparticle-based delivery systems and structural modifications (cross-linking, covalent bonding)—aim to overcome bioavailability limitations. This review underscores FCD’s potential as a functional food or adjuvant therapy for UC, while advocating for rigorous clinical validation to bridge translational gaps, Enrichment of SCFAs-producing taxa and suppression of pathobionts (Escherichia coli, Candida albicans), mediated through prebiotic fermentation. Suppression of NF-κB activation via IκBα stabilization and inhibition of p65 nuclear translocation, and downregulation of MAPK phosphorylation (ERK1/2, JNK, p38), reducing proinflammatory cytokines (IL-6, TNF-α, IL-1β). FCD can be used as a potential treatment for UC.

Ulcerative colitis (UC) is driven by disruptions in host–microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how host–microbiota interactions become disrupted in UC, we collected and analysed six faecal- or serum-based omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic and amplicon sequencing profiles of faecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn’s disease, 20 healthy controls) was collected and analysed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an overabundance of proteases that originated from the bacterium Bacteroides vulgatus. To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus-induced barrier dysfunction in vitro, and prevented colitis in B. vulgatus monocolonized, IL10-deficient mice. Furthermore, transplantation of faeces from UC patients with a high abundance of B. vulgatus proteases into germfree mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provide a resource for identifying other pathways that could be inhibited as a strategy to treat this disease. Multi-omics analyses of faecal samples from patients with ulcerative colitis reveal a link between Bacteroides vulgatus protease activity and severity of disease symptoms.

Probiotics are potential treatments for ulcerative colitis (UC), but their efficacy is frequently compromised by gastrointestinal conditions that limit adhesion and activity. Here, we use machine learning and bioinformatics to confirm that patients with UC have decreased prevalence of Lactobacillus genus and increased oxidative stress, which correlate with inflammation severity. Accordingly, we developed a probiotic-based therapeutic that synergistically restores intestinal redox and microbiota homeostasis. Lactobacillus casei (Lac) were induced to form a pericellular film, providing a polysaccharide network for spatially confined crystallization of ultrasmall but highly active selenium dots (Se-Lac). Upon oral administration, the selenium dot-embedded pericellular film efficiently enhanced gastric acid resistance and intestinal mucoadhesion of Lac cells. At the lesion site, the selenium dots scavenged reactive oxygen species, while Lac modulated the gut microbiota. In multiple mouse models and non-human primates, this therapeutic effectively relieved inflammation and reduced colonic damage, thus showing promise as a UC treatment.

Ulcerative colitis (UC) is a leading health challenge worldwide. The evidence of the benefits of gut microbiota metabolites for the treatment of ulcerative colitis is accumulating, but the underlying mechanism remains to be further elucidated. Hence, the aim of this study was to decipher the role of gut microbiota metabolites in the management of UC through employing network pharmacology approach. The targets of gut microbiota metabolites were acquired from gutMgene database, similarity ensemble approach (SEA) and SwissTargetPrediction (STP) respectively. The ulcerative colitis related targets were acquired from GeneCards and DisGeNet database. DAVID platform was used to identify key pathways. Molecular docking was used to assess the binding affinity of metabolites with targets. The final core targets were PPARG, IL6 and AKT1. IL-17 signaling pathway and Toll-like receptor signaling pathway were regarded as critical pathway involved in the development of ulcerative colitis. Equol, Butyrate, Acetate and Propionate were identified as the key metabolites against ulcerative colitis. Molecular docking results demonstrated that Equol displayed strong binding affinity to the core targets. the key gut microbiota metabolites exerted beneficial effects on ulcerative colitis through interacting with multi-targets and multi-pathways, these findings highlighted the potential clinical application of gut microbiota metabolites to the treatment of ulcerative colitis.

ABSTRACT Quercetin, a natural flavonoid in traditional Chinese medicinal plants, has shown promise in alleviating ulcerative colitis symptoms despite uncertainties about its exact mode of action. This study explored how quercetin influences tryptophan breakdown and gut bacterial populations in mice with chemically induced colitis. The treatment demonstrated measurable improvements—normalizing body weight, reducing spleen enlargement, lowering clinical severity scores, preserving colon structure, and healing tissue damage. Through advanced microbiome profiling and metabolic analysis, researchers observed increased populations of helpful gut microbes alongside higher concentrations of tryptophan byproducts. These biochemical shifts stimulated the aryl hydrocarbon receptor system, which plays a key role in restoring gut lining integrity. The collective evidence points to quercetin’s therapeutic potential through its dual action on microbial ecology and tryptophan-derived signaling pathways. IMPORTANCE Ulcerative colitis is a chronic inflammatory disease with limited effective therapeutic options. In this study, quercetin—a flavonoid commonly found in traditional Chinese medicinal herbs—was shown to relieve colitis symptoms by reshaping gut microbiota and restoring tryptophan metabolism. Notably, the increase in indolelactic acid, a key microbial metabolite, led to activation of the aryl hydrocarbon receptor, which supports intestinal barrier integrity and dampens inflammation. These findings reveal a gut microbiota-derived metabolite-host signaling axis as a central mechanism of action, highlighting the potential of quercetin as a microbiota-targeted therapeutic approach for UC. Ulcerative colitis is a chronic inflammatory disease with limited effective therapeutic options. In this study, quercetin—a flavonoid commonly found in traditional Chinese medicinal herbs—was shown to relieve colitis symptoms by reshaping gut microbiota and restoring tryptophan metabolism. Notably, the increase in indolelactic acid, a key microbial metabolite, led to activation of the aryl hydrocarbon receptor, which supports intestinal barrier integrity and dampens inflammation. These findings reveal a gut microbiota-derived metabolite-host signaling axis as a central mechanism of action, highlighting the potential of quercetin as a microbiota-targeted therapeutic approach for UC.

ETHNOPHARMACOLOGICAL RELEVANCE Banxia Xiexin decoction (BXD) is a classic traditional Chinese medicine prescription for treating ulcerative colitis (UC). However, its potential mechanism of action is still unclear. AIM OF THE STUDY Reveal the correlation between the beneficial impacts of BXD on UC and the composition of the gut microbiota. MATERIALS AND METHODS The major constituents of BXD were identified using the HPLC-DAD technique. An experimental model of UC was induced in male C57BL/6 mice by administering dextran sodium sulfate (DSS). A total of 48 mice were divided into different groups, including control, model, high-dose BXD treatment, medium-dose BXD treatment, low-dose BXD treatment, and a group treated with 5-amino acid salicylic acid (5-ASA). Body weight changes and disease activity index (DAI) scores were documented; colon length, colon index, spleen index, and thymus index scores were determined; myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) activities were assessed; and histological staining with hematoxylin-eosin and alcian blue/phosphate Schiff was performed. The immunofluorescence technique was employed to examine the presence of ZO-1 and occludin in the colon tissue. 16S rRNA sequencing was employed to assess the gut microbiota's diversity and metabolomics was utilized to examine alterations in metabolites within the gut microbiota. The impact of BXD on the gut microbiota was confirmed through fecal microbiota transplantation (FMT). RESULTS BXD exhibited a positive impact on UC mice, particularly in the high-dose BXD treatment group. The BXD group experienced weight recovery, decreased DAI scores, improved colon length, and restored of spleen and thymus index scores compared to the DSS group. Additionally, BXD alleviated colon damage and the inflammatory response while restoring intestinal barrier function. FMT in BXD-treated mice also showed therapeutic effects in UC mice. At the phylum level, the relative abundance of Desulfobacterota, Deferribacterota and Actinobacteriota increased; at the genus level, g__norank__f__Muribaculaceae, Dubosiella, Akkermansia, and Lactobacillus increased, whereas Faecalibaculum, Alloprevotella, Turicibacter, and g_Paraprevotella decreased. g__norank_f__Muribaculaceae was positively correlated with body weight and colon length and negatively with colon index scores, splenic index scores, and MPO levels; Alloprevotella was positively correlated with splenic index scores, histological scores, and TNF-α levels and negatively with thymus index scores and thymus index scores. Faecalibaculum was positively correlated with colon index scores and MPO levels. Metabolic investigations revealed 58 potential indicators, primarily associated with the metabolism of amino acids, purines, and lipids. Alloprevotella, g_Paraprevotella, and Bifidobacterium were strongly associated with metabolic pathways. CONCLUSION BXD showed beneficial therapeutic effects in UC mice. The mechanism may be by promoting the balance and variety of gut microbiota, as well as regulating the metabolism of amino acids, purines, and lipids.

Ulcerative colitis (UC) involves chronic, complex pathology of the intestinal mucosa. Current treatments are limited in efficacy and associated with adverse effects, highlighting the urgent need for improved therapeutic options. Lentinan (LNT), a polysaccharide drug commonly used in clinical immune modulation therapies, shows potential for UC treatment, though its specific targets and mechanisms remain unclear. In this study, LNT administration effectively mitigated DSS-induced colitis in mice, enhanced mucosal barrier function and antimicrobial defense. Specifically, LNT modulated the balance between tissue-resident and infiltrating macrophages, thereby improving pathogen clearance and enhancing the immunological barrier. Notably, we identified a novel effect of LNT in regulating the macrophage Dectin-1-ILC3 axis to increase IL-22 secretion. This led to the modulation of epithelial O-glycan fucosylation, antimicrobial peptides, and epithelial stem cells, thereby strengthening antimicrobial defenses and the physicochemical barrier. Neutralization with anti-IL-22 antibodies diminished the therapeutic effect of LNT in UC, underscoring the critical role of IL-22 in LNT-mediated treatment. Overall, this study highlights the potential of LNT as a novel therapeutic agent for UC, offering new insights into its molecular mechanisms and clinical application.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon and rectum, associated with epithelial barrier defects and dysregulated immune responses. Here, we developed Eudragit S100-coated mucin/CyA co-loaded calcium alginate microspheres (E-CMAMs) for synergistic UC therapy via immunosuppression and mucosal barrier repair. E-CMAMs were prepared by a high-voltage electrostatic method and an emulsification-solvent evaporation method. Their characteristics were analyzed by inverted optical microscope, SEM, FTIR, and DSC. E-CMAMs exhibited excellent pH-responsive behavior, as they remained stable in acidic gastric fluid, swelled moderately in neutral intestinal fluid, and rapidly disintegrated in the alkaline colonic environment, which enabled the colon-specific release of CyA. Moreover, E-CMAMs effectively protected CyA from degradation by gastric acid and proteolytic enzymes. In vivo gastrointestinal fate and distribution study showed that E-CMAMs maintained structural integrity in the upper gastrointestinal tract and released fluorescent dye upon reaching the colon. In DSS-induced UC mice, E-CMAMs significantly alleviated colitis symptoms, suppressed inflammatory responses (MPO, TNF-α, IL-1β, and IL-6 reduced), and restored intestinal barrier integrity by reconstructing the mucus layer and upregulating tight junction proteins (Occludin and ZO-1). Finally, E-CMAMs demonstrated excellent biosafety, with no detectable toxicity in major organs. The combination of CyA-mediated immunosuppression and mucin-mediated mucosal repair achieved superior efficacy, with excellent biosafety. This colon-targeted co-delivery strategy offers a promising approach for more effective and safer UC therapy.

No abstract available

Hypoxia-inducible factor prolyl hydroxylase (PHD) inhibitors have been approved for treating renal anemia yet have failed clinical testing for inflammatory bowel disease because of a lack of efficacy. Here we used a multimodel multimodal generative artificial intelligence platform to design an orally gut-restricted selective PHD1 and PHD2 inhibitor that exhibits favorable safety and pharmacokinetic profiles in preclinical studies. ISM012-042 restores intestinal barrier function and alleviates gut inflammation in multiple experimental colitis models. Generative artificial intelligence is used to design an effective treatment for inflammatory bowel disease in preclinical models.

No abstract available

Ulcerative colitis is characterized by oxidative stress, epithelial barrier dysfunction and persistent mucosal injury. Mesenchymal stem cells (MSCs) have barrier-supportive and tissue-reparative properties, but oxidative inflammatory conditions may impair their survival and functional activity. Nuclear factor erythroid 2-related factor 2 (NRF2) is a central regulator of cellular antioxidant responses and may improve MSC adaptation to oxidative stress. Here, stable NRF2-overexpressing MSCs (MSCs-NRF2) were generated by lentiviral transduction and evaluated in an H2O2-induced Caco-2/HT-29 epithelial injury model and a dextran sulfate sodium (DSS)-induced acute colitis mouse model. qRT-PCR, immunofluorescence staining, transcriptomic analysis and 16S rRNA sequencing were used to assess oxidative-stress responses, epithelial barrier restoration, mucosal injury and microbial alterations. NRF2 overexpression enhanced antioxidant and anti-inflammatory gene expression in MSCs and improved MSC viability under oxidative stress. Conditioned medium from MSCs-NRF2 more effectively supported ZO-1 and occludin recovery in injured epithelial co-cultures than conditioned medium from control MSCs. In DSS-induced colitis, MSCs-NRF2 were associated with reduced mucosal injury, improved tight-junction and mucus-barrier markers, and altered gut microbial profiles. These responses were accompanied by increased NRF2-related antioxidant signalling in intestinal tissue. These findings indicate that NRF2 overexpression strengthens MSC adaptation to oxidative inflammatory stress and supports epithelial barrier repair and mucosal tissue recovery in experimental colitis.

No abstract available

Montmorillonite (MMT), a layered aluminosilicate, has a mucosal nutrient effect and restores the gut barriers integrity. However, orally administrating MMT is not effective to combat the reactive oxygen species (ROS) and alleviate the acute inflammatory relapse for colitis patients. Herein, polydopamine-doped montmorillonite micro-sheets (PDA/MMT) have been developed as a therapeutic platform for colitis treatment. SEM and EDS analysis showed that dopamine monomer (DA) was easily polymerized in alkaline condition and polydopamine (PDA) was uniformly cladded on the surface of MMT micro-sheets. The depositing amount of PDA was reaching to 2.06 ± 0.08%. Moreover, in vitro fluorescence probes experiments showed that PDA/MMT presented the broad spectra of scavenging various ROS sources including •OH, •O2−, and H2O2. Meanwhile, the intracellular ROS of Rosup/H2O2 treated Caco-2 cell was also effectively scavenged by PDA/MMT, which resulted in the obvious improvement of the cell viability under oxidative stress. Moreover, most of orally administrated PDA/MMT was transited to the gut and form a protective film on the diseased colon. PDA/MMT exhibited the obvious therapeutic effect on DSS-induced ulcerative colitis mouse. Importantly, the gut mucosa of colitis mouse was well restored after PDA/MMT treatment. Moreover, the colonic inflammation was significantly alleviated and the goblet cells were obliviously recovered. The therapeutic mechanism of PDA/MMT was highly associated with inhibiting oxidative stress. Collectively, PDA/MMT micro-sheets as a therapeutic platform may provide a promising therapeutic strategy for UC treatment.

No abstract available

This study aimed to investigate the regulatory effects of Glehnia littoralis polysaccharides (GLP) on lung and intestinal mucosal barriers in rats with ulcerative colitis (UC). The results demonstrated that GLP inhibited the levels of TNF-α, IL-6, and MPO in colon tissues, alleviated colonic pathological damage, and reduced the expression of TNF-α, IL-6, IL-1β, and MPO in lung tissues, thereby ameliorating lung injury secondary to intestinal inflammation. Further analysis revealed that GLP restored the integrity of lung and intestinal mucosal barriers by upregulating the expression of mucin, ZO-1, and Occludin. In addition, GLP modulated the gut microbiota composition and increased the levels of tryptophan metabolites, including indole-3-carboxaldehyde (IAId), indole-3-acetic acid (IAA), and 5-hydroxyindoleacetic acid (5-HIAA), thereby activating the aryl hydrocarbon receptor (AhR) to further promote mucosal barrier repair. In vitro experiments showed that GLP reduced the levels of TNF-α, IL-6, IL-1β, MDA, and ROS, while increasing SOD activity and the expression of ZO-1, Occludin, Claudin-1, AhR, and CYP1A1 in lipopolysaccharide (LPS)-induced human normal colonic epithelial cells (NCM460) and human bronchial epithelial cells (BEAS-2B). However, the epithelial barrier protective effects of GLP in cells were abolished following the addition of an AhR antagonist. Collectively, these findings suggest that GLP may restore lung and intestinal mucosal barrier damage in UC by activating the shared AhR signaling pathway in both the lung and intestine.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by the superficial mucosa ulcer and inflammation. Spermidine (SPD) has been demonstrated to alleviate the relapse of acute colitis without the systemic immune function compromise via restoring the intestinal mucosal barrier. However, due to its rapid systemic absorption in small intestine and extensive metabolism in liver, the orally administered spermidine had limited access to the diseased colon. Herein, a thermosensitive and mucoadhesive hydrogel (PA) composed of poloxamer 407 and sodium alginate has been developed to rectally deliver SPD for UC treatment. SPD-loaded PA hydrogel (PA-SPD) exhibited the rapid gelation within 1 min at 37 °C, and the adhesive strength of 3.3 × 103 mN toward fresh colon tissues, both of which ensured its effective retention on the ulcer colon. Moreover, the sustained-release profile of SPD from PA-SPD was presented, with just 23 % of SPD was released at 2 h while more than 80 % was released at 6 h. In DSS-induced colitis mice, PA-SPD significantly reduced disease severity, restored colon length (8.2 cm vs. 5.3 cm in controls), and lowered the level of IL-6, TNF-α, IL-1β. Moreover, PA-SPD treatment could restore gut epithelial barrier integrity via upregulating expression of ZO-1, occludin, claudin-5, and MUC2. The repairing mechanism of PA-SPD was highly associated with activating the autophagy of gut epithelial to induce stem cell proliferation and differentiation. Collectively, PA might be a promising topical delivery carrier of SPD for ulcerative colitis treatment.

In this study, FeMoO4/MoO3 nanoparticles (Fe/Mo NPs) were coated with mannose-modified chitosan (CM) to form Fe/Mo@CM nanozyme. Fe/Mo@CM exhibited strong self-cascading multiple antioxidant enzyme-mimicking activities. It simulated the natural antioxidant defense system composed of superoxide dismutase (SOD), glutathione peroxidase (GPx) and peroxidase (POD), catalyzing the decomposition of superoxide anions (O2-) and hydrogen peroxide (H2O2), while scavenging reactive oxygen species and reactive nitrogen species (RO/NS). Moreover, Fe/Mo@CM effectively alleviated inflammatory damage by inhibiting the excessive immune process and significantly reducing the number of inflammatory macrophages in the colon, thereby lowering the levels of pro-inflammatory cytokines. Furthermore, treatment with Fe/Mo@CM enhanced the expression of gut barrier proteins, which effectively mitigated DSS-induced colon shortening and histopathological damage. These findings suggest that Fe/Mo@CM can prevent oxidative stress, inflammation, and intestinal barrier disruption. Notably, Fe/Mo@CM also demonstrated potential in modulating the inflammatory microenvironment and immune process, with good gastrointestinal tolerance and strong therapeutic efficacy.

Impairment of intestinal epithelium is a typical feature of inflammatory bowel disease (IBD) that causes leakage of bacteria and antigens from the intestinal lumen and thus results in persistent immune activation. Hence, healing and regeneration of the damaged gut mucosa is a promising therapeutic approach to achieve deep remission in IBD. Currently, available systemic therapies have moderate effects and are often associated with numerous side effects and malignancies. In this study, we aimed to develop a topical therapy by chemically conjugating a temperature-responsive polymer, i.e., poly(N-isopropylacrylamide), along with hyaluronic acid to obtain a sprayable therapeutic formulation that upon colon instillation adheres to the damaged gut mucosa due to its temperature-induced phase transition and mucoadhesive properties. An ex vivo adhesion experiment demonstrates that this therapeutic formulation forms a thin physical coating on the mucosal lining at a physiological temperature within 5 min. Physicochemical characterization of (P(NIPAM-co-NTBAM)-HA) established this formulation to be biocompatible, hemo-compatible, and non-immunogenic. Prednisolone was encapsulated within the polymer formulation to achieve maximum therapeutic efficacy in the case of IBD-like conditions as assessed in a custom-fabricated perfusion-based ex vivo model system. Histological analysis suggests that the prednisolone-encapsulated polymer formulation nearly restored the mucosal architecture after 2,4,6-trinitrobenzenesulfonic acid-induced damage. Furthermore, a significant (p ≤ 0.001) increase in mRNA levels of Muc-2 and ZO-1 in treated groups further confirmed the mucosal epithelial barrier restoration.

Abstract Background To protect the gastrointestinal tract from infection, intestinal epithelial cells (IECs) lining the mucosa possess cytosolic complexes called inflammasomes which detect pathogenic insult and rapidly initiate inflammation to stop infectious spread. Active inflammasomes mediate crucial effector functions such as epithelial cell extrusion, pyroptotic cell death, and the release of interleukin (IL)-18 and prostaglandin E2 (PGE2). Recent literature has shown that IL-18 and PGE2 mediate intestinal repair following epithelial damage from DSS-induced colitis. Exogenous administration of IL-18 in inflammasome deficient mice improves survival and reduces pathology. PGE2 activates intestinal cellular reprogramming to drive intestinal wound healing. Whether inflammasome derived IL-18 and PGE2 mediate epithelial repair during enteric infection is unclear. Aims Using murine small intestinal organoids (mSIOs), we will investigate how IL-18 and PGE2 production by intestinal inflammasomes directly impacts IECs at both transcriptional and physiological levels. We hypothesize that inflammasome derived IL-18 and PGE2 will act on the intestinal epithelium resulting in transcriptional reprogramming that promotes tissue regeneration and barrier reinforcement. Methods WT and Nlrc4-/- mSIOs were stimulated with flagellin or FlaTox to activate the NAIP-NLRC4 inflammasome. The transcriptomic landscape was assessed with bulk-RNA sequencing and inflammasome activation was assessed by Western blot. IL-18 and PGE2 dependent gene targets were identified using Il-18-/- and indomethacin treated mSIOs by RT-qPCR. Results Bulk-RNA sequencing revealed an inflammasome activation dependent transcriptional signature in murine IECs upon NAIP-NLRC4 inflammasome activation. GO term analysis showed these genes to be involved in actin cytoskeleton rearrangement, epidermal growth factor signaling, and regulation of cell-cell adhesion. The expression of PGE2 gene targets were significantly reduced by indomethacin treatment while IL-18 gene targets remained unaffected in Il-18-/- IECs. FlaTox induced the same transcriptional changes but substantially amplified their expression. FlaTox but not flagellin led to a significant drop in Lgr5 (stem cells) and Lyz1 (Paneth cell) expression and an increase in Ly6a, a marker of fetal-like stem cells. Conclusions This data demonstrates that inflammasome signaling causes transcriptional reprogramming of IECs that activates pathways involved in maintaining epithelial barrier integrity. While IL-18 had no effects on gene expression at 4 hours, PGE2 paracrine signaling contributed to the expression of wound healing genes. Stronger inflammasome mediated damage with FlaTox amplified the repair response at the transcript level and we observed transient reprogramming of IECs into a fetal-like state suggesting active tissue regeneration. Funding Agencies CCC, CIHREPIC: Emerging & Pandemic Infections Consortium

BACKGROUND Aryl hydrocarbon receptor (AhR) activation promotes intestinal barrier repair and enhances the gut mucosal barrier function in inflammatory bowel diseases (IBD). Spermidine is beneficial in several murine models of IBD and may affect AhR activity. However, the precise effects of spermidine on the intestinal barrier and AhR remain unclear. This study was designed to investigate whether spermidine affects AhR and gut barrier function in IBD models as well as, its underlying mechanism. METHODS We used dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mice, as well as, Caco2 cells incubated with TNF-α and IFN-γ to establish multiple IBD models, followed by spermidine intervention. Alcian blue/Periodic acid-Schiff (AB/PAS) staining, Fluorescein isothiocyanate (FITC)-dextran permeability assay, transepithelial electrical resistance (TER), tight junction protein (TJs) expression, and 16S rRNA scope in situ hybridization were performed to assess intestinal barrier function. AhR expression and the associated pathways were measured. AhR-targeted adeno-associated virus (AAV) and siRNA were used to explore the related molecular mechanisms. RESULTS Spermidine significantly attenuated the increased intestinal permeability, decreased TER, abnormal distribution of TJs in colitis, and bacterial translocation from the gut tract. Additionally, it significantly increased AhR and Nrf2 expression and inhibited STAT3 phosphorylation. However, the protective effects of spermidine and the related alterations in pathway proteins were largely abolished by the specific inhibition of AhR. CONCLUSION Our study demonstrated that spermidine rescues intestinal barrier defects in mice with colitis via the AhR-Nrf2 and AhR-STAT3 pathways, providing a potential therapeutic agent for IBD and other conditions associated with dysregulated gut barrier function.

Ulcerative colitis (UC) is a chronic nonspecific inflammatory bowel disease whose pathogenesis remains unclear. Dysfunction of the intestinal mucosal barrier is closely related to the pathogenesis of UC, which is characterised by damage to the colon epithelial barrier, disruption of immune homeostasis, and persistent inflammatory cell infiltration. MicroRNAs (miRNAs) exhibit specific or differential expression in both UC animal models and patients, implicating their involvement in the pathogenesis of UC. In recent years there has been progress in using Traditional Chinese medicine (TCM) to regulate miRNA expression for repairing the intestinal mucosal barrier in UC, as demonstrated in animal and cell experiments. However, it has not been applied in a clinical setting and its underlying molecular mechanisms require further investigation. Therefore, this study systematically described the role of miRNAs in UC-induced intestinal barrier damage and the application of TCM to repair this intestinal barrier by regulating miRNA expression, offering new therapeutic targets for UC treatment.

Mucosal epithelia are constantly exposed to damaging stimuli from mechanical, chemical, or biologic entities, and depend on rapid repair mechanisms to maintain tissue homeostasis and immunological quiescence. The reparative cytokine Trefoil factor 2 (TFF2) serves to enforce mucosal barrier integrity, but whether TFF2 receptor(s) exist is controversial. Herein, we demonstrate leucine rich repeat and immunoglobulin like domain containing nogo receptor interacting protein 3 (LINGO3) is a necessary transmembrane component for TFF2-mediated ERK signaling, proliferation, and recovery of trans-epithelial resistance of primary epithelia during wound healing. Human respiratory and intestinal epithelia express LINGO3 and mice lacking Lingo3 have impaired intestinal barrier function and fail to recover from DSS-induced colitis. Compared to wild-type controls, LINGO3 deficiency impairs both crypt regeneration and expression of the intestinal stem cell marker Lgr5. Importantly, Lingo3-/- mice display a phenotype similar to that previously reported for Tff2 deficiency, with increased paracellular permeability, and significant accumulation of mucosal CD4+ TH1 cells expressing IFNγ+ TNF+ even under steady-state conditions. Combined, these data reveal a previously unrecognized role for LINGO3 as a putative TFF2 receptor that regulates mucosal barrier integrity and GI inflammation. Significance Intestinal epithelial cells (IEC) are necessary for maintenance of homeostasis, resistance to infectious organisms, and overall organismal health. When injured the IEC and the underlying stroma and progenitor cell pool undergo restitutive and regenerative processes driven by the reparative cytokine Trefoil factor 2 (TFF2). This report identifies a novel receptor component for TFF2 signaling expressed on both human and mouse epithelial cells that is necessary for barrier integrity at the steady state and during colitic disease. The discovery of a novel TFF2-LINGO3 axis sheds new light on the processes controlling tissue repair, restitution, and regeneration at the mucosal interface.

Inflammatory bowel disease (IBD) remains a global health challenge linked to intestinal barrier disruption, microbiota dysbiosis, and immune dysregulation, though the interplay of these mechanisms remains poorly defined. Here, we investigated the therapeutic potential of Lactobacillus johnsonii N5 in a murine dextran sulfate sodium (DSS)-induced colitis model. Prophylactic N5 administration alleviated colitis symptoms (weight loss, colon shortening), reduced fecal and serum lipocalin-2 levels, and suppressed colonic pro-inflammatory cytokines (IL-1β, IL-6). N5 preserved microbial diversity, enhanced mucus secretion, and reinforced mucosal barrier integrity, preventing colitis onset. Therapeutically, N5 attenuated disease progression by downregulating IL-1β, IL-6, IL-8 expression, restoring Lactobacillus populations, and suppressing Escherichia-Shigella expansion, thereby reducing bacterial translocation and systemic inflammation. N5 promoted Ki67+ epithelial proliferation, accelerating mucosal repair. Mechanistically, N5 targeted neutrophil-mediated gut-liver injury, suppressing coagulation pathways in colon-liver transcriptomes, reducing hepatic lesions, platelet aggregation, CD162+ neutrophil recruitment, and H3cit + neutrophil extracellular trap (NET) formation. N5’s effects were partially recapitulated by DNase I in vivo and/or by its metabolites in vitro, suggesting its action involves metabolite-driven NET inhibition alongside DNase-like NET clearance. These findings illuminate N5’s dual role in IBD-prophylactic barrier fortification and therapeutic resolution of neutrophilic inflammation, and highlight its potential as a multifaceted probiotic therapy. Lactobacillus johnsonii N5 prevents colitis by fortifying the mucosal barrier and alleviates disease by inhibiting NETosis and gut-liver inflammation, promoting mucosal repair.

Introduction The global health challenge of ulcerative colitis (UC) has been classified by the WHO as a modern refractory disease, commonly referred to as green cancer, with limited treatment options still available, highlighting the urgent need for the development of new therapeutic strategies. Recent pharmacological research has shown that traditional Chinese medicine saussurea costus (SC) possesses beneficial antibacterial and anti-inflammatory properties. Nevertheless, its underlying mechanism remains elusive. Methods Firstly, we identified the main active components of SC through UHPLC-QTOF-MS analysis. Subsequently, UC mice were induced using DSS and administered different doses of SC to evaluate its efficacy. Additionally, the impact of SC on the repair of the intestinal mucosal barrier was evaluated through immunofluorescence and western blot. Furthermore, 16s rRNA gene sequencing was conducted to elucidate the contribution of gut microbiota to UC pathogenesis. Results The primary components of SC include Proline, Phenylalanine, Isoleucine, Lucidenic acid M, and Pyroglutamic acid. The efficacy of SC was concurrently assessed, revealing its potential to ameliorate histological injury in colitis mice. Furthermore, SC was found to decrease levels of TNF-α, IL-1β, IL-8, and IL-18 while promoting the expression of IL-10 and IL-22. Similarly, we also found that the expression of ZO-1 and Occludin was reversed by SC in colitis mice. In addition, analysis of 16S rRNA gene sequencing indicated that SC reduced harmful bacterial populations, such as Proteobacteria, while simultaneously enhancing the levels of beneficial bacteria like Lactobacillus, thereby contributing to the improvement of UC pathology. Conclusion This study highlights the therapeutic potential of SC in managing UC through its ability to attenuate inflammatory responses, restore intestinal barrier functionality, and modulate gut microbiota composition, which findings offer insights into potential strategies for advancing UC treatment.

Designing innovative strategies for oral delivery of active compounds is particularly promising for the treatment of intestinal diseases such as ulcerative colitis (UC). However, obstacles like poor therapeutic efficacy, low bioavailability, and limited biocompatibility need to be addressed. Here, via the Schiff base reaction, we developed nanoparticles based on PT (PT NPs) and incorporated them into ascorbate palmitate hydrogels (AP-Gel) to create nanoparticle-hydrogel composites (PT NPs-Gel). In vitro studies showed that PT NPs-Gel reduced pro-inflammatory cytokines (NO, iNOS, TNF-α, and IL-1β), increased the anti-inflammatory cytokine IL-10, and enhanced antioxidant enzyme activities (SOD and CAT) with effect. In the DSS-induced UC mouse model, PT NPs-Gel significantly alleviated UC symptoms, improved the length of colon, and lowered the disease activity index (DAI) score. Histological analysis indicated that PT NPs-Gel protected the colonic epithelial barrier and reduced inflammation. The PT NPs-Gel formulation utilizes the biological properties of the hydrogel carrier to improve the bioavailability of active compounds and demonstrates effective anti-inflammatory and antioxidant properties, making it a promising oral delivery system for the treatment of UC and potentially other inflammatory bowel diseases.

Background Ulcerative colitis (UC) is a major type of inflammatory bowel disease (IBD), which could induce bloody stool, diarrhea, colon atrophy and eventually lead to colorectal cancer. The conventional daily oral administration of drugs only relieve the inflammatory response of colon in the short term, Biological agents such as antibody drugs has proven its efficiency in inhibiting colitis, while the low drug bioavailability means that large doses of antibodies are required, ultimately causing systemic toxicity. Small interfering RNA (siRNA) has significant advantages over antibody drugs in terms of safety and efficacy, and it have been widely applied as potential candidates for a variety of inflammation-related diseases. However, oral delivery of siRNA fails to overcome the degradation of the gastrointestinal environment to produce a significant therapeutic effect in ulcerative colitis. Herein, we design the hybrid delivery system that the siRNA loaded MOF encapsulated in the sodium alginate particles to overcome the barriers in the oral process. Results The hybrid delivery system (SA@MOF-siRNA TNFα ) was successfully constructed, and it could not only survive the low pH environment in the stomach and small intestine, but also taken up more by inflammatory macrophages, as well as released much more MOF-siRNA TNFα . Moreover, SA@MOF-siRNA TNFα tended to enriched and infiltrated into local colon tissues. As a result, SA@MOF-siRNA TNFα significantly reduced the progression of colitis, of which the treated mice did not experience significant weight loss, bloody stools and diarrhea. Conclusion We confirmed that the formulation of hydrogel–metal-organic framework hybrids could improve the protection of incorporated payload in the gastric and early small intestine, enhancing the delivery of MOF-siRNA to colon.

Celastrol (Cel), a highly promising natural product isolated from traditional Chinese medicine, exhibits potent therapeutic efficacy against ulcerative colitis (UC). Nevertheless, its poor colon-targeting efficiency, insufficient capacity to penetrate the intestinal mucus layer, and low cellular internalization significantly compromise therapeutic outcomes in UC treatment. To address these critical limitations, herein we rationally designed a exosome-hydrogel hybrid system (Cel-GDNPs@Gel) by first encapsulating Cel into ginger-derived exosome-like nanoparticles (GDNPs), which were subsequently dispersed within a glycyrrhizic acid (GA) hydrogel matrix. Experimental studies confirmed that GDNPs were successfully isolated and characterized with uniform size distribution and round- or cup-shaped morphology, and Cel was successful encapsulated into GDNPs. The GA hydrogel endowed the system with excellent pH-sensitivity and robust mucoadhesive properties, thereby facilitating enhanced accumulation and prolonged retention at the colon site. Moreover, GDNPs promoted efficient mucus penetration and cellular uptake of Cel. Notably, both GDNPs and GA could exert synergistic therapeutic effects with Cel. Accordingly, in vitro and in vivo studies demonstrated that Cel-GDNPs@Gel significantly alleviated colitis symptoms, suppressed the expression of pro-inflammatory cytokines, attenuated oxidative stress, regulated macrophage polarization, promoted intestinal mucosal barrier repair, and restored intestinal homeostasis. Furthermore, this delivery system exhibited favorable biosafety with no obvious systemic toxicity. Collectively, this multifunctional Cel-GDNPs@Gel platform offers a safe and effective strategy for the oral treatment of UC.

Elevated intestinal inflammation, reactive oxygen species (ROS), and gut microbiota dysbiosis are prominent features of various intestinal disorders. In this work, we develop an oral inulin-based hydrogel delivery system (LICH) containing living probiotics and hyaluronic acid (HA)-modified carbon dot (CD) nanoenzymes to orchestrate gut disorders. Utilizing the hydrophobic properties of HA under acidic conditions, LICH contracts its network to safeguard probiotics during gastric transit. Upon reaching the intestine, HA-modified CD enables spatiotemporal targeting of lesion sites, achieving anti-inflammatory and ROS-scavenging effects. Concurrently, probiotics and inulin synergistically restore a balanced gut microbiota. In a murine model of ulcerative colitis, LICH exhibits prolonged intestinal retention and significantly ameliorates the pathological microenvironment. Transcriptomic and metabolomic analyses further reveal that LICH exerts its therapeutic effects primarily by modulating inflammation, scavenging ROS, and promoting intestinal barrier repair. This study provides a versatile oral platform to regulate multifaceted pathological characteristics for the treatment of intestinal disorders.

Gut microbiota editing represents a promising therapeutic strategy for dysbiosis-associated diseases. Bacteriophages (phages), with their host specificity, enable precise microbial manipulation but face challenges such as environmental vulnerability and low bioavailability, which limit their in vivo efficacy. Here, we develop double-responsive hydrogel microspheres (HMs) via electrohydrodynamic spraying to enhance oral phage delivery. Composed of sodium alginate, hyaluronic acid, and Eudragit S100, these HMs achieve 90% encapsulation efficiency for a Salmonella-targeting phage cocktail. Such formulation significantly protects phages from gastric conditions, prolongs their intestinal retention, and enables responsive payload release in the colon. In a murine model of Salmonella Typhimurium (STm)-induced colitis, HMs-encapsulated phages (HMs-Phages) reduce intestinal STm burden by nearly 2000-fold and lower levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β) to 60% of those in infected group. Notably, HMs-Phages achieve potent antibacterial efficacy comparable to ciprofloxacin while selectively targeting STm. This targeted strategy circumvents antibiotics-associated microbiota dysbiosis and diarrhea, thereby effectively restoring gut homeostasis and improving host physical health. By integrating targeted pathogen eradication with microbiota conservation, this work provides a precise toolkit for gut microbiota editing and phage therapy, offering substantial advantages over antibiotics for managing dysbiosis-related diseases. Gut microbiota editing is a promising strategy for dysbiosis-related diseases. Here, the authors develop an oral phage delivery platform that enables precise microbiota editing, facilitates functional analysis of single species, and supports therapeutic intervention in dysbiosis.

Midbrain astrocyte-derived neurotrophic factor (MANF) is a secreted protein induced by endoplasmic reticulum stress. Previous studies have indicated that intravenous administration of 1 mg/kg/day recombinant human MANF protein with His tag (His-MANF) for 3 days can ameliorate acute ulcerative colitis in mice. However, long-term intravenous therapy has many disadvantages. In this paper, His-MANF protein was successfully encapsulated into alginate and hyaluronic acid hybrid hydrogel microcapsules in one step using the gas shear method and then coated by Eudragit S100 to construct an oral colon-targeted delivery system (MSH@E). The MSH@E microcapsules exhibited controlled and sustained release behavior and colon-targeting properties. Both fluorescent imaging and immunohistochemistry staining results showed that His-MANF protein could accumulate in the colitis colon for a longer residence time after oral delivery. In vivo studies demonstrated that oral administration of MSH@E microcapsules could alleviate DSS-induced colitis in mice without systemic toxicity. Importantly, even if the oral His-MANF dose was half of the intravenous His-MANF dose, oral delivery was still much more effective than intravenous injection, suggesting the development of the oral colon-targeted delivery system (MSH@E) has great significance and makes a breakthrough from intravenous to oral administration for His-MANF treatment of ulcerative colitis (UC).

Ulcerative colitis (UC) remains a major challenge in clinical treatment due to its multivariate pathology. Developing an oral formulation that encapsulates and delivers multiple active ingredients to target colon tissues by suppressing intestinal inflammation and restoring the intestinal barrier is crucial for effectively treating UC. Here, we developed rhubarb-derived nanovesicles (RNs) and a supramolecular hydrogel platform formed by furfural-functionalized chitosan-mannose polymer and synthesized 3-maleimide HP-β-CD, with kaempferol (Kae) integrated into the hydrophobic cavity. The hydrogel's cross-linking network effectively encapsulates RNs, forming the Kae/CMCHD@RNs system. Rheology, SEM, TGA, degradation behavior, in vitro drug release, and a macrophage-targeted permeability test were performed. The results indicate that the hydrogel utilizes pH/enzyme sensitivity to ensure sustained release in the colon, while also facilitating targeted delivery to macrophages. In vivo imaging further reveals a prolonged local drug retention time in the colon. Moreover, both in vitro and in vivo studies demonstrate RNs and Kae exhibit synergistic therapeutic effects for UC, including inflammation reduction, oxidative stress alleviation, M1-to-M2 macrophage repolarization, and restoration of the intestinal barrier. Consequently, this study underscores the potential of Kae/CMCHD@RNs as a promising therapeutic approach for managing UC.

No abstract available

Hydrogel drug delivery systems (DDSs) for treating ulcerative colitis (UC) have garnered attention. However, there is a lack of meta-analysis summarizing their effectiveness. Therefore, this study aimed to conduct a meta-analysis of pre-clinical evidence comparing hydrogel DDSs with free drug administration. Subgroup analyses were performed based on hydrogel materials (polysaccharide versus non-polysaccharide) and administration routes of the hydrogel DDSs (rectal versus oral). The outcome indicators included colon length, histological scores, tumor necrosis factor-α (TNF-α), zonula occludens protein 1(ZO-1), and area under the curve (AUC). The results confirmed the therapeutic enhancement of the hydrogel DDSs for UC compared with the free drug group. Notably, no significant differences were found between polysaccharide and non-polysaccharide materials, however, oral administration was found superior regarding TNF-α and AUC. In conclusion, oral hydrogel DDSs can serve as potential excellent dosage forms in oral colon -targeting DDSs, and in the design of colon hydrogel delivery systems, polysaccharides do not show advantages compared with other materials.

Resolving inflammation and promoting intestinal tissue regeneration are critical for inflammatory bowel disease (IBD) treatment. Bioactive glass (BG) is a clinically approved bone graft material and has been shown to modulate inflammatory response, but it is unknown whether BG can be applied to treat IBD. Here, it is reported that BG attenuates pro‐inflammatory response of lipopolysaccharide (LPS)‐stimulated macrophages and hence reduces inflammatory damage to intestinal organoids in vitro. In addition, zein/sodium alginate‐based core–shell microspheres (Zein/SA/BG) are developed for oral delivery of BG, which helps prevent premature dissolution of BG in the stomach. The results show that Zein/SA/BG protects BG from a gastric‐simulated environment while dissolved in an intestinal‐simulated environment. When administered to acute and chronic colitis mice model, Zein/SA/BG significantly reduces intestinal inflammation, promotes epithelial tissue regeneration, and partially restores microbiota homeostasis. These findings are the first to reveal the therapeutic efficacy of BG against IBD, which may provide a new therapeutic approach at low cost for effective IBD treatment.

Although magnolol (Mag), an anti-inflammatory natural compound, has been demonstrated to play protective effects on ulcerative colitis (UC), its application as an alternative therapeutic reagent for UC treatment is still greatly impeded due to its poor stability in the gastrointestinal tract and insufficient accumulation in the inflamed colon lesion. Nano-/microsized drug delivery systems can potentially overcome some challenges regarding the oral administration of phytochemicals, which still confront premature early drug release, degradation of NPs, or the sustained drug release of MPs. In this study, we primarily loaded Mag into the core-shell zein-based nanoparticles with chondroitin sulfate coating (Mag@CS-Zein NPs) with an average size of 142.27 ± 5.11 nm, showing significant macrophage-targeting and enhanced colon epithelial cellular uptake capacity. Then, we embedded Mag@CS-Zein NPs into hydrogel microspheres via an electrospraying technology. The Mag@CS-Zein NPsinMPs presented a uniform-sized sphere with an average size of 164.36 ± 6.29 μm and sustained drug-release profiles. Compared to CS-Zein NPs, the developed CS-Zein NPsinMPs exhibited prolonged colon retention on the inflammatory surface, as seen from ex vivo and in vivo imaging fluorescence adhesion experiments. Based on the advantage of the combination of hybrid nanoparticles-in-microparticles, oral administration of Mag@CS-Zein NPsinMPs significantly alleviated colitis symptoms in DSS-treated mice by regulating the expression levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) and anti-inflammatory cytokines (IL-10) and factor accelerated colonic mucosal barrier repair via upregulating the expression of ZO-1 and occludin. This study provides great insights into the oral drug delivery of natural compounds for UC therapy.

Developing innovative strategies for the oral administration of phytochemicals presents a promising approach to addressing intestinal diseases. However, numerous challenges persist, including limited therapeutic efficacy, poor bioavailability, and inadequate biocompatibility. In this study, we employed a cross-linked cyclodextrin-metal organic framework (CDF) to encapsulate resveratrol (Res), generating Res-CDF, which was subsequently incorporated into natural polysaccharide hydrogel microspheres (Res-CDF in MPs) for targeted oral delivery to alleviate ulcerative colitis (UC). The underlying adsorption mechanism of Res by γ-CD elucidated by molecular dynamics simulations. Importantly, the Res-CDF in MPs formulation protected against gastric acid degradation while preserving the bioactivity of Res. Moreover, the design enabled specific release of Res-CDF in response to the mildly alkaline environment of the intestinal tract, followed by sustained Res release. In UC mice model, Res-CDF in MPs demonstrated potent anti-inflammatory effects by attenuating pro-inflammatory cytokine production and exhibited antioxidant properties. Additionally, Res-CDF in MPs enhanced the expression of tight junction proteins ZO-1, Occludin, and mucin-2 (Muc-2), thereby maintaining normal intestinal barrier function. This innovative oral delivery strategy capitalizes on the advantageous properties of polysaccharide hydrogel and CDF to augment bioavailability of phytochemicals, laying the groundwork for developing novel oral interventions employing natural phytochemicals to address intestinal-related diseases.

Oral probiotic biotherapies hold significant promise for addressing intestinal inflammatory disorders. Nonetheless, due to the challenging pathological microenvironment of the gastrointestinal tract, it is difficult to achieve deliver probiotics in an inflammation-targeted manner while improving their intestinal colonization and minimizing the impact of gastrointestinal environment on their vitality. To address this, an innovative probiotics oral delivery system (EcN-Apt@HG) against ulcerative colitis (UC) was developed by conjugating IL-6 aptamer to the surface of EcN and subsequently encapsulating the probiotics in a hydrogel consisting of aldehyde-functionalized chondroitin sulfate (CS) and Poly(amidoamine) (PAMAM). As expected, the encapsulated EcN demonstrated resistance to gastrointestinal conditions, and the colonization duration of probiotics in the colon was enhanced via the preferential adhesion effect of IL-6 aptamer on the inflammatory site. The EcN-Apt@HG system restored the damaged mucosal layer, suppressed hyperactive immune responses, and reshaped the dysbiosis of intestinal microflora, thereby synergistically alleviating dextran sulfate sodium (DSS)-induced colitis. Notably, EcN-Apt@HG significantly alleviated depression-like behaviors and cognitive impairment in colitis mice through gut-brain axis interaction. This approach provides a simple and promising strategy for inflammation-targeted delivery of probiotics to the intestine and shows great potential for UC therapy and associated cognitive disorders.

Inflammatory bowel disease (IBD) encompasses chronic or relapsing inflammation within different regions of the gastrointestinal tract. Pentoxifylline (PTX), a methylxanthine derivative primarily used to improve blood flow in peripheral vascular diseases, has demonstrated anti-inflammatory and immunomodulatory properties, suggesting its potential in attenuating IBD-associated inflammation. However, its clinical application in IBD remains limited, partly due to its short half-life and poor targeting to inflamed intestinal tissues, necessitating strategies to enhance its bioavailability and tissue-specific delivery. To address this limitation, we developed a targeted drug delivery system utilizing a microfluidic approach to fabricate pH-responsive core–shell hydrogel microcapsules encapsulating PTX, referred to as PTX-loaded hydrogel microcapsules (PHM), for enhanced delivery to inflamed colonic tissue. These microcapsules were generated via photopolymerization of triple emulsion droplets, resulting in a structure composed of a poly (acrylic acid)-poly (ethylene glycol) diacrylate (PAA–PEGDA) shell and a PEGDA core, separated by a thin oil layer. The oil layer serves as a protective barrier against the acidic gastric environment, while the pH-responsive swelling of the PAA–PEGDA shell at basic pH (7.5) compresses and destabilizes the oil layer, thereby enabling controlled PTX release specifically in the colonic environment. In vivo studies using dextran sulfate sodium (DSS)-induced IBD in ICR mice demonstrate that PHM significantly mitigates disease severity, as evidenced by an approximately 38.5% reduction in disease activity index scores, restoration of mucosal architecture, and decreased infiltration of colonic macrophages. In parallel, PHM treatment markedly suppresses colonic inflammatory responses, lowering IL-1β by 40%, IL-6 by 66.2%, and TNF-α by 36.2% compared to DSS-treated mice, along with a broader reduction of pro-inflammatory mediators, highlighting its anti-inflammatory potential. Notably, PHM also contributes to the rebalancing of dysbiotic gut microbiota, including the restoration of beneficial genera such as Bacteroides acidifaciens and PAC001120_s, thereby promoting microbial homeostasis. Collectively, these findings underscore PHM as a promising PTX-based therapeutic strategy for effective IBD intervention.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease for which effective oral colon-targeted therapies remain limited. Sinapic acid (Sin), a dietary polyphenol, has demonstrated therapeutic potential in UC due to its antioxidant and anti-inflammatory properties; however, its clinical application is hindered by poor stability and low water solubility. To address these limitations, we designed a smart macromolecular double-network hydrogel based on quaternized chitosan (QCTS) derivatives and glycyrrhizic acid (GA) self-assembled hydrogel to enhance targeted Sin delivery for UC treatment. Specifically, Sin was conjugated to QCTS via reduction-cleavable disulfide linkages and dynamically crosslinked with aldehyde-functionalized GA through Schiff-base reactions, yielding the double-network hydrogel, QSAG. QSAG demonstrated structural robustness, colon-targeting capability, and reduction-responsive drug release under inflammatory conditions, which was evidenced by swelling equilibrium within 120 min, 94.23% degradation in simulated colonic fluid within 24 h, and a cumulative Sin release of 83.66% under 10 mM GSH. In vivo imaging confirmed prolonged colonic retention of QSAG in the inflamed colon for at least 24 h and localized drug accumulation. Therapeutic efficacy was evaluated in a 3% DSS-induced UC mouse model following 5 days of treatment. Both in vitro and in vivo studies revealed that QSAG effectively alleviated colitis by suppressing oxidative stress and inflammation while promoting intestinal barrier repair. Collectively, this dual-crosslinked QSAG hydrogel, with its structural stability and inflammation-responsive drug release, represents a promising oral platform for targeted and enhanced UC therapy.

Ulcerative colitis (UC) is manifested by excessive oxidative stress and immune dysregulation in the colonic microenvironment. To address these pathological features, we developed a microfluidics-engineered oral delivery system comprising methacrylated hyaluronic acid (HAMA) hydrogel microspheres encapsulating polydopamine-coated selenium nanoparticles (CS-Se@PDA). The uniform microspheres featured a microfluidics-enabled structure that enabled stable CS-Se@PDA nanoparticles anchoring via electrostatic and covalent interactions. The PDA coating enhanced the stability, mucosal adhesion, and scavenging of reactive oxygen species (ROS) of the nanoparticles. At the same time, the HAMA shell provided pH-responsive protection and CD44-mediated targeting to inflamed colonic tissues. In vitro studies demonstrated excellent biocompatibility, effective ROS neutralization, and macrophage polarization toward the anti-inflammatory M2 phenotype. In a dextran sulfate sodium-induced colitis mouse model, oral administration of these microspheres significantly alleviated clinical symptoms, including ∼25 % mitigation of weight loss, increased colon length from 4.78 ± 0.3 cm to 6.83 ± 0.25 cm, and reduced histological damage. Furthermore, the treatment restored tight junction protein expression to approximately 60 % of normal levels for ZO-1 and about 55 % for Occludin, indicating substantial epithelial barrier repair, and effectively suppressed pro-inflammatory cytokines such as TNF-α and IL-6. Overall, this microfluidics-enabled, colon-targeted delivery system with integrated antioxidative and immunomodulatory functions offers a promising strategy for the non-invasive treatment of UC and other inflammation-associated gastrointestinal disorders.

Fucoidan, a marine-derived polysaccharide with versatile biological functions, holds strong potential for biomedical applications but is limited by low viscosity and poor gelling capacity. To address these challenges, we developed a bioengineered fucoidan-based hydrogel (Fuco-PGAB) by modulating intermolecular interactions with functionalized polyglutamic acid. This molecular design increased hydrogen-bonding density, yielding a hydrogel with robust rheological properties, including pronounced shear-thinning behavior and instantaneous self-healing. These features enable the material to dissipate peristaltic stress while protecting encapsulated bacteria during gastrointestinal transit. The Fuco-PGAB hydrogel enabled efficient oral delivery of both Gram-positive (Lactiplantibacillus plantarum 90) and Gram-negative (Escherichia coli Nissle 1917) probiotics. In simulated digestive fluids, probiotic survival increased by more than two orders of magnitude compared to free cells, and in vivo viability was sustained for up to 96 h. Beyond protection, the hydrogel alleviated oxidative stress in intestinal epithelial cells by maintaining glutathione redox balance, inhibiting lipid peroxidation, enhancing superoxide dismutase activity, and scavenging reactive oxygen species. In a mouse colitis model, probiotic-loaded Fuco-PGAB restored microbial composition by reducing pathogenic species, enriching beneficial taxa, and suppressing inflammation. By integrating the intrinsic properties of fucoidan with a tunable cross-linking strategy, this hydrogel prolongs intestinal retention, enhances probiotic colonization, and improves intervention impact. These findings establish Fuco-PGAB as a promising oral delivery platform for collaborative intervention in inflammatory bowel disease.

No abstract available

Ulcerative colitis (UC) presents considerable challenges in clinical treatment due to its multifaceted and complex nature. Efficacious therapy technique in developing an oral formulation that can encapsulate and deliver therapeutic drugs directly to the colon to diminish intestinal inflammation and restore the impaired intestinal barrier is of great interest. Herein, we developed a supramolecular hydrogel platform composed of 2-hydroxypropyl-β-cyclodextrin/chitosan in which curcumin and berberine (HCD/CH-CUR-BBR) are loaded in the hydrophobic cavity of HP-β-CD. BET surface area was measured to be 198.3 m2g− 1 with a pore diameter of 3.56 μm which improved in vitro drug release. The results demonstrate that the HCD/CH-CUR-BBR hydrogel leverages pH sensitivity to achieve sustained drug release in the colon while promoting targeted delivery to colonic tissues. Interestingly, in vitro and in vivo evaluation confirms that HCD/CH-CUR-BBR hydrogel formulation alleviates the progression of UC via downregulating IL-6 and TNF-α expression. Subsequently, in vivo anti-colitis investigation demonstrated notable enhancement in tight junction protein expression, underscoring anti-inflammatory efficiency of CUR and BBR loaded HCD/CH hydrogel. These findings indicate that the HCD/CH hydrogel infused with CUR and BBR displayed potential as an effective targeted drug delivery strategy for UC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s13036-026-00621-4.

Ulcerative colitis (UC) is associated with epithelial barrier disruption, oxidative stress, inflammation, and gut microbiota dysbiosis. Oral colon-localized delivery remains challenging because therapeutic cargos must resist gastric exposure, avoid premature release, be retained at inflamed colonic sites, and respond to pathological microenvironments. Herein, a pH/reactive oxygen species (ROS) dual-responsive calcium alginate microalgal hydrogel, denoted SP@GaTa@ALG (SGA), was developed for localized UC therapy. Gallium-tannic acid nanoparticles (GaTa NPs) were loaded onto Spirulina (SP) and encapsulated within a Ca2+-crosslinked alginate matrix. The calcium alginate network provided gastric protection and pH-dependent control over Ga3+ diffusion, while GaTa enabled ROS-responsive Ga3+ release and antioxidant activity. In vitro, SGA scavenged free radicals, reduced intracellular ROS accumulation, protected epithelial cells against H2O2-induced injury, preserved mitochondrial membrane potential, and promoted an anti-inflammatory-like macrophage phenotype. After oral administration, SGA showed prolonged gastrointestinal retention and enhanced colonic localization compared with non-encapsulated SP@GaTa (SG). In dextran sulfate sodium (DSS)-induced colitis mice, SGA alleviated body-weight loss, reduced disease activity, restored colon length, improved zonula occludens-1 (ZO-1) and Occludin expression, suppressed inflammatory mediators, and was associated with gut microbiota remodeling. These findings support SGA as a traceable, carbohydrate-polymer-based oral platform for inflammation-responsive UC intervention.

Ulcerative colitis (UC) is a chronic inflammatory disease that needs lifelong treatment with medicines but cannot be cured. Additionally, harsh gastrointestinal environment often compromises the therapeutic effects of oral drugs. Fisetin (FIS) is a promising natural flavonoid that exhibits potent anti-inflammatory and antioxidant activities, but fails to translate into clinical benefits due to poor solubility and permeability. Here, we developed an oral colon-targeted nanoparticle formulation based on natural polysaccharides chitosan/chondroitin sulfate polyelectrolytes to deliver FIS (FIS@CS/ChS) to improve its bioavailability. FIS@CS/ChS possessed remarkable stability in a wide range of pH, and highly enhanced the colonic retention and mucus penetration of FIS. In both in vivo and in vitro studies, FIS@CS/ChS effectively promoted M2 macrophage polarization, attenuated inflammatory responses and oxidative stress, improved epithelial barrier function, and restored the gut microbial richness and diversity. As a result, this approach was significantly enhanced the therapeutic efficacy of FIS against UC across a range of severities, from mild to severe, and proved superior to conventional therapy with 5-aminosalicylic acid for these conditions. In conclusion, our data suggest that FIS@CS/ChS exclusively constituted by natural compounds represented a cost-effective, highly safe and minimally invasive therapy strategy to treat UC with different severity.

The therapeutic efficacies of oral nanotherapeutics for ulcerative colitis (UC) are seriously hindered by the lack of mucus-penetrating capacity and uncontrolled drug release. To overcome these limitations, the surface of poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) was functionalized with pluronic F127 (PF127), and catalase (CAT)/curcumin (CUR) was co-encapsulated into these NPs. The obtained P-CUR/CAT-NPs had a hydrodynamic particle size of approximately 274.1 nm, narrow size distribution, negative zeta potential (-14.0 mV), and smooth surface morphology. Moreover, the introduction of PF127 to the surface of NPs not only facilitated their mucus penetration, but also improved their cellular uptake efficiency by the target cells (macrophages). We further found that the encapsulation of CAT could remarkably increase the release rate of CUR from NPs in the presence of an H2O2-rich environment. Additionally, P-CUR/CAT-NPs showed the strongest capacity to suppress the secretion of the main pro-inflammatory cytokines, in comparison with their counterparts (CUR-NPs and P-CUR-NPs). Importantly, oral administration of P-CAT/CUR-NPs showed the best therapeutic outcomes than the other NPs. Collectively, these results clearly demonstrate that these mucus-penetrating NPs loaded with CAT and CUR can be exploited as an efficient nanotherapeutic for UC therapy.

The physicochemical properties of oral drug delivery carriers significantly influence their interactions with the intestinal barrier, which, in turn, affect their in vivo fate and therapeutic efficacy. As a delivery system with a hierarchical structure and high stability, Pickering emulsions have demonstrated significant advantages in enhancing the bioavailability of encapsulated bioactive compounds. However, the specific role of their inherent flexibility in modulating interactions with the intestinal barrier and influencing delivery efficiency remains poorly understood. In this study, a flexible Pickering emulsion (FPPE) stabilized by chitosan nanoparticles was developed for encapsulating epigallocatechin gallate, aiming to investigate the role and underlying mechanism of its flexible structure in mucus penetration, cellular uptake, and biodistribution in the intestinal tract. Upon reaching the intestinal tissue, FPPE exhibited deformable adaptation, facilitating efficient mucus permeation, prolonged gastrointestinal retention, and enhanced drug absorption. Moreover, FPPE enhanced macrophage uptake and mitochondrial membrane potential, reduced reactive oxygen species scavenging, and triggered macrophage reprogramming. Compared to rigid chitosan microspheres, FPPE more effectively alleviated intestinal inflammation and promoted intestinal barrier repair in a dextran sulfate sodium-induced acute colitis mouse model. This study reveals how Pickering emulsion flexibility facilitates intestinal mucus delivery, guiding their future design and application.

The latest advancements in nanomedicine have led to increased therapeutic efficacy and reduced complications. However, nanoparticle penetration is significantly influenced by biological hydrogels, such as mucus, the extracellular matrix, biofilms, and nucleoporins. Solely modifying well-studied physicochemical properties like size, charge, and surface chemistry is insufficient to fully elucidate or overcome these barriers. Recent studies have investigated the impact of particle elasticity, a relatively unexplored yet crucial physicochemical property influencing many biological processes. Hence, it is important to explore the impact of particle elasticity on penetrating biological hydrogels. This review examines biological hydrogels’ structural and functional features as diffusion barriers, provides an overview of particle elasticity, key elasticity measurement techniques, and explores strategies for elasticity modulation in nanoparticles, such as composition, crosslinking density, and structural design. Furthermore, nanoparticle penetration mechanisms, influenced by particle deformability, hydrogel mesh size, and adhesive interactions, are investigated by integrating theoretical and experimental findings. The evaluation of experimental data reveals the commonly observed particle elasticity trends in mucus penetration, extracellular matrix permeation, and corneal penetration of nanoparticles. Overall, this review offers valuable insights into designing next-generation nanomedicines capable of overcoming biological barriers.

Selenium deficiency associated with a high risk of many diseases remains a global challenge. Owing to the narrow margin between "nutrition-toxicity" doses of selenium, it is imperative to achieve accurate selenium supplement. Nano‑selenium (SeNPs) is a novel form of selenium supplement with low toxicity, but it could be trapped and removed by intestinal mucus, thus limiting its oral delivery. The mucus penetration of SeNPs is highly associated with interactions between SeNPs and mucin (the structural component of mucus). In this study, we selected four polysaccharides with different functional groups and molecular weights, i.e. chitosan oligosaccharide (COS), chitosan (CS), chitosan quaternary ammonium salt (HACC), and carboxymethyl cellulose (CMC) as templates to modify SeNPs. Then we systematically explored the non-covalent interactions between polysaccharides stabilized nano-Se (PS-SeNPs) and mucin, determined and examined mucus penetration behavior and mechanism of different PS-SeNPs by coarse-grained molecular dynamics simulations, both in vitro and in vivo. It could be observed that penetration of PS-SeNPs depends on their distinct surface properties and mucus pH conditions. COS-SeNPs with short oligosaccharide chains accumulated and bridged with mucin, hindering its mucus penetration at pH 7.4. While HACC-SeNPs with NH3+ and N+ exhibited high binding affinity with mucin, inducing its mucus penetration. The negatively charged CMC-SeNPs diffused freely in mucus due to their electrostatic-repelled interaction and hydrophobic interaction with mucin. This study establishes a theoretical foundation for precise application of SeNPs in oral administration and offers valuable insights into the precise utilization of polysaccharides as tailored carriers of nanoparticles in mucus-covered tissues.

Inflammatory bowel disease (IBD), includes ulcerative colitis (UC) and Crohn's disease (CD), is characterised by recurrent, chronic inflammation of the gastrointestinal system. For the treatment of UC, oral medication delivery to the colon is largely favoured since it increases their effectiveness while lowering systemic toxicity. To deliver oral a medication to the colon, which is at the distal end of the gastrointestinal system is however challenging, because of physiological difficulties, biochemical barriers and environmental obstacles, such as those brought on by mucus and epithelium. Recent preclinical studies have suggested that targeted medication administration to the colon using nanoparticle-based drug delivery systems (DDS) may be a promising strategy for the treatment of UC. Additionally, this study offers a thorough assessment of newly discovered naturally produced nanoparticles (such as extracellular vesicles and plant-derived nanoparticles) as well as DDS based on synthetic nanoparticles. These innovative UC treatment plans based on nanoparticles may present a chance for the clinical application of nanoparticle formulae.

Oral delivery of peptide and protein drugs (PDs) is hindered by the impermeable intestinal mucosa, which consists of both the mucus layer and the epithelium. Therefore, double-layer (mucus layer and epithelium) overcoming nanocarriers need to be designed to enhance the transporting efficiency of PDs. However, the requirements for surface properties to penetrate these two barriers are quite distinct. In this study, nanoparticles (NPs) with balanced mucus permeation and cellular uptake were developed by modulating surface properties to improve the endocytosis efficiency of exenatide (EXT). The EXT-loaded ovolecithin (Lipoid E 80)/dextran/bovine serum albumin (EDB) NPs, solidified by sodium trimetaphosphate (STMP), were prepared through double emulsification combined with interfacial crosslinking solidification. The EDB NPs were then coated with cationic polyelectrolyte chitosan (CS) shell to form CS-EDB NPs, which exhibited 83.50 ± 0.44 % of encapsulation efficiency (EE), a particle size of approximately 277.0 ± 3.96 nm, and a Zeta potential of -16.2 ± 0.71 mV. Compared to uncoated EDB NPs, CS-EDB NPs showed a 1.1-fold reduction in mucus penetration (Papp), as measured using the Transwell mucus-penetrating model. However, CS-EDB NPs demonstrated a 2.15-fold and 1.77-fold increase in cellular uptake and transepithelial transport efficiency across a Caco-2/E-12 co-culture model, respectively, primarily driven by energy-dependent endocytosis and partially mediated by macropinocytosis. Furthermore, CS-EDB NPs achieved 13.29 % of pharmacological bioavailability and effectively regulated blood glucose, serum lipid levels, and improved islet function upon long-term administration. In conclusion, the core-shell structured CS-EDB NPs successfully protected against the harsh gastrointestinal tract (GIT) environment, providing improved endocytosis efficiency by slightly compromising mucus penetration while significantly enhancing cellular uptake, offering a promising approach for the oral delivery of PDs.

A mucus gel layer lines the luminal surface of tissues throughout the body to protect them from infectious agents and particulates. As a result, nanoparticle drug delivery systems delivered to these sites may become trapped in mucus and subsequently cleared before they can reach target cells. As such, optimizing the properties of nanoparticle delivery vehicles, such as their surface chemistry and size, is essential to improving their penetration through the mucus barrier. In previous work, we developed a mucin-based hydrogel that has viscoelastic properties like that of native mucus which can be further tailored to mimic specific mucosal tissues and disease states. Using this biomimetic hydrogel system, a 3D-printed array containing synthetic mucus barriers was created that is compatible with a 96-well plate enabling its use as a high-throughput screening platform for nanoparticle drug delivery applications. To validate this system, we evaluated several established design parameters to determine their impact on nanoparticle penetration through synthetic mucus barriers. Consistent with the literature, we found nanoparticles of smaller size and coated with a protective PEG layer more efficiently penetrated through synthetic mucus barriers. In addition, we evaluated a mucolytic (tris(2-carboxyethyl) phosphine, TCEP) for use as a permeation enhancer for mucosal drug delivery. In comparison to N-acetyl cysteine (NAC), we found TCEP significantly improved nanoparticle penetration through a disease-like synthetic mucus barrier. Overall, our results establish a new high-throughput screening approach using synthetic mucus barrier arrays to identify promising nanoparticle formulation strategies for drug delivery to mucosal tissues.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that poses significant therapeutic challenges due to the intestinal mucus and epithelial barriers. In this study, ultra-small zwitterionic nanoparticles (HC-CB NPs) is developed based on glutathione (GSH)-responsive hyperbranched polycarbonate to enhance the oral delivery of drugs and overcome these physiological barriers. HC-CB NPs demonstrate high colloidal stability across a wide range of pH environments and physiological fluids, preventing premature drug release within the gastrointestinal tract. The ultra-small sized HC-CB NPs demonstrate minimal mucin adsorption and effectively penetrate through the mucus layer, and the zwitterion surface further facilitate epithelial barrier crossing via the proton-assisted amino acid transporter 1 (PAT1) pathway. HC-CB NPs mediate enhanced macrophage uptake via monocarboxylate transporters (MCTs) pathway and ultimately improved therapy efficacy on colitis. The in vivo results reveal that FK506-loaded HC-CB NPs (HC-CB NPs@FK506) significantly reduce inflammatory markers (TNF-α, IL-6) and myeloperoxidase (MPO) levels, while promoting epithelial integrity by increasing E-cadherin expression. This study offers a promising approach to overcoming intestinal barriers in oral UC treatment, offering biocompatibility and potential for clinical translation. STATEMENT OF SIGNIFICANCE: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that poses significant therapeutic challenges due to the intestinal mucus and epithelial barriers. This study explores an oral UC therapy using ultra-small zwitterionic nanoparticles (HC-CB NPs) constructed from GSH-responsive hyperbranched polycarbonate. Compared to existing strategies, HC-CB NPs demonstrate minimal mucin adsorption and effectively penetrate through the mucus layer, and the zwitterion surface further facilitate epithelial barrier crossing via the proton-assisted amino acid transporter 1 (PAT1) pathway. Additionally, HC-CB NPs mediate enhanced macrophage uptake via monocarboxylate transporters (MCTs) pathway, resulting in improved therapeutic efficacy. These findings underscore the potential of HC-CB NPs as a transformative platform for overcoming intestinal barriers in UC treatment.

Abstract Over the last years nanoparticles (NP) have become a promising vehicle as drug delivery systems for photodynamic therapy (PDT), combining the advantages of an effective drug transport to the target cells and the reduction of undesired side effects. The in vitro evaluation of new nanoparticulate formulations has become a rising problem since cell culture models differ from the in vivo situation of the human body to a large extent. Particularly, in case of gastrointestinal tumors, after peroral application nanoparticles are challenged by overcoming the mucus layer as a first physical barrier before reaching the target cells, an aspect often neglected in literature. However, the presence of mucus is crucial for in vitro models to evaluate mucus‐penetrating potential of surface‐modified nanoparticulate drug carrier systems. Biodegradable poly(dl‐lactide‐co‐glycolide) (PLGA) NP loaded with the model photosensitizer 5,10,15,20‐tetrakis(m‐hydroxyphenyl)porphyrin (mTHPP) were surface modified with either poly(ethylene glycol) (PEG) or chitosan (CS) to gain mucus‐penetrating or mucoadhesive particle properties. All NP systems were compared to each other and to free mTHPP regarding cytotoxicity and cellular uptake in HT‐29 cells and mucus producing HT‐29‐MTX cells. For PEGylated mTHPP‐PLGA‐PEG‐NP a significantly higher accumulation was obtained in HT‐29‐MTX cells compared to all other tested nanoparticles and the free drug. Additionally, a mucus‐containing Transwell® model, consisting of HT‐29‐MTX cells, confirmed these results, representing a promising in vitro screening method for mucus‐penetrating particle properties. Graphical abstract Figure. No Caption available.

Mucus, a viscoelastic gel composed of dense mucin glycoprotein networks, acts as a major barrier to therapeutic delivery across all epithelial surfaces by trapping nanoparticles (NPs) and preventing access to the underlying cells. To address this, we developed mucus-evading yet cell-sticky (MECS) NPs with tunable surface charge using Flash NanoPrecipitation. These 100-nanometer-diameter MECS NPs incorporate a small amount (5 wt %) of polycationic dimethylaminoethyl methacrylate (PDMAEMA) into a dense, neutral poly(ethylene glycol) (PEG) corona, which enables mucus penetration while also driving epithelial cell adhesion. In vitro cell culture and physiologically relevant gut-on-a-chip organoids demonstrate MECS NPs penetrate mucus as effectively as purely PEGylated control NPs, while exhibiting a 45-fold increase in binding to epithelial cells. This dual functionality represents a generalizable strategy for overcoming the long-standing trade-off between mucodiffusion and cellular uptake in mucosal drug delivery.

Lipid nanoparticles (LNPs) have emerged as clinically validated drug delivery vehicles, as demonstrated by the successful deployment of COVID-19 mRNA vaccines (Comirnaty and Spikevax) and siRNA therpy (Patisiran). Building on these achievements, we investigated the functional roles of free polyethylene glycol (PEG) molecules in optimizing LNP performance. This study focused on enhancing mucus penetration capability and maintaining storage stability under various storage conditions. We found PEG molecules (MW 400–6000 Da) significantly improved LNP penetrate through mucosal barriers, with PEG 2000 demonstrating optimal penetration efficiency. Stability assessments showed that LNPs remained stable in PEG media at −20 °C for 4 weeks. However, none of the tested PEG formulations prevented LNPs aggregation during lyophilization.

Abstract The use of probiotics to regulate the intestinal microbiota to prevent and treat a large number of disorders and diseases has been an international research hotspot. Although conventional probiotics have a certain regulatory role in nutrient metabolism, inhibiting pathogens, inducing immune regulation, and maintaining intestinal epithelial barrier function, they are unable to treat certain diseases. In recent years, aided by the continuous development of synthetic biology, engineering probiotics with desired characteristics and functionalities to benefit human health has made significant progress. In this article, we summarise the mechanism of action of conventional probiotics and their limitations and highlight the latest developments in the design and construction of probiotics as living diagnostics and therapeutics for the detection and treatment of a series of diseases, including pathogen infections, cancer, intestinal inflammation, metabolic disorders, vaccine delivery, cognitive health, and fatty liver. Besides we discuss the concerns regarding engineered probiotics and corresponding countermeasures and outline the desired features in the future development of engineered live biotherapeutics.

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BACKGROUND Gastrointestinal (GI) diseases are a major cause of emergency department visits requiring hospitalizations leading to considerable burden on global economy. Several factors contribute to the onset of gastrointestinal diseases such as pathogens (parasites, bacteria, virus, toxins etc.), autoimmune disorders and severe inflammation of intestine. OBJECTIVE One common feature among all these diseases is the dysentery and alteration of gut microbiota composition (gut dysbiosis). Apart from conventional therapies such as antibiotics and ORS supplementation, gut microbiota modulation with probiotic supplementation has emerged as a successful and healthy alternative in mitigating GI diseases. In this review our goal is to discuss the causes of gastrointestinal diseases and the present state of various therapeutic strategies such as probiotics as live biotherapeutics and Fecal Microbial Transplants (FMT's). CONCLUSION Several reports and clinical trials point out to the beneficial effects of probiotics in modulating the gut microbiota and improving the side effects of gastrointestinal diseases. Live biotherapeutics and FMT's could be suitable and successful alternatives to conventional therapies in mitigating the gastrointestinal pathogens.

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In the recent years, various strains of the gut microbiota have been discovered to possess significant therapeutic potential, they are defined as next‐generation probiotics (NGPs). Akkermansia, Faecalibacterium, Bacteriodes, Eubacterium, and Bifidobacteria are among the typical NGP strains which exhibit several interesting bioactivities as live biotherapeutics. However, some strains of NGP are extremely sensitive to oxygen, such as Faecalibacterium prausnitzii. This hinders their cultivation and large‐scale production. Therefore, it is essential to develop a strategy to protect them during production, storage, and colonic administration. This review, highlights key NGP strains developed in recent years, alongside the encapsulation strategies used to protect them. The primary criterion for selecting encapsulating techniques is their feasibility to be performed under strictly anaerobic conditions. Various processes have been selected according to the physical forms of the products, including liquid, gel, and solid forms, as well as the final shaping of the product. The critical factors for selecting encapsulation materials include biocompatibility, safety, effective oxygen barrier properties, and an optimal release profile in the gastrointestinal tract. This review discusses protection strategies aimed at improving the survival and thereby effectiveness of NGPs.

Despite the immense potential against diverse chronic inflammatory and metabolic disorders, the clinical translation of microbial therapies is largely thwarted by the delivery challenges of live biotherapeutics. Probiotics often succumb to harsh gastrointestinal conditions and oxidative stress. We report ARMOG, a microenvironment responsive platform achieving in situ biointerfacial transformation. Composed of hyaluronic acid with an increased dopamine grafting ratio cross-linked by arylboronic acid, the matrix undergoes cleavage triggered by the inflammatory microenvironment, leading to localized dopamine polymerization directly onto bacterial surfaces. This "armoring" mechanism creates a resilient interface that enhances survival and mucosal anchoring. This stable scaffold operates without species-specific constraints, optimizing both single-strain delivery and fecal microbiota transplantation (FMT). Demonstrated in representative models of acute/chronic colitis and cancer, ARMOG effectively remodels the gut microbiota and promoting commensals while suppressing pro-inflammatory cell infiltration. By transforming microbial colonization into sustainable ecological restoration using biocompatible materials, ARMOG offers a generalizable strategy for restoring host-microbe homeostasis and intercepting the progression toward severe pathologies.

ABSTRACT About 100 years ago, the first antibiotic drug was introduced into health care. Since then, antibiotics have made an outstanding impact on human medicine. However, our society increasingly suffers from collateral damage exerted by these highly effective drugs. The rise of resistant pathogen strains, combined with a reduction of microbiota diversity upon antibiotic treatment, has become a significant obstacle in the fight against invasive infections worldwide. Alternative and complementary strategies to classical “Fleming antibiotics” comprise microbiota-based treatments such as fecal microbiota transfer and administration of probiotics, live-biotherapeutics, prebiotics, and postbiotics. Other promising interventions, whose efficacy may also be influenced by the human microbiota, are phages and vaccines. They will facilitate antimicrobial stewardship, to date the only globally applied antibiotic resistance mitigation strategy. In this review, we present the available evidence on these nontraditional interventions, highlight their interaction with the human microbiota, and discuss their clinical applicability.

Strategies aimed at modulating the gut microbiota by using live microbes range from single strains (probiotics or live biotherapeutics) to whole non-defined fecal transplants. Although often clinically efficacious, our understanding on how microbial-based strategies modulate gut microbiome composition and function is vastly incomplete. In this review, we present a framework based on ecological theory that provides mechanistic explanations for the findings obtained in studies that attempted to modulate the gut microbiota of humans and animals using live microbes. We argue that an ecological perspective grounded in theory is necessary to interpret, design, and predict the impact of microbiome-modulating strategies and thus advance our ability to develop novel and improved approaches with enhanced therapeutic efficiency.

The human microbiome has emerged as a central focus of biomedical research, driven by interest in its translational potential for chronic diseases. Although compelling associations link microbial alterations to gastrointestinal, metabolic, neuropsychiatric and systemic conditions, successful clinical translation remains limited. This perspective contends that the principal barrier is not biological relevance but the application of reductionist thinking to an inherently complex ecological system, compounded by an incomplete understanding of causality. This review examines the gradient of causal confidence across gut–organ axes, from established roles in digestive disorders to less established distal associations, as well as highlights the epistemological challenges underlying microbiome research. A critical appraisal of current strategies, including probiotics, live biotherapeutics and faecal microbiota transplantation, suggests that progress requires ecological reasoning, causal rigour and systems-level integration. Moving from association to intervention demands approaches that account for host–microbiome complexity rather than oversimplified microbial targeting.

Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease that imposes a growing socioeconomic burden worldwide. Among emerging live biotherapeutics, the probiotic Pediococcus pentosaceus has shown therapeutic promise against UC, yet its molecular mode of action remains poorly understood. In this study, we isolated a novel strain P. pentosaceus JNL0053 from traditional Inner Mongolian cheese. By integrating transcriptomics, untargeted metabolomics, and 16 S rRNA gene profiling, we elucidated its protective efficacy in the dextran sulfate sodium (DSS)-induced murine colitis model. Mice receiving P. pentosaceus JNL0053 exhibited reduced body-weight loss, lower disease activity index scores and attenuated histopathological damage. This treatment reshaped the gut microbiota and was accompanied by a more balanced immune microenvironment, as evidenced by markedly decreased serum levels of pro-inflammatory cytokines interleukin (IL)-6 and IL-1β, alongside significantly elevated anti-inflammatory IL-10. N-acetylmuramate, identified as a key differential metabolite, potently promoted Th17 cell differentiation, leading to the secretion of IL-22 and IL-17 F. This, in turn, increased the expression of mucin 2 and occludin, thereby protecting the intestinal barrier against pathogens. Collectively, P. pentosaceus JNL0053 orchestrated multi-level crosstalk between host immunity and the gut microbiome to alleviate DSS-induced colitis. By activating the IL-22–MUC axis and restoring epithelial integrity, this food-derived P. pentosaceus JNL0053 represents a compelling therapeutic strategy for UC.

Although probiotics have been used in food products and supplements for decades, there has been a considerable increase in their use more recently. Recent technological advances have thus led to major advances in knowledge of the gut microbiota, enabling a significant development of biotics. In this review, we discuss the uses of traditional probiotics but also the discovery of next-generation probiotics that could be used as live biotherapeutics. These novel preventive and therapeutic strategies hold promise for the treatment of numerous diseases such as inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Probiotic bacteria can be consumed alone, or in combination with prebiotics as synbiotics, or mixed with other probiotic strains to form a consortium for enhanced effects. We also discuss the benefits of using postbiotics.

The human microbiome shapes immune development and maintains homeostasis. Cumulative evidence has linked dysbiosis to the initiation and progression of autoimmune diseases. In this review, we summarize disease-specific microbial signatures and immunologic axes of rheumatoid arthritis, axial spondylarthritis, systemic lupus erythematosus, inflammatory bowel disease, and type 1 diabetes. Despite the promise of microbiome-based therapeutics, including probiotics, next-generation probiotics, engineered live biotherapeutics, and fecal microbiota transplantation, their translation into clinical practice is limited by heterogeneity, low-biomass contamination issues, and reliance on relative abundance metrics. We highlight the requirement for standardized sampling/analytics and absolute-quantitative approaches, multicenter validation of biomarker panels, and mechanism-driven interventional trials. The integration of microbial, metabolomic, and host immune response aspects is a pivotal step in the transition from association to causation and in the development of precise and safe microbiome-based diagnostics and therapeutics for autoimmune diseases.

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In the last years several human commensals have emerged from the gut microbiota studies as potential probiotics or therapeutic agents. Strains of human gut inhabitants such as Akkermansia, Bacteroides, or Faecalibacterium have shown several interesting bioactivities and are thus currently being considered as food supplements or as live biotherapeutics, as is already the case with other human commensals such as bifidobacteria. The large-scale use of these bacteria will pose many challenges and drawbacks mainly because they are quite sensitive to oxygen and/or very difficult to cultivate. This review highlights the properties of some of the most promising human commensals bacteria and summarizes the most up-to-date knowledge on their potential health effects. A comprehensive outlook on the potential strategies currently employed and/or available to produce, stabilize, and deliver these microorganisms is also presented.

Ulcerative colitis (UC) is a chronic or relapsing inflammatory disease with limited therapeutic outcomes. Pterostilbene (PSB) is a polyphenol-based anti-oxidant, which has received extensive interest for their intrinsic anti-inflammatory and anti-oxidative activities. This work aims to develop a reactive oxygen species (ROS)-responsive, folic acid (FA)-functionalized nanoparticle (NP) for efficient PSB delivery to treat UC. The resulting PSB@NP-FA had a nano-scaled diameter of 231 nm and a spherical shape. With ROS-responsive release and ROS-scavenging properties, PSB@NP could effectively scavenge H2O2, thereby protecting cells from H2O2-induced oxidative damage. After FA modification, the resulting PSB@NP-FA could be internalized by RAW 264.7 and Colon-26 cells efficiently and preferentially localized to the inflamed colon. In dextran sulfate sodium (DSS)-induced colitis models, PSB@NP-FA showed a prominent ROS-scavenging capacity and anti-inflammatory activity, therefore relieving murine colitis effectively. Mechanism results suggested that PSB@NP-FA ameliorated colitis by regulating dendritic cells (DCs), promoting macrophage polarization, and regulating T cells infiltration. Both innate and adaptive immunity were involved. More importantly, the combination of the PSB and dexamethasone (DEX) enhanced the therapeutic efficacy of colitis. This nanocarrier with ROS-responsive and ROS-scavenging represents an alternative therapeutic approach to UC. It can also be used as an enhancer for classic anti-inflammatory drugs.

Inflammatory bowel disease (IBD) represents a chronic inflammatory disorder characterized by excessive reactive oxygen species (ROS) generation, persistent inflammatory response, and gut microbiota dysbiosis. Herein, a novel colon-targeted composite hydrogel (FTS/Gel) consisting of metal-polyphenol nanozymes (FTS) embedded in an inulin-based gel was developed for efficient oral treatment of IBD. This nanozyme (FTS) was synthesized by coordination between Fe3+ ions and the anti-inflammatory drugs taxifolin (Tax) and L-Se-methylselenocysteine (SeMC), exhibiting remarkable superoxide dismutase (SOD)-like and catalase (CAT)-like activities. Moreover, FTS nanozymes significantly scavenged intracellular ROS and suppressed inflammation in RAW264.7 cells. Incorporating FTS into an inulin hydrogel notably enhanced colon-targeting efficiency, bio-adhesion, and retention time in vivo. Oral administration of FTS/Gel effectively alleviated colitis, as evidenced by increased colon length, reduced splenomegaly, restored intestinal epithelial barrier integrity, and enhanced mucin secretion. Furthermore, FTS/Gel treatment rebalanced gut microbiota composition by promoting beneficial bacteria and suppressing pernicious bacteria. Collectively, this study presents a promising therapeutic strategy combining antioxidant nanozymes and prebiotic-based hydrogel delivery systems for effectively managing and treating IBD.

Excessive reactive oxygen species (ROS) play a central role in the development of inflammatory bowel disease (IBD). A promising therapeutic strategy involves delivering probiotics alongside polyphenolic antioxidants, which can protect the probiotics while scavenging ROS. Although biomass is a versatile source of polyphenols, abundant agro-industrial waste remains largely untapped, despite its food-grade safety, anti-inflammatory properties, and sustainability. In this study, we focused on spent black tea (SBT), a widely available food processing byproduct, as a rich source of polyphenols. We developed a simple and environmentally friendly method to coordinate polyphenols extracted from SBT using hot water with ferric ions, creating a self-assembled metal-polyphenol network on the surface of Escherichia coli Nissle 1917 (ECN), resulting in the formation of ECN@SBT-Fe. This biomass-derived coating provided ECN with enhanced ROS scavenging abilities, improved survival under simulated gastrointestinal stress, and extended intestinal retention. In a mouse model of DSS-induced colitis, oral administration of ECN@SBT-Fe significantly reduced inflammation, restored epithelial barrier integrity, decreased oxidative stress, and effectively modulated gut microbiota by increasing diversity and promoting beneficial commensal bacteria. This research demonstrates a biomass-derived coating that serves as both a protective shield and a therapeutic agent, presenting a simple and sustainable encapsulation strategy for IBD treatment.

Inflammation and oxidative stress pathways have emerged as novel targets in the management of inflammatory bowel diseases (IBD). Targeting the drug to the inflamed colon remains a challenge. Nanostructured lipid carriers (NLCs) have been reported to accumulate in inflamed colonic mucosa. The antioxidant/antiinflamatory polyphenol oleuropein (OLE) was loaded in NLCs (NLC-OLE). NLC-OLE showed to be more effective in decreasing the TNF-α secretion and intracellular reactive oxygen species (ROS) by activated macrophages (J774) compared to the conventional form of OLE. OLE efficacy was preserved within NLC-OLE ameliorating inflammation in a murine model of acute colitis: reduced levels of TNF-α and IL-6, decreased neutrophil infiltration and improved histopathology of the colon were reported. In addition, NLC-OLE enhanced the ROS scavenging activity of OLE in the colon after oral administration. These data suggest that the proposed NLC-OLE could be a promising drug delivery system for OLE in IBD treatment.

The therapeutic potential of nanomaterials toward oxidative damage relevant diseases has attracted great attentions by offering promising advantages compared with conventional antioxidants. Although different kinds of nanoantioxidants have been well developed, the facile fabrication of robust and efficient nanoscavengers is still met with challenges like the use of toxic and high-cost subunits, the involvement of multistep synthetic process, and redundant purification work. Herein, a direct fabrication strategy toward polyphenol nanoparticles with tunable size, excellent biocompatibility, and reactive oxygen species (ROS) scavenging capacities from grape seed via an enzymatic polymerization method is reported. The resulting nanoparticles can efficiently prevent cell damage from ROS and exert promising in vivo antioxidant therapeutic effects on several oxidative stress-related diseases, including accelerating wound healing, inhibiting ulcerative colitis, and regulating the oxidative stress in dry eye disease. This study can stimulate the development of more kinds of low-cost, safe, and efficient biomass-based antioxidative nanomaterials via similar fabrication methodologies.

Despite compelling progression of current inflammatory bowel disease (IBD) therapy, restoring immune homeostasis in the gut has been a critically important issue. Here, we report a prebiotic-integrated, reactive oxygen species (ROS)-scavenging nanotherapeutic for the targeted treatment of acute colonic inflammation. Porous polydopamine nanoparticles (PNPs), exhibiting inherent antioxidant properties, were attached with the immunomodulatory drug metformin (Met) and subsequently coated with prebiotic tannic acid (TA), forming TA-Met-PNPs. In a dextran sulfate sodium (DSS)-induced colitis mouse model, orally administered TA-Met-PNPs strongly adhered to the inflamed colonic lesions and exhibited high cellular uptake by colon-resident macrophages and dendritic cells, subsequently ameliorating their inflammatory immune responses. Moreover, their prolonged residence in colitis lesions enhanced accumulation in mesenteric lymph nodes (MLNs) and further induction of tolerogenic dendritic cells via intracellular ROS scavenging. Finally, TA-Met-PNPs prominently enhanced butyrate production in the gut, which recovered immune tolerance by increasing the regulatory T (Treg) to T-helper 17 (Th17) cell ratio in MLNs. Our work highlights that the prebiotic-combined ROS-scavenging treatment can remodel the inflammatory gut microenvironment to an immunosuppressive state, offering a promising strategy for treating IBD.

Functional porous materials hold significant promise for biomedical applications owing to their high surface area and customizable pore architectures. However, the complex gastrointestinal environment poses considerable challenges for conventional nanomaterials in achieving targeted accumulation and controlled drug release. Herein, a kind of novel probiotic‐enhanced porous bio‐hybrids (E‐xPAM@ASA) is designed via bio‐hybridization of 5‐aminosalicylic acid‐loaded hairy microporous nanospheres (xPAM@ASA) with probiotic Escherichia coli Nissle 1917. Benefiting from the intrinsic inflammatory‐targeting capability of EcN, the E‐xPAM@ASA can accumulate in the inflammatory sites of the intestine. The unique porous architecture of xPAM@ASA not only facilitates high drug loading and long‐term release but also provides abundant adsorption sites for effective reactive oxygen species scavenging. In a dextran sulfate sodium‐induced ulcerative colitis murine model, E‐xPAM@ASA demonstrate superior therapeutic outcomes, including mucosal repair, inflammation alleviation, and microbiota regulation. These findings highlight the potential of the multifunctional nanocomposite as a precise therapeutic platform for the treatment of intestinal inflammation.

Background/Objectives: Ulcerative colitis (UC) involves chronic colon inflammation and oxidative stress. Treating UC is challenging due to systemic drug side effects and poor targeted delivery. Nanocarriers responsive to the UC microenvironment, particularly elevated reactive oxygen species (ROS), could overcome these limitations. This study developed an oral delivery system for ROS-triggered drug release and active targeting. Using ferulic acid (FER), a system was designed to enhance site-specific accumulation and therapeutic efficacy against colitis. Methods: A ROS-sensitive covalent organic framework (COF) was synthesized from γ-cyclodextrin and functionalized with folic acid (FA) to create a carrier (COF-FA) designed for potential active targeting. This carrier was loaded with FER to form FER@COF-FA. The system was characterized (SEM, FTIR, TGA), and its ROS scavenging and sustained drug release profiles were confirmed in vitro. Biocompatibility was evaluated in cell lines, and therapeutic efficacy was tested in a DSS-induced murine colitis model. Results: The synthesized FER@COF-FA demonstrated high drug loading, potent ROS-scavenging capability, and a sustained drug release profile. It showed excellent biocompatibility and, in the murine model, significantly outperformed free FER. Treatment alleviated disease severity, prevented colon shortening, restored healthy tissue histology, and rebalanced pro- and anti-inflammatory cytokines. Conclusions: The FER@COF-FA system represents a highly promising therapeutic strategy for UC. Its superior efficacy is attributed to a synergistic multi-mechanism approach, combining sustained release, ROS-responsive drug delivery, intrinsic antioxidant activity, and potential folate receptor-mediated targeting, which collectively enhance site-specific accumulation and therapeutic outcomes in the inflammatory colon microenvironment.

Excess reactive oxygen species (ROS) and persistent oxidative stress can cause mucosal damage and epithelial dysfunction, accelerating inflammation and the development of inflammatory bowel diseases (IBD). Thus, ROS-scavenging and anti-inflammatory nanomaterials have emerged as promising strategies for treating IBD. Herein, we developed ROS-scavenging anti-inflammatory tannic acid (TA)-iron ion (Fe2+)-quercetin (QCT) (TFQ) nanocomplexes via a coordination-based self-assembly process, and evaluated their therapeutic effects on dextran sulphate sodium (DSS)-induced acute colitis mouse model. The prepared TFQ nanocomplexes exhibited good colloidal and storage stabilities under aqueous condition. In addition, they showed excellent free radical- and hydrogen peroxide (H2O2)-scavenging activities. Further, the cytocompatible TFQ nanocomplexes inhibited pro-inflammatory cytokines (i.e. IL-6 and IL-1β), achieving remarkable anti-inflammatory effects against lipopolysaccharide (LPS)-treated macrophages and cytoprotective effects against H2O2-treated macrophages. Moreover, systemically administered TFQ nanocomplexes alleviated disease symptoms, including colon shortening and inflammation, in a DSS-induced acute colitis mouse model. These findings suggested that the ROS-scavenging anti-inflammatory TFQ nanocomplexes are a promising therapeutic approach for IBD therapy.

The oral administration of drugs for treating ulcerative colitis (UC) is hindered by several factors, including inadequate gastrointestinal stability, insufficient accumulation in colonic lesions, and uncontrolled drug release. A multiple sensitive nano-delivery system comprising β-cyclodextrin (CD) and 4-(hydroxymethyl)phenylboronic acid (PAPE) with enzyme/reactive oxygen species (ROS) sensitivity was developed to load celastrol (Cel) as a comprehensive treatment for UC. Owing to the positive charge in the site of inflamed colonic mucosa, the negatively charged nanomedicine (Cel/NPs) could efficiently accumulate. Expectedly, Cel/NPs showed excellent localization ability to colon in vitro and in vivo tests. The elevated concentration of ROS and intestinal enzymes in the colon microenvironment quickly break the CD, resulting in Cel release partially to rebalance microbiota and recover the intestinal barrier. The accompanying cellular internalization of residual Cel/NPs, along with the high concentration of cellular ROS to trigger Cel burst release, could decrease the expression of inflammatory cytokines, inhibit colonic cell apoptosis, promote the macrophage polarization, scavenge ROS, and regulate the TLR4/NF-κB signaling pathway, which certified that Cel/NPs possessed a notably anti-UC therapy outcome. We provide a promising strategy for addressing UC symptoms via an enzyme/ROS-sensitive oral platform capable of releasing drugs on demand.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by the disruption of the intestinal epithelial barrier. This study described the synthesis and characterization of CCM-Co-ZIF-8, a novel composite material with enzyme-like activities similar to catalase, peroxidase, and superoxide dismutase. CCM-Co-ZIF-8 demonstrated the ability to scavenge reactive oxygen species that play a critical role in UC pathogenesis. In vitro studies using lipopolysaccharide-induced RAW264.7 cells showed that CCM-Co-ZIF-8 exhibited anti-inflammatory activity by promoting the transition of macrophages from an M1 to an M2 phenotype. In vivo experiments using a mouse model of UC demonstrated that CCM-Co-ZIF-8 suppressed the expression of proinflammatory cytokines. These findings suggested that CCM-Co-ZIF-8 might hold promise as a therapeutic strategy for the treatment of UC.

Inflammatory bowel disease (IBD) is a refractory gastrointestinal disorder characterized by sustained intestinal inflammation, mucosal barrier dysfunction, and gut dysbiosis. Excess reactive oxygen species (ROS) is a key driver of these pathological processes. Although CeO2-based nanozymes can scavenge ROS, their clinical application is limited by poor aqueous stability. Here, we developed an oral nanozyme by co-encapsulating ultrasmall CeO2 nanoparticles and the clinical drug 5-aminosalicylic acid (5-ASA) within liposomes. The resulting formulation (CeLA) exhibited excellent colloidal stability and robust ROS-scavenging activity and provided marked cytoprotection against oxidative stress in vitro. In a dextran sulfate sodium (DSS)-induced colitis model, CeLA alleviated clinical symptoms, restored intestinal barrier integrity, and suppressed pro-inflammatory cytokine expression. Notably, CeLA also reshaped the dysbiotic gut microbiome by reducing pro-inflammatory bacterial taxa. This multifunctional nanozyme integrates antioxidant, anti-inflammatory, and microbiome-modulating effects, offering a promising therapeutic strategy for IBD.

Overexpression of classically activated macrophages (M1) subtypes and assessed reactive oxygen species (ROS) levels are often observed in patients with ulcerative colitis. At present, the treatment system of these two problems has yet to be established. Here, the chemotherapy drug curcumin (CCM) is decorated with Prussian blue analogs in a straightforward and cost‐saving manner. Modified CCM can be released in inflammatory tissue (acidic environment), eventually causing M1 macrophages to transform into M2 macrophages and inhibiting pro‐inflammatory factors. Co(III) and Fe(II) have abundant valence variations, and the lower REDOX potential in CCM‐CoFe PBA enables ROS clearance through multi‐nanomase activity. In addition, CCM‐CoFe PBA effectively alleviated the symptoms of UC mice induced by DSS and inhibited the progression of the disease. Therefore, the present material may be used as a new therapeutic agent for UC.

Ulcerative colitis (UC) faces some barriers in oral therapy, such as how to safely deliver drugs to the colon and accumulate in the colon lesions. Hence, we report an advanced yeast particles system loaded with supramolecular nanoparticles with ROS scavenger (curcumin) to treat UC by reducing oxidative stress state and inflammatory response and accelerating the reprogramming of macrophages. In this study, the dual-sensitive materials are bonded on β-cyclodextrin (β-CD), the D-mannose (Man) is modified to adamantane (ADA), and then loaded with curcumin (CUR), to form a functional supramolecular nano-delivery system (Man-CUR NPs) through the host-guest interaction. To improve gastrointestinal stability and colonic accumulation of Man-CUR NPs, yeast cell wall microparticles (YPs) encapsulated Man-CUR NPs to form Man-CUR NYPs via electrostatic adsorption and vacuum extrusion technologies. As expected, the YPs showed the strong stability in complex gastrointestinal environment. In addition, the Man modified supramolecular nanoparticles demonstrated excellent targeting ability to macrophages in the in vitro cellular uptake study and the pH/ROS sensitive effect of Man-CUR NPs was confirmed by the pH/ROS-dual stimulation evaluation. They also enhanced lipopolysaccharide (LPS)-induced inflammatory model in macrophages through downregulation of pro-inflammatory factors, upregulation of anti-inflammatory factors, M2 macrophage polarization, and scavenging the excess ROS. Notably, in DSS-induced mice colitis model, Man-CUR NYPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways, alleviate oxidative stress by Nrf2/HO-1 signaling pathway, promote macrophages reprogramming and improve the favorable recovery of the damaged colonic tissue. Taken together, this study not only provides strategy for “supramolecular curcumin nanoparticles with pH/ROS sensitive and multistage therapeutic effects” in “advanced yeast particles”, but also provided strong theoretical support multi-effect therapy for UC.

Ulcerative colitis (UC) as an important type of inflammatory bowel disease is a chronic disease characterized by intestinal dyshomeostasis. The UC treatment is challenged by the insufficiency of drug delivery and retention. Herein, we fabricated an intrarectal formulation of olsalazine (Olsa)-loaded hydrogel microspheres (LDKT/Olsa) with good bio-adhesiveness and reactive oxygen species (ROS)-scavenging ability to enhance drug retention and therapeutic effect. Low methoxy pectin-dopamine conjugate/konjac glucomannan composite hydrogel microspheres (LDKT) with a size ranging from 10 to 100 μm were prepared by using Zn2+ and ROS-sensitive thioketal as crosslinkers. Upon intrarectal administration, the negatively charged and dopamine-functionalized hydrogel microspheres efficiently adhered to cationic surface of inflammatory mucosa, scavenging ROS and releasing Zn2+ and Olsa for antibacterial and anti-inflammatory effects. In the dextran sodium sulfate (DSS)-induced mouse UC model, the microspheres significantly reduced the levels of colonic ROS and pro-inflammatory cytokines, improved gut mucosal barrier integrity, and remarkably relieved colitis. Overall, the LDKT microspheres are promising carriers to deliver drugs for UC treatment.

Ulcerative colitis (UC), a refractory disease, has become a global problem. Herein, a biomimetic nanoplatform (AU‐LIP‐CM) comprising Au cluster enzymes (AU)‐loaded liposomes (AU‐LIP) camouflaged with the fusion membrane (CM) consisting of neutrophil (NC) and red blood cell (RBC) membrane is designed for the treatment of UC. Briefly, revealed by second near‐infrared (NIR‐II) imaging through collection of fluorescence emitting >1200 nm from AU, the improved inflammatory targeting behavior contributed by CM cloaking, which inherits abilities of inflammatory targeting and immune escape from NC and RBC, respectively, promotes specific accumulation of AU within inflammatory intestines with up to ≈11.5 times higher than that of bare AU. Afterward, AU possessing superoxide dismutase‐ and catalase‐like activities realizes high‐efficiency scavenging of reactive oxygen species (ROS), leading to repair of intestinal barriers, regulation of the immune system, and modulation of gut microbiota, which surpass first‐line UC drug. In addition, study of underlying therapeutic mechanism demonstrated that the treatment with AU‐LIP‐CM can alter the gene signature associated with response to ROS for UC mice to a profile similar to that of healthy mice, deciphering related signal pathways. The strategy developed here provides insights of learning from properties of natural bio‐substances to empower biomimetic nanoplatform to confront diseases.

Overproduction of reactive oxygen species (ROS), a key characteristic of inflammatory bowel disease (IBD), is responsible for dysregulation of signal transduction, inflammatory response, and DNA damage, which ultimately leads to disease progression and deterioration. Thus, ROS scavenging has become a promising strategy to navigate IBD. Inspired by the targeting capability of hyaluronic acid (HA) to CD44-overexpressed inflammatory cells together with the redox regulation capacity of diselenide compounds, we developed an oral nanoformulation, i.e., diselenide-bridged hyaluronic acid nanogel (SeNG), with a view to treat colitis through a ROS scavenging mechanism. Our data demonstrated that SeNG specifically accumulated in colitis tissue that was mediated by highly efficient CD44-HA interaction. This has allowed us to demonstrate a significant anti-inflammatory effect in an acute colitis mouse model induced by dextran sulfate sodium and trinitrobenzenesulfonic acid. Mechanistically, we continued to show SeNG reduced the ROS level via both direct elimination and up-regulation of the Nrf2/HO-1 signal pathway. Collectively, our work provides proof-of-principle evidence for a SeNG-mediated nano-antioxidant strategy, by which colitis could be effectively managed.