茶多酚 神经 肠道菌群

Tea polyphenols (TPs) are the general compounds of natural polyhydroxyphenols extracted in tea. Although a large number of studies have shown that TPs have obvious neuroprotective and neuro repair effects, they are limited due to the low bioavailability in vivo. However, TPs can act indirectly on the central nervous system by affecting the “microflora–gut–brain axis”, in which the microbiota and its composition represent a factor that determines brain health. Bidirectional communication between the intestinal microflora and the brain (microbe–gut–brain axis) occurs through a variety of pathways, including the vagus nerve, immune system, neuroendocrine pathways, and bacteria-derived metabolites. This axis has been shown to influence neurotransmission and behavior, which is usually associated with neuropsychiatric disorders. In this review, we discuss that TPs and their metabolites may provide benefits by restoring the imbalance of intestinal microbiota and that TPs are metabolized by intestinal flora, to provide a new idea for TPs to play a neuroprotective role by regulating intestinal flora.

Depressive disorders can affect up to 350 million people worldwide, and in developed countries, the percentage of patients with depressive disorders may be as high as 10%. During depression, activation of pro-inflammatory pathways, mitochondrial dysfunction, increased markers of oxidative stress, and a reduction in the antioxidant effectiveness of the body are observed. It is estimated that approximately 30% of depressed patients do not respond to traditional pharmacological treatments. However, more and more attention is being paid to the influence of active ingredients in food on the course and risk of neurological disorders, including depression. The possibility of using foods containing polyphenols as an element of diet therapy in depression was analyzed in the review. The possibility of whether the consumption of products such as polyphenols could alleviate the course of depression or prevent the progression of it was also considered. Results from preclinical studies demonstrate the potential of phenolic compounds have the potential to reduce depressive behaviors by regulating factors related to oxidative stress, neuroinflammation, and modulation of the intestinal microbiota.

Oolong tea polyphenols (OTP) have attracted wide attention due to their ability to reduce inflammatory response, regulate gut microbiota, and improve cognitive function. However, exactly how the gut microbiota modulates nervous system activity is still an open question. We previously expounded that supplementing with OTP alleviated neuroinflammation in circadian rhythm disorder (CRD) mice. Here, we showed that OTP can relieve microglia activation by reducing harmful microbial metabolites lipopolysaccharide (LPS) that alleviate CRD-induced cognitive decline. Mechanistically, OTP suppressed the inflammation response by regulating the gut microbiota composition, including upregulating the relative abundance of Muribaculaceae and Clostridia_UCG-014 and downregulating Desulfovibrio, promoting the production of short-chain fatty acids (SCFAs). Moreover, the use of OTP alleviated intestinal barrier damage and decreased the LPS transport to the serum. These results further inhibited the activation of microglia, thus alleviating cognitive impairment by inhibiting neuroinflammation, neuron damage, and neurotoxicity metabolite glutamate elevation. Meanwhile, OTP upregulated the expression of synaptic plasticity-related protein postsynaptic density protein 95 (PSD-95) and synaptophysin (SYN) by elevating the brain-derived neurotrophic factor (BDNF) level. Taken together, our findings suggest that the OTP has the potential to prevent CRD-induced cognition decline by modulating gut microbiota and microbial metabolites.

… on neurodegenerative diseases mediated by the gut microbiota. This review discussed the … host gut microbiota, and TPs may be regarded as potential neuroprotective substances with …

Tea polyphenols (TP) are one of the most functional and bioactive substances in tea. The interactions between TP and intestinal microbiota suggest that probiotics intervention is a useful method to ameliorate neurological diseases. Now, numerous researches have suggested that TP plays a significant role in modulating intestinal bacteria, especially in the area of sustaining a stable state of intestinal microbial function and abundance. Furthermore, homeostatic intestinal bacteria can enhance the immunity of the host. The close reciprocity between intestinal microbiota and the central nervous system provides a new chance for TP to modulate neural-related diseases depending on intestinal microbiota. Therefore, based on the bidirectional relationship between the brain and the intestines, this review provides a new clue to solve insomnia symptoms and related neurological diseases that will enable us to better study the bidirectional effects of TP and intestinal microbiota on the improvement of host health. PRACTICAL APPLICATIONS: This review provides a new clue to solve insomnia symptoms and related neurological diseases that will enable us to better study bidirectional effects of TP and intestinal microbiota on the improvement of host health.

… Oolong tea polyphenols (OTP) has received increasing attention for their … the gut microbiota and related metabolites. In our study, the circadian rhythm disorder (CRD) mice showed gut …

… However, its mechanism of action in aging-related intestinal flora dysbiosis mediated … explore whether tea polyphenols (TP) can improve memory by regulating intestinal flora mediated …

ABSTRACT Many epidemiological studies have shown the beneficial effects of a largely plant-based diet, and the strong association between the consumption of a Mediterranean-type diet with healthy aging including a lower risk of cognitive decline. The Mediterranean diet is characterized by a high intake of olive oil, fruits and vegetables and is rich in dietary fiber and polyphenols – both of which have been postulated to act as important mediators of these benefits. Polyphenols are large molecules produced by plants to protect them from environmental threats and injury. When ingested by humans, as little as 5% of these molecules are absorbed in the small intestine with the majority metabolized by the gut microbiota into absorbable simple phenolic compounds. Flavan-3-ols, a type of flavonoid, contained in grapes, berries, pome fruits, tea, and cocoa have been associated with many beneficial effects on several risk factors for cardiovascular disease, cognitive function and brain regions involved in memory formation. Both preclinical and clinical studies suggest that these brain and heart benefits can be attributed to endothelial vascular effects and anti-inflammatory properties among others. More recently the gut microbiota has emerged as a potential modulator of the aging brain and intriguingly polyphenols have been shown to alter microbiota composition and be metabolized by different microbial species. However, there is a need for well controlled studies in large populations to identify predictors of response, particularly given the vast inter-individual variation of human gut microbiota.

Sleep deprivation (SD) is a prevalent health risk factor in modern society. It can lead to gut microbiota dysbiosis and related cognitive impairment, so natural intervention strategies targeting the microbiota-gut-brain axis have significant research significance. As the main active components in oolong tea, Oolong Tea Polyphenols (OTPs) possess neuroprotective potential and gut microbiota-regulating potential. However, their role and mechanism in cognitive impairment induced by SD remain unclear. In this study, a mouse model of sleep deprivation was established using the modified multiple platform water environment method. Through techniques including behavioral experiments, 16S rRNA sequencing and other methods, the intrinsic mechanism by which OTPs ameliorate cognitive impairment induced by sleep deprivation was systematically evaluated. The results showed that OTP supplementation significantly improved various behavioral indicators of sleep-deprived mice, reversed the dysbiosis of the microbiota structure, increased the abundance of beneficial bacteria such as Lactobacillus, reduced the abundance of harmful bacteria such as Desulfovibrio and thus promoted the production of short-chain fatty acids. Meanwhile, OTPs improved intestinal barrier function, reduced the levels of serum lipopolysaccharide and inflammatory factors, protected the integrity of the blood-brain barrier (BBB), inhibited the excessive activation of neuroglial cells in the hippocampal region, downregulated the activity of the TLR4/NF-κB signaling pathway and restored the balance of neurotransmitters in the hippocampus. In conclusion, OTPs significantly alleviate SD-induced cognitive impairment via the microbiota-gut-brain axis, which provides a theoretical basis for their application as a food-derived intervention strategy.

… with potential neuroprotective effects. This study investigates their neuroprotective effects … The two teas differed in their contents of tea polyphenols, soluble sugar, soluble protein, …

Tea polyphenols (TP) are important functional components in tea. TP can regulate the composition of human intestinal flora, meanwhile, TP can be bio-transformed by the intestinal microbiota, resulting in relative metabolites, which prevent nerve damage, promote neurocognition, and increase resistance to oxidative stress. In recent years, cerebral nerves have become a hot topic of research, and studies have marked the importance of microbial flora and TP in protecting cerebral nerves. This paper reviews the effects of TP on intestinal microflora and the microbial degradation of TP. Furthermore, the potential effects of TP on cerebral nerves have been highlighted. PRACTICAL APPLICATIONS: Neuroscience studies are primarily focused on discerning the functional mechanism of the nervous system. The functional role of intestinal microbiota in host physiology regulation, especially neurological functions, has become a hotspot for neurological research. TP play a vital role in maintaining the steady status of intestinal flora and protecting cerebral nerve damage. An in-depth understanding of the TP and intestinal microbiota interaction, its implication on cerebral nerve protection, and the associated underlying mechanism will allow us to expand the therapeutic applications of TP.

The number of hydroxyl groups and existence of characteristic structural groups in tea polyphenols (TP) make them have antioxidant activity, which gives TP anti-inflammatory effects, toward protecting the intestinal flora and brain neurons. Host-associated microbial metabolites are emerging as dominant modifiers of the central nervous system. As yet, the investigations on host-microbiota crosstalking remain challenging, studies focusing on metabolites such as serotonin, short-chain fatty acids, and others have pinpointed multiple actionable signaling pathways relevant to host health. However, there are still complexities and apparent limitations inherent in transforming complex human diseases to corresponding animal models. Here, we choose to discuss several intestinal metabolites with research value, as crucial areas for assessing TP-mediated chronic brain diseases interactions with microbial.

… gut microbiota structure in AG mice To investigate the influence of tea-gut microbiota interactions on the gut microbiota … to a significant reduction in tea polyphenols and catechins, while …

ABSTRACT Objectives: The study aimed to explore whether TP could improve memory in the aged type 2 diabetic rat model by regulating microbiota-immune-synaptic plasticity axis. Methods: The experiment was divided into two parts. Firstly, to investigate the effects of TP on the physiopathology of the aged T2DM model rats, rats were randomly divided into the Normal control group, the aged group, the Aged T2DM model group, the TP 75, 150, 300 mg/kg groups, the 150 mg/kg Piracetam group and the 3 mg/kg Rosiglitazone group. Then, to further verify whether TP improved memory in aged T2DM rat model by regulating intestinal flora, the fecal microbiota transplantation (FMT) from the rats in the 300 mg/kg TP group into the rats in the aged T2DM model group was carried out. Effects on gut microbiota, colonic integrity (epithelial tight junction proteins), and endotoxemia (serum LPS) were examined, along with synaptic structure, synaptic plasticity-related structural proteins and inflammation signaling of the hippocampus in our study. Results: Our results demonstrated that TP alleviated memory impairments in the aged T2DM rat model. The specific outcomes were as follows: TP 300 mg/kg corrected the gut dysbacteriosis, alleviated intestinal permeability reduction and peripheral/central inflammation, inhibited the TLR4/NF-κB signaling pathway. Meanwhile, TP improved the synaptic plasticity in the hippocampus of the aged T2DM model rats, whose expressions of SYN, PSD 95, NMDAR1 and GluR1 in hippocampus were significantly up-regulated. Surprisingly, rats of the FMT group displayed the same changes. Discussion: TP improves the memory in aged T2DM rat model. The mechanism may be related to the alteration of gut flora, which can inhibit hippocampal TLR4/NF-κB signaling to attenuate neuroinflammation, then improve synaptic plasticity. The study proposes that TP interventions aimed at manipulating the gut microbiota may hold great potential as an effective approach for preventing and treating this disease.

Gut microbiota (GM) play a role in the metabolic health, gut eubiosis, nutrition, and physiology of humans. They are also involved in the regulation of inflammation, oxidative stress, immune responses, central and peripheral neurotransmission. Aging and unhealthy dietary patterns, along with oxidative and inflammatory responses due to gut dysbiosis, can lead to the pathogenesis of neurodegenerative diseases, especially Alzheimer’s disease (AD). Although the exact mechanism between AD and GM dysbiosis is still unknown, recent studies claim that secretions from the gut can enhance hallmarks of AD by disturbing the intestinal permeability and blood–brain barrier via the microbiota–gut–brain axis. Dietary polyphenols are the secondary metabolites of plants that possess anti-oxidative and anti-inflammatory properties and can ameliorate gut dysbiosis by enhancing the abundance of beneficial bacteria. Thus, modulation of gut by polyphenols can prevent and treat AD and other neurodegenerative diseases. This review summarizes the role of oxidative stress, inflammation, and GM in AD. Further, it provides an overview on the ability of polyphenols to modulate gut dysbiosis, oxidative stress, and inflammation against AD.

Multiple sclerosis (MS) is a multifactorial, immune-mediated disease caused by complex gene-environment interactions. Dietary factors modulating the inflammatory status through the control of the metabolic and inflammatory pathways and the composition of commensal gut microbiota, are among the main environmental factors involved in the pathogenesis of MS. There is no etiological therapy for MS and the drugs currently used, often accompanied by major side effects, are represented by immunomodulatory substances capable of modifying the course of the disease. For this reason, nowadays, more attention is paid to alternative therapies with natural substances with anti-inflammatory and antioxidant effects, as adjuvants of classical therapies. Among natural substances with beneficial effects on human health, polyphenols are assuming an increasing interest due to their powerful antioxidant, anti-inflammatory, and neuroprotective effects. Beneficial properties of polyphenols on the CNS are achieved through direct effects depending on their ability to cross the blood-brain barrier and indirect effects exerted in part via interaction with the microbiota. The aim of this review is to examine the literature about the molecular mechanism underlying the protective effects of polyphenols in MS achieved by experiments conducted in vitro and in animal models of the disease. Significant data have been accumulated for resveratrol, curcumin, luteolin, quercetin, and hydroxytyrosol, and therefore we will focus on the results obtained with these polyphenols. Clinical evidence for the use of polyphenols as adjuvant therapy in MS is restricted to a smaller number of substances, mainly curcumin and epigallocatechin gallate. In the last part of the review, a clinical trial studying the effects of these polyphenols in MS patients will also be revised.

… functions and in polyphenols metabolism. Finally, the role of polyphenols in neuroprotection is discussed, highlighting the importance of polyphenols in modulating both gut bacterial …

Polyphenols are secondary metabolites of plants and play a potential role in the prevention and treatment of neurodegenerative diseases (NND) such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) due to their unique physiological functions such as acting as antioxidants, being anti-inflammatory, being neuroprotective, and promoting intestinal health. Since dietary polyphenols exist in plant foods in the form of glycosylation or esterification or are combined with polymers, they need to undergo extensive metabolism through phase I and phase II biotransformations by various intestinal enzymes, as well as metabolism by the intestinal microbiota before they can be fully absorbed. Polyphenols improve intestinal microbiota disorders by influencing the structure and function of intestinal microbiota, inducing beneficial bacteria to produce a variety of metabolites such as short-chain fatty acids (SCFAs), promoting the secretion of hormones and neurotransmitters, and playing an important role in the prevention and treatment of NND by affecting the microbe–gut–brain axis. We review the ways in which some polyphenols can change the composition of the intestinal microbiota and their metabolites in AD or PD animal models to exert the role of slowing down the progression of NND, aiming to provide evidence for the role of polyphenols in slowing the progression of NND via the microbiota–gut–brain (MGB) axis.

Abstract Epigallocatechin gallate (EGCG), a naturally occurring active ingredient unique to tea, has been shown to have neuroprotective potential. There is growing evidence of its potential advantages in the prevention and treatment of neuroinflammation, neurodegenerative diseases, and neurological damage. Neuroimmune communication is an important physiological mechanism in neurological diseases, including immune cell activation and response, cytokine delivery. EGCG shows great neuroprotective potential by modulating signals related to autoimmune response and improving communication between the nervous system and the immune system, effectively reducing the inflammatory state and neurological function. During neuroimmune communication, EGCG promotes the secretion of neurotrophic factors into the repair of damaged neurons, improves intestinal microenvironmental homeostasis, and ameliorates pathological phenotypes through molecular and cellular mechanisms related to the brain-gut axis. Here, we discuss the molecular and cellular mechanisms of inflammatory signaling exchange involving neuroimmune communication. We further emphasize that the neuroprotective role of EGCG is dependent on the modulatory role between immunity and neurology in neurologically related diseases.

Dietary components significantly impact human health, influencing diverse physiological processes from metabolic homeostasis to cognitive function and aging. Tea, a widely consumed functional beverage rich in antioxidants, has gained attention for its health benefits. Epigallocatechin gallate (EGCG), the most abundant and bioactive catechin in green tea, is renowned for its potent biological activities. However, the direct absorption of EGCG is limited due to its low oral bioavailability, with a substantial portion reaching the colon where it interacts extensively with gut microbiota. This microbial interplay is crucial for EGCG’s biotransformation and the realization of its health-promoting potential, yet the underlying mechanisms remain to be fully elucidated. This review synthesizes EGCG's structural features, metabolism, and interactions with gut microbiota, summarizing its roles in gut health and systemic effects through gut-related axes, and outlines future research. First, it elaborates EGCG's structural features, as a flavan-3-ol with a polyphenolic structure containing multiple hydroxyl groups, whose antioxidant and bioactive properties are associated with the specific arrangement of benzene rings and the gallate moiety. Second, it outlines its metabolic process, limited absorption in the small intestine, enzymatic metabolism in the small intestine and liver (including methylation, glucuronidation, and sulfation), and extensive biotransformation in the colon by gut microbiota into metabolites such as epigallocatechin and gallic acid. Third, it explores its effects on the gut, modulating gut microbiota composition by promoting beneficial bacteria and inhibiting pathogenic strains, enhancing intestinal barrier function by upregulating tight junction proteins, and promoting the production of short-chain fatty acids. Finally, it elucidates how EGCG modulates key gut-related health pathways and its broader implications for systemic health through various interconnected gut axes, including the gut–liver, gut–brain, gut–renal, and gut–lung axes, and concludes by outlining prospective research directions aimed at further elucidating the potential of EGCG in promoting health.

Abstract Supplementing with edible herbal medicine is an important strategy because of its role in nutrition. Many polyphenols, which are universal components in edible herbal medicines, have low bioavailability. Therefore, gut microbiota is a key determinant of polyphenol bioactivity. Polyphenols can alter the abundance of flora associated with neuroinflammation by reversing intestinal microbiota dysbiosis. Intestinal flora-mediated chemical modification of polyphenols can result in their conversion into active secondary metabolites. The current review summarizes the main edible medicines used in anti-depression and details the interactions between polyphenols and gut microbiota; in addition, it provides insights into the mechanisms underlying the possible suppression of neuroinflammation associated with depression, by polyphenols in edible herbal medicine. A better understanding of polyphenols with bioactivities that are crucial in edible herbal medicine may facilitate their use in the prevention and treatment of neuroinflammation associated with depression. Graphical Abstract As active components universal exist in edible herbal medicine, many polyphenols rely on intestinal microbes for absorption and metabolism. Interaction with gut microbes emerges as a novel target for suppressing depressive symptoms by herbal medicine. The interaction between polyphenols and intestinal flora is reflected in two aspects: ①Polyphenols can alter the abundance of flora associated with neuroinflammation by reversing intestinal microbiota dysbiosis. ②Through chemical modification mediated by intestinal flora, polyphenols can be converted into secondary metabolites with biological functions of inhibiting neuroinflammation in the CNS.

Depression, a serious mental illness, is characterized by high risk, high incidence, persistence, and tendency to relapse, posing a significant burden on global health. The connection between depression and gut microbiota is an emerging field of study in psychiatry and neuroscience. Understanding the gut–brain axis is pivotal for understanding the pathogenesis and treatment of depression. Gut microbes influence depression-like behaviors by impacting the hypothalamic–pituitary–adrenal axis (HPA), monoamine neurotransmitters, immune responses, cell signaling, and metabolic pathways. Tea, widely used in clinical practice to improve neuropsychiatric disorders, contains Epigallocatechin gallate (EGCG), a major ingredient of green tea, which effectively regulates intestinal flora. This review examined the risks and causes of depression, the complications associated with intestinal flora, their role in the development and treatment of depression, and how EGCG may alleviate depression through interactions with gut microbiota and other mechanisms.

… EGCG as an effective nutritional strategy to mitigate obesity-related metabolic disorders through the gut–brain axis … In this study, EGCG ameliorated HFD-induced intestinal inflammation …

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that significantly impacts patient health and quality of life. (-)-Epigallocatechin-3-gallate (EGCG), a potent plant polyphenol from green tea, exhibits superior anti-inflammatory and antioxidative properties; however, its therapeutic potential is hindered by poor stability and bioavailability. Methods and results: Inspired by the tea plant (Camellia sinensis), we developed EGCG-loaded tea supraparticles (TSPs) as an oral dietary supplement, utilizing tea proteins, an eco-friendly byproduct with inherent antioxidative potential, to deliver EGCG. TSPs greatly improved EGCG's stability during gastrointestinal transport, preserving its antioxidant properties and its ability to modulate the immune microenvironment. In a dextran sulfate sodium salt-induced colitis mouse model, TSPs treatment reduced the disease activity index by more than 70% and showed a 1.53-fold improvement in efficacy than EGCG alone. Enhanced colonic barrier integrity and anti-inflammatory effects were observed by oral administration of TSPs. Furthermore, TSPs modulated gut microbiota, promoting microbial diversity and homeostasis thereby alleviating systemic inflammation. This reduction in inflammation contributed to improved blood-brain barrier integrity, potentially mitigating anxiety and depressive-like behaviors associated with colitis. Conclusion: These findings highlight the potential of TSPs as a sustainable nanotechnology-based strategy for enhancing the efficacy of EGCG and effectively addressing IBD and its associated complications.

Abstract Advanced glycation end products (AGEs) are formed in non-enzymatic reaction, oxidation, rearrangement and cross-linking between the active carbonyl groups of reducing sugars and the free amines of amino acids. The Maillard reaction is related to sensory characteristics in thermal processed food, while AGEs are formed in food matrix in this process. AGEs are a key link between carbonyl stress and neurodegenerative disease. AGEs can interact with receptors for AGEs (RAGE), causing oxidative stress, inflammation response and signal pathways activation related to neurodegenerative diseases. Neurodegenerative diseases are closely related to gut microbiota imbalance and intestinal inflammation. Polyphenols with multiple hydroxyl groups showed a powerful ability to scavenge ROS and capture α-dicarbonyl species, which led to the formation of mono- and di- adducts, thereby inhibiting AGEs formation. Neurodegenerative diseases can be effectively prevented by inhibiting AGEs production, and interaction with RAGEs, or regulating the microbiota-gut-brain axis. These strategies include polyphenols multifunctional effects on AGEs inhibition, RAGE-ligand interactions blocking, and regulating the abundance and diversity of gut microbiota, and intestinal inflammation alleviation to delay or prevent neurodegenerative diseases progress. It is a wise and promising strategy to supplement dietary polyphenols for preventing neurodegenerative diseases via AGEs-RAGE axis and microbiota-gut-brain axis regulation.

Tea polyphenols (TP) have been shown multiple biological activities and ability to modulate the composition and the function of intestinal microbiota. Certain human metabolic diseases are engendered by the disruption of circadian rhythm. Circadian rhythm oscillations exist in both intestinal microbiota and hypothalamus. The brain-gut-microbiome axis enables intestinal microorganisms to communicate with the brain. The close reciprocity between intestinal microbiota and circadian rhythm supplies a new opportunity for TP to regulate circadian rhythm-related diseases relying on intestinal microbiota. Therefore, based on the potential bidirectional association of the brain and gut microbes, this review mainly discussed the interaction between TP and intestinal microbiota from the perspective of gut-brain axis (GBA) to improve the theory of metabolic diseases prevention. This article is protected by copyright. All rights reserved.

With the recognition of the importance of the gut–brain axis in Parkinson’s disease (PD) etiology, there is increased interest in developing therapeutic strategies that target α-synuclein, the hallmark abhorrent protein of PD pathogenesis, which may originate in the gut. Research has demonstrated that inhibiting the aggregation, oligomerization, and fibrillation of α-synuclein are key strategies for disease modification. Polyphenols, which are rich in fruits and vegetables, are drawing attention for their potential role in this context. In this paper, we reviewed how polyphenols influence the composition and functional capabilities of the gut microbiota and how the resulting microbial metabolites of polyphenols may potentially enhance the modulation of α-synuclein aggregation. Understanding the interaction between polyphenols and gut microbiota and identifying which specific microbes may enhance the efficacy of polyphenols is crucial for developing therapeutic strategies and precision nutrition based on the microbiome.

… by mediating the gut-brain axis are mainly through inhibiting nervous system inflammation, Aβ … EGCG not only optimized gut microbial composition and gut barrier function, but also …

Depression is a chronic mental disorder that impacts human health. The potential antidepressant effects of teadenol A—the primary cleavage product of the EGCG B‐ring formed during dark tea processing—remain unclear. In this study, a CUMS‐induced rat model of depression was used to preliminarily investigate the potential antidepressant effects of teadenol A through the microbiota–gut–brain axis. The results indicated that teadenol A alleviated depressive behaviors, reduced serum inflammatory factors, improved hippocampal morphology, and upregulated BDNF expression in CUMS‐induced depressed rats. Additionally, teadenol A reshaped the gut microbiota profile, leading to an increased relative abundance of beneficial bacteria, such as Monoglobus , Akkermansia , Quinella , and the Lachnospiraceae NK4A136 group . Untargeted metabolomics analysis revealed that teadenol A mitigated metabolic dysregulation in feces, colon, serum, and cerebral cortex of depressed rats, while partially restoring metabolite profiles to a homeostatic state. Targeted metabolomics results further showed that teadenol A promoted BAs and SCFAs metabolism in feces, while significantly increasing Trp contents in serum. Collectively, these findings suggest that teadenol A has potential antidepressant effects in alleviating CUMS‐induced depression‐like behaviors by regulating gut microbiota and metabolomic imbalances through the microbiota–gut–brain axis.

Excessive dietary intake of advanced glycation end products (AGEs) is a potential risk factor for neurodegenerative diseases (NDDs). The underlying mechanism may involve AGEs-induced impairment of intestinal barrier and disturbance of gut microbiota homeostasis, which in turn triggers neuroinflammation and oxidative stress via the microbiota-gut-brain (MGB) axis. Plant extracellular vesicles (PEVs), as natural nanocarriers, can not only enhance the bioavailability of polyphenols but also, in synergy with polyphenols, exhibit antioxidant, anti-inflammatory, and gut-microenvironment-modulating properties. This review summarizes and discusses the potential and mechanisms by which PEVs-polyphenols delivery systems may mitigate AGEs-related neurotoxicity by preserving MGB axis function, thereby providing a theoretical foundation for the development of prospective intervention strategies in this field.

Our investigations on GABA-enriched tea and the reduction of stress in a student cohort have shown that more than just GABA may be involved. The effects of other constituents that are changed in the enrichment process are likely to be important. We have concentrated on GABA as well as the major tea flavonoid, epigallocatechin gallate. While this flavonoid is known to get to the brain on oral administration, it is far from clear that GABA does the same. GABA may act primarily on the gut and influence brain function via the gut-brain axis and the gut microbiome. In addition, there may be a microbiome in the brain that has a role. The situation is complex and not clearly understood. Mixtures of bioactive compounds are always difficult to investigate, but even the precise mechanisms of how pure oral GABA acts as a neuro-nutraceutical is unclear.

Background Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with limited effective treatments. Emerging evidence implicates dysregulation of the microbiota-gut-brain axis in ASD pathogenesis. Oolong tea (OT), a traditional Chinese tea with neuroprotective properties, may modulate this axis, but its effects and mechanisms in ASD remain unclear. We investigated whether OT attenuates neuroinflammation in a valproic acid (VPA)-induced rat model of autism through the microbiota-gut-brain axis and the TLR-4/IκB-α/NF-κB signaling pathway. Methods An ASD model was established by prenatal VPA exposure (500 mg/kg, i.p., E12.5). Postnatal VPA-treated rats received OT (100, 200, or 400 mg/kg/day) for 4 weeks. Behavioral assessments included self-grooming, marble burying, and three-chamber social interaction tests. Nissl staining evaluated neuropathology. Gut microbiota composition was analyzed using 16S rRNA sequencing of fecal samples. Lipopolysaccharide (LPS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were measured in the plasma, intestine, and brain using enzyme-linked immunosorbent assay. Intestinal and blood-brain barrier (BBB) integrity (claudin-1/5, occludin, ZO-1) and TLR-4/IκB-α/NF-κB pathway activation were assessed by Western blot/immunofluorescence. Microglial (Iba-1) and astrocytic (GFAP) activation and neuronal TLR-4 localization (co-staining with Neun) were examined. Antibiotic cocktail (ABX)-induced microbiota depletion validated gut microbiota dependency. Results OT (400 mg/kg/day) significantly ameliorated repetitive behaviors (reduced self-grooming duration and marble burying), sociability deficits (improved sociability/social preference index), and attenuated cortical neuronal loss in VPA-treated rats. OT restored gut microbiota dysbiosis, specifically reducing pathogenic Ruminococcaceae and Bacteroides abundances. It decreased LPS, IL-6, and TNF-α levels in the plasma, intestine, and cortex, while enhancing intestinal and BBB tight junction protein expression. OT suppressed TLR-4/IκB-α/NF-κB activation in both intestine and cortex, with TLR-4 predominantly localized to neurons, and reduced microglial/astrocytic activation. Critically, ABX treatment abolished OT’s neuroprotective effects and restored neuroinflammation. Conclusion OT attenuates ASD-like phenotypes and neuroinflammation in VPA-treated rats by rebalancing gut microbiota, restoring intestinal/BBB barriers, and inhibiting neuronal TLR-4/IκB-α/NF-κB signaling. This study highlights OT’s potential as a microbiota-targeted therapeutic strategy for ASD.

A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this review article will discuss the implications of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.

Abstract The human gut microbiota is a complex community of micro-organisms that play a crucial role in maintaining overall health. Recent research has shown that gut microbes also have a profound impact on brain function and cognition, leading to the concept of the gut–brain axis. One way in which the gut microbiota can influence the brain is through the bioconversion of polyphenols to other bioactive molecules. Phenolic compounds are a group of natural plant metabolites widely available in the human diet, which have anti-inflammatory and other positive effects on health. Recent studies have also suggested that some gut microbiota–derived phenolic metabolites may have neurocognitive effects, such as improving memory and cognitive function. The specific mechanisms involved are still being studied, but it is believed that phenolic metabolites may modulate neurotransmitter signaling, reduce inflammation, and enhance neural plasticity. Therefore, to exert a protective effect on neurocognition, dietary polyphenols or their metabolites must reach the brain, or act indirectly by producing an increase in bioactive molecules such as neurotransmitters. Once ingested, phenolic compounds are subjected to various processes (eg, metabolization by gut microbiota, absorption, distribution) before they cross the blood–brain barrier, perhaps the most challenging stage of their trajectory. Understanding the role of phenolic compounds in the gut–brain axis has important implications for the development of new therapeutic strategies for neurological and psychiatric disorders. By targeting the gut microbiota and its production of phenolic metabolites, it may be possible to improve brain function and prevent cognitive decline. In this article, the current state of knowledge on the endogenous generation of phenolic metabolites by the gut microbiota and how these compounds can reach the brain and exert neurocognitive effects was reviewed.

Cognitive, mood and sleep disorders are common and intractable disorders of the central nervous system, causing great inconvenience to the lives of those affected. The gut–brain axis plays a vital role in studying neurological disorders such as neurodegenerative diseases by acting as a channel for a bidirectional information exchange between the gut microbiota and the nervous system. Dietary polyphenols have received widespread attention because of their excellent biological activity and their wide range of sources, structural diversity and low toxicity. Dietary intervention through the increased intake of dietary polyphenols is an emerging strategy for improving circadian rhythms and treating metabolic disorders. Dietary polyphenols have been shown to play an essential role in regulating intestinal flora, mainly by maintaining the balance of the intestinal flora and enhancing host immunity, thereby suppressing neurodegenerative pathologies. This paper reviewed the bidirectional interactions between the gut microbiota and the brain and their effects on the central nervous system, focusing on dietary polyphenols that regulate circadian rhythms and maintain the health of the central nervous system through the gut–brain axis.

Brain ageing is a complex physiological process that includes several mechanisms. It is characterized by neuronal/glial dysfunction, alterations in brain vasculature and barriers, and the decline in brain repair systems. These disorders are triggered by an increase in oxidative stress and a proinflammatory state, without adequate antioxidant and anti-inflammatory systems, as it occurs in young life stages. This state is known as inflammaging. Gut microbiota and the gut–brain axis (GBA) have been associated with brain function, in a bidirectional communication that can cause loss or gain of the brain’s functionality. There are also intrinsic and extrinsic factors with the ability to modulate this connection. Among the extrinsic factors, the components of diet, principally natural components such as polyphenols, are the most reported. The beneficial effects of polyphenols in brain ageing have been described, mainly due to their antioxidants and anti-inflammatory properties, including the modulation of gut microbiota and the GBA. The aim of this review was, by following the canonical methodology for a state-of-the-art review, to compose the existing evidenced picture of the impact of the gut microbiota on ageing and their modulation by polyphenols as beneficial molecules against brain ageing.

The modulation of the microbiota-gut-brain axis with a view to preventing and treating brain disorders became recently a hot topic for the scientific community. Dietary polyphenols are multifaceted compounds that have demonstrated to be highly advantageous to counteract inflammation, oxidative stress, and neurodegeneration, among other pathological conditions, being useful in the prevention and treatment of several chronic disorders. The potential of these compounds to prevent and treat brain disorders has not been only related to their capacity to reach the brain, depending on their chemical structure, and interact directly with brain cells, but also to their ability to modulate the communication between the brain and the gut, interfering with multiple branches of this axis. Preclinical studies have demonstrated the potential of these food bioactive compounds in brain diseases, namely, neurodevelopmental, such as Down's syndrome and Autism spectrum disorder, neurodegenerative, such as Parkinson's disease and Alzheimer's disease, and psychiatric disorders, such as depression and anxiety. Until now, dietary polyphenols have been recognized as promising nutraceuticals to combat brain disorders. However, the impact of these compounds on the gut-brain interconnection remains poorly elucidated. Also, clinical assays are crucial to further support the beneficial effects of these compounds as demonstrated in preclinical research.

… , and gut microbiota, highlighting their collective role in brain … (ie, polyphenols-gut microbiota and polyphenols-brain health, … as polyphenols-gut microbiota-brain health and polyphenols-…

The number of individuals affected by dementia and cognitive decline is progressively increasing, becoming a serious global health challenge. Several investigations underline the role of nutrition and dietary habits as a preventive strategy. Recent studies suggest that dietary supplementation with polyphenols may constitute an efficient preventive strategy. Indeed, it is emerging that polyphenols exhibit a neuroprotective effect because of their pronounced antioxidant and anti-inflammatory activity. Notably, several studies underline the role of the gut microbiota in the metabolism of the polyphenols, producing bioactive molecules that are absorbed through the gastrointestinal tract. They may exhibit beneficial effects on the central nervous system. Moreover, dietary polyphenols modulate gut microbiota composition, demonstrating a reciprocal regulation between gut microbiota and polyphenol-induced effects on brain functions. Thus, polyphenols are proposed to have an important role on the gut–microbiota–brain axis regulation. The literature search for this narrative review was conducted across three electronic databases PubMed, Scopus, and Web of Science as well as the NIH ClinicalTrials.gov registry, covering the period from January 2000 to 10 February 2026. The following search terms were used: “polyphenols”, “microbiota”, “gut–brain axis”, “dementia”, “cognitive function”, “polyphenols and cognitive dysfunction”, and “polyphenols and microbiota”. The study selection process was performed in two sequential stages: (i) screening of titles and abstracts, followed by (ii) full-text assessment for eligibility. Articles were included if they were peer-reviewed studies (in vitro, in vivo, or clinical trials), published in English, and addressed the effects of polyphenols on cognitive outcomes, gut microbiota composition, or the gut–microbiota–brain axis. Exclusion criteria included non-peer-reviewed sources, studies lacking relevant cognitive or microbiota-related endpoints, and publications not available in full.

Oxidative stress causes various diseases, such as type II diabetes and dyslipidemia, while antioxidants in foods may prevent a number of diseases and delay aging by exerting their effects in vivo. Phenolic compounds are phytochemicals such as flavonoids which consist of flavonols, flavones, flavanonols, flavanones, anthocyanidins, isoflavones, lignans, stilbenoids, curcuminoids, phenolic acids, and tannins. They have phenolic hydroxyl groups in their molecular structures. These compounds are present in most plants, are abundant in nature, and contribute to the bitterness and color of various foods. Dietary phenolic compounds, such as quercetin in onions and sesamin in sesame, exhibit antioxidant activity and help prevent cell aging and diseases. In addition, other kinds of compounds, such as tannins, have larger molecular weights, and many unexplained aspects still exist. The antioxidant activities of phenolic compounds may be beneficial for human health. On the other hand, metabolism by intestinal bacteria changes the structures of these compounds with antioxidant properties, and the resulting metabolites exert their effects in vivo. In recent years, it has become possible to analyze the composition of the intestinal microbiota. The augmentation of the intestinal microbiota by the intake of phenolic compounds has been implicated in disease prevention and symptom recovery. Furthermore, the “brain–gut axis”, which is a communication system between the gut microbiome and brain, is attracting increasing attention, and research has revealed that the gut microbiota and dietary phenolic compounds affect brain homeostasis. In this review, we discuss the usefulness of dietary phenolic compounds with antioxidant activities against some diseases, their biotransformation by the gut microbiota, the augmentation of the intestinal microflora, and their effects on the brain–gut axis.

The pathophysiology of depression is multifactorial yet generally aggravated by stress and its associated physiological consequences. To effectively treat these diverse risk factors, a broad acting strategy is required and is has been suggested that gut-brain-axis signaling may play a pinnacle role in promoting resilience to several of these stress-induced changes including pathogenic load, inflammation, HPA-axis activation, oxidative stress and neurotransmitter imbalances. The gut microbiota also manages the bioaccessibility of phenolic metabolites from dietary polyphenols whose multiple beneficial properties have known therapeutic efficacy against depression. Although several potential therapeutic mechanisms of dietary polyphenols toward establishing cognitive resilience to neuropsychiatric disorders have been established, only a handful of studies have systematically identified how the interaction of the gut microbiota with dietary polyphenols can synergistically alleviate the biological signatures of depression. The current review investigates several of these potential mechanisms and how synbiotics, that combine probiotics with dietary polyphenols, may provide a novel therapeutic strategy for depression. In particular, synbiotics have the potential to alleviate neuroinflammation by modulating microglial and inflammasome activation, reduce oxidative stress and balance serotonin metabolism therefore simultaneously targeting several of the major pathological risk factors of depression. Overall, synbiotics may act as a novel therapeutic paradigm for neuropsychiatric disorders and further understanding the fundamental mechanisms of gut-brain-axis signaling will allow full utilization of the gut microbiota’s as a therapeutic tool.

There is a growing dissatisfaction at the lack of progress in treating neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. No current pharmaceuticals have any significant impact on the pathophysiological changes occurring in such neurodegenerative conditions. More promising has been the utilization of nutraceuticals, a number of which show preventative and treatment benefits. This article reviews the beneficial effects of melatonin, sodium butyrate and epigallocatechin gallate (EGCG) in the management of the pathophysiological changes underpinning neurodegenerative conditions. It is proposed that all three nutraceuticals upregulate the tryptophan-melatonin pathway, which may be particularly important in astrocytes given astrocyte regulation of neuronal energy supply and antioxidants, including released melatonin. Alterations in the tryptophan-melatonin pathway are intimately intertwined with changes in the kynurenine pathway and its neuroregulatory products, including kynurenic acid and quinolinic acid. This article places these changes in the tryptophan-melatonin pathways within a novel circadian-systemic interaction, involving the regulation of the night-time rise in cortisol culminating in the morning cortisol awakening response that mediates effects via glucocorticoid receptor (GR) activation. The night-time and morning GR activation is suppressed by melatonin, gut microbiome derived butyrate and bcl2-associated athanogene (BAG)-1. As melatonin, butyrate and BAG-1 decrease over age, there is a heightened level of GR nuclear translocation with age at night and early morning. This is exemplified by the 10-fold decrease in pineal melatonin in people in their 9th, versus 2nd, decade of life. The ‘battle’ of melatonin/butyrate/EGCG versus cortisol/GR for influence on cellular function, microenvironment homeostasis and systemic system (immune) regulation at night and early morning shapes how the body and brain are prepared for the coming day and drives the emergence of aging associated neurodegenerative conditions. It is upon such processes that melatonin, butyrate and EGCG have their impacts.    

Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They have received considerable attention as potential therapeutic agents in biomedicine and have been widely used in traditional complimentary medicine for generations. Such complimentary medical herbal formulations are extremely complex mixtures of many pharmacologically active compounds that provide a therapeutic outcome through a network pharmacological effects of considerable complexity. Methods are emerging to determine the active components used in complimentary medicine and their therapeutic targets and to decipher the complexities of how network pharmacology provides such therapeutic effects. The gut microbiome has important roles to play in the generation of bioactive flavonoid metabolites retaining or exceeding the antioxidative and anti-inflammatory properties of the intact flavonoid and, in some cases, new antitumor and antineurodegenerative bioactivities. Certain food items have been identified with high prebiotic profiles suggesting that neutraceutical supplementation may be beneficially employed to preserve a healthy population of bacterial symbiont species and minimize the establishment of harmful pathogenic organisms. Gut health is an important consideration effecting the overall health and wellbeing of linked organ systems. Bioconversion of dietary flavonoid components in the gut generates therapeutic metabolites that can also be transported by the vagus nerve and systemic circulation to brain cell populations to exert a beneficial effect. This is particularly important in a number of neurological disorders (autism, bipolar disorder, AD, PD) characterized by effects on moods, resulting in depression and anxiety, impaired motor function, and long-term cognitive decline. Native flavonoids have many beneficial properties in the alleviation of inflammation in tissues, however, concerns have been raised that therapeutic levels of flavonoids may not be achieved, thus allowing them to display optimal therapeutic effects. Dietary manipulation and vagal stimulation have both yielded beneficial responses in the treatment of autism spectrum disorders, depression, and anxiety, establishing the vagal nerve as a route of communication in the gut-brain axis with established roles in disease intervention. While a number of native flavonoids are beneficial in the treatment of neurological disorders and are known to penetrate the blood–brain barrier, microbiome-generated flavonoid metabolites (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain the antioxidant and anti-inflammatory potency of the native flavonoid in addition to bioactive properties that promote mitochondrial health and cerebrovascular microcapillary function, should also be considered as potential biotherapeutic agents. Studies are warranted to experimentally examine the efficacy of flavonoid metabolites directly, as they emerge as novel therapeutic options.

ABSTRACT Neurodegenerative and neuropsychiatric diseases have attracted global attention with an overwhelming burden on families and society. Tea contains many bioactive compounds, such as polyphenols and theanine, which could contribute to the neuroprotective effects of tea. The possible mechanisms of action include regulating signaling pathways and gut microbiota; inhibiting abnormal protein aggregation; normalizing the hyperactivity of the hypothalamic-pituitary-adrenal axis; as well as antioxidant and anti-inflammatory properties of tea for Parkinson’s disease, Alzheimer’s disease, and depression. In this narrative revie w, the effects of tea on these diseases were summarized, and special attention was paid to the mechanisms of action. Abbreviations: AChE, acetylcholinesterase; ACTH, adrenocorticotropin; AKT, serine-threonine protein kinase; BChE, butyrylcholinesterase; BDNF, brain-derived neurotrophic factor; CI, confidence interval; COX-2, cyclooxygenase-2; CRH, corticotrophin-releasing hormone; CREB, cyclic adenosine monophosphate response element-binding protein; EC, epicatechin; ECG, epicatechin-3-gallate; EGC, epigallocatechin; EGCG, epigallocatechin gallate; ERK, extracellular signal-regulated kinase; GABA, gamma-aminobutyric acid; GSK-3β, glycogen synthase kinase-3β; HPA, hypothalamic-pituitary-adrenal; HR, hazard ratio; IL, interleukin; MAOB, monoamine oxidase B; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2-related factor 2; NOS, nitric oxide species; OR, odds ratio; PGC-1α; peroxisome proliferator-activated receptor gamma coactivator-1α; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; ROS, reactive oxygen species; RR, risk ratio; TLR4, Toll-like receptor 4; TNF-α; umor necrosis factor alpha; 6-OHDA, 6-hydroxydopamine.

Tea flower polysaccharides (TFPS) have prominent anti-aging effect. In this study, we used an animal model of aging induced by D-galactose in mice to investigate the effect of TFPS on reducing inflammatory factors, lowering oxidative stress levels, and inhibiting oxidative damage to microglia from the perspective of regulating gut microbiota. The results showed that TFPS could improve the homeostasis of gut microbiota in aging mice, reduce the ratio of Firmicutes to Bacteroidota, and significantly increase the abundance of Lactobacillus. At the same time, TFPS reduced the excessive activation of hippocampal microglia in aging mice, significantly down-regulated the levels of pro-inflammatory factors IL-6, IL-1β, TNF-α, and nuclear transcription factor NF-κB, increased the activity of antioxidant enzymes SOD, CAT, and POD, and reduced the content of MDA. Our research results indicate that TFPS can improve the disorder of gut microbiota, alleviate oxidative damage to glial cells, alleviate neuroinflammation, and play a role in delaying aging.

Aging-associated cognitive dysfunction has a great influence on the lifespan and healthspan of the elderly. Theaflavins (TFs), a mixture of ingredients formed from enzymatic oxidation of catechins during the manufacture of tea, have a positive contribution to the qualities and antiaging activities of black tea. However, the role of TFs in mitigating aging-induced cognitive dysfunction and the underlying mechanism remains largely unknown. Here, we find that TFs effectively improve behavioral impairment via the microbiota-gut-brain axis: TFs maintain gut homeostasis by improving antioxidant ability, strengthening the immune response, increasing the expression of tight junction proteins, restructuring the gut microbiota, and altering core microbiota metabolites, i.e., short-chain fatty acids and essential amino acids (SCFAs and AAs), and upregulating brain neurotrophic factors. Removing the gut microbiota with antibiotics partly abolishes the neuroprotective effects of TFs. Besides, correlation analysis indicates that the decrease in gut microbiota, such as Bacteroidetes and Lachnospiraceae, and the increase in microbiota metabolites' levels are positively correlated with behavioral improvements. Taken together, our findings reveal a potential role of TFs in mitigating aging-driven cognitive dysfunction via the microbiota-gut-brain axis. The intake of TFs can be translated into a novel dietary intervention approach against aging-induced cognitive decline.

BACKGROUND The gut-brain axis is considered a neuroendocrine system, which connects the brain and gastrointestinal tract and plays an important role in stress response. The homeostasis of gut-brain axis is important for health conditions and its alterations are associated to neurological disorders and neurodegenerative diseases. METHOD We selected recent papers analysing the association among alterations in the homeostasis of the gut-brain axis and neurological disorders. In addition, we described how bioactive natural molecules - such as polyphenols - by influencing gut microbiota composition may help rescue neural signalling pathways impaired in neurodegenerative diseases. RESULTS Recent studies show that gut microbiota is a dynamic ecosystem that can be altered by external factors such as diet composition, antibiotics or xenobiotics. Gut bacterial community plays a key role in maintaining normal brain functions. Metagenomic analyses have elucidated that the relationship between gut and brain, either in normal or in pathological conditions, reflects the existence of a "microbiota-gut-brain" axis. Gut microbiota composition can be influenced by dietary ingestion of probiotics or natural bioactive molecules such as prebiotics and polyphenols. Their derivatives coming from microbiota metabolism can affect both the gut bacterial composition and brain biochemistry. CONCLUSION This review highlights the role of gut microbiota in regulating regulates brain biochemistry and the role of microbiota metabolites on neuropathologies. Dietary ingestion of probiotics, prebiotics and polyphenols affect gut microbiota composition underlining the key role played by specific metabolites not only in the gut microbiota composition but also in the brain health maintenance.

ABSTRACT The interplay among diabetes, cognitive decline, and the gut microbiome represents an emerging field of scientific inquiry. The gut‐brain axis serves as a crucial communication network between the gastrointestinal system and the central nervous system, playing a significant role in diabetes‐related cognitive deterioration. Fermented tea, enriched with bioactive constituents, offers a promising therapeutic strategy by modulating this axis. Specifically, compounds including catechins in fermented tea positively modulate gut microbiota composition, promoting commensal bacteria while suppressing pathogenic strains. This microbial shift enhances the production of short‐chain fatty acids, which may strengthen gut barrier integrity, attenuate systemic inflammation, and thereby influence cognitive health via the gut‐brain axis. Concurrently, the antioxidant properties of tea polyphenols and catechins mitigate oxidative stress, a key pathogenic factor in diabetic cognitive impairment. Furthermore, the anti‐inflammatory effects of fermented tea may potentially ameliorate chronic low‐grade inflammation in diabetes, offering a plausible pathway for cognitive improvement. This systematic review, conducted through comprehensive searches of PubMed, Web of Science, CNKI (China National Knowledge Infrastructure), and Wanfang databases, synthesizes evidence supporting fermented tea as a natural intervention to preserve cognitive function in diabetic individuals by targeting the gut microbiome and the gut‐brain axis. Notably, it also explores the potential application of Chibi Green Brick tea as a regionally specific intervention for diabetes‐related cognitive dysfunction. Collectively, these insights underscore the necessity for rigorous mechanistic investigations and robust clinical validation to fully elucidate therapeutic mechanisms of fermented tea and translate these findings into clinical practice.

This narrative review presents the role of antioxidants in regulating the gut microbiota and the impact on the gut–brain axis, with a particular focus on neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s disease (PD). These diseases are characterised by cognitive decline, motor dysfunction, and neuroinflammation, all of which are significantly exacerbated by oxidative stress. This review elucidates the contribution of oxidative damage to disease progression and explores the potential of antioxidants to mitigate these pathological processes through modulation of the gut microbiota and associated pathways. Based on recent studies retrieved from reputable databases, including PubMed, Web of Science, and Scopus, this article outlines the mechanisms by which antioxidants influence gut health and exert neuroprotective effects. Specifically, it discusses how antioxidants, including polyphenols, vitamins, and flavonoids, contribute to the reduction in reactive oxygen species (ROS) production and neuroinflammation, thereby promoting neuronal survival and minimising oxidative damage in the brain. In addition, the article explores the role of antioxidants in modulating key molecular pathways involved in oxidative stress and neuroinflammation, such as the NF-κB, Nrf2, MAPK, and PI3K/AKT pathways, which regulate ROS generation, inflammatory cytokine expression, and antioxidant responses essential for maintaining cellular homeostasis in both the gut and the central nervous system. In addition, this review explores the complex relationship between gut-derived metabolites, oxidative stress, and neurodegenerative diseases, highlighting how dysbiosis—an imbalance in the gut microbiota—can exacerbate oxidative stress and contribute to neuroinflammation, thereby accelerating the progression of such diseases as AD and PD. The review also examines the role of short-chain fatty acids (SCFAs) produced by beneficial gut bacteria in modulating these pathways to attenuate neuroinflammation and oxidative damage. Furthermore, the article explores the therapeutic potential of microbiota-targeted interventions, including antioxidant delivery by probiotics and prebiotics, as innovative strategies to restore microbial homeostasis and support brain health. By synthesising current knowledge on the interplay between antioxidants, the gut–brain axis, and the molecular mechanisms underlying neurodegeneration, this review highlights the therapeutic promise of antioxidant-based interventions in mitigating oxidative stress and neurodegenerative disease progression. It also highlights the need for further research into antioxidant-rich dietary strategies and microbiota-focused therapies as promising avenues for the prevention and treatment of neurodegenerative diseases.

Polyphenols and regular physical activity are increasingly recognized as complementary lifestyle interventions that influence the gut-brain axis and contribute to neuroprotection. Emerging evidence highlights the central role of the gut microbiota in mediating these effects by transforming dietary and host-derived substrates into bioactive metabolites. These metabolites can activate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, a key regulator of cellular antioxidant defenses, mitochondrial function, and anti-inflammatory responses processes that are critically impaired in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review synthesizes current mechanistic insights into how polyphenol-derived metabolites and exercise-induced alterations in gut microbial composition converge to modulate Nrf2 signaling. We discuss the roles of key microbiota-derived metabolites, including short-chain fatty acids, urolithins, and indole derivatives, in regulating oxidative stress, neuroinflammation, and synaptic function. Furthermore, we examine evidence from preclinical models supporting the synergistic effects of dietary polyphenols and physical activity on gut microbiota-mediated neuroprotection. Finally, we address translational challenges and highlight the potential of integrating dietary and exercise-based strategies to harness microbiota-dependent Nrf2 activation. This integrative framework provides a basis for developing personalized, microbiome-informed interventions aimed at delaying or mitigating neurodegeneration.

Intracerebral hemorrhage (ICH) is one of the most devastating subtypes of stroke, with limited preventive options and a challenging recovery process. This study presents a translational framework that integrates tea polyphenols (TPPs) and exercise-induced metabolites as dual modulators of neurovascular stability, with a focus on patient education for enhancing post-stroke recovery. By synthesizing preclinical and clinical evidence, we demonstrate how TPPs, particularly epigallocatechin gallate (EGCG), and key exercise metabolites such as lactate, β-hydroxybutyrate, and short-chain fatty acids (SCFAs) interact with shared redox-sensitive and inflammatory signaling pathways (Nrf2/NF-κB/AMPK axis) to reinforce endothelial integrity, preserve blood-brain barrier function, and maintain cerebral perfusion. These interventions also reshape the gut microbiota, promoting an SCFA-enriched, anti-inflammatory profile that fosters bidirectional gut-brain communication, further stabilizing vascular homeostasis. Multi-omics evidence suggests that TPPs and exercise metabolites may jointly regulate metabolic and immune pathways, enhancing resilience against oxidative and inflammatory injuries in the vasculature. We propose a mechanistic model in which TPPs and exercise-derived metabolites synergistically support neurovascular function and reduce neurovascular vulnerability associated with ICH, while promoting cognitive recovery and metabolic health. Incorporating these findings into patient rehabilitation education may help individuals make informed decisions about lifestyle changes that enhance vascular health. Future research should explore the dose-response relationship, the optimal timing between tea and exercise, and individual variations, using metabolomic, microbiomic, and imaging biomarkers to personalize cerebrovascular prevention strategies.

ABSTRACT Polyphenols from plant foods (tea, cocoa, berries, grapes, and extra‐virgin olive oil) modulate oxidative stress, inflammation, vascular function, and the gut microbiome—axes central to non‐communicable chronic diseases (NCCDs) that involve the brain and enteric nervous system (ENS). Recent randomized trials and longitudinal studies report modest but reproducible benefits on cognitive domains and vascular/endothelial function with berry/grape extracts, matcha/green tea, and high‐polyphenol extra‐virgin olive oil; effects appear stronger in older adults or those with metabolic risk. Complementary evidence in irritable bowel syndrome (IBS)—a prototypical gut–brain disorder—suggests polyphenol‐based combinations (often with probiotics/fiber) can improve quality of life and inflammatory markers, supporting enteric–central crosstalk. Emerging genetics (Mendelian randomization) and multi‐omics readouts strengthen causal inferences for tea polyphenols in neurodegeneration‐adjacent outcomes and outline mechanistic mediators (endothelial/BBB function, cytokine tone, microbiome‐derived metabolites). Key gaps remain: heterogeneous formulations/doses, limited head‐to‐head trials, sparse target engagement biomarkers, and uncertain durability after discontinuation. We synthesize clinical and mechanistic advances, propose a standardized biomarker set (neurocognitive, endothelial, immune, and microbiome‐metabolome), and outline designs for mechanism‐anchored RCTs that integrate ENS endpoints with brain outcomes to translate associative signals into precision nutrition strategies for NCCDs.

Abstract Circadian rhythm is an intrinsic mechanism developed by organisms to adapt to external environmental signals. Nowadays, owing to the job and after-work entertainment, staying up late – Circadian rhythm disorders (CRD) are common. CRD is linked to the development of fatty liver, type 2 diabetes, and chronic gastroenteritis, which affecting the body’s metabolic and inflammatory responses via multi-organ crosstalk (gut-liver-brain axis, etc.). However, studies on the mechanisms of multi-organ interactions by CRD are still weak. Current studies on therapeutic agents for CRD remain inadequate, and phytochemicals have been shown to alleviate CRD-induced syndromes that may be used for CRD-therapy in the future. Tea, a popular phytochemical-rich beverage, reduces glucolipid metabolism and inflammation. But it is immature and unclear in the mechanisms of alleviation of CRD-mediated syndrome. Here, we have analyzed the threat of CRD to hosts and their offspring’ health from the perspective of the “gut-liver-brain” axis. The potential mechanisms of tea in alleviating CRD were further explored. It might be by interfering with bile acid metabolism, tryptophan metabolism, and G protein-coupled receptors, with FXR, AHR, and GPCR as potential targets. We hope to provide new perspectives on the role of tea in the prevention and mitigation of CRD. Highlights The review highlights the health challenges of CRD via the gut-liver-brain axis. CRD research should focus on the health effects on healthy models and its offspring. Tea may prevent CRD by regulating bile acid, tryptophan, and GPCR. Potential targets for tea prevention and mitigation of CRD include FXR, AHR and GPCR. A comprehensive assessment mechanism for tea in improving CRD should be established.

Depression is strongly linked to dysfunctions in the microbiota-gut-brain axis. Jasmine tea, a traditional Chinese beverage made by combining green tea with Jasminum sambac, has potential antidepressant effects. However, its potential to alleviate depression via modulation of the microbiota-gut-brain axis remains largely unstudied. In this study, we used a rat model of depression induced by chronic unpredictable mild stress (CUMS) to investigate the effects of jasmine tea extract (JT) on depression-related symptoms. Behavioral assessments, inflammatory marker analysis, hippocampal histology, and brain-derived neurotrophic factor (BDNF) expression assays demonstrated that JT alleviated depressive behaviors, reduced brain tissue damage, and restored cognitive function in CUMS-exposed rats. JT also significantly reduced intestinal levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and modulated oxidative stress markers (MDA, SOD, and CAT), suggesting a role in preserving intestinal integrity. Further, 16S rRNA sequencing revealed that JT shifted the gut microbiota composition in favor of beneficial bacteria such as Romboutsia, Blautia, and Monoglobus, while decreasing the abundance of potentially harmful bacteria, including Bifidobacterium, Clostridium_sensu_stricto_1, and Escherichia-Shigella. Meanwhile, non-targeted and targeted metabolomics analyses showed that JT influenced key metabolic pathways involving tryptophan, short-chain fatty acids, and bile acids, helping to restore metabolic balance across various tissues (feces, colon, serum, and cerebral cortex) in the depressed rats. These findings indicate that JT may alleviate depression by modulating the microbiota-gut-brain axis, highlighting its potential as a dietary intervention for depression management.

… on the gut-brain axis. While the relationship between gut phenolic metabolites derived from … resulting from colonic fermentation through metabolomics approaches offer a powerful tool …

In today's fast-paced modern lifestyle, sleep disorders have become a pervasive challenge for many individuals. Conventional treatments often rely on pharmacological interventions, which carry risks of dependency and adverse effects. In recent years, the gut microbiota has gained increasing recognition as a "second brain," engaging in bidirectional communication with the central nervous system via the microbiota-gut-brain axis (MGB axis). Tea polyphenols (TP), the primary bioactive compounds derived from tea, show considerable potential in improving sleep quality through this microbial-gut-brain circuitry. This review systematically elucidates how TP reshape the gut microbiota by selectively enriching beneficial bacteria such as Lactobacillus and Bifidobacterium, while suppressing pathogenic species. These structural changes are accompanied by functional benefits, including enhanced intestinal barrier integrity and attenuated systemic inflammation. Furthermore, gut microbiota metabolize TP into bioactive small molecules that enter systemic circulation, cross the blood-brain barrier (BBB), and modulate central neurotransmitters, notably serotonin (5-HT) and γ-aminobutyric acid (GABA). By delineating this gut-mediated neuromodulatory network, our study provides a novel theoretical foundation for the use of TP as a dietary strategy to ameliorate sleep disorders.

Alzheimer’s disease (AD) represents an increasingly severe global health challenge. Recently, the role of the gut–brain axis in AD pathogenesis has garnered significant attention. Dysbiosis of the gut microbiota can exacerbate core pathologies such as neuroinflammation, amyloid beta (Aβ) deposition, and tau hyperphosphorylation through neural, endocrine, and immune pathways. Polyphenolic compounds have emerged as a focal point in neuroprotective research owing to their pronounced anti-inflammatory and antioxidant properties. Notably, polyphenols exert effects not only by directly influencing the central nervous system (CNS) but also through indirectly modulating the composition and function of the gut microbiota, thereby impacting bidirectional gut–brain communication. This dual mechanism offers a potential avenue for their application in the prevention and treatment of AD. This review aims to compile recent research on the relationship between polyphenols and the gut microbiota. We assessed the literature from PubMed, Google Scholar, and Web of Science databases, published from the establishment of the database to 24 November 2025. The keywords used include “Polyphenols”, “Gut–brain axis”, “Gut microbiota”, “Alzheimer’s disease”, “Epigallocatechin gallate”, “Quercetin”, “Curcumin”, “Ferulic acid”, “Resveratrol”, “Anthocyanin”, “Myricetin”, “Chlorogenic acid”, etc. This review discusses the various mechanisms by which polyphenols influence AD through modulating the gut microbiota. Polyphenols and gut microbiota exhibit critical bidirectional interactions. On one hand, the bioavailability and activity of polyphenols are highly dependent on metabolic conversion by gut microbiota. On the other hand, polyphenols selectively promote the proliferation of beneficial bacteria such as bifidobacteria and lactobacilli like prebiotics, while inhibiting the growth of pathogenic bacteria. This reshapes the intestinal microecology, enhances barrier function, and regulates beneficial metabolites. Utilizing a nanotechnology-based drug delivery system, the pharmacokinetic stability and brain targeting efficacy of polyphenols can be significantly enhanced, providing innovative opportunities for the targeted prevention and management of AD.

Hormonal decline, chronic low-grade inflammation, metabolic alterations and polypharmacy shape the postmenopausal period. These factors remodel the gut microbiota and influence the production of microbial metabolites that modulate immune, endocrine, and neural communication. The gut-brain axis provides a framework for understanding how microbial activity affects cognition, mood, stress responses, neuroinflammation, and gastrointestinal function. Dietary (poly)phenols depend on gut microbial transformation to generate metabolites with distinct biological activity targeting mechanisms, such as intestinal and blood-brain barrier integrity, inflammatory signalling, redox balance, neurotransmitter synthesis, tryptophan metabolism, short-chain fatty acid production, and bile acid remodelling. These pathways are sensitive to hormonal decline, inflammaging, and polypharmacy, which modify microbial metabolism, host conjugation processes, enterohepatic cycling, and physiological response to dietary compounds. Despite this mechanistic basis, no human intervention study has examined these interactions in postmenopausal women. This perspective integrates three dimensions that are usually addressed separately: the physiological and pharmacological characteristics of postmenopause, the communication pathways of the gut-brain axis, and the gut microbial transformation of dietary (poly)phenols. We review human trials assessing (poly)phenols and gut-brain outcomes and highlight the scarcity of mechanistic endpoints, including microbial metabolites, barrier markers, neuroimmune mediators, and bile acid profiles. We also highlight how chronic medications reshape microbial composition and functionality, and how host targets of (poly)phenols, together with interindividual variability in polyphenol-related microbiota metabotypes, such as equol- and urolithin-producing metabotypes, influence biological responses and support personalised strategies. By identifying gaps and research priorities, this perspective provides a conceptual basis for developing precision health for postmenopausal women.

Fatigue seriously affects people’s work efficiency and quality of life and has become a common health problem in modern societies around the world. The pathophysiology of fatigue is complex and not fully clear. To some degree, interactions between gut microbiota and host may be the cause of fatigue progression. Polyphenols such as tannin, tea polyphenols, curcumin, and soybean isoflavones relieve fatigue significantly. Studies have shown that the gut microbiota is able to convert these active compounds into more active metabolites through intestinal fermentation. However, the mechanism of anti-fatigue polyphenols is currently mainly analyzed from the perspective of antioxidant and anti-inflammatory effects, and changes in gut microbiota are rarely considered. This review focuses on gut microecology and systematically summarizes the latest theoretical and research findings on the interaction of gut microbiota, fatigue, and polyphenols. First, we outline the relationship between gut microbiota and fatigue, including changes in the gut microbiota during fatigue and how they interact with the host. Next, we describe the interactions between the gut microbiota and polyphenols in fatigue treatment (regulation of the gut microbiota by polyphenols and metabolism of polyphenols by the gut microbiota), and how the importance of potential active metabolites (such as urolithin) produced by the decomposition of polyphenols by gut microbiota is emerging. Based on the new perspective of gut microbiota, this review provides interesting insights into the mechanism of polyphenols in fatigue treatment and clarifies the potential of polyphenols as targets for anti-fatigue product development, aiming to provide a useful basis for further research and design.

Polyphenols are widely studied phytochemicals with well-known antioxidant and anti-inflammatory properties. They are commonly present in fruits, vegetables, and plant-based foods. Beyond these classical roles, growing evidence shows that polyphenol-derived bioactive metabolites—produced or modified by the gut microbiota—can promote host health. These metabolites are increasingly recognized for shaping host–microbe interactions and influencing neurophysiological functions via the gut–brain axis. This review provides an overview of polyphenol transformation rates by the gut microbiome, highlighting their microbial transformation, anti-biofilm effects, and neuroprotective potential. In our opinion, a deeper understanding of the properties of these metabolites can significantly impact food science and biotechnology.

ABSTRACT Alterations in the gut microbiota composition have been associated with a range of neurodevelopmental, neurodegenerative, and neuropsychiatric disorders. The gut microbes transform and metabolize dietary- and host-derived molecules generating a diverse group of metabolites with local and systemic effects. The bi-directional communication between brain and the microbes residing in the gut, the so-called gut–brain axis, consists of a network of immunological, neuronal, and endocrine signaling pathways. Although the full variety of mechanisms of the gut–brain crosstalk is yet to be established, the existing data demonstrates that a single metabolite or its derivatives are likely among the key inductors within the gut–brain axis communication. However, more research is needed to understand the molecular mechanisms underlying how gut microbiota associated metabolites alter brain functions, and to examine if different interventional approaches targeting the gut microbiota could be used in prevention and treatment of neurological disorders, as reviewed herein. Abbreviations:4-EPS 4-ethylphenylsulfate; 5-AVA(B) 5-aminovaleric acid (betaine); Aβ Amyloid beta protein; AhR Aryl hydrocarbon receptor; ASD Autism spectrum disorder; BBB Blood–brain barrier; BDNF Brain-derived neurotrophic factor; CNS Central nervous system; GABA ɣ-aminobutyric acid; GF Germ-free; MIA Maternal immune activation; SCFA Short-chain fatty acid; 3M-4-TMAB 3-methyl-4-(trimethylammonio)butanoate; 4-TMAP 4-(trimethylammonio)pentanoate; TMA(O) Trimethylamine(-N-oxide); TUDCA Tauroursodeoxycholic acid; ZO Zonula occludens proteins

Increasing evidence supports the beneficial effects of polyphenol-rich diets, including the traditional Mediterranean diet, for the management of cardiovascular disease, obesity and neurodegenerative diseases. However, a common concern when discussing the protective effects of polyphenol-rich diets against diseases is whether these compounds are present in systemic circulation in their intact/parent forms in order to exert their beneficial effects in vivo. Here, we explore two common classes of dietary polyphenols, namely isoflavones and lignans, and their gut microbial-derived metabolites for gut and blood–brain barrier predicted permeability, as well as protection against neuroinflammatory stimuli in murine BV-2 microglia. Polyphenol microbial metabolites (PMMs) generally showed greater permeability through artificial gut and blood–brain barriers compared to their parent compounds. The parent polyphenols and their corresponding PMMs were evaluated for protective effects against lipopolysaccharide-induced inflammation in BV-2 microglia. The lignan-derived PMMs, equol and enterolactone, exhibited protective effects against nitric oxide production, as well as against pro-inflammatory cytokines (IL-6 and TNF-α) in BV-2 microglia. Therefore, PMMs may contribute, in large part, to the beneficial effects attributed to polyphenol-rich diets, further supporting the important role of gut microbiota in human health and disease prevention.

Abstract Flavonoids, a class of polyphenolic compounds, are widely distributed in plant-based foods and have been recognized for their potential to promote overall health and well-being. Flavonoids in fruits and vegetables offer various beneficial effects such as anti-aging, anticancer, and anti-inflammatory properties. Flavonoids have been extensively studied for their neuroprotective properties, which are attributed to their ability to cross the blood-brain barrier and interact with neural cells. Factors like gut microbiota composition, age, genetics, and diet can impact how well flavonoids are absorbed in the gut. The gut microbiota can enhance the absorption of flavonoids through enzymatic processes, making microbiota composition a key factor influenced by age, genetics, and diet. Flavonoids can modulate the gut microbiota through prebiotic and antimicrobial effects, affecting the production of beneficial microbial metabolites like short-chain fatty acids (SCFAs) such as butyrate, which play a role in brain function and health. The gut microbiome also modulates the immune system, which is critical for preventing neuroinflammation. Additionally, flavonoids can benefit mental and psychological health by influencing anti-inflammatory signaling pathways in brain cells and increasing the absorption of tyrosine and tryptophan, precursors to neurotransmitters like serotonin, dopamine, norepinephrine, adrenaline, and gamma-aminobutyric acid (GABA). The flavonoid-gut microbiome axis is a complex and multifaceted relationship that has significant implications for neurological health. This review will explore how genetic and environmental factors can impact flavonoid absorption and the positive effects of flavonoids on brain health and the gut microbiota network. Graphical abstract Neurologically, there are numerous benefits in eating of flavonoids that are aboundant in fruits and vegetables. In the gastro intestinal system, flavonoids under take many alterations that mostly are exerted by small intestine microbiota. Small intestinal Colonized microbiom through secretion of different metabolizing enzymes make flavonoids more absorbable in the gut. When flavonoid pass the small intestine epithelial cells and find their way in the blood stream, can directly penetrate into the blood brain barrier which is associated with numerous positive effects including, neuromodulator effects, neurogenesis, secretion of anti-inflammatory cytokines, and releasing of neurotropic factors. in the intestine, flavonoids can interrupt balanced micrbiota structure, initiating gut dysbiosis which is associated with negative consequences, including local and systemic inflammation, and secretion of inflammatory cytokines, mitochondrial dysfunctions and induction of apoptosis. HIGHLIGHTS Flavonoids alter gut microbiota by replacing pathogens with beneficial bacteria and enhancing SCFA production. Gut microbiota metabolizes flavonoids into bioactive metabolites that influence brain health. Gut microbiota metabolizes flavonoids, turning them to more bioactive metabolites Flavonoids are potential neuroprotective agents that affect neurological health through their interactions with the gut microbiome. Diet, age, genetics, and epigenetics influence brain health through flavonoid modification and gut microbiome.

Nutrition is now well recognized to be an environmental factor which positively or negatively influences the risk to develop neurological and psychiatric disorders. The gut microbiota has recently been shown to be an important actor mediating the relationship between environmental factors, including nutrition, and brain function. While its composition has been widely studied and associated with the risk of brain diseases, the mechanisms underlying the relationship between the gut and brain diseases remain to be explored. The wide range of bioactive molecules produced by the gut microbiota, called gut-derived metabolites (GDM), represent new players in the gut to brain interactions and become interesting target to promote brain health. The aim of this narrative review is to highlight some GDMs of interest that are produced in response to healthy food consumption and to summarize what is known about their potential effects on brain function. Overall, GDMs represent future useful biomarkers for the development of personalized nutrition. Indeed, their quantification after nutritional interventions is a useful tool to determine individuals’ ability to produce microbiota-derived bioactive compounds upon consumption of specific food or nutrients. Moreover, GDMs represent also a new therapeutic approach to counteract the lack of response to conventional nutritional interventions.

The dynamic protective capacity of (poly)phenols, attributed to their potent antioxidant and anti-inflammatory properties, has been consistently reported. Due to their capacity to alter gut microbiome composition, further actions of (poly)phenols may be exerted through the modulation of the microbiota-gut-brain axis. However, the underlying mechanisms remain poorly defined. Here, we investigated the protective effect of a (poly)phenol-rich grape and blueberry extract (Memophenol™), on the microbiota-gut-brain axis in a model of chronic low-grade inflammation (0.5 mg/kg/wk lipopolysaccharide (LPS) for 8 weeks). Dietary supplementation of male C57BL/6J mice with Memophenol™ prevented LPS-induced increases in the microbe-derived uremia-associated molecules, indoxyl sulfate (IS) and trimethylamine N-oxide (TMAO). These changes coincided with shifts in gut microbiome composition, notably Romboutsia and Desulfovibrio abundance, respectively. In the brain, LPS exposure disrupted the marginal localisation of the endothelial tight junction ZO-1 and downregulated ZO-1 mRNA expression to an extent closely correlated with TMAO and IS levels; a process prevented by Memophenol™ intake. Hippocampal mRNA sequencing analysis revealed significant downregulation in regulatory pathways of neurodegeneration with Memophenol™ intake. These findings may indicate a novel protective role of the (poly)phenol-rich grape and blueberry extract on the endothelial tight junction component ZO-1, acting through modulation of gut microbial metabolism.

(Poly)phenols are a group of naturally occurring phytochemicals present in high amounts in plant food and beverages with various structures and activities. The impact of (poly)phenols on brain function has gained significant attention due to the growing interest in the potential benefits of these dietary bioactive molecules for cognitive health and neuroprotection. This review will therefore summarise the current knowledge related to the impact of (poly)phenols on brain health presenting evidence from both epidemiological and clinical studies. Cellular and molecular mechanisms in relation to the observed effects will also be described, including their impact on the gut microbiota through the modulation of the gut‐brain axis. Although (poly)phenols have the potential to modulate the gut‐brain axis regulation and influence cognitive function and decline through their interactions with gut microbiota, anti‐inflammatory and antioxidant properties, further research, including randomised controlled trials and mechanistic studies, is needed to better understand the underlying mechanisms and establish causal relationships between (poly)phenol intake and brain health.

The blood–brain barrier (BBB), a selective interface regulating cerebral substance exchange, plays a crucial role in maintaining cognitive function and metabolic balance. While tea consumption has been traditionally associated with health benefits, its specific effects on BBB integrity warrant systematic investigation. This review demonstrates that tea bioactive compounds can cross the BBB through systemic absorption and metabolism, with their permeability determined by physicochemical properties, including molecular weight and lipophilicity. Notably, the tea bioactive compounds exhibit strong functional properties but low bioavailability. On one hand, tea can directly modulate the development of the BBB through vascular endothelial growth factor (VEGF), Wnt, and Notch1 signaling pathways, and delay BBB aging and dysfunction by alleviating CNS inflammation, oxidative stress, and p‐glycoprotein (P‐gp) activity. On the other hand, tea indirectly influences BBB homeostasis via gut microbiota‐mediated pathways, by regulating circadian rhythm disruptions, reducing psychosocial stress, and preventing metabolic syndrome. The review also discusses potential strategies to enhance tea's BBB‐protective effects, including optimization of tea leaf processing, beverage production, and nanoencapsulation of bioactive compounds. These findings provide valuable insights into the tea–BBB interaction and establish a theoretical framework for future research. This framework will support the development of dietary interventions for brain health.

Neuroinflammatory disorders, such as Alzheimer’s disease (AD) and multiple sclerosis (MS), are increasingly recognized as systemic inflammatory syndromes rather than isolated brain pathologies. A central regulator of this systemic response is the microbiota–gut–brain axis (MGBA), where dysbiosis‐induced disruption accelerates neuroinflammation and compromises blood‐brain barrier (BBB) integrity. Plant‐derived compounds (PDCs) offer a promising multitarget approach for these complex disorders; however, their clinical translation is frequently hindered by poor bioavailability and chemical complexity. This review evaluates how computational methods facilitate the discovery of PDCs that modulate the MGBA. Network pharmacology maps the interactions between these compounds and multiple molecular targets involved in inflammation and gut homeostasis. Furthermore, molecular docking and molecular dynamics simulations characterize the binding affinity and structural stability of these interactions. In silico ADMET models are additionally employed to predict pharmacokinetic profiles, safety, and BBB permeability. Together, these approaches provide a robust, time‐efficient strategy to identify natural therapies, including bioactive microbial metabolites that bypass traditional bioavailability constraints. Future integration of artificial intelligence (AI) and multiomics holds the potential to further decode the synergistic interactions between PDCs and the gut microbiome, paving the way for personalized neuroprotective strategies.

Diet is increasingly recognized as a potential upstream modulator of the gut-brain axis (GBA) through its effects on the microbiome, microbial metabolites, and host immune and endocrine responses. The GBA is a complex, bidirectional network connecting the gastrointestinal tract and central nervous system, with diet influencing microbial community structure and metabolic output. Plant-based diets, such as Mediterranean and MIND, have been associated with increased production of anti-inflammatory microbial metabolites and improved barrier function, while high calorie/low nutrient diets are often linked to increased immune activation and barrier dysfunction. However, while microbial metabolites, especially short-chain fatty acids, indoles, bile acids, and isothiocyanates, have been proposed as mediators of neuroprotective effects, their role in neurodegenerative diseases remains an area of active investigation, with evidence largely derived from preclinical and associative human studies. Cruciferous vegetables, especially broccoli sprouts, are an emerging focus of research for their bioactive compound sulforaphane, which activates Nrf2-centered cytoprotective pathways. Animal and early human studies suggest sulforaphane can improve cognitive and behavioral outcomes, though larger clinical trials are needed. Personalized, microbiota-targeted dietary interventions may offer scalable strategies for managing neuroinflammatory and neurodegenerative conditions, and we emphasize the need for integrated research across diet, microbiome, and brain health.

Background The gut–brain axis (GBA) has emerged as a critical pathway in the pathogenesis of Alzheimer’s disease (AD), offering a potential target for dietary interventions. This study aimed to explore the neuroprotective effects of a polyphenol-enriched extract from Morus nigra L. fruits (MMF) in an AD rat model, focusing on gut-brain communication. Methods AD-like pathology was induced in rats using a combination of D-galactose and aluminum chloride, followed by a 10-week MMF treatment. Cognitive performance was evaluated using the Morris water maze, and brain Aβ1-42 accumulation and neuroinflammation (Iba1, GFAP) were assessed. Multi-omics approaches, including 16S rDNA sequencing and untargeted colonic metabolomics, were applied. Results MMF treatment significantly enhanced spatial memory, reduced hippocampal Aβ burden, and attenuated glial activation. Furthermore, MMF restored gut microbial diversity and increased the abundance of short-chain fatty acid–producing Firmicutes taxa, which were inversely correlated with inflammation. Metabolomics analysis revealed that MMF modulated bile acid and lipid metabolic pathways, with β-muricholic acid, DHA, and ergosterol identified as key effectors. Conclusion MMF alleviates AD pathology through modulation of the gut microbiota and metabolic reprogramming, suggesting a promising microbiota-targeted strategy for AD prevention.

… , TCA cycle, and hormone metabolism. Guanosine and estradiol phenylpropionate correlated … This highlights the potential of gut-derived metabolites in mediating (poly)phenol-driven …