阿尔兹海默；微生物

Abstract 证据图是一种非常实用的证据总结方法，通过证据图可以全面检 索所关注问题的相关研究，准确展示该领域科学文章存在的问题。利 用证据图，可实现文献的系统检索，提取研究关键信息，形成信息数 据库。塔夫茨大学和国际生命科学学会(ILSI)北美分会创建了膳食 纤维和人类健康证据数据库，并公开，每年都会定期更新。该数据库 汇编了膳食纤维干预研究，包括10 种预先设定的生理健康结局指标， 包括体重/肥胖、血压、肠道微生物群和骨骼健康。根据美国食品和药 品监督管理局(FDA)颁布的新版食品标签要求，只有在有足够证据 支持膳食纤维与某种生理健康益处相关时，才能在标签上标识“膳食 纤维”。因此，该数据库和证据图的应用潜力就显得特别重要。基于膳 食纤维数据库的成功案例，塔夫茨大学和通用磨坊贝尔健康与营养研 究所又合作开发了一个全谷物数据库和证据图。该项工作强调了所报 告的全谷物数据一致性的重要性，包括全谷物的消费量和类型以及干 预的依从性。

微生物与人体疾病、健康密切相关,如何理解微生物群落的组成及其发挥的功能是一大亟需研究的问题。近年来,宏蛋白质组学已经成为研究微生物组成与功能的重要技术手段。然而,由于微生物群落样本的复杂性与高度异质性,样品处理、质谱数据采集与数据分析成为宏蛋白质组目前面临的三大挑战。在宏蛋白质组分析中往往需要针对不同类型的样品进行前处理优化,采取不同的微生物分离富集、提取和裂解方案。与单一物种蛋白质组相类似,宏蛋白质组学中的质谱数据采集模式有数据依赖性采集(data-dependent acquisition, DDA)模式和数据非依赖性采集(data-independent acquisition, DIA)模式。DIA数据采集模式可以完整地采集样品的肽段信息,具有很强的发展潜力。但是由于宏蛋白质组样品的复杂性,其DIA数据解析已成为阻碍宏蛋白质组深度覆盖的一大难题。在数据解析方面,最重要的步骤在于蛋白质序列数据库的构建。数据库的大小和完整性不仅对鉴定数量有很大影响,还会影响物种和功能水平上的分析。目前宏蛋白质组数据库构建的金标准是基于宏基因组的蛋白质序列数据库。同时,基于迭代搜库的公共数据库过滤方法也已被证明具有很强的实用价值。从具体的数据解析策略角度,以肽段为中心的DIA数据解析方法占据了绝对的主流。随着深度学习和人工智能的发展,其会极大地推动宏蛋白质组数据解析的准确度、覆盖度与分析速度。在下游生物信息学分析方面,近年来开发了一系列注释工具,可以在蛋白水平、肽段水平、基因水平上进行物种注释来获得微生物群落组成。与其他组学方法相比,微生物群落的功能分析是宏蛋白质组学的一个独特特征。宏蛋白质组已经成为微生物群落多组学分析中的重要组成部分,并且仍在覆盖深度、检测灵敏度、数据解析完整度等方面具有很大的发展潜力。

目的 稀土元素(rare earth elements，REEs)暴露与多种全身性疾病有关，但其通过肠-脑轴对子代血脑屏障(blood-brain barrier，BBB)的影响尚不清楚。本研究通过对亲代暴露于氧化钕(neodymium oxide，Nd2O3)的子代大鼠组织进行检测，以探究亲代Nd2O3暴露对子代BBB完整性的影响，并探讨双歧杆菌四联活菌片(bifidobacterium tetrad viable tablet，BTVT)对Nd2O3所致子代肠道及BBB损伤的改善作用。 方法 选取健康成年SD大鼠，按雌雄1꞉1的比例进行合笼，次日清晨检查是否出现阴栓，发现阴栓的当天标记为妊娠第0天。将60只妊娠大鼠随机分为Control组、50 mg/(kg·d) Nd2O3组、100 mg/(kg·d) Nd2O3组、200 mg/(kg·d) Nd2O3组及200 mg/(kg·d) Nd2O3+BTVT组，分别给予10 mL/(kg·d)的0.9% NaCl溶液、50 mg/(kg·d) Nd2O3、100 mg/(kg·d) Nd2O3、200 mg/(kg·d) Nd2O3及200 mg/(kg·d) Nd2O3+BTVT灌胃。所有组别均在妊娠期和哺乳期每日灌胃1次。在子代大鼠出生后第21天(断乳期)取其粪便、脑组织和结肠组织进行检测。采用苏木精-伊红(hematoxylin and eosin，HE)染色观察脑组织和肠黏膜结构的改变。采用气相色谱-质谱法(gas chromatography-mass spectrometry，GC-MS)检测子代大鼠粪便中短链脂肪酸(short-chain fatty acid，SCFAs)乙酸、丙酸、丁酸、戊酸、异丁酸和异戊酸含量的变化。尾静脉注射伊文思蓝(evans blue，EB)后进行心内灌注，取灌注后的脑组织检测BBB通透性变化。采用逆转录聚合酶链反应(reverse transcription PCR，RT-PCR)检测紧密连接相关基因闭锁蛋白(occludin)、闭锁小带蛋白1(zonula occludens-1，ZO-1)的表达水平。采用蛋白质印迹法(Western blotting，WB)检测occludin、ZO-1蛋白的表达水平。通过电感耦合等离子体质谱法(inductively coupled plasma mass spectrometry，ICP-MS)检测子代大鼠脑组织中钕元素含量。 结果 HE染色结果显示：亲代母鼠Nd2O3暴露后，子代大鼠结肠黏膜下间隙增大、水肿，并伴有淋巴细胞等炎症细胞浸润，脑组织出现空泡，神经元大量变性；BTVT干预后，子代大鼠肠黏膜结构接近正常，炎症细胞浸润和神经元变性得到改善。GC-MS检测结果显示：亲代母鼠暴露于Nd2O3后，子代大鼠粪便中乙酸、丙酸、丁酸和异丁酸含量均较Control组显著降低，戊酸和异戊酸含量均显著升高(均P<0.05)；BTVT干预后，粪便中乙酸、丙酸和异丁酸的含量均较200 mg/(kg·d) Nd2O3组显著上升(均 P<0.05)，戊酸含量下降(P<0.05)，均接近Control组含量。EB染色结果显示：亲代母鼠暴露于Nd2O3后，子代大鼠脑组织内EB渗透量显著增加(P<0.05)；BTVT干预后的子代大鼠脑组织内EB渗透量较200 mg/(kg·d) Nd2O3组显著减少(P<0.05)。RT-PCR和蛋白质印迹结果均显示：亲代母鼠暴露于Nd2O3后，子代大鼠脑组织的occludin和ZO-1基因和蛋白质表达水平均较Control组显著下降(均P<0.05)；BTVT干预后的子代大鼠脑组织内occludin和ZO-1基因和蛋白质表达水平均较200 mg/(kg·d) Nd2O3组显著升高(均P<0.05)。ICP-MS结果显示：与Control组相比，亲代母鼠Nd2O3暴露均可显著增加子代大鼠脑组织内钕含量(均P<0.05)；BTVT干预后的子代大鼠脑组织内钕含量显著低于200 mg/(kg·d) Nd2O3组(P<0.05)。 结论 亲代妊娠期及哺乳期暴露于Nd2O3改变了子代肠黏膜的健康状态，增加了BBB通透性和脑中钕元素含量，导致神经元大量变性，BTVT共处理能够缓解Nd2O3所造成的子代肠道及BBB损伤。

BACKGROUND Alzheimer's disease (AD), which is a chronic neurodegenerative disorder, is marked by the progressive deteriorations in learning and memory capabilities. The microbiota-gut-brain axis has come to be regarded as a crucial element in relation to the pathogenesis as well as the treatment of AD. Eucommiae cortex polysaccharides (EPs), being among the most plentiful substances present in the Eucommiae cortex, show the potential to exert immunomodulatory and neuroprotective function. However, whether EPs are protective against AD and their mechanism of action remain to be investigated OBJECTIVES: We hypothesize that EPs can regulate brain glutamine metabolism through gut microbiota and the butyric acid metabolized by them, improve oxidative stress and autophagy in the brain, and thus alleviate AD. METHODS In the present study, we used EPs (0.25 % w/w in food) and fecal microbiota transplantation, as well as butyrate supplementation (0.1 M in water), to intervene in AD mice. Multi-omics were used to determine the mechanism by which EPs improve AD-related learning and memory impairments. RESULTS Our results suggest that EPs, functioning as a prebiotic, alleviated learning and memory impairments in AD mice. Mechanistically, EPs are able to reshape the gut microbiota, promote the growth of gut microbiota involved in short-chain fatty acid metabolism, particularly butyrate-producing microbes. The butyrate produced by these microbes improves the brain microenvironment by modulating oxidative stress and autophagy mediated by brain glutamate metabolism, improving learning and memory impairments in AD mice, and inhibiting the formation and deposition of beta-amyloid proteins. Fecal microbiota transplantation (FMT) and butyrate supplementation further confirm this conclusion. CONCLUSIONS Our results highlighted that EPs can alleviate learning and memory impairments in AD with a gut microbiota-dependent manner and that butyric acid metabolized by butyric acid-metabolizing bacteria in the gut plays a central role in regulating brain glutamine metabolism to improve brain microenvironmental homeostasis. Meanwhile, the present study provides new insights into the treatment of AD with natural products.

Evidence indicates that Poria cocos polysaccharide (PCP) improves cognitive impairment in Alzheimer's disease (AD); however, its underlying mechanism, particularly its relationship with the gut microbiota, remains unclear. In the current study, we aimed to investigate the mechanism of PCP in improving cognitive impairment in AD. The results demonstrated that PCP markedly enhanced cognitive function and mitigated AD-related pathological alterations in 3 × Tg-AD mice. PCP treatment reversed the age-dependent gut microbiota dysbiosis in 3 × Tg-AD mice by 16S rDNA sequencing. The contents of propanoic acid, butanoic acid and isohexanoic acid were increased by short-chain fatty acid determination. In addition, PCP could restore both the intestinal barrier and the blood-brain barrier, as demonstrated by immunofluorescence staining of tight junction proteins. Furthermore, PCP alleviated systemic inflammation and neuroinflammation, as evidenced by reduced LPS levels in circulation and decreased IL-6 levels in the brain, likely by inhibiting the TLR4/NF-κB signaling pathway. In conclusion, PCP can reshape gut microbiota to regulate short-chain fatty acids and alleviate neuroinflammation-related cognitive impairment in AD mice.

Plant-based foods with low methionine contents have gained increasing interest for their potential health benefits, including neuroprotective effects. Methionine restriction (MR) linked to a plant-based diet has been shown to mitigate neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that involve the gut microbiota. In this study, a 16-week MR diet (0.17% methionine, w/w) improved working memory and reduced neuronal damage exclusively in 4-month-old male APP/PS1 AD mice. Transcriptomic analysis revealed the activation of serum- and glucose-corticoid-regulated kinase 1 (SGK1) and peroxisome proliferator-activated receptor α (PPARα) pathways. Furthermore, metabolomics demonstrated increased serum indole-3-propionic acid (IPA) levels and an enhanced expression of gut barrier proteins Claudin-1 and MUC2 in male mice. MR significantly altered the gut microbiota composition, notably increasing indole-producing bacteria such as Lactobacillus reuteri (L. reuteri). Multiomics integration linked L. reuteri, IPA, and PPARα signaling to improved cognitive outcomes. Molecular docking and RT-qPCR analyses confirmed IPA's interaction with PPARα, leading to the activation of neuroprotective targets (Bdnf, Pparα, Acsbg1, Scd2, and Scd3). These results highlight the role of methionine restriction in modulating gut microbiota and metabolites, offering a promising dietary approach to managing neurodegenerative diseases with sex-specific effects.

Silica nanoparticles (SiO2 NPs) are widely used in the food and pharmaceutical industries and dramatically increase the health risks associated with gastrointestinal exposure. However, the neurotoxicological effects and mechanisms of exposure to SiO2 NPs and their relationship with the gut microbiome require further in-depth investigation. Here, we performed a systematic assessment of the toxicity of gavage containing 20 nm SiO2 NPs to C57BL/6 J mice. After 14 weeks administration, we comprehensively discovered that gastrointestinal exposure to SiO2 NPs led to mice Alzheimer’s disease (AD)-like neurotoxicity, including Aβ accumulation, cognitive impairment, oxidative stress burden, and neuroinflammation, which was microbiota-gut-brain axis-dependent and proven using a low-load gut-bacteria experiment and antibiotic treatment. Mechanistically, gastrointestinal exposure to SiO2 NPs disrupted intestinal homeostasis. Specifically, the total faecal short-chain fatty acid (SCFA) levels were reduced as analysed by 16S rRNA gene sequencing and liquid chromatography mass-spectrometry (LC–MS) analysis. The reduced SCFA content damaged the integrity of gut-brain axis by increasing gut permeability, which may have caused metabolite redistribution, brain basement membrane dissolution, activated the neuroinflammation signalling pathway TLR4/NF-κB, and interfered with HDAC3 and HDAC1/OGG1 pathways. We showed for the first time that gastrointestinal exposure to SiO2 NPs depends on the gut microbiome and causes neurological and cognitive impairment via gut-brain axis information transmission. These findings suggest that the gut microbiota, as a mediator between intestinal and brain information communications, contributes to gastrointestinal exposure to SiO2 NPs-induced neurotoxicity. The health risks of exposure to SiO2 NPs should be recognised, and addressing strategies should be extensively reconsidered.

Introduction The gut microbiota composition and the expression profiles of microRNAs (miRNAs) in the brain tissue, cerebrospinal fluid, and blood of patients with Alzheimer’s disease (AD) differ significantly from those with normal cognition function. The study aimed to initially explore the relationship between plasma exosomal microRNAs, gut microbiota, and cognitive impairment, providing insights into the pathogenesis and treatment of AD. Methods The study enrolled 8 participants with AD and 8 participants with normal cognition. The Mini-Mental State Examination (MMSE) was utilized to evaluate cognitive function. High-throughput sequencing was used to identify differentially expressed miRNAs in plasma exosomes, while metagenomic sequencing was employed to detect differences in the abundance of gut microbiota. Furthermore, the associations among them were analyzed. Results Four exosomal miRNAs and 14 microbiota taxa, which exhibited differential expression and abundance, respectively, in comparison between AD group and normal cognition group, were identified to be significantly associated with MMSE scores. Notably, the abundance of potential probiotics, including Faecalibacterium prausnitzii, Roseburia intestinalis and Roseburia inulinivorans, which was decreased in AD patients, exhibited positive correlations with specific exosomal miRNAs: Roseburia intestinalis correlated with miR-3120-3p and miR-6529-5p; Roseburia inulinivorans correlated with miR-3120-3p, miR-6529-5p and miR-124-3p; Faecalibacterium prausnitzii correlated with miR-3120-3p. Discussion The study revealed a close association among gut microbiota, plasma exosomal miRNAs, and cognitive impairment in AD, and suggested that specific components of gut microbiota and exosomal miRNAs may serve as potential biomarkers and therapeutic targets for AD on the microbiota-gut-brain axis.

ABSTRACT Emerging clinical and experimental evidence highlight the involvement of gut microbiota in the onset and progression of neurodegenerative diseases such as Alzheimer’s disease (AD) via neuroinflammatory processes along the gut–brain axis. Despite this, the precise mechanisms governing gut microbial involvement in AD remain elusive. In this study, we observed that AppNL-G-F AD mice raised under germ-free (GF) conditions, display a reduced amyloid-β (Aβ) pathology, accompanied by a shift in microglial cells toward a less inflammatory state and increased phagocytotic efficiency. In addition, we demonstrate that gut microbiota depletion can protect against synaptic deficits in AD mice. Notably, administering bacterial extracellular vesicles (bEVs), i.e. nano-sized particles packed with bacterial components, derived from fecal slurry from specific pathogen-free housed AppNL-G-F AD mice, reversed the effects of GF conditions on both microglial activation and Aβ plaque accumulation. These findings reveal for the first time that commensal gut microbiota-derived bEVs have a major impact on AD pathology progression.

Background/Objectives: Neuroinflammation, a hallmark of Alzheimer’s disease (AD), is characterized by elevated levels of inflammatory signaling molecules, including cytokines and eicosanoids, as well as increased microglial reactivity, and is augmented by gut microbiota dysbiosis via the gut–brain axis. We conducted a pilot experiment to elucidate the anti-inflammatory effects of dietary omega-3 polyunsaturated fatty acid (ω-3 PUFA) eicosapentaenoic acid (EPA) on the gut microbiota and neuroinflammation. Methods: Female APP/PS1 mice (TG) and non-transgenic littermates (WT), 13–14 months old, were fed a diet supplemented with 0.3% EPA or control chow for 3 weeks. The gut microbiota composition, hippocampal and plasma eicosanoids levels, platelet activation, and microglial phagocytosis, as well as the brain and retinal genes and protein expression, were analyzed. Results: EPA supplementation decreased the percentage of Bacteroidetes and increased bacteria of the phylum Firmicutes in APP/PS1 and WT mice. Inflammatory lipid mediators were elevated in the hippocampus of the TG mice, accompanied by a reduction in the endocannabinoid docosahexaenoyl ethanolamide (DHEA). Dietary EPA did not affect hippocampal lipid mediators, but reduced the levels of arachidonic-derived 5-HETE and N-arachidonoylethanolamine (AEA) in WT plasma. Moreover, EPA supplementation decreased major histocompatibility complex class II (MHCII) gene expression in the retina in both genotypes, and MHCII+ cells in the hippocampus of TG mice. Conclusions: This pilot study showed that short-term EPA supplementation shaped the gut microbiota by increasing butyrate-producing bacteria of the Firmicutes phylum and decreasing Gram-negative LPS-producing bacteria of the Bacteroidetes phylum, and downregulated the inflammatory microglial marker MHCII in two distinct regions of the central nervous system (CNS). Further investigation is needed to determine whether EPA-mediated effects on the microbiome and microglial MHCII have beneficial long-term effects on AD pathology and cognition.

ABSTRACT The gut microbiota (GM) and its metabolites affect the host nervous system and are involved in the pathogeneses of various neurological diseases. However, the specific GM alterations under pathogenetic pressure and their contributions to the “microbiota – metabolite – brain axis” in Alzheimer’s disease (AD) remain unclear. Here, we investigated the GM and the fecal, serum, cortical metabolomes in APP/PS1 and wild-type (WT) mice, revealing distinct hub bacteria in AD mice within scale-free GM networks shared by both groups. Moreover, we identified diverse peripheral – central metabolic landscapes between AD and WT mice that featured bile acids (e.g. deoxycholic and isodeoxycholic acid) and unsaturated fatty acids (e.g. 11Z-eicosenoic and palmitoleic acid). Machine-learning models revealed the relationships between the differential/hub bacteria and these metabolic signatures from the periphery to the brain. Notably, AD-enriched Dubosiella affected AD occurrence via cortical palmitoleic acid and vice versa. Considering the transgenic background of the AD mice, we propose that Dubosiella enrichment impedes AD progression via the synthesis of palmitoleic acid, which has protective properties against inflammation and metabolic disorders. We identified another association involving fecal deoxycholic acid-mediated interactions between the AD hub bacteria Erysipelatoclostridium and AD occurrence, which was corroborated by the correlation between deoxycholate levels and cognitive scores in humans. Overall, this study elucidated the GM network alterations, contributions of the GM to peripheral – central metabolic landscapes, and mediatory roles of metabolites between the GM and AD occurrence, thus revealing the critical roles of bacteria in AD pathogenesis and gut – brain communications under pathogenetic pressure.

Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuronal loss, commonly linked to amyloid‐β plaques, neurofibrillary tangles, and neuroinflammation. Recent research highlights the gut microbiota as a key player in modulating neuroinflammation, a critical pathological feature of AD. Understanding the role of the gut microbiota in this process is essential for uncovering new therapeutic avenues and gaining deeper insights into AD pathogenesis.

Amyloid-β (Aβ) aggregation is a hallmark of Alzheimer's disease (AD), characterized by cognitive impairment, and there remains a lack of effective functional compound with Aβ clearance activity. To elucidate the effect of exopolysaccharide (EPS) extracted from Agaricus sinodeliciosus var. Chaidam on Aβ1-42- induced AD rat and uncover the underlying mechanism, the neuroprotective activity of EPS was evaluated using immunofluorescence, immunohistochemistry, western blot, RT-qPCR, microbiomics and metabolomics. The results demonstrated that EPS exhibited significant anti-AD efficacy, as evidenced by improved cognitive function and spatial memory, balanced brain redox status, suppressed neuroinflammatory responses. EPS substantially reduced Aβ1-42 accumulation in the hippocampus by activating Aβ-phagocytic microglia through the mTOR-HIF-1α pathway. Importantly, EPS reconstructed gut microbiota composition by increasing the relative abundance of Ruminococcaceae and reduced Erysipelotrichaceae. The reshaped gut microbiome and the formation of the metabolite serotonin were associated with behavioral alterations, neuroinflammation, and brain oxidative status. Thus, EPS significantly alleviated cognitive deficit and neuroinflammation in Aβ1-42-induced AD rats, potentially by enhancing microglial phagocytosis of Aβ1-42 and modulating the gut microbiome and serotonin production. Collectively, EPS from A. sinodeliciosus var. Chaidam polysaccharide may serve as a novel Aβ1-42-targeted approach for anti-AD therapy.

The relationship between alterations in brain microstructure and dysbiosis of gut microbiota in Alzheimer’s disease (AD) has garnered increasing attention, although the functional implications of these changes are not yet fully elucidated. This research examines how neuroinflammation, systemic inflammation, and gut microbiota interact in male 3 × Tg-AD and B6129SF1/J wild-type (WT) mice at 6 months-old (6-MO) and 12 months-old (12-MO). Employing a combination of behavioral assessments, diffusion kurtosis imaging (DKI), microbiota profiling, cytokine analysis, short-chain fatty acids (SCFAs), and immunohistochemistry, we explored the progression of AD-related pathology. Significant memory impairments in AD mice at both assessed ages were correlated with altered DKI parameters that suggest neuroinflammation and microstructural damage. We observed elevated levels of pro-inflammatory cytokines, such as IL-1β, IL-6, TNFα, and IFN-γ, in the serum, which were associated with increased activity of microglia and astrocytes in brain regions critical for memory. Although gut microbiota analysis did not reveal significant changes in alpha diversity, it did show notable differences in beta diversity and a diminished Firmicutes/Bacteroidetes (F/B) ratio in AD mice at 12-MO. Furthermore, a reduction in six kinds of SCFAs were identified at two time points of 6-MO and 12-MO, indicating widespread disruption in gut microbial metabolism. These findings underscore a complex bidirectional relationship between systemic inflammation and gut dysbiosis in AD, highlighting the gut-brain axis as a crucial factor in disease progression. This study emphasizes the potential of integrating DKI metrics, microbiota profiling, and SCFA analysis to enhance our understanding of AD pathology and to identify new therapeutic targets.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by neuroinflammation, for which gut dysbiosis may be implicated. Our previous study showed that treatment with Pseudostellaria heterophylla aqueous extract and one of its cyclopeptides, heterophyllin B, attenuate memory deficits via immunomodulation and neurite regeneration. However, whether Pseudostellaria heterophylla polysaccharide (PH-PS) exerts neuroprotective effects against AD and its underlying mechanisms remain unclear. The infrared spectrum, molecular weight, and carbohydrate composition of the PH-PS were determined. The results showed that PH-PS (Mw 8.771 kDa) was composed of glucose (57.78 %), galactose (41.52 %), and arabinose (0.70 %). PH-PS treatment ameliorated learning and spatial memory deficits, reduced amyloid β build-up, and suppressed reactive glia and astrocytes in 5 × FAD mice. 16S rRNA sequencing further showed that PH-PS remodelled the intestinal flora composition by promoting probiotic microbiota, such as Lactobacillus, Muribaculum, Monoglobus, and [Eubacterium]_siraeum_group, and suppressing inflammation-related UCG-009 and Blautia. Additionally, PH-PS restored intestinal barrier function; ameliorated peripheral inflammation by reducing the secretion of inflammatory cytokines, thereby converting M1 microglia and A1 astrocyte toward beneficial M2 and A2 phenotypes; and contributed to Aβ plaques clearance by upregulation of insulin degradation enzyme and neprilysin. Collectively, our findings demonstrate that PH-PS may prevent the progression of AD via modulation of the gut microbiota and regulation of glial polarisation, which could provide evidence to design a potential diet therapy for preventing or curing AD.

Background: Alzheimer’s disease (AD), an age-associated neurodegenerative disorder, currently lacks effective clinical therapeutics. Traditional Chinese Medicine (TCM) holds promising potential in AD treatment, exemplified by Danggui Shaoyao San (DSS), a TCM formulation. The precise therapeutic mechanisms of DSS in AD remain to be fully elucidated. This study aims to uncover the therapeutic efficacy and underlying mechanisms of DSS in AD, employing an integrative approach encompassing gut microbiota and metabolomic analyses. Methods: Thirty Sprague-Dawley (SD) rats were allocated into three groups: Blank Control (Con), AD Model (M), and Danggui Shaoyao San (DSS). AD models were established via bilateral intracerebroventricular injections of streptozotocin (STZ). DSS was orally administered at 24 g·kg−1·d−1 (weight of raw herbal materials) for 14 days. Cognitive functions were evaluated using the Morris Water Maze (MWM) test. Pathological alterations were assessed through hematoxylin and eosin (HE) staining. Bloodstream metabolites were characterized, gut microbiota profiled through 16S rDNA sequencing, and cortical metabolomics analyzed. Hippocampal proinflammatory cytokines (IL-1β, IL-6, TNF-α) were quantified using RT-qPCR, and oxidative stress markers (SOD, CAT, GSH-PX, MDA) in brain tissues were measured with biochemical assays. Results: DSS identified a total of 1,625 bloodstream metabolites, predominantly Benzene derivatives, Carboxylic acids, and Fatty Acyls. DSS significantly improved learning and spatial memory in AD rats and ameliorated cerebral tissue pathology. The formulation enriched the probiotic Ligilactobacillus, modulating metabolites like Ophthalmic acid (OA), Phosphocreatine (PCr), Azacridone A, Inosine, and NAD. DSS regulated Purine and Nicotinate-nicotinamide metabolism, restoring balance in the Candidatus Saccharibacteria-OA interplay and stabilizing gut microbiota-metabolite homeostasis. Additionally, DSS reduced hippocampal IL-1β, IL-6, TNF-α expression, attenuating the inflammatory state. It elevated antioxidative enzymes (SOD, CAT, GSH-PX) while reducing MDA levels, indicating diminished oxidative stress in AD rat brains. Conclusion: DSS addresses AD pathology through multifaceted mechanisms, encompassing gut microbiome regulation, specific metabolite modulation, and the mitigation of inflammation and oxidative stress within the brain. This holistic intervention through the Microbial-Gut-Brain Axis (MGBA) underscores DSS’s potential as an integrative therapeutic agent in combatting AD.

Neuroinflammation contributes to the pathology and progression of Alzheimer's disease (AD), and it can be observed even with mild cognitive impairment (MCI), a prodromal phase of AD. Free water (FW) imaging estimates the extracellular water content and has been used to study neuroinflammation across several neurological diseases including AD. Recently, the role of gut microbiota has been implicated in the pathogenesis of AD. The relationship between FW imaging and gut microbiota was examined in patients with AD and MCI. Fifty-six participants underwent neuropsychological assessments, FW imaging, and gut microbiota analysis targeting the bacterial 16S rRNA gene. They were categorized into the cognitively normal control (NC) (n = 19), MCI (n = 19), and AD (n = 18) groups according to the neuropsychological assessments. The correlations of FW values, neuropsychological assessment scores, and the relative abundance of gut microbiota were analyzed. FW was higher in several white matter tracts and in gray matter regions, predominantly the frontal, temporal, limbic and paralimbic regions in the AD/MCI group than in the NC group. In the AD/MCI group, higher FW values in the temporal (superior temporal and temporal pole), limbic and paralimbic (insula, hippocampus and amygdala) regions were the most associated with worse neuropsychological assessment scores. In the AD/MCI group, FW values in these regions were negatively correlated with the relative abundances of butyrate-producing genera Anaerostipes, Lachnospiraceae UCG-004, and [Ruminococcus] gnavus group, which showed a significant decreasing trend in the order of the NC, MCI, and AD groups. The present study showed that increased FW in the gray matter regions related to cognitive impairment was associated with low abundances of butyrate producers in the AD/MCI group. These findings suggest an association between neuroinflammation and decreased levels of the short-chain fatty acid butyrate that is one of the major gut microbial metabolites having a potentially beneficial role in brain homeostasis.

Recently, studies have reported a correlation that individuals with diabetes show an increased risk of developing Alzheimer’s disease (AD). Mulberry leaves, serving as both a traditional medicinal herb and a food source, exhibit significant hypoglycemic and antioxidative properties. The flavonoid compounds in mulberry leaf offer therapeutic effects for relieving diabetic symptoms and providing neuroprotection. However, the mechanisms of this effect have not been fully elucidated. This investigation aimed to investigate the combined effects of specific mulberry leaf flavonoids (kaempferol, quercetin, rhamnocitrin, tetramethoxyluteolin, and norartocarpetin) on both type 2 diabetes mellitus (T2DM) and AD. Additionally, the role of the gut microbiota in these two diseases’ treatment was studied. Using network pharmacology, we investigated the potential mechanisms of flavonoids in mulberry leaves, combined with gut microbiota, in combating AD and T2DM. In addition, we identified protein tyrosine phosphatase 1B (PTP1B) as a key target for kaempferol in these two diseases. Molecular docking and molecular dynamics simulations showed that kaempferol has the potential to inhibit PTP1B for indirect treatment of AD, which was proven by measuring the IC50 of kaempferol (279.23 μM). The cell experiment also confirmed the dose-dependent effect of kaempferol on the phosphorylation of total cellular protein in HepG2 cells. This research supports the concept of food–medicine homology and broadens the range of medical treatments for diabetes and AD, highlighting the prospect of integrating traditional herbal remedies with modern medical research.

Gender is a significant risk factor for late-onset Alzheimer’s disease (AD), often attributed to the decline of estrogen. The plant estrogen secoisolariciresinol diglucoside (SDG) has demonstrated anti-inflammatory and neuroprotective effects. However, the protective effects and mechanisms of SDG in female AD remain unclear. Ten-month-old female APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with SDG to assess its potential ameliorative effects on cognitive impairments in a female AD model through a series of behavioral and biochemical experiments. Serum levels of gut microbial metabolites enterodiol (END) and enterolactone (ENL) were quantified using HPLC-MS. Correlation analysis and broad-spectrum antibiotic cocktail (ABx) treatment were employed to demonstrate the involvement of END and ENL in SDG’s cognitive improvement effects in female APP/PS1 mice. Additionally, an acute neuroinflammation model was constructed in three-month-old C57BL/6J mice treated with lipopolysaccharide (LPS) and subjected to i.c.v. injection of G15, an inhibitor of G protein-coupled estrogen receptor (GPER), to investigate the mediating role of the estrogen receptor GPER in the cognitive benefits conferred by SDG. SDG administration resulted in significant improvements in spatial, recognition, and working memory in female APP/PS1 mice. Neuroprotective effects were observed, including enhanced expression of CREB/BDNF and PSD-95, reduced β-amyloid (Aβ) deposition, and decreased levels of TNF-α, IL-6, and IL-10. SDG also altered gut microbiota composition, increasing serum levels of END and ENL. Correlation analysis indicated significant associations between END, ENL, cognitive performance, hippocampal Aβ-related protein mRNA expression, and cortical neuroinflammatory cytokine levels. The removal of gut microbiota inhibited END and ENL production and eliminated the neuroprotective effects of SDG. Furthermore, GPER was found to mediate the inhibitory effects of SDG on neuroinflammatory responses. These findings suggest that SDG promotes the production of gut microbial metabolites END and ENL, which inhibit cerebral β-amyloid deposition, activate GPER to enhance CREB/BDNF signaling pathways, and suppress neuroinflammatory responses. Consequently, SDG exerts neuroprotective effects and ameliorates cognitive impairments associated with AD in female mice.

BACKGROUND Current therapeutic agents for AD have limited efficacy and often induce undesirable side effects. Gegen Qinlian tablets (GGQLT) are a well-known clearingheat formula used in clinical treatment of inflammatory diseases. Based on traditional Chinese medicine (TCM) theory, the strategy of clearing-heat is then compatible with the treatment of AD. However, it remains unknown whether GGQLT can exert neuroprotective effects and alleviate neuroinflammation in AD. PURPOSE This study aimed to evaluate the anti-AD effects of GGQLT and to decipher its intricate mechanism using integrative analyses of network pharmacology, transcriptomic RNA sequencing, and gut microbiota. METHODS The ingredients of GGQLT were analyzed using HPLC-ESI-Q/TOF-MS. The AD model was established by bilateral injection of Aβ1-42 into the intracerebroventricular space of rats. The Morris water maze was used to evaluate the cognitive function of the AD rats. The long-term toxicity of GGQLT in rats was assessed by monitoring their body weights and pathological alterations in the liver and kidney. Reactive astrocytes and microglia were assessed by immunohistochemistry by labeling GFAP and Iba-1. The levels of inflammatory cytokines in the hippocampus were evaluated using ELISA kits, RT-PCR, and Western blot, respectively. The potential anti-AD mechanism was predicted by analyses of RNA-sequencing and network pharmacology. Western blot and immunohistochemistry were utilized to detect the phosphorylation levels of IκBα, NF-κB p65, p38, ERK and JNK. The richness and composition of gut bacterial and fungal microflora were investigated via 16S rRNA and ITS sequencing. RESULTS Typical ingredients of GGQLT were identified using HPLC-ESI-Q/TOF-MS. GGQLT significantly improved the cognitive function of AD rats by suppressing the activation of microglia and astrocytes, improving glial morphology, and reducing the neuroinflammatory reactions in the hippocampus. RNA-sequencing, network and experimental pharmacological studies demonstrated that GGQLT inhibited the activation of NF-κB/MAPK signaling pathways in the hippocampus. GGQLT could also restore abnormal gut bacterial and fungal homeostasis and no longer-term toxicity of GGQLT was observed. CONCLUSIONS Our findings, for the first time, demonstrate GGQLT exhibit anti-AD effects and is worthy of further exploration and development.

BACKGROUND Growing evidence highlights the vital role by gut microbiota in brain health through the gut-brain axis, which involves neural, immune, endocrine, and metabolic signaling pathways. Disruption of this axis through microbial dysbiosis is increasingly linked to cognitive disorders, including dementia. However, the specific taxa and pathways involved remain poorly characterized. This study investigates taxonomic and functional shifts in the gut microbiome across healthy individuals, mild dementia, and dementia patients, aiming to identify microbial signatures and metabolic alterations associated with cognitive decline. METHODS A total of 184 participants (aged 60-98) were recruited and grouped into healthy, mild dementia, and dementia categories based on Clinical Dementia Rating scores. Demographic and clinical data were collected through structured interviews. Fecal samples were collected from participants and DNA was extracted and subjected to 16S rRNA gene sequencing. Sequencing data were processed using QIIME2 and classified using the SILVA database. Alpha (Shannon, Inverse Simpson) and beta diversity (Bray-Curtis PCoA) were analyzed between participant groups. Functional prediction was performed with PICRUSt2 to estimate KEGG orthologs from normalized ASVs. Statistical analyses were conducted in R using Kruskal-Wallis and PERMANOVA tests to assess group-level differences. RESULTS Dementia patients exhibited the highest proportion of unique ASVs (32.1%) but showed reduced alpha diversity compared to mild dementia and healthy controls. PCoA revealed distinct microbial clustering across groups, explaining 19.3% of total variance, with dementia samples forming a unique cluster. Taxonomically, dementia samples were enriched in Firmicutes and pro-inflammatory genera such as Peptoclostridium and Scardovia, while healthy controls harbored more SCFA-producing taxa like Lachnospiraceae_UCG-001. Co-occurrence networks in dementia were more complex, with increased inter-species connectivity and key drivers including Dorea and Clostridium innocuum. Functionally, dementia samples showed enrichment of vanillate degradation pathways and depletion of neuroprotective pathways like ergothioneine and vitamin E biosynthesis, correlating with specific microbial signatures. CONCLUSIONS Cognitive decline was associated with reduced microbial diversity and selective enrichment of pro-inflammatory taxa, reflecting gut ecological instability due to dementia. Microbial composition shifted progressively with dementia severity, indicating disease-specific gut microbial restructuring. Moreover, the loss of key functional microbial metabolites such as neuroprotective and anti-inflammatory metabolites supports targeting such metabolites and their producing gut microbiota as a therapeutic strategy for dementia. Future studies should ensure generalization by recruiting multi-center participants with strict guidelines for monitoring confounders.

Alterations in the gut microbiome are associated with the pathogenesis of Alzheimer’s disease (AD) and can be used as a diagnostic measure. However, longitudinal data of the gut microbiome and knowledge about its prognostic significance for the development and progression of AD are limited. The aim of the present study was to develop a reliable predictive model based on gut microbiome data for AD development. In this longitudinal study, we investigated the intestinal microbiome in 49 mild cognitive impairment (MCI) patients over a mean (SD) follow-up of 3.7 (0.6) years, using shotgun metagenomics. At the end of the 4-year follow-up (4yFU), 27 MCI patients converted to AD dementia and 22 MCI patients remained stable. The best taxonomic model for the discrimination of AD dementia converters from stable MCI patients included 24 genera, yielding an area under the receiver operating characteristic curve (AUROC) of 0.87 at BL, 0.92 at 1yFU and 0.95 at 4yFU. The best models with functional data were obtained via analyzing 25 GO (Gene Ontology) features with an AUROC of 0.87 at BL, 0.85 at 1yFU and 0.81 at 4yFU and 33 KO [Kyoto Encyclopedia of Genes and Genomes (KEGG) ortholog] features with an AUROC of 0.79 at BL, 0.88 at 1yFU and 0.82 at 4yFU. Using ensemble learning for these three models, including a clinical model with the four parameters of age, gender, body mass index (BMI) and Apolipoprotein E (ApoE) genotype, yielded an AUROC of 0.96 at BL, 0.96 at 1yFU and 0.97 at 4yFU. In conclusion, we identified novel and timely stable gut microbiome algorithms that accurately predict progression to AD dementia in individuals with MCI over a 4yFU period.

Background Both inflammatory cytokines and the gut microbiome are susceptibility factors for vascular dementia (VaD). The trends in the overall changes in the dynamics of inflammatory cytokines and in the composition of the gut microbiome are influenced by a variety of factors, making it difficult to fully explain the different effects of both on the different subtypes of VaD. Therefore, this Mendelian randomization (MR) study identified the inflammatory cytokines and gut microbiome members that influence the risk of developing VaD and their causal effects, and investigated whether inflammatory cytokines are gut microbiome mediators affecting VaD. Methods We obtained pooled genome-wide association study (GWAS) data for 196 gut microbiota and 41 inflammatory cytokines and used GWAS data for six VaD subtypes, namely, VaD (mixed), VaD (multiple infarctions), VaD (other), VaD (subcortical), VaD (sudden onset), and VaD (undefined). We used the inverse-variance weighted (IVW) method as the primary MR analysis method. We conducted sensitivity analyses and reverse MR analyses to examine reverse causal associations, enhancing the reliability and stability of the conclusions. Finally, we used multivariable MR (MVMR) analysis to assess the direct causal effects of inflammatory cytokines and the gut microbiome on the risk of VaD, and performed mediation MR analysis to explore whether inflammatory factors were potential mediators. Results Our two-sample MR study revealed relationships between the risk of six VaD subtypes and inflammatory cytokines and the gut microbiota: 7 inflammatory cytokines and 14 gut microbiota constituents were positively correlated with increased VaD subtype risk, while 2 inflammatory cytokines and 11 gut microbiota constituents were negatively correlated with decreased VaD subtype risk. After Bonferroni correction, interleukin-18 was correlated with an increased risk of VaD (multiple infarctions); macrophage migration inhibitory factor was correlated with an increased risk of VaD (sudden onset); interleukin-4 was correlated with a decreased risk of VaD (other); Ruminiclostridium 6 and Bacillales were positively and negatively correlated with the risk of VaD (undefined), respectively; Negativicutes and Selenomonadales were correlated with a decreased risk of VaD (mixed); and Melainabacteria was correlated with an increased risk of VaD (multiple infarctions). Sensitivity analyses revealed no multilevel effects or heterogeneity and no inverse causality between VaD and inflammatory cytokines or the gut microbiota. The MVMR results further confirmed that the causal effects of Negativicutes, Selenomonadales, and Melainabacteria on VaD remain significant. Mediation MR analysis showed that inflammatory cytokines were not potential mediators. Conclusion This study helps us to better understand the pathological mechanisms of VaD and suggests the potential value of targeting increases or decreases in inflammatory cytokines and gut microbiome members for VaD prevention and intervention.

Abstract Early diagnosis and monitoring of clinical progression are crucial for managing dementia. While the relationship between oral health, brain health, and dementia has recently received increased attention, the oral microbiome in dementia patients remains uncharacterized. Therefore, this study aimed to identify the diversity and composition of the oral microbiome in older adults with dementia using next-generation sequencing, and compare it to healthy individuals without dementia to determine whether the oral microbiome could serve as a potential biomarker for the diagnosis and prevention of dementia. A total of 58 older adults aged 65 years and older participated in the study, 30 with dementia and 28 cognitively intact healthy individuals. All participants were screened and clinically diagnosed by a neurologist using the Korean version of the Mini-Mental State Examination (K-MMSE), the Clinical Dementia Rating scale (CDR), and brain magnetic resonance imaging (MRI). 1ml of unstimulated saliva was collected from each subject, the tongue was swabbed with a sterile swab for 20 seconds to collect samples, and full-length 16S rRNA amplicon sequencing was performed on all the samples. Statistical analysis was performed using MaAsLin2, and it was found that Fusobacteriota was more abundant in both the tongue and saliva of the dementia group compared to the healthy group, while Pseudomonadota is more dominant in the healthy group. Fusobacterium periodonticum was found to be more abundant as the K-MMSE scores decreased. Prevotella jejuni, Streptococcus anginosus, and Streptococcus gordonii are more enriched in the Dementia group compared to the healthy group.

Background: Alterations of the gut microbiome may accelerate the course of Alzheimer’s dementia through the enhancement of inflammatory and neurodegenerative processes. Prebiotic galactooligosaccharides increase the abundance of Bifidobacterium species and may have beneficial effects on disease progression. Methods: In a group of Alzheimer patients taking a galactooligosaccharide preparation for 12 weeks, the effects on bacterial abundances and Shannon index of the gut microbiome as well as neurofilament light-chain serum concentration were assessed. Results: There was an increase of the abundance of the genus Bifidobacterium and an increase of the Shannon index when taking galactooligosaccharides. The increase of the Shannon index was correlated with a decrease of the neurofilament light-chain serum concentration. Discussion: These findings suggest a beneficial effect of galactooligosaccharides on the gut microbiome and an inhibition of neurodegeneration in patients with Alzheimer’s dementia. Further clinical studies may be warranted.

The gut microbiome may be involved in the occurrence of dementia primarily through the molecular mechanisms of producing bioactive molecules and promoting inflammation. Epidemiological evidence linking gut microbiome molecules and inflammatory markers to dementia risk has been mixed, and the intricate interplay between these groups of biomarkers suggests that their joint investigation in the context of dementia is warranted. We aimed to simultaneously investigate the association of circulating levels of selected gut microbiome molecules and inflammatory markers with dementia risk. This case–cohort epidemiological study included 805 individuals (83 years, 66% women) free of dementia at baseline. Plasma levels of 19 selected gut microbiome molecules comprising lipopolysaccharide, short-chain fatty acids, and indole-containing tryptophan metabolites as well as four inflammatory markers measured at baseline were linked to incident all-cause (ACD) and Alzheimer’s disease dementia (AD) in binary outcomes and time-to-dementia analyses. Independent of several covariates, seven gut microbiome molecules, 5-hydroxyindole-3-acetic acid, indole-3-butyric acid, indole-3-acryloylglycine, indole-3-lactic acid, indole-3-acetic acid methyl ester, isobutyric acid, and 2-methylbutyric acid, but no inflammatory markers discriminated incident dementia cases from non-cases. Furthermore, 5-hydroxyindole-3-acetic acid (hazard ratio: 0.58; 0.36–0.94, P = 0.025) was associated with time-to-ACD. These molecules underpin gut microbiome-host interactions in the development of dementia and they may be crucial in its prevention and intervention strategies. Future larger epidemiological studies are needed to confirm our findings, specifically in exploring the repeatedly measured circulating levels of these molecules and investigating their causal relationship with dementia risk.

S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-β. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40–70% of East Asians produce S-equol, whereas 20–30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood–brain barrier than soy isoflavones, although their affinity to estrogen receptor-β is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia.

No abstract available

Summary Evidence linking the gut-brain axis to Alzheimer’s disease (AD) is accumulating, but the characteristics of causally important microbes are poorly understood. We perform a fecal microbiome analysis in healthy subjects and those with mild cognitive impairment (MCI) and AD. We find that Faecalibacterium prausnitzii (F. prausnitzii) correlates with cognitive scores and decreases in the MCI group compared with the healthy group. Two isolated strains from the healthy group, live Fp360 and pasteurized Fp14, improve cognitive impairment in an AD mouse model. Whole-genome comparison of isolated strains reveals specific orthologs that are found only in the effective strains and are more abundant in the healthy group compared with the MCI group. Metabolome and RNA sequencing analyses of mouse brains provides mechanistic insights into the relationship between the efficacy of pasteurized Fp14, oxidative stress, and mitochondrial function. We conclude that F. prausnitzii strains with these specific orthologs are candidates for gut microbiome-based intervention in Alzheimer's-type dementia.

Dysregulation of the gut microbiome is associated with dementia. However, the relationship between microbiome-associated metabolites and dementia has yet to be identified. Outpatients visiting a memory clinic in Japan enrolled in this cross-sectional study; 107 subjects were eligible for the study, 25 of which had dementia. We collected demographics, activities of daily living, risk factors, cognitive function, and brain imaging data. The gut microbiome was assessed using terminal restriction fragment length polymorphism analysis. Concentrations of faecal metabolite were measured. We used multivariable logistic regression analyses to identify whether metabolites were independently related to dementia. The concentrations of metabolites were significantly different between subjects with and those without dementia. Every 1 standard deviation increment in faecal ammonia concentration was associated with around a 1.6-fold risk for the presence of dementia. A higher faecal lactic acid concentration was related to a lower risk of dementia, by around 60%. A combination of higher faecal ammonia and lactic acid concentrations was indicative of the presence of dementia, and had a similar predictive value as traditional biomarkers of dementia. Thus, faecal ammonia and lactic acid are related to dementia, independently of the other risk factors for dementia and dysregulation of the gut microbiome.

Dysregulation of the gut microbiome is associated with several life-threatening conditions and thus might represent a useful target for the prevention of dementia. However, the relationship between the gut microbial population and dementia has not yet been fully clarified. We recruited outpatients visiting our memory clinic to participate in this study. Information on patient demographics, risk factors, and activities of daily living was collected, and cognitive function was assessed using neuropsychological tests and brain magnetic resonance imaging scans. Faecal samples were obtained, and the gut microbiome was assessed by terminal restriction fragment length polymorphism (T-RFLP) analysis, one of the most well-established and reliable 16S ribosomal RNA-based methods for classifying gut microbiota. Patients were divided into two groups, demented and non-demented. Multivariable logistic regression models were used to identify the variables independently associated with dementia. The T-RFLP analysis revealed differences in the composition of the gut microbiome: the number of Bacteroides (enterotype I) was lower and the number of ‘other’ bacteria (enterotype III) was higher in demented than non-demented patients. Multivariable analyses showed that the populations of enterotype I and enterotype III bacteria were strongly associated with dementia, independent of the traditional dementia biomarkers. Further studies of the metabolites of gut microbes are needed to determine the mechanism underlying this association.

Recent studies have revealed an association between the dysregulation of the gut microbiome and dementia. However, whether this dysregulation is associated with mild cognitive impairment (MCI), an early stage of cognitive decline, in patients without dementia remains unclear. We performed a cross-sectional analysis to determine the association between the gut microbiome and MCI. Data, including patient demographics, risk factors, cognitive function, and brain imaging, were collected. The gut microbiome was assessed through terminal restriction fragment length polymorphism analysis. Multivariable logistic regression models were used to identify factors independently associated with MCI. Graphical modelling was used to illustrate mutual associations between MCI and identified factors. We analysed 82 patients, 61 of whom exhibited MCI. Patients with MCI had a higher prevalence of Bacteroides. Furthermore, patients with more Bacteroides were more likely to present with white matter hyperintensity and high voxel-based specific regional analysis system for Alzheimer’s Disease (VSRAD) scores, indicating cortical and hippocampal atrophy. A multivariable logistic regression analysis revealed that a greater prevalence of Bacteroides was independently associated with MCI. Graphical modelling also showed a close association between Bacteroides and MCI. In conclusion, an increased prevalence of Bacteroides is independently associated with the presence of MCI in patients without dementia.

Cognitive decline, obesity and gut dysfunction or microbial dysbiosis occur in association. Our aim was to identify gut microbiota-metabolomics signatures preceding dementia in genetically prone (3xtg) mice, with and without superimposed high-fat diet. We examined the composition and diversity of their gut microbiota, and serum and faecal metabolites. 3xtg mice showed brain hypometabolism typical of pre-demented stage, and lacked the physiological bacterial diversity between caecum and colon seen in controls. Cluster analyses revealed distinct profiles of microbiota, and serum and fecal metabolome across groups. Elevation in Firmicutes-to-Bacteroidetes abundance, and exclusive presence of Turicibacteraceae, Christensenellaceae, Anaeroplasmataceae and Ruminococcaceae, and lack of Bifidobacteriaceae, were also observed. Metabolome analysis revealed a deficiency in unsaturated fatty acids and choline, and an overabundance in ketone bodies, lactate, amino acids, TMA and TMAO in 3xtg mice, with additive effects of high-fat diet. These metabolic alterations were correlated with high prevalence of Enterococcaceae, Staphylococcus, Roseburia, Coprobacillus and Dorea, and low prevalence of S24.7, rc4.4 and Bifidobacterium, which in turn related to cognitive impairment and cerebral hypometabolism. Our results indicate an effect of transgenic background on gut microbiome-metabolome, enhanced by high-fat diet. The resulting profiles may precede overt cognitive impairment, suggesting their predictive or risk-stratifying potential.

No abstract available

Emerging evidence has highlighted that olfactory dysfunction, a common feature of aging, is increasingly linked to cognitive decline in older adults. However, research on the underlying mechanism, particularly the role of nasal microbiome, remains limited. In this study, we investigated the associations between olfactory function, the nasal microbiome, and cognition among 510 older adults with an average age of 77.9 years. Olfactory function was assessed using the brief Chinese Smell Identification Test, and cognitive assessments were conducted via the Mini-Mental State Examination and the Revised Hasegawa Dementia Scale. Nasal microbiome profiles were generated through 16S RNA gene sequencing. We observed that olfactory dysfunction (i.e., hyposmia) was associated with a higher richness of nasal bacteria, and such observation was replicated in an external dataset. A total of 18 nasal bacterial genera were identified to be associated with olfactory function, with eight genera such as Acidovorax and Morganella being enriched in the hyposmic group. A composite microbial index of nasal olfactory function significantly improved the reclassification accuracy of traditional risk model in distinguishing hyposmic from normosmic participants (P = 0.008). Furthermore, participants with a nasal biotype dominated by Corynebacterium had a lower prevalence of mild cognitive impairment compared to those dominated by Dolosigranulum or Moraxella. Our findings suggested that the nasal microbiome may play a role in the association of olfactory function with cognition in older adults, providing new insights into the microbial mechanisms underlying hyposmia and cognitive decline.

The gut microbiome is a potentially modifiable risk factor for Alzheimer's disease (AD); however, understanding of its composition and function regarding AD pathology is limited.

The human oral microbiota is a community of microorganisms that reside in the oral cavity, including lingual, buccal, and saliva, each niche with a distinct microbial composition. Alterations in oral microbiota have been associated with an increased risk of Alzheimer’s disease (AD). This study used data from 143 older adults in the MIND trial to evaluate the association between oral microbiome and cognitive function. Oral niche-specific differences (saliva, buccal, and lingual), as well as the microbiome composition differences (α and β diversity), were associated with cognitive function. A lower abundance of Gemella and a higher abundance of anaerobic pro-inflammatory bacteria (e.g., Parvimonas, Treponema, Dialister) were linked to a lower Cognitive Z Score. Porphyromonas, previously linked to AD, was not associated with cognition. The outcomes suggest that oral microbiota may be a biomarker for cognitive function. Further research is required to assess whether oral microbiota-directed strategies can positively impact cognitive decline.

BACKGROUND An altered gut microbiome characterized by reduced abundance of butyrate producing bacteria and reduced gene richness is associated with type 2 diabetes (T2D). An important complication of T2D is increased risk of cognitive impairment and dementia. The biguanide metformin is a commonly prescribed medication for the control of T2D and metformin treatment has been associated with a significant reduction in the risk of dementia and improved cognition, particularly in people with T2D. AIM To investigate the associations of metformin use with cognition exploring potential mechanisms by analyzing the gut microbiome and plasma metabolome using shotgun metagenomics and HPLC-ESI-MS/MS, respectively. METHODS We explored two independent cohorts: an observational study (Aging Imageomics) and a phase IV, randomized, double-blind, parallel-group, randomized pilot study (MEIFLO). From the two studies, we analyzed four study groups: (1) individuals with no documented medical history or medical treatment (n = 172); (2) people with long-term T2D on metformin monotherapy (n = 134); (3) people with long-term T2D treated with oral hypoglycemic agents other than metformin (n = 45); (4) a newly diagnosed T2D subjects on metformin monotherapy (n = 22). Analyses were also performed stratifying by sex. RESULTS Several bacterial species belonging to the Proteobacteria (Escherichia coli) and Verrucomicrobia (Akkermansia muciniphila) phyla were positively associated with metformin treatment, while bacterial species belonging to the Firmicutes phylum (Romboutsia timonensis, Romboutsia ilealis) were negatively associated. Due to the consistent increase in A. muciniphila and decrease in R.ilealis in people with T2D subjects treated with metformin, we investigated the association between this ratio and cognition. In the entire cohort of metformin-treated T2D subjects, the A.muciniphila/R.ilealis ratio was not significantly associated with cognitive test scores. However, after stratifying by sex, the A.muciniphila/R. ilealis ratio was significantly and positively associated with higher memory scores and improved memory in men. Metformin treatment was associated with an enrichment of microbial pathways involved in the TCA cycle, and butanoate, arginine, and proline metabolism in both cohorts. The bacterial genes involved inarginine metabolism, especially in production of glutamate (astA, astB, astC, astD, astE, putA), were enriched following metformin intake. In agreement, in the metabolomics analysis, metformin treatment was strongly associated with the amino acid proline, a metabolite involved in the metabolism of glutamate. CONCLUSIONS The beneficial effects of metformin may be mediated by changes in the composition of the gut microbiota and microbial-host-derived co-metabolites.

Alzheimer’s disease (AD) is the most common form of dementia. However, the etiopathogenesis of this devastating disease is not fully understood. Recent studies in rodents suggest that alterations in the gut microbiome may contribute to amyloid deposition, yet the microbial communities associated with AD have not been characterized in humans. Towards this end, we characterized the bacterial taxonomic composition of fecal samples from participants with and without a diagnosis of dementia due to AD. Our analyses revealed that the gut microbiome of AD participants has decreased microbial diversity and is compositionally distinct from control age- and sex-matched individuals. We identified phylum- through genus-wide differences in bacterial abundance including decreased Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium in the microbiome of AD participants. Furthermore, we observed correlations between levels of differentially abundant genera and cerebrospinal fluid (CSF) biomarkers of AD. These findings add AD to the growing list of diseases associated with gut microbial alterations, as well as suggest that gut bacterial communities may be a target for therapeutic intervention.

The involvement of the oral microbiome (OM) in the pathophysiology of Alzheimer's disease and vascular dementia has been recognized epidemiologically, but the molecular mechanisms remain elusive. In this study, we uncovered the presence of OM-derived proteins (OMdPs) in brain extracellular vesicles (bEVs) from post-mortem Alzheimer's disease and vascular dementia subjects using unbiased metaproteomics. OMdP circulation in blood EVs was also confirmed in an independent cohort. Our findings also reveal that specific OMdPs are present in bEVs, with their levels varying with disease progression. Peptidome-wide correlation analyses further explored their exchange dynamics and composition within bEVs. In addition, we validated the ability of OM-derived EVs to cross the blood–brain barrier using a blood–brain barrier–on-a-chip model, confirming a potential route for bacterial-derived molecules to reach the central nervous system. Bioinformatics-driven interaction analyses indicated that OMdPs engage with key neuropathological proteins, including amyloid-beta and tau, suggesting a novel mechanism linking dysbiotic OM to dementia. These results provide new insights into the role of the OM in neurodegeneration and highlight OMdPs as potential biomarkers and therapeutic targets.

Alzheimer‘s disease (AD) is the leading cause of cognitive impairment and dementia in elderly patients worldwide. There is increasing evidence that periodontal disease may have an important role in the complex, multifactorial pathogenesis of AD.

Abstract Background Over recent decades, growing evidence has highlighted the pivotal role of the microbiome in Alzheimer's disease (AD) and dementia. Studies suggests the disruptions in the gut microbiome may contribute to cognitive impairment, but the association between the oral microbiome and cognitive impairment remains unclear. This study aims to characterize the oral microbiome and investigate its role in cognitive decline among elderly participants of MiaGB cohort. Method Whole‐genome metagenomics sequencing was performed on 368 samples (Controls: 236, MCI: 107, and Dementia: 25) collected from the MiaGB (Microbiome in Aging Gut and Brain) consortium, a multi‐site, clinical research study. The data was processed and analyzed using KneadData, MetaPhlAn, and HUMAnNnn tools. Result Taxonomic analysis revealed an increasing abundance of the genus Porphyromonas, and species Neisseria subflava, Neisseria sicca, and Streptococcus australis from controls to MCI to dementia participants. Random forest (RF) and LEfSe analysis identified significant increase in abundance of species N. subflava, Veillonella parvula, N. sicca, and Neisseria flavescens in MCI and dementia participants compared to controls. Additionally, Lautropia mirabilis, Eubacterium sulci, and Gemella sanguinis species were enriched in MCI compared to Controls and Dementia participants. Genera Porphyromonas are associated with cognitive impairment in other studies. Also, S. australis and V. parvula and Gemella sanguinis has been linked to neurodegenerative diseases and infective endocarditis. Distinct microbial profiles specific to each group could serve as biomarkers to identify the risk of cognitive impairment. Conclusion This study revealed a strong link between oral microbiome alterations and cognitive impairment. Further analysis will provide a more comprehensive understanding about the role of these microbes in cognitively impaired participants. These findings offer new insights into early biomarkers for cognitive impairment and the development of potential therapeutic approaches for the prevention and intervention of Alzheimer's disease (AD).

Abstract Background The increasing prevalence of cognitive decline and dementia poses a significant public health challenge for older adults, and effective preventive and therapeutic strategies remain elusive. This is largely due to an incomplete understanding of the precise etiology and contributing factors underlying these conditions. Increased systemic inflammation is suspected to elevate the risk of dementia and cognitive decline, yet the causes of chronic inflammation remain poorly understood. Emerging evidence suggests that gut microbiome abnormalities are linked to increased inflammation and a higher risk of dementia. However, it remains unclear whether the rate of cognitive impairment differs with higher systemic inflammation and whether unique microbiome signatures are associated with inflamed cognitive decline and dementia. Method Using 165 samples from the Microbiome in Aging Gut and Brain (MiaGB) consortium cohort, systemic inflammatory marker interleukin‐6 (IL‐6) was measured in human plasma via ELISA. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) questionnaire, and fecal microbiomes were analyzed through shotgun metagenomic sequencing. Subjects were grouped based on IL‐6 levels (high and low) and cognitive status (normal cognition and cognitive impairment), and their corresponding microbiome signatures were analyzed. Result Interestingly, individuals with high IL‐6 levels (IL‐6High) exhibited over twice the prevalence of mild cognitive impairment (MCI) compared to those with low IL‐6 levels (IL‐6Low) (n = 41 IL‐6High vs. 18 IL‐6Low). Older adults with low IL‐6 and MCI displayed higher abundances of Bacteroides, Prevotella, Alistipes, Fusicatenibacter, and Parabacteroides, but lower levels of Lachnospira, Akkermansia, and Subdoligranulum compared to sex‐ and age‐matched cognitively healthy controls with low IL‐6. Conversely, those with high IL‐6 and MCI exhibited higher abundances of Blautia, Prevotella, and Fusicatenibacter and lower abundances of Lachnospira, Akkermansia, and Subdoligranulum compared to IL‐6High controls with normal cognition. Conclusion These findings reveal that butyrate‐producing genera such as Lachnospira, Akkermansia, and Subdoligranulum are significantly reduced, while potentially pathogenic Fusicatenibacter and commensal Prevotella are elevated in individuals with MCI and high IL‐6 levels. These distinct microbial profiles may serve as biomarkers for the early detection of cognitive decline in older adults, highlighting potential targets for therapeutic strategies to preserve brain health during aging.

With differences apparent in the gut microbiome in mild cognitive impairment (MCI) and dementia, and risk factors of dementia linked to alterations of the gut microbiome, the question remains if gut microbiome characteristics may mediate associations of education with MCI. We sought to examine potential mediation of the association of education and MCI by gut microbiome diversity or composition. Cross-sectional study. Luxembourg, the Greater Region (surrounding areas in Belgium, France, Germany). Control participants of the Luxembourg Parkinson’s Study. Gut microbiome composition, ascertained with 16S rRNA gene amplicon sequencing. Differential abundance, assessed across education groups (0–10, 11–16, 16+ years of education). Alpha diversity (Chao1, Shannon and inverse Simpson indices). Mediation analysis with effect decomposition was conducted with education as exposure, MCI as outcome and gut microbiome metrics as mediators. After exclusion of participants below 50, or with missing data, n=258 participants (n=58 MCI) were included (M [SD] Age=64.6 [8.3] years). Higher education (16+ years) was associated with MCI (Odds ratio natural direct effect=0.35 [95% CI 0.15–0.81]. Streptococcus and Lachnospiraceae-UCG-001 genera were more abundant in higher education. Education is associated with gut microbiome composition and MCI risk without clear evidence for mediation. However, our results suggest signatures of the gut microbiome that have been identified previously in AD and MCI to be reflected in lower education and suggest education as important covariate in microbiome studies.

Periodontal inflammation has been implicated in Alzheimer’s Disease (AD) through systemic inflammatory and neurodegenerative pathways, including microbial dysbiosis and cytokine signaling and microbial infiltration. While the oral microbiome’s role in cognitive decline has gained momentumrecently, there is limited research on these associations in Hispanic population, underrepresented in Alzheimer’s research and facing disproportionately high burden of both dementia and oral disease.

No abstract available

Background Increasing evidence links the gut microbiota (GM) to Alzheimer’s disease (AD) but the mechanisms through which gut bacteria influence the brain are still unclear. This study tests the hypothesis that GM and mediators of the microbiota-gut-brain axis (MGBA) are associated with the amyloid cascade in sporadic AD. Methods We included 34 patients with cognitive impairment due to AD (CI-AD), 37 patients with cognitive impairment not due to AD (CI-NAD), and 13 cognitively unimpaired persons (CU). We studied the following systems: (1) fecal GM, with 16S rRNA sequencing; (2) a panel of putative MGBA mediators in the blood including immune and endothelial markers as bacterial products (i.e., lipopolysaccharide, LPS), cell adhesion molecules (CAMs) indicative of endothelial dysfunction (VCAM-1, PECAM-1), vascular changes (P-, E-Selectin), and upregulated after infections (NCAM, ICAM-1), as well as pro- (IL1β, IL6, TNFα, IL18) and anti- (IL10) inflammatory cytokines; (3) the amyloid cascade with amyloid PET, plasma phosphorylated tau (pTau-181, for tau pathology), neurofilament light chain (NfL, for neurodegeneration), and global cognition measured using MMSE and ADAScog. We performed 3-group comparisons of markers in the 3 systems and calculated correlation matrices for the pooled group of CI-AD and CU as well as CI-NAD and CU. Patterns of associations based on Spearman’s rho were used to validate the study hypothesis. Results CI-AD were characterized by (1) higher abundance of Clostridia_UCG-014 and decreased abundance of Moryella and Blautia ( p  < .04); (2) elevated levels of LPS ( p  < .03), upregulation of CAMs, Il1β, IL6, and TNFα, and downregulation of IL10 ( p  < .05); (3) increased brain amyloid, plasma pTau-181, and NfL ( p  < 0.004) compared with the other groups. CI-NAD showed (1) higher abundance of [Eubacterium] coprostanoligenes group and Collinsella and decreased abundance of Lachnospiraceae_ND3007_group , [Ruminococcus]_gnavus_group and Oscillibacter ( p  < .03); (2) upregulation of PECAM-1 and TNFα ( p  < .03); (4) increased plasma levels of NfL ( p  < .02) compared with CU. Different GM genera were associated with immune and endothelial markers in both CI-NAD and CI-AD but these mediators were widely related to amyloid cascade markers only in CI-AD. Conclusions Specific bacterial genera are associated with immune and endothelial MGBA mediators, and these are associated with amyloid cascade markers in sporadic AD. The physiological mechanisms linking the GM to the amyloid cascade should be further investigated to elucidate their potential therapeutic implications.

BACKGROUND The microbiota-gut-brain axis (MGBA) has been implicated in the pathophysiology of Alzheimer's Disease (AD).Probiotics reduced the progression of ADin different mouse models, possibly through MGBA modulation, but human data are still limited. OBJECTIVE Here, we evaluated whether differences in the gut microbiome (GM), pro-inflammatory markers and other MGBA mediators were associated with probable AD (pAD). We also assessed the impact of a 12-week probiotic treatment on MGBA. METHODS Forty-five pAD patients and 47 healthy subjects (HC) were recruited at IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli of Brescia (Italy). An uncontrolled clinical investigation was performed to test the effects of 12-week probiotic supplementation in the pAD group. Fecal microbiota composition, intestinal and blood inflammatory markers, and microbiota-related metabolites were assessed before supplementation in all participants and after only in pAD. RESULTS pAD patients showed intestinal inflammation, an altered GM profile, blood changes in the tryptophan metabolism, and reduced glutamate levels compared with HC (p-value < 0.049). Probiotic supplementation partially modulated these alterations, determining a reduction in several pro-inflammatory mediators, and an increase of GM-related protective factors, such as butyrate (p-value < 0.040) in pAD. CONCLUSIONS These findings confirmed the presence of MGBA alterations in AD and suggested a potential beneficial effect of probiotic supplementation through modulation of GM functionality rather than composition. Further research is required to confirm these results and their clinical relevance.

The microbial-gut-brain axis and oxidative stress may be important to the pathogenesis of Alzheimer’s disease (AD). Rosa roxburghii Tratt polysaccharides (RRTP) have a strong antioxidant effect and can affect the gut microbiota, and whether it can affect AD is unknown. So, AlCl3 and d-galactose were used to establish AD model rats, and RRTP was used as an intervention treatment. Morris water maze test was used to detect cognitive functions. The hippocampus was used to observe the pathological changes, and the cortex was used to measure antioxidant markers. The stool was collected for 16S rDNA sequencing. Morris water maze test showed that the learning ability and memory level of AD group rats were decreased, and RRTP intervention could mitigate the injury to a certain extent. In the AD group, hematoxylin-eosin staining revealed changes in the morphology of neurons, silver glycine staining revealed neurofibrillary tangles and Congo red staining revealed β-amyloid. RRTP could ameliorate the above changes to some extent. The results of superoxide dismutase, malondialdehyde, and glutathione peroxidase showed that the antioxidant capacity in the RRTP intervention group was significantly higher than that in the AD group. 16S rDNA sequencing results showed that there were differences in the species composition of gut microbiota, and the ratio of Firmicutes to Bacteroidetes in the AD group was decreased. After RRTP intervention, the proportion of Lactobacillus increased. In conclusion, RRTP may prevent AD pathology and cognitive functions in rats to a certain extent through the microbiota-gut-brain axis and oxidative stress.

Background Porphyromonas gingivalis (P. gingivalis) has been found to enter the brain and induce inflammation, contributing to Alzheimer's disease (AD). P. gingivalis is also closely linked to gut dysbiosis. However, does P. gingivalis induce AD-like pathology through the microbiota-gut-brain axis? There is limited literature on this topic. Objective To determine the precise causal link among P. gingivalis, intestinal inflammation, and AD-related pathology. Methods 12- to 13-month-old female C57BL/6J mice were subjected to ligature placement and oral administration of P. gingivalis over a 24-week period. Then, cognitive performance was evaluated with behavioral tests, while AD neuropathological changes, neuroinflammation, and intestinal inflammation were assessed through qPCR, immunofluorescence, and western blot, and gut microbiota was analyzed by 16S rRNA. Results Mice exposed to P. gingivalis showed impaired behavior in open field test, novel object recognition, and Y-maze tests. The bacterium infiltrated their brains, increasing Aβ42, AβPP, and Aβ fragments, promoting tau phosphorylation and microglial activation, and reducing levels of ZO-1, PSD95, SYP, and NeuN proteins. Inflammatory factors like NLRP3, caspase-1, IL-1β, IL-6, and TNF-α were elevated in both brains and intestine, while ZO-1 and occludin levels decreased in intestine. P. gingivalis also altered gut microbial compositions. Conclusions P. gingivalis induced gut dysbiosis and activated the NLRP3 inflammasome in the intestine and brains of mice. This led to impairment of both the intestinal and brain-blood barriers, triggering neuroinflammation and promoting the progression of AD. These findings highlight the critical role of NLRP3 inflammasome activation in the microbiota-gut-brain axis in the AD-like pathology induced by P. gingivalis.

Evidence suggests that exposure to organophosphate pesticides increases the risk of neurodegenerative diseases, but the mechanisms remain unclear. This study investigated the effects of malathion on Alzheimer's disease (AD)-like symptoms at environmentally relevant concentrations using wild-type (WT) and APP/PS1 transgenic mouse models. Results showed that malathion exposure induced AD-like cognitive impairment, amyloid-β (Aβ) accumulation, and neuroinflammation in WT mice, with worsened symptoms in APP/PS1 mice. Mechanistic studies revealed that malathion induced AD-like gut microbiota dysbiosis (reduced Lactobacillus and Akkermansia, and increased Dubosiella), causing gut barrier impairment and tryptophan metabolism disruptions. This resulted in a significant increase in indole derivatives and activation of the colonic aryl hydrocarbon receptor (AhR), promoting the kynurenine (KYN) pathway while inhibiting the serotonin (5-HT) pathway. Increased neurotoxic KYN metabolites (3-hydroxykynurenine and quinolinic acid) triggered gut and systemic inflammation, upregulating hippocampal IL-6 and IL-1β mRNA levels and thereby causing neuroinflammation. Gut tryptophan metabolism disruptions caused hippocampal neurotransmitter imbalances, reducing the levels of 5-HT and its derivatives. These effects promoted AD progression in both WT and APP/PS1 mice. This study highlights the crucial role of the microbiota-gut-brain axis in AD-like cognitive impairment induced by malathion exposure, providing insights into the neurodegenerative disease risks posed by organophosphate pesticides.

No abstract available

Ganoderma lucidum (Curtis) P. Karst.(G. lucidum) is a kind of fungi, which also a traditional Chinese medicine used for "wisdom growth" in China. Triterpenoids from G. lucidum (GLTs) are one of the main active ingredients. Based on the strategy of early intervention on Alzheimer's disease (AD) and the inextricable association between disordered gut microbiota and metabolites with AD, this study aimed to explore the mechanisms of GLTs in the protection against AD via microbiota-gut-brain axis with the aid of network pharmacology. In this study, LC-MS/MS was used to identify the main active ingredients of GLTs. Network pharmacology was used to predict the potential target and validated with Caco-2 cell model. D-galactose was used to induce the slow-onset AD on rats. Metabolomics methods basing on GC-MS combined with 16S rRNA sequencing technology was used to carry out microbiota-gut-metabolomics analysis in order to reveal the potential mechanisms of GLTs in the protection of AD. As results, GLTs showed a protection against AD effect on rats by intervening administration. The mechanisms were inextricably linked to GLTs interference with the balance of gut microbiota and metabolites. The main fecal metabolites involved were short-chain fatty acids and aromatic amino acid metabolites.

Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer’s disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer’s disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer’s disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer’s disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1 (APP/PS1). Here, we performed 16S rRNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-L-threonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesium-L-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins (zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer’s disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer’s disease.

The current opinion paper puts into perspective how altered microbiota transplanted from Alzheimer’s patients initiates the impairment of the microbiota–gut–brain axis of a healthy recipient, leading to impaired cognition primarily arising from the hippocampus, dysfunctional adult hippocampal neurogenesis, dysregulated systemic inflammation, long-term spatial memory impairment, or chronic pain with hippocampal involvement. This altered microbiota may induce acquired Piezo2 channelopathy on enterochromaffin cells, which, in turn, impairs the ultrafast long-range proton-based oscillatory synchronization to the hippocampus. Therefore, an intact microbiota–gut–brain axis could be responsible for the synchronization of ultradian and circadian rhythms, with the assistance of rhythmic bacteria within microbiota, to circadian regulation, and hippocampal learning and memory formation. Hippocampal ultradian clock encoding is proposed to be through a Piezo2-initiated proton-signaled manner via VGLUT3 allosteric transmission at a distance. Furthermore, this paper posits that these unaccounted-for ultrafast proton-based long-range oscillatory synchronizing ultradian axes may exist not only within the brain but also between the periphery and the brain in an analogous way, like in the case of this depicted microbiota–gut–brain axis. Accordingly, the irreversible Piezo2 channelopathy-induced loss of the Piezo2-initiated ultradian prefrontal–hippocampal axis leads to Alzheimer’s disease pathophysiology onset. Moreover, the same irreversible microdamage-induced loss of the Piezo2-initiated ultradian muscle spindle–hippocampal and cerebellum–hippocampal axes may lead to amyotrophic lateral sclerosis and Parkinson’s disease initiation, respectively.

Alzheimer's disease (AD) is an irreversible neurodegenerative disease that may cause neurotoxicity and imbalance in gut microbiota. A polysaccharide derived from Sparassis crispa-1 (SCP-1) acts as a neuroprotective agent in vitro. There is, however, no clarity on the mechanism responsible for SCP-1's neuroprotective effects against AD. In this study, C57BL/6J male mice were treated with D-galactose and AlCl3 to establish an animal model of AD, followed by treatment with SCP-1. As evidenced by behavioral tests and brain pathology, SCP-1 treatment ameliorated learning deficits and defective spatial recognition, reduced amyloidogenesis, and modulated the neurotransmitter levels (γ-aminobutyric acid, glutamate, and acetylcholine) in the brain of AD mice. The results of 16S rRNA sequencing revealed that SCP-1 reshaped the gut microbiota composition, especially by promoting the proliferation of butyrate-producing genera, such as Intestinaimonas, [Eubacterium] ventriosum group, Lachnospiraceae_UCG_010, and Lachnospiraceae_UCG_001, and suppressing the growth of inflammation-related bacteria (i.e., Escherichia/Shigella). Furthermore, SCP-1 significantly attenuated inflammation by reducing the levels of inflammatory cytokines, maintaining intestinal barrier function, inhibiting glial activation, and decreasing the expression of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB). Collectively, our findings suggest that SCP-1 may prevent the development of AD via modulation of gut microbiota and suppression of inflammation, for a potential application in preventing or managing AD.

Objective(s): We aimed to observe the effects of preventive electroacupuncture (EA) on the microbiota–gut–brain axis and spatial learning and memory deficits and to investigate the possible mechanism using D-galactose (D-gal)-induced aging rats. Materials and Methods: D-gal was intraperitoneally injected to establish the aging model. We used Morris water maze to detect spatial learning and memory function of rats. RT-PCR was applied to test targeted gut microbes. The expression of zonula occludens-1 (ZO-1) and Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB pathway proteins were detected by Western blotting. ELISA was employed to evaluate the level of lipopolysaccharides (LPS), diamine oxidase (DAO) and S-100β. Additionally, we observed ionized calcium-binding adapter molecule-1 (Iba-1) expression in the hippocampal CA1 area by immunofluorescence. Results: Morris water maze test showed decreased mean escape latency and increased target quadrant time after EA treatment. The gut microbiota composition has been modified in EA treated rats. Molecular examination indicated that expression of ZO-1 was improved and the the concentration of LPS in blood and hippocampus were reduced in EA treated rats. Further, we observed an inhibition of activated microglia and TLR4/NF-κB pathway in EA groups. Conclusion: Preventive EA may alleviate the impairments of the microbiota–gut–brain axis and spatial learning and memory in aging, and the mechanism may be related to the inhibition of TLR4/NF-kB signaling pathway. The combination of acupoints GV20 and ST36 can enhance the therapeutic effect in aging rats.

ABSTRACT Cannabidiol (CBD), a natural component extracted from Cannabis sativa L. exerts neuroprotective, antioxidant, and anti-inflammatory effects in Alzheimer’s disease (AD), a disease characterized by impaired cognition and accumulation of amyloid-B peptides (Aβ). Interactions between the gut and central nervous system (microbiota-gut-brain axis) play a critical role in the pathogenesis of neurodegenerative disorder AD. At present investigations into the mechanisms underlying the neuroprotective action of CBD in AD are not conclusive. The aim of this study was thus to examine the influence of CBD on cognition and involvement of the microbiota-gut-brain axis using a senescence-accelerated mouse prone 8 (SAMP8) model. Data demonstrated that administration of CBD to SAMP8 mice improved cognitive function as evidenced from the Morris water maze test and increased hippocampal activated microglia shift from M1 to M2. In addition, CBD elevated levels of Bacteriodetes associated with a fall in Firmicutes providing morphologically a protective intestinal barrier which subsequently reduced leakage of intestinal toxic metabolites. Further, CBD was found to reduce the levels of hippocampal and colon epithelial cells lipopolysaccharide (LPS), known to be increased in AD leading to impaired gastrointestinal motility, thereby promoting neuroinflammation and subsequent neuronal death. Our findings demonstrated that CBD may be considered a beneficial therapeutic drug to counteract AD-mediated cognitive impairment and restore gut microbial functions associated with the observed neuroprotective mechanisms.

Alzheimer’s disease (AD) is a prevalent and progressive neurodegenerative disorder that is the leading cause of dementia. The underlying mechanisms of AD have not yet been completely explored. Neuroinflammation, an inflammatory response mediated by certain mediators, has been exhibited to play a crucial role in the pathogenesis of AD. Additionally, disruption of the gut microbiota has been found to be associated with AD, and fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach. However, the precise mechanism of FMT in the treatment of AD remains elusive. In this study, FMT was performed by transplanting fecal microbiota from healthy wild-type mice into APP/PS1 mice (APPswe, PSEN1dE9) to assess the effectiveness of FMT in mitigating AD-associated inflammation and to reveal its precise mechanism of action. The results demonstrated that FMT treatment improved cognitive function and reduced the expression levels of inflammatory factors by regulating the TLR4/MyD88/NF-κB signaling pathway in mice, which was accompanied by the restoration of gut microbial dysbiosis. These findings suggest that FMT has the potential to ameliorate AD symptoms and delay the disease progression in APP/PS1 mice.

A growing body of evidence suggests a link between the gut microbiota and Alzheimer's disease (AD), although the underlying mechanisms remain elusive. This study aimed to investigate the impact of fecal microbiota transplantation (FMT) on cognitive function in a mouse model of AD.

Alzheimer’s disease (AD) is marked by impaired cognitive functions, particularly in learning and memory, owing to complex and diverse mechanisms. Methionine restriction (MR) has been found to exert a mitigating effect on brain oxidative stress to improve AD. However, the bidirectional crosstalk between the gut and brain through which MR enhances learning and memory in AD, as well as the effects of fecal microbiota transplantation (FMT) from MR mice on AD mice, remains underexplored. In this study, APP/PS1 double transgenic AD mice were used and an FMT experiment was conducted. 16S rRNA gene sequencing, targeted metabolomics, and microbial metabolite short-chain fatty acids (SCFAs) of feces samples were analyzed. The results showed that MR reversed the reduction in SCFAs induced by AD, and further activated the free fatty acid receptors, FFAR2 and FFAR3, as well as the transport protein MCT1, thereby signaling to the brain to mitigate inflammation and enhance the learning and memory capabilities. Furthermore, the FMT experiment from methionine-restricted diet mouse donors showed that mice receiving FMT ameliorated Alzheimer’s learning and memory ability through SCFAs. This study offers novel non-pharmaceutical intervention strategies for AD prevention.

Human microbiota‐associated murine models, using fecal microbiota transplantation (FMT) from human donors, help explore the microbiome's role in diseases like Alzheimer's disease (AD). This study examines how gut bacteria from donors with protective factors against AD influence behavior and brain pathology in an AD mouse model. Female 3xTgAD mice received weekly FMT for 2 months from (i) an 80‐year‐old AD patient (AD‐FMT), (ii) a cognitively healthy 73‐year‐old with the protective APOEe2 allele (APOEe2‐FMT), (iii) a 22‐year‐old healthy donor (Young‐FMT), and (iv) untreated mice (Mice‐FMT). Behavioral assessments included novel object recognition (NOR), Y‐maze, open‐field, and elevated plus maze tests; brain pathology (amyloid and tau), neuroinflammation (in situ autoradiography of the 18 kDa translocator protein in the hippocampus); and gut microbiota were analyzed. APOEe2‐FMT improved short‐term memory in the NOR test compared to AD‐FMT, without significant changes in other behavioral tests. This was associated with increased neuroinflammation in the hippocampus, but no effect was detected on brain amyloidosis and tauopathy. Specific genera, such as Parabacteroides and Prevotellaceae_UGC001, were enriched in the APOEe2‐FMT group and associated with neuroinflammation, while genera like Desulfovibrio were reduced and linked to decreased neuroinflammation. Gut microbiota from a donor with a protective factor against AD improved short‐term memory and induced neuroinflammation in regions strategic to AD. The association of several genera with neuroinflammation in the APOEe2‐FMT group suggests a collegial effect of the transplanted microbiome rather than a single‐microbe driver effect. These data support an association between gut bacteria, glial cell activation, and cognitive function in AD.

Arsenic exposure and intestinal microbiota disorders may be related with Alzheimer's disease (AD), but the mechanism has not been elucidated. This study conducted chronic arsenic exposure from rat's maternal body to adult offspring to investigate the mechanisms of the characteristic effects of chronic arsenic exposure on AD, and further explored the intervention effect of fecal microbiota transplantation (FMT) on arsenic‐mediated neurotoxicity. Transmission electron microscopy, HE staining, and related indicators were measured in the control group, the exposed group, and the FMT intervention group. Western blot was used to determine microtubule‐associated proteins Tau and p‐Tau396, intestinal–brain barrier–related proteins Claudin‐1 and Occludin, ELISA was used to detect the content of Aβ1–42, and 16S rRNA sequencing was used to detect the intestinal flora of feces. Results showed that chronic arsenic exposure could lead to neurobehavioral defects in rats, increase the expression levels of Tau, p‐Tau396, and Aβ1–42 in hippocampus (p < 0.05), increase the abundance of Clostridium _ UCG‐014, decrease the abundance of Roseburia, and decrease the expression levels of Claudin‐1 and Occludin in colon and hippocampus (p < 0.05). After FMT intervention, the expression levels of Tau and p‐Tau396 were decreased (p < 0.05), and the abundance of Roseburia was increased. In summary, chronic arsenic exposure caused intestinal flora disorder by changing the abundance of inflammation‐related flora, thereby destroying the gut–brain barrier and causing AD characteristic effects in rats. Although the bacterial specific genus was improved and the expression of AD‐related proteins was reduced after transplantation, it could not alleviate the neurobehavioral defects and neurotoxicity caused by arsenic exposure.

Background Traumatic brain injury (TBI) accelerates Alzheimer’s disease (AD) pathology and neuroinflammation, potentially via gut-brain axis disruptions. Whether restoring gut microbial homeostasis mitigates TBI-exacerbated AD features remains unclear, particularly with respect to sex differences. Objective The goal of our study was to test whether fecal microbiota transplantation (FMT) modifies amyloid pathology, neuroinflammation, gut microbial composition, metabolites, and motor outcomes in male and female 5xFAD mice subjected to TBI. Methods Male and female 5xFAD mice received sham treatments or controlled cortical impact, followed 24 hours later by vehicle (VH) or sex-matched FMT from C57BL/6 donors. Assessments at baseline, 1, and 3 days post-injury included Thioflavin-S and 6E10 immunostaining for Aβ, Iba-1 and GFAP for glial activation, lesion volume, rotarod performance, 16S rRNA sequencing for microbiome profiling, serum short-chain fatty acids (SCFAs), and gut histology. Results TBI increased cortical and dentate gyrus Aβ burden, with females showing greater vulnerability. FMT reduced Aβ deposition in sham animals and shifted plaque morphology but did not attenuate TBI-induced amyloid escalation. FMT differentially modulated glial responses by sex and region (reduced microgliosis in males) without altering lesion volume. Rotarod performance was better in sham females compared to males and declined in FMT-treated TBI females. Fecal microbiome alpha diversity and richness were unchanged, while beta diversity revealed marked, time-dependent community shifts after TBI that were slightly altered by FMT. Gut morphology remained broadly intact, but crypt width increased after TBI, particularly in males. Conclusion In 5xFAD mice, TBI drives sex-dependent worsening of amyloid pathology, neuroinflammation, and dysbiosis. Acute FMT partially restores microbial composition and plaque features in sham animals but fails to reverse TBI-induced neuroinflammation or motor deficits. These findings underscore the context- and sex-dependence of microbiome interventions and support longer-term, sex-specific strategies for AD with comorbid TBI.

Background: The brain–gut axis has emerged as a potential target in neurodegenerative diseases, including dementia, as individuals with dementia exhibit distinct gut microbiota compositions. Fecal microbiota transplantation (FMT), the transfer of fecal solution from a healthy donor to a patient, has shown promise in restoring homeostasis and cognitive enhancement. Objective: This study aimed to explore the effects of FMT on specific cognitive performance measures in Alzheimer’s dementia (AD) patients and investigate the relationship between cognition and the gut microbiota by evaluating changes in gene expression following FMT. Methods: Five AD patients underwent FMT, and their cognitive function [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)] was assessed before and after FMT. The patients’ fecal samples were analyzed with 16S rRNA to compare the composition of their gut microbiota. We also assessed modifications in the serum mRNA expression of patients’ genes related to lipid metabolism using serum RNA sequencing and quantitative real-time polymerase chain reaction. Results: Significant improvements in cognitive function, as measured by the MMSE (pre- and post-FMT was 13.00 and 18.00) and MoCA were seen. The MoCA scores at 3 months post-FMT (21.0) were the highest (12.0). The CDR-SOB scores at pre- and post-FMT were 10.00 and 5.50, respectively. Analysis of the gut microbiome composition revealed changes via 16S rRNA sequencing with an increase in Bacteroidaceae and a decrease in Enterococcaceae. Gene expression analysis identified alterations in lipid metabolism-related genes after FMT. Conclusion: These findings suggest a link between alterations in the gut microbiome, gene expression related to lipid metabolism, and cognitive function. The study highlights the importance of gut microbiota in cognitive function and provides insights into potential biomarkers for cognitive decline progression. FMT could complement existing therapies and show potential as a therapeutic intervention to mitigate cognitive decline in AD.

Abstract After fecal microbiota transplantation (FMT) to treat Clostridioides difficile infection (CDI), cognitive improvement is noticeable, suggesting an essential association between the gut microbiome and neural function. Although it is known that the gut microbiome is linked with cognitive function, whether FMT may lead to cognitive improvement in patients with neurodegenerative disorders remains to be elucidated. We present the case of a 90-year-old woman with Alzheimer's dementia and severe CDI who underwent FMT. Cognitive function testing (Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating assessment) was performed one month before FMT and one week and one month after FMT. We collected the patients’ fecal samples before FMT and 3 weeks after FMT to compare the microbiota composition. The 16S rRNA gene amplicons were analyzed using the QIIME2 platform (version 2020.2) and the Phyloseq R package. The linear discriminant analysis effect size was performed to determine the taxonomic difference between pre- and post-FMT. Functional biomarker analysis using the Kruskal–Wallis H test was performed between the pre- and post-FMT. The cognitive function tests after FMT showed an improvement compared to the tests before the procedure. FMT changed the microbiota composition in recipient feces. We found that the genera were reported to be associated with cognitive function. In addition, short-chain fatty acids were found to be significantly different between before and after FMT. This finding suggests the presence of an association between the gut microbiome and cognitive function. Further, it emphasizes the need for clinical awareness regarding the effect of FMT on the brain-gut-microbiome axis and its potential as a therapy for patients with dementia.

Alzheimer’s disease (AD), the most common form of dementia, is a leading cause of death and a major cause of morbidity in older people. The disease is characterized by progressive memory loss, cognitive impairment, and the cerebral accumulation of amyloid-β peptide. Given the health and economic impacts of AD, treatments that target the underlying etiology of AD or modify the course of the disease are of significant interest. The gut microbiome has been increasingly implicated in the pathogenesis of several neurological diseases, including multiple sclerosis and Parkinson’s disease. Furthermore, emerging evidence has demonstrated that there are alterations in gut microbiome composition in patients with AD, suggesting involvement of the microbiome–gut–brain axis. We present symptom improvement in a patient with AD following fecal microbiota transplantation for a Clostridioides difficile infection.

Alzheimer’s disease (AD) is the most common dementia in the elderly. Treatment for AD is still a difficult task in clinic. AD is associated with abnormal gut microbiota. However, little is known about the role of fecal microbiota transplantation (FMT) in AD. Here, we evaluated the efficacy of FMT for the treatment of AD. We used an APPswe/PS1dE9 transgenic (Tg) mouse model. Cognitive deficits, brain deposits of amyloid-β (Aβ) and phosphorylation of tau, synaptic plasticity as well as neuroinflammation were assessed. Gut microbiota and its metabolites short-chain fatty acids (SCFAs) were analyzed by 16S rRNA sequencing and 1H nuclear magnetic resonance (NMR). Our results showed that FMT treatment could improve cognitive deficits and reduce the brain deposition of amyloid-β (Aβ) in APPswe/PS1dE9 transgenic (Tg) mice. These improvements were accompanied by decreased phosphorylation of tau protein and the levels of Aβ40 and Aβ42. We observed an increases in synaptic plasticity in the Tg mice, showing that postsynaptic density protein 95 (PSD-95) and synapsin I expression were increased after FMT. We also observed the decrease of COX-2 and CD11b levels in Tg mice after FMT. We also found that FMT treatment reversed the changes of gut microbiota and SCFAs. Thus, FMT may be a potential therapeutic strategy for AD.

Background Traumatic brain injury (TBI) accelerates Alzheimer’s disease (AD) pathology and neuroinflammation, potentially via gut-brain axis disruptions. Whether restoring gut microbial homeostasis mitigates TBI-exacerbated AD features remains unclear, particularly with respect to sex differences. Objective The goal of our study was to test whether fecal microbiota transplantation (FMT) modifies amyloid pathology, neuroinflammation, gut microbial composition, metabolites, and motor outcomes in male and female 5xFAD mice subjected to TBI. Methods Male and female 5xFAD mice received sham treatments or controlled cortical impact, followed 24 h later by vehicle (VH) or sex-matched FMT from C57BL/6 donors. Assessments at baseline, 1-, and 3-days post-injury (dpi) included Thioflavin-S and 6E10 immunostaining for Aβ, Iba-1 and GFAP for glial activation, lesion volume, rotarod performance, 16S rRNA sequencing for microbiome profiling, serum short-chain fatty acids (SCFAs), and gut histology. Results TBI increased cortical and dentate gyrus Aβ burden, with females showing greater vulnerability. FMT reduced Aβ deposition in sham animals and shifted plaque morphology but did not attenuate TBI-induced amyloid escalation. FMT differentially modulated glial responses by sex and region (reduced microgliosis in males) without altering lesion volume at 3 dpi. Rotarod performance was better in sham females compared to males and declined in FMT-treated TBI females. Fecal microbiome alpha diversity and richness were unchanged, while beta diversity revealed marked, time-dependent community shifts after TBI that were slightly altered by FMT. Gut morphology remained broadly intact, but crypt width increased after TBI, particularly in males. Conclusion In 5xFAD mice, TBI drives sex-dependent worsening of amyloid pathology, neuroinflammation, and dysbiosis. Acute FMT partially restores microbial composition and plaque features in sham animals but fails to reverse TBI-induced neuroinflammation or motor deficits. These findings underscore the context- and sex-dependence of microbiome interventions and support longer-term, sex-specific strategies for AD with comorbid TBI.

Characterized by the presence of amyloid plaques, neurofibrillary tangles and neuroinflammation, Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no known treatment or cure. Global disease projections warrant an urgent and rapid therapeutic for the treatment of this devastating disease. Fecal microbiota transplantation (FMT) is a widely accepted and safely used treatment for recurrent Clostridium difficile infection and other metabolic diseases such as diabetes mellitus. FMT has also been demonstrated to be a possible AD therapeutic. We examined the potential of FMT for the treatment of AD in a robust, mouse model of the disease and report that a brief, 7-day treatment regimen demonstrated ‘plaque-busting’ and behavior-modifying effects in treated 5xFAD mice. Importantly, we show that donor age plays an important role in the efficacy of the treatment and these findings warrant further investigation in human trials.

Several studies have confirmed that the pathophysiological progression of Alzheimer’s disease (AD) is closely related to changes in the intestinal microbiota; thus, modifying the intestinal microbiota has emerged as a new way to treat AD. Effective interventions for gut microbiota include the application of probiotics and other measures such as fecal microbiota transplantation (FMT). However, the application of probiotics ignores that the intestine is a complete microecosystem with competition among microorganisms. FMT also has issues when applied to patient treatment. In a previous study, we found that eight species of bacteria that are isolated with high frequency in the normal intestinal microbiota (i.e., intestinal dominant microbiota) have biological activities consistent with the effects of FMT. In this article, we confirmed that the treatment of intestinal dominant microbiota significantly restored intestinal microbiota abundance and composition to normal levels in APP/PS1 mice; downregulated brain tissue pro-inflammatory cytokines (IL-1β and IL-6) and amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1) expression levels; and reduced the area of Aβ plaque deposition in the brain hippocampus. Our study provides a new therapeutic concept for the treatment of AD, adjusting the intestinal microecological balance through dominant intestinal microbiota may be an alternative to FMT.

Gut microbiota is proven to be involved in the development of beta amyloid (Aβ) pathology in Alzheimer's disease (AD). Since there are difficulties in translating microbiota findings based on germ-free mice into clinical practice, here, we used short-term antibiotic cocktail treatment to develop a novel model with a near-germ-free status and without impacting Aβ pathology. Three months old APPSWE/PS1ΔE9 mice were fed with antibiotic cocktails for two weeks by gavage to obtain a near "germ-free" status, and then received the donor fecal matter from the 16 months old APP/PS1 mice for 7 consecutive days. Fecal pellets were collected prior to antibiotics treatment, following antibiotic exposure, prior to and following fecal microbiota transplantation for gut microbiota analysis. Also, Aβ pathology, astrocyte and microglia morphology were further explored. Pre-antibiotic-treated mice successfully allowed engraftment of gut microbiota following 7 consecutive days gavage with aged APP/PS1 mice microbiota. Microbiota reconstitution by transplantation was largely attributable to the donor source (e.g. g_Coriobacteriaceae and g_Clostridium) and led to a significant increase in Aβ plaques. Surprisingly, astrocyte activation around Aβ plaques was suppressed rather than microglia, the well-recognized plaque phagocytic cell type in Aβ clearance, following microbiota engraftment. Our findings provide a novel framework for understanding the mechanisms of AD through the gut-brain axis and the translation of gut microbiota manipulation from bench to clinical practice.

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration, both which increase the risk and accelerate the progression of Alzheimer’s disease (AD). The gut microbiome is an essential modulator of the immune system, impacting in the brain. AD has been related with reduced diversity and alterations in the community composition of the gut microbiota. This study aimed to determine whether the gut microbiota from AD mice exacerbates neurological deficits after TBI in control mice. We prepared fecal microbiota transplants from 18-24 months old 3xTg-AD (FMT-AD) and from healthy controls (FMT-young) mice. FMTs were administered orally to young control C57BL/6 (wild-type, WT) mice after they underwent controlled cortical impact (CCI) injury, as a model of TBI. Then, we characterized the microbiota composition of the fecal samples by full-length 16S rRNA gene sequencing analysis. We collected the blood, brain, and gut tissues for protein and immunohistochemical analysis. Our results showed that FMT-AD administration stimulates a higher relative abundance of the genus Muribaculum and a decrease in Lactobacillus johnsonii compared to FMT-young in WT mice. Furthermore, WT mice exhibited larger lesion, increased activated microglia/macrophages, and reduced motor recovery after FMT-AD compared to FMT-young one day after TBI. In summary, we observed gut microbiota from AD mice to have a detrimental effect and aggravate the neuroinflammatory response and neurological outcomes after TBI in young WT mice.

Background and purpose The gut-brain axis is bidirectional and the imbalance of the gut microbiota usually coexists with brain diseases, including Alzheimer’s disease (AD). Accumulating evidence indicates that endoplasmic reticulum (ER) stress is a core lesion in AD and persistent ER stress promotes AD pathology and impairs cognition. However, whether the imbalance of the gut microbiota is involved in triggering the ER stress in the brain remains unknown. Materials and methods In the present study, fecal microbiota transplantation (FMT) was performed with gut microbiota from AD patients and APP/PS1 mice, respectively, resulting in two mouse models with dysregulated gut microbiota. The ER stress marker protein levels in the cerebral cortex were assessed using western blotting. The composition of the gut microbiota was assessed using 16S rRNA sequencing. Results Excessive ER stress was induced in the cerebral cortex of mice after FMT. Elevated ER stress marker proteins (p-perk/perk, p-eIF2α/eIF2α) were observed, which were rescued by 3,3-dimethyl-1-butanol (DMB). Notably, DMB is a compound that significantly attenuates serum trimethylamine-N-oxide (TMAO), a metabolite of the gut microbiota widely reported to affect cognition. Conclusion The findings indicate that imbalance of the gut microbiota induces ER stress in the cerebral cortex, which may be mediated by TMAO.

Introduction Emerging evidence implicates gut microbiota dysbiosis as a key modulator for the pathogenesis of Alzheimer’s disease (AD) via the gut-brain axis. To investigate the causal role of microbial communities in AD progression, we performed fecal microbiota transplantation (FMT) in APP/PS1 transgenic mice using donor microbiota from healthy wild-type mice or dextran sulfate sodium (DSS)-induced colitis mice. Methods Cognitive function, amyloid-beta (Aβ) pathology, and pro-inflammatory cytokine levels were assessed in mice. 16S ribosomal RNA sequencing of gut microbiota and bioinformatic functional analyses were applied to identify the specific microbial communities potentially involved in AD progression. Results FMT-WT mice (fecal microbiota transplantation from healthy wild-type mice) exhibited significant improvements in spatial memory (Morris Water Maze), exploratory behavior (Y-maze), and locomotor activity (Open Field Test), alongside reduced Aβ plaque burden and normalized expression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) in both gut and brain tissues. Conversely, FMT-DSS mice (fecal microbiota transplantation from DSS-treated donors) displayed exacerbated cognitive deficits, heightened Aβ deposition, and elevated pro-inflammatory cytokine levels. Microbial profiling revealed stark contrasts: FMT-WT mice harbored beneficial taxa (Bacteroides, Lachnospiraceae) linked to anti-inflammatory products like short-chain fatty acid, while FMT-DSS mice showed blooms of pathogenic genera (Erysipelatoclostridium, Enterobacteriaceae) associated with neurotoxic metabolites. Functional analyses predicted enrichment of neuroprotective pathways (e.g., lysine metabolism) in FMT-WT and pro-inflammatory pathways (e.g., carbon metabolism) in FMT-DSS. Crucially, neuroinflammation occurred independently of gut barrier disruption, implicating circulating microbial metabolites as key mediators. Discussion Our findings demonstrate that gut microbiota composition bidirectionally influences AD progression, with FMT from healthy donors attenuating neuroinflammation and pathology, while colitis-associated dysbiosis exacerbates disease hallmarks. Our study positions microbiota-targeted therapies as a promising strategy to modulate AD progression through the gut-brain axis.

Background Recent studies have reported that gut microbiota is closely associated with cognitive fuction. Fecal microbiota transplantation (FMT) may be a potential treatment for cognitive impairment, but its efficacy in patients with cognitive impairment is unknown. Objectives This study aimed to investigate the safety and efficacy of FMT for cognitive impairment treatment. Methods Five patients aged 54–80 years (three women) were enrolled in this single-arm clinical trial from July 2021 to May 2022. The Montreal Cognitive Assessment-B (MoCA-B), Activities of Daily Living (ADL), and the cognitive section of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) were assessed at days 0, 30, 60, 90, and 180. Additionally, stool and serum samples were obtained twice before FMT was administered and six months after the treatment. The structure of fecal microbiota was analyzed by 16S RNA gene sequencing. Serum samples were analyzed for metabolomics and lipopolysaccharide (LPS)-binding proteins by liquid chromatography-mass spectrometry and enzyme-linked immunosorbent assay, respectively. Safety was assessed based on adverse events, vital signs, and laboratory parameters during FMT and the follow-up period. Results The MoCA, ADL, and ADAS-Cog scores of patients with mild cognitive impairment (patients C and E) after FMT were improved or maintained compared with those before transplantation. However, patients with severe cognitive impairment (patients A, B, and D) had no worsening of cognitive scores. Fecal microbiota analysis showed that FMT changed the structure of gut microbiota. The results of serum metabolomics analysis suggested that there were significant changes in the serum metabolomics of patients after FMT, with 7 up-regulated and 28 down-regulated metabolites. 3b,12a-dihydroxy-5a-cholanoic acid, 25-acetylvulgaroside, deoxycholic acid, 2(R)-hydroxydocosanoic acid, and P-anisic acid increased, while bilirubin and other metabolites decreased. KEFF pathway analysis indicated that the main metabolic pathways were bile secretion and choline metabolism in cancer. No adverse effects were reported throughout the study. Conclusions In this pilot study, FMT could maintain and improve cognitive function in mild cognitive impairment by changing gut microbiota structure and affecting serum metabolomics. Fecal bacteria capsules were safe. However, further studies are needed to evaluate the safety and efficacy of fecal microbiota transplantation. ClinicalTrials.gov Identifier: CHiCTR2100043548.

Manganese (Mn) is an environmental pollutant, and overexposure can cause neurodegenerative disorders similar to Alzheimer's disease and Parkinson's disease that are characterized by β-amyloid (Aβ) overexpression, Tau hyperphosphorylation and neuroinflammation. However, the mechanisms of Mn neurotoxicity are not clearly defined. In our study, a knockout mouse model of Mn exposure combined with gut flora-induced neurotoxicity was constructed to investigate the effect of gut flora on Mn neurotoxicity. The results showed that the levels of Tau, p-Tau and Aβ in the hippocampus of C57BL/6 mice were greater than those in the hippocampus of control mice after 5 weeks of continuous exposure to manganese chloride (Mn content of 200 mg/L). Transplanted normal and healthy fecal microbiota from mice significantly downregulated Tau, p-Tau and Aβ expression and ameliorated brain pathology. Moreover, Mn exposure activated the cGAS-STING pathway and altered the cecal microbiota profile, characterized by an increase in Clostridiales, Pseudoflavonifractor, Ligilactobacillus and Desulfovibrio, and a decrease in Anaerotruncus, Eubacterium_ruminantium_group, Fusimonas and Firmicutes, While fecal microbiome transplantation (FMT) treatment inhibited this pathway and restored the microbiota profile. FMT alleviated Mn exposure-induced neurotoxicity by inhibiting activation of the NLRP3 inflammasome triggered by overactivation of the cGAS-STING pathway. Deletion of the cGAS and STING genes and FMT altered the gut microbiota composition and its predictive function. Phenotypic prediction revealed that FMT markedly decreased the abundances of anaerobic and stress-tolerant bacteria and significantly increased the abundances of facultative anaerobic bacteria and biofilm-forming bacteria after blocking the cGAS-STING pathway compared to the Mn-exposed group. FMT from normal and healthy mice ameliorated the neurotoxicity of Mn exposure, possibly through alterations in the composition and function of the microbiome associated with the cGAS-STING/NLRP3 pathway. This study provides a prospective direction for future research on the mechanism of Mn neurotoxicity.

Alzheimer's disease (AD) is a neurodegenerative disease that causes memory and cognitive decline. Although many studies have attempted to clarify the causes of AD occurrence, it is not clearly understood. Recently, the emerging role of the gut microbiota in neurodegenerative diseases, including AD, has received much attention. The gut microbiota composition of AD patients and AD mouse models is different from that of healthy controls, and these changes may affect the brain environment. However, the specific mechanisms by which gut microbiota that influence memory decline are currently unclear. In this study, we performed fecal microbiota transplantation (FMT) to clarify the role of 5xFAD mouse-derived microbiota in memory decline. We observed that FMT from 5xFAD mice into normal C57BL/6 mice (5xFAD-FMT) decreased adult hippocampal neurogenesis and brain-derived neurotrophic factor expression and increased p21 expression, resulting in memory impairment. Microglia in the hippocampus of the 5xFAD-FMT mice were activated, which caused the elevation of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1β). Moreover, we observed that pro-inflammatory cytokines increased in the colon and plasma of 5xFAD-FMT mice. The gut microbiota composition of the 5xFAD-FMT mice was different from that of the control mice or wild type-FMT mice. Collectively, 5xFAD mouse-derived microbiota decreased neurogenesis by increasing colonic inflammation, thereby contributing to memory loss. Our findings provide further evidence concerning the role of gut microbial dysbiosis in AD pathogenesis and suggest that targeting the gut microbiota may be a useful therapeutic strategy for the development of novel candidates for the treatment of AD.

Tg2576 transgenic mice for Alzheimer’s disease (AD) exhibited significant phenotypes for neuropathological constipation, but no research has been conducted on the association of the fecal microbiota with dysbiosis. The correlation between fecal microbiota composition and neuropathological constipation in Tg2576 mice was investigated by examining the profile of fecal microbiota and fecal microbiota transplantation (FMT) in 9–10-month-old Tg2576 mice with the AD phenotypes and constipation. Several constipation phenotypes, including stool parameters, colon length, and histopathological structures, were observed prominently in Tg2576 mice compared to the wild-type (WT) mice. The fecal microbiota of Tg2576 mice showed decreases in Bacteroidetes and increases in the Firmicutes and Proteobacteria populations at the phylum level. The FMT study showed that stool parameters, including weight, water content, and morphology, decreased remarkably in the FMT group transplanted with a fecal suspension of Tg2576 mice (TgFMT) compared to the FMT group transplanted with a fecal suspension of WT mice (WFMT). The distribution of myenteric neurons and the interstitial cells of Cajal (ICC), as well as the enteric nervous system (ENS) function, remained lower in the TgFMT group. These results suggest that the neuropathological constipation phenotypes of Tg2576 mice may be tightly linked to the dysbiosis of the fecal microbiota.

No abstract available

Emerging evidence implicates the gut microbiome in Alzheimer’s disease (AD) pathogenesis, yet the underlying mechanisms remain elusive. This study elucidates the bidirectional relationship between gut microbiota and AD using fecal microbiota transplantation (FMT) in a mouse model. Through meticulous experimentation, we conducted reciprocal FMT between AD (5xFAD) and healthy (C57BL/6) mice to unravel the impact of gut microbiome alterations on cognitive function and neuroinflammation. FMT from 5xFAD to C57BL/6 mice induced profound memory impairment and cognitive deficits, accompanied by elevated inflammatory cytokine levels, oxidative stress markers, and systemic inflammation, as evidenced by increased plasma cytokines. Conversely, transplanting healthy microbiota into 5xFAD mice yielded remarkable behavioral improvements, including enhanced spatial memory performance in the Morris water maze, directly correlating with cognitive recovery. Our findings underscore the pivotal role of the gut microbiome in AD pathogenesis and offer a promising therapeutic avenue. Targeted modulation of the gut microbiome through strategies like FMT may offer potential benefits in Alzheimer’s disease by influencing neuroinflammation, oxidative stress, and cognitive function. This comprehensive study provides novel insights into the gut-brain axis dynamics and paves the way for innovative microbiome-based interventions in AD management.

The growing body of evidence linking the gut microbiota to neurodegenerative disorders has revealed the gut–brain axis as a fundamental determinant in the pathogenesis of Alzheimer’s disease (AD). This review integrates molecular, clinical, and regional data to elucidate how intestinal dysbiosis contributes to neuroinflammation, amyloidogenesis, and cognitive decline. Studies consistently demonstrate a reduction in beneficial bacteria such as Bifidobacterium, Lactobacillus, and Faecalibacterium prausnitzii, accompanied by an increase in pro-inflammatory taxa including Escherichia/Shigella, Enterobacteriaceae, and Bacteroides. These alterations reduce short-chain fatty acid (SCFA) production, increase lipopolysaccharide (LPS) translocation, and disrupt intestinal and blood–brain barrier integrity, resulting in microglial activation, oxidative stress, and neuronal degeneration. Emerging therapeutic strategies—such as probiotics, prebiotics, fecal microbiota transplantation (FMT), polyphenols, and high-fiber diets—demonstrate significant promise in modulating microbial composition, reducing systemic inflammation, and improving cognitive outcomes. The analysis also incorporates perspectives from Mexico, Colombia, and Ecuador, emphasizing that cultural dietary practices and metabolic health disparities shape regional microbiome patterns and Alzheimer’s susceptibility. The integration of Latin American contexts underscores the need for population-specific studies that combine metagenomics, metabolomics, and clinical data to design preventive and therapeutic interventions. Altogether, this work supports a paradigm shift that redefines Alzheimer’s disease as a multisystemic inflammatory condition influenced by gut ecology and systemic metabolism. By preserving microbial diversity and intestinal health through nutritional, clinical, and policy-based strategies, it may be possible to delay neurodegenerative progression and protect cognitive function in aging populations worldwide. Protecting the gut means protecting the mind.

The gut microbiota has emerged as a fundamental regulator of sleep physiology, influencing neural, endocrine, and immune pathways through the gut-microbiota-brain axis (GMBA). This bidirectional communication system modulates neurotransmitter production, circadian rhythms, and metabolic homeostasis, while disruptions in microbial composition have been linked to sleep disorders, neuroinflammation, and systemic immune dysfunction. Recent findings suggest that gut dysbiosis contributes to sleep disturbances by altering serotonin, GABA, and short-chain fatty acid (SCFA) metabolism, with implications for neurodegenerative diseases, metabolic syndromes, and mood disorders. Additionally, the gut microbiota interacts with the endocrine and immune systems, shaping inflammatory responses and stress adaptation mechanisms. This review explores the intricate connections between sleep and the gut microbiota, integrating emerging research on microbiota-targeted therapies, such as probiotics, fecal microbiota transplantation (FMT), and chrononutrition, as potential interventions to restore sleep homeostasis and improve health outcomes

Alzheimer's disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. We generated a germ-free mouse model of Alzheimer's disease and discovered a drastic reduction of cerebral Ab amyloid pathology when compared to control Alzheimer's disease animals with intestinal microbiota. Sequencing bacterial 16S rRNA from fecal samples revealed a remarkable shift in the gut microbiota of conventionally-raised Alzheimer's disease mice as compared to healthy, wild-type mice. Colonization of germ-free Alzheimer mice with harvested microbiota from conventionally-raised Alzheimer mice dramatically increased cerebral Ab pathology. In contrast, colonization with microbiota from control wild-type mice was ineffective in increasing cerebral Ab levels. Our results indicate a microbial involvement in the development of Alzheimer's disease pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.

A system-level framework of complex microbe-microbe and host-microbe chemical cross-talk would help elucidate the role of our gut microbiota in health and disease. Here we report a literature-curated interspecies network of the human gut microbiota, called NJS16. This is an extensive data resource composed of ~570 microbial species and 3 human cell types metabolically interacting through >4,400 small-molecule transport and macromolecule degradation events. Based on the contents of our network, we develop a mathematical approach to elucidate representative microbial and metabolic features of the gut microbial community in a given population, such as a disease cohort. Applying this strategy to microbiome data from type 2 diabetes patients reveals a context-specific infrastructure of the gut microbial ecosystem, core microbial entities with large metabolic influence, and frequently-produced metabolic compounds that might indicate relevant community metabolic processes. Our network presents a foundation towards integrative investigations of community-scale microbial activities within the human gut.

Alzheimer's disease (AD) has emerged as a progressively pervasive neurodegenerative disorder worldwide. Bile acids, synthesized in the liver and modified by the gut microbiota, play pivotal roles in diverse physiological processes, and their dysregulation in individuals with AD has been well-documented. However, the protein targets associated with microbiota-derived bile acids in AD have received limited attention. To address this gap, we conducted comprehensive thermal proteomic analyses to unravel and comprehend the protein targets affected by microbiota-derived bile acids in AD. Our investigation identified sixty-five unique proteins as potential targets of deoxycholic acid (DCA), a primary component of the bile acid pool originating from the gut microbiota. Particularly noteworthy among these proteins were Nicastrin and Casein kinase 1 epsilon. We found that DCA, through its interaction with the Nicastrin subunit of γ-secretase, significantly contributed to the formation of amyloid beta, a key hallmark of AD pathology. Additionally, We observed substantial elevations in the urine levels of four bile acids (DCA, GHCA, GHDCA, and GUDCA) in AD patients compared to healthy controls. Moreover, the ratios of DCA to cholic acid (CA) and glycodeoxycholic acid (GDCA) to DCA were significantly increased in AD patients, indicating aberrations in the biosynthetic pathway responsible for bile acid dehydroxylation. The augmented levels of microbiota-derived bile acids and their altered ratios to primary bile acids exhibited notable associations with AD. Collectively, our findings provide crucial insights into the intricate interplay between microbiota-derived bile acids and the pathogenesis of AD, thereby shedding light on potential therapeutic targets for this debilitating disease.

The gut-brain axis has emerged as a key player in the regulation of brain function and cognitive health. Gut microbiota dysbiosis has been observed in preclinical models of Alzheimer's disease and patients. Manipulating the composition of the gut microbiota enhances or delays neuropathology and cognitive deficits in mouse models. Accordingly, the health status of the animal facility may strongly influence these outcomes. In the present study, we longitudinally analysed the faecal microbiota composition and amyloid pathology of 5XFAD mice housed in a specific opportunistic pathogen-free (SOPF) and a conventional facility. The composition of the microbiota of 5XFAD mice after aging in conventional facility showed marked differences compared to WT littermates that were not observed when the mice were bred in SOPF facility. The development of amyloid pathology was also enhanced by conventional housing. We then transplanted faecal microbiota (FMT) from both sources into wild-type (WT) mice and measured memory performance, assessed in the novel object recognition test, in transplanted animals. Mice transplanted with microbiota from conventionally bred 5XFAD mice showed impaired memory performance, whereas FMT from mice housed in SOPF facility did not induce memory deficits in transplanted mice. Finally, 18 weeks of housing SOPF-born animals in a conventional facility resulted in the reappearance of specific microbiota compositions in 5XFAD vs WT mice. In conclusion, these results show a strong impact of housing conditions on microbiota-associated phenotypes and question the relevance of breeding preclinical models in specific pathogen-free (SPF) facilities.

The intricate interplay between host organisms and their gut microbiota has catalyzed research into the microbiome's role in disease, shedding light on novel aspects of disease pathogenesis. However, the mechanisms through which the microbiome exerts its influence on disease remain largely unclear. In this study, we first introduce a structural equation model to delineate the pathways connecting the microbiome, metabolome, and disease processes, utilizing a target multiview microbiome data. To mitigate the challenges posed by hidden confounders, we further propose an integrative approach that incorporates data from an external microbiome cohort. This method also supports the identification of disease-specific and microbiome-associated metabolites that are missing in the target cohort. We provide theoretical underpinnings for the estimations derived from our integrative approach, demonstrating estimation consistency and asymptotic normality. The effectiveness of our methodologies is validated through comprehensive simulation studies and an empirical application to inflammatory bowel disease, highlighting their potential to unravel the complex relationships between the microbiome, metabolome, and disease.

Microbiota profiles measure the structure of microbial communities in a defined environment (known as microbiomes). In the past decade, microbiome research has focused on health applications as a result of which the gut microbiome has been implicated in the development of a broad range of diseases such as obesity, inflammatory bowel disease, and major depressive disorder. A key goal of many microbiome experiments is to characterise or describe the microbial community. High-throughput sequencing is used to generate microbiota profiles, but data gathered via this method are extremely challenging to analyse, as the data violate multiple strong assumptions of standard models. Rough Set Theory (RST) has weak assumptions that are less likely to be violated, and offers a range of attractive tools for extracting knowledge from complex data. In this paper we present the first application of RST for characterising microbiomes. We begin with a demonstrative benchmark microbiota profile and extend the approach to gut microbiomes gathered from depressed subjects to enable knowledge discovery. We find that RST is capable of excellent characterisation of the gut microbiomes in depressed subjects and identifying previously undescribed alterations to the microbiome-gut-brain axis. An important aspect of the application of RST is that it provides a possible solution to an open research question regarding the search for an optimal normalisation approach for microbiome census data, as one does not currently exist.

The human microbiome is a complex ecological system, and describing its structure and function under different environmental conditions is important from both basic scientific and medical perspectives. Viewed through a biostatistical lens, many microbiome analysis goals can be formulated as latent variable modeling problems. However, although probabilistic latent variable models are a cornerstone of modern unsupervised learning, they are rarely applied in the context of microbiome data analysis, in spite of the evolutionary, temporal, and count structure that could be directly incorporated through such models. We explore the application of probabilistic latent variable models to microbiome data, with a focus on Latent Dirichlet Allocation, Nonnegative Matrix Factorization, and Dynamic Unigram models. To develop guidelines for when different methods are appropriate, we perform a simulation study. We further illustrate and compare these techniques using the data of [10], a study on the effects of antibiotics on bacterial community composition. Code and data for all simulations and case studies are available publicly.

Studying the human microbiome has gained substantial interest in recent years, and a common task in the analysis of these data is to cluster microbiome compositions into subtypes. This subdivision of samples into subgroups serves as an intermediary step in achieving personalized diagnosis and treatment. In applying existing clustering methods to modern microbiome studies including the American Gut Project (AGP) data, we found that this seemingly standard task, however, is very challenging in the microbiome composition context due to several key features of such data. Standard distance-based clustering algorithms generally do not produce reliable results as they do not take into account the heterogeneity of the cross-sample variability among the bacterial taxa, while existing model-based approaches do not allow sufficient flexibility for the identification of complex within-cluster variation from cross-cluster variation. Direct applications of such methods generally lead to overly dispersed clusters in the AGP data and such phenomenon is common for other microbiome data. To overcome these challenges, we introduce Dirichlet-tree multinomial mixtures (DTMM) as a Bayesian generative model for clustering amplicon sequencing data in microbiome studies. DTMM models the microbiome population with a mixture of Dirichlet-tree kernels that utilizes the phylogenetic tree to offer a more flexible covariance structure in characterizing within-cluster variation, and it provides a means for identifying a subset of signature taxa that distinguish the clusters. We perform extensive simulation studies to evaluate the performance of DTMM and compare it to state-of-the-art model-based and distance-based clustering methods in the microbiome context. Finally, we report a case study on the fecal data from the AGP to identify compositional clusters among individuals with inflammatory bowel disease and diabetes.

Advances in next-generation sequencing technology have enabled the high-throughput profiling of metagenomes and accelerated the microbiome study. Recently, there has been a rise in quantitative studies that aim to decipher the microbiome co-occurrence network and its underlying community structure based on metagenomic sequence data. Uncovering the complex microbiome community structure is essential to understanding the role of the microbiome in disease progression and susceptibility. Taxonomic abundance data generated from metagenomic sequencing technologies are high-dimensional and compositional, suffering from uneven sampling depth, over-dispersion, and zero-inflation. These characteristics often challenge the reliability of the current methods for microbiome community detection. To this end, we propose a Bayesian stochastic block model to study the microbiome co-occurrence network based on the recently developed modified centered-log ratio transformation tailored for microbiome data analysis. Our model allows us to incorporate taxonomic tree information using a Markov random field prior. The model parameters are jointly inferred by using Markov chain Monte Carlo sampling techniques. Our simulation study showed that the proposed approach performs better than competing methods even when taxonomic tree information is non-informative. We applied our approach to a real urinary microbiome dataset from postmenopausal women, the first time the urinary microbiome co-occurrence network structure has been studied. In summary, this statistical methodology provides a new tool for facilitating advanced microbiome studies.

Many studies have been performed to characterize the dynamics and stability of the microbiome across a range of environmental contexts [Costello et al., 2012, Faust et al., 2015]. For example, it is often of interest to identify time intervals within which certain subsets of taxa have an interesting pattern of behavior. Viewed abstractly, these problems often have a flavor not just of time series modeling but also of regime detection, a problem with a rich history across a variety of applications, including speech recognition [Fox et al., 2011], finance [Lee, 2009], EEG analysis [Camilleri et al., 2014], and geophysics [Weatherley and Mora, 2002]. In spite of the parallels, regime detection methods are rarely used in microbiome analysis, most likely due to the fact that references for these methods are scattered across several literatures, descriptions are inaccessible outside limited research communities, and implementations are difficult to come across. We distill the core ideas of different regime detection methods, provide example applications, and share reproducible code, making these techniques more accessible to microbiome researchers. We re-analyze data of Dethlefsen and Relman [2011], a study of the effects of antibiotics on the microbiome, using Classification and Regression Trees (CART) [Breiman et al., 1984], Hidden Markov Models (HMMs) [Rabiner and Juang, 1986], Bayesian nonparametric HMMs [Teh and Jordan, 2010, Fox et al., 2008], mixtures of Gaussian Processes (GPs) [Rasmussen and Ghahramani, 2002], switching dynamical systems [Linderman et al., 2016], and multiple changepoint detection [Fan and Mackey, 2015]. Along the way, we summarize each method, their relevance to the microbiome, and tradeoffs associated with using them. Ultimately, our goal is to describe types of temporal or regime switching structure that can be incorporated into studies of microbiome dynamics.

The human microbiome is the ensemble of genes in the microbes that live inside and on the surface of humans. Because microbial sequencing information is now much easier to come by than phenotypic information, there has been an explosion of sequencing and genetic analysis of microbiome samples. Much of the analytical work for these sequences involves phylogenetics, at least indirectly, but methodology has developed in a somewhat different direction than for other applications of phylogenetics. In this paper I review the field and its methods from the perspective of a phylogeneticist, as well as describing current challenges for phylogenetics coming from this type of work.

The gut-brain axis is the communication link between the gut and the brain. Although it is known that the gut-brain axis plays a pivotal role in homeostasis, its overall mechanism is still not known. However, for neural synapses, classical molecular communication is described by the formation of ligand-receptor complexes, which leads to the opening of ion channels. Moreover, there are some conditions that need to be fulfilled before the opening of the ion channel. In this study, we consider the gut-brain axis, where neurotransmitters diffuse through the synaptic cleft, considering molecular communication. On the vagus nerve (VN) membrane, i.e., the post-synaptic membrane of the synapse, it undergoes a quantum communication (QC), which initiates the opening of the ion channel, thus initiating the communication signal from the gut to the brain. It evolves a new paradigm of communication approach, Molecular Quantum (MolQ) communication. Based on the QC model, we theoretically analyze the output states, and QC is simulated considering the incoming neurotransmitter's concentration and validated by analyzing the entropy and the mutual information of the input, i.e., neurotransmitter's concentration, and output, i.e., ion channel opening.

Molecular communication (MC) is a bio-inspired communication paradigm that utilizes molecules to transfer information and offers a robust framework for understanding biological signaling systems. This paper introduces a novel end-to-end MC framework for short-chain fatty acid (SCFA)-driven vagus nerve signaling within the gut-brain axis (GBA) to enhance our understanding of gut-brain communication mechanisms. SCFA molecules, produced by gut microbiota, serve as important biomarkers in physiological and psychological processes, including neurodegenerative and mental health disorders. The developed end-to-end model integrates SCFA binding to vagal afferent fibers, G protein-coupled receptor (GPCR)-mediated calcium signaling, and Hodgkin-Huxley-based action potential generation into a comprehensive vagus nerve signaling mechanism through GBA. Information-theoretic metrics such as mutual information and delay are used to evaluate the efficiency of this SCFA-driven signaling pathway model. Simulations demonstrate how molecular inputs translate into neural outputs, highlighting critical aspects that govern gut-brain communication. In this work, the integration of SCFA-driven signaling into the MC framework provides a novel perspective on gut-brain communication and paves the way for the development of innovative therapeutic advancements targeting neurological and psychiatric disorders.

There has been a growing acknowledgement of the involvement of the gut microbiome - the collection of microbes that reside in our gut - in regulating our mood and behaviour. This phenomenon is referred to as the microbiome-gut-brain axis. While our techniques to measure the presence and abundance of these microbes have been steadily improving, the analysis of microbiome data is non-trivial. Here, we present a perspective on the concepts and foundations of data analysis and interpretation of microbiome experiments with a focus on the microbiome-gut-brain axis domain. We give an overview of foundational considerations prior to commencing analysis alongside the core microbiome analysis approaches of alpha diversity, beta diversity, differential feature abundance and functional inference. We emphasize the compositional data analysis (CoDA) paradigm. Further, this perspective features an extensive and heavily annotated microbiome analysis in R in the supplementary materials, as a resource for new and experienced bioinformaticians alike.

Molecular communication (MC) provides a quantitative framework for analyzing information transfer within biological systems. This paper introduces a novel and comprehensive MC framework for the gut-brain axis (GBA) as a system of six coupled, nonlinear delay differential equations (DDEs). The proposed model defines a bidirectional feedback loop with a gut-to-brain inflammatory channel and a brain-to-gut neuroendocrine channel. Under prolonged stress, this feedback loop becomes self-perpetuating and drives the system into a pathological state. We evaluate the end-to-end channel across varying conditions using time-domain simulations, small-signal frequency-domain characterization, and an information-theoretic capacity analysis. At homeostasis, the system maintains stable circadian dynamics with higher information throughput, whereas sustained stress drives a shift to dysregulated hypercortisolism. In this pathological state, spectral efficiency decreases due to a narrowed effective bandwidth and a lower passband gain driven by neuroendocrine delays and saturating cytokine-hormone kinetics. These results quantify the impact of these signaling mechanisms on stability and information processing, elucidating the transition from healthy circadian rhythms to a persistent pathological state of hypercortisolism.

We present q2-fmt, a QIIME 2 plugin that provides diverse methods for assessing the extent of microbiome engraftment following fecal microbiota transplant. The methods implemented here were informed by a recent literature review on approaches for assessing FMT engraftment, and cover aspects of engraftment including Chimeric Asymmetric Community Coalescence, Donated Microbiome Indicator Features, and Temporal Stability. q2-fmt is free for all use, and detailed documentation illustrating worked examples on a real-world data set are provided in the project's documentation.

Computational topologists recently developed a method, called persistent homology to analyze data presented in terms of similarity or dissimilarity. Indeed, persistent homology studies the evolution of topological features in terms of a single index, and is able to capture higher order features beyond the usual clustering techniques. There are three descriptive statistics of persistent homology, namely barcode, persistence diagram and more recently, persistence landscape. Persistence landscape is useful for statistical inference as it belongs to a space of $p-$integrable functions, a separable Banach space. We apply tools in both computational topology and statistics to DNA sequences taken from Clostridioides difficile infected patients treated with an experimental fecal microbiota transplantation. Our statistical and topological data analysis are able to detect interesting patterns among patients and donors. It also provides visualization of DNA sequences in the form of clusters and loops.

Fecal Microbiota Transplant (FMT) is an FDA approved treatment for recurrent Clostridium difficile infections, and is being explored for other clinical applications, from alleviating digestive and neurological disorders, to priming the microbiome for cancer treatment, and restoring microbiomes impacted by cancer treatment. Quantifying the extent of engraftment following an FMT is important in determining if a recipient didn't respond because the engrafted microbiome didn't produce the desired outcomes (a successful FMT, but negative treatment outcome), or the microbiome didn't engraft (an unsuccessful FMT and negative treatment outcome). The lack of a consistent methodology for quantifying FMT engraftment extent hinders the assessment of FMT success and its relation to clinical outcomes, and presents challenges for comparing FMT results and protocols across studies. Here we review 46 studies of FMT in humans and model organisms and group their approaches for assessing the extent to which an FMT engrafts into three criteria: 1) Chimeric Asymmetric Community Coalescence investigates microbiome shifts following FMT engraftment. 2) Donated Microbiome Indicator Features tracks donated microbiome features as a signal of engraftment with methods such as differential abundance testing based on the current sample collection, or tracking changes in feature abundances that have been previously identified. 3) Temporal Stability examines how resistant post-FMT recipient's microbiomes are to reverting back to their baseline microbiome. Investigated together, these criteria provide a clear assessment of microbiome engraftment. We discuss the pros and cons of each of these criteria, providing illustrative examples of their application. We also introduce key terminology and recommendations on how FMT studies can be analyzed for rigorous engraftment extent assessment.

This study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer's disease (AD) pathogenesis. We analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors. Microbial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients' gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors' microbiota transplants. These findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of Bacteroides and LPC. This study thus identifies a B.ovatus-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.

The oral cavity is the initial chamber of digestive tract; the saliva swallowed daily contains an estimated 1.5 × 10

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Currently, no effective treatment is available that can slow or halt the progression of the disease. The gut microbiota can modulate the host immune system in the peripheral and central nervous system through the microbiota-gut-brain axis. Growing evidence indicates that gut microbiota dysbiosis plays an important role in the pathogenesis of AD, and modulation of the gut microbiota may represent a new avenue for treating AD. Immunotherapy targeting Aβ and tau has emerged as the most promising disease-modifying therapy for the treatment of AD. However, the underlying mechanism of AD immunotherapy is not known. Importantly, preclinical and clinical studies have highlighted that the gut microbiota exerts a major influence on the efficacy of cancer immunotherapy. However, the role of the gut microbiota in AD immunotherapy has not been explored. We found that immunotherapy targeting tau can modulate the gut microbiota in an AD mouse model. In this article, we focused on the crosstalk between the gut microbiota, immunity, and AD immunotherapy. We speculate that modulation of the gut microbiota induced by AD immunotherapy may partially underlie the efficacy of the treatment.

Previous studies suggest that gut microbiota is associated with neuropsychiatric disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, and depression. However, whether the composition and diversity of gut microbiota is altered in patients with Alzheimer's disease (AD) remains largely unknown. In the present study, we collected fecal samples from 43 AD patients and 43 age- and gender-matched cognitively normal controls. 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. The composition of gut microbiota was different between the two groups. Several bacteria taxa in AD patients were different from those in controls at taxonomic levels, such as Bacteroides, Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales. Our findings suggest that gut microbiota is altered in AD patients and may be involved in the pathogenesis of AD.

Some studies have shown that gut microbiota may be associated with dementia. However, the causal effects between gut microbiota and different types of dementia and whether cytokines act as a mediator remain unclear. Gut microbiota, cytokines, and five dementia types, including Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy body (DLB), vascular dementia (VD), and Parkinson's disease dementia (PDD) were identified from large-scale genome-wide association studies (GWAS) summary data. We used Mendelian randomization (MR) to investigate the causal relationships between gut microbiota, cytokines, and five types of dementia. Inverse variance weighting (IVW) was used as the main statistical method. In addition, we explored whether cytokines act as a mediating factor in the pathway from gut microbiota to dementia. There were 20 positive and 16 negative causal effects between genetic liability in the gut microbiota and dementia. Also, there were five positive and four negative causal effects between cytokines and dementias. Cytokines did not act as mediating factors. Gut microbiota and cytokines were causally associated with five types of dementia, and cytokines seemed not to be the mediating factors in the pathway from gut microbiota to dementia.

Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

Alzheimer's disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with β-amyloid (Aβ) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.

Clinical and animal studies have shown that gut microbiome disturbances can affect neural function and behaviors via the microbiota-gut-brain axis, and may be implicated in the pathogenesis of several brain diseases. However, exactly how the gut microbiome modulates nervous system activity remains obscure. Here, using a single-cell nucleus sequencing approach, we sought to characterize the cell type-specific transcriptomic changes in the prefrontal cortex and hippocampus derived from germ-free (GF), specific pathogen free, and colonized-GF mice. We found that the absence of gut microbiota resulted in cell-specific transcriptomic changes. Furthermore, microglia transcriptomes were preferentially influenced, which could be effectively reversed by microbial colonization. Significantly, the gut microbiome modulated the mutual transformation of microglial subpopulations in the two regions. Cross-species analysis showed that the transcriptome changes of these microglial subpopulations were mainly associated with Alzheimer's disease (AD) and major depressive disorder (MDD), which were further supported by animal behavioral tests. Our findings demonstrate that gut microbiota mainly modulate the mutual transformation of microglial subtypes, which may lead to new insights into the pathogenesis of AD and MDD.

Alzheimer's disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer's disease by showing specific alterations in the gut microbiome composition of Alzheimer's patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer's symptoms. To understand the involvement of Alzheimer's patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer's patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer's patient transplants. Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer's systemic environment on proxy neurogenesis readouts. Serum from Alzheimer's patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer's symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer's disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer's.

Several studies have reported alterations in gut microbiota composition of Alzheimer's disease (AD) patients. However, the observed differences are not consistent across studies. We aimed to investigate associations between gut microbiota composition and AD biomarkers using machine learning models in patients with AD dementia, mild cognitive impairment (MCI) and subjective cognitive decline (SCD). We included 170 patients from the Amsterdam Dementia Cohort, comprising 33 with AD dementia (66 ± 8 years, 46%F, mini-mental state examination (MMSE) 21[19-24]), 21 with MCI (64 ± 8 years, 43%F, MMSE 27[25-29]) and 116 with SCD (62 ± 8 years, 44%F, MMSE 29[28-30]). Fecal samples were collected and gut microbiome composition was determined using 16S rRNA sequencing. Biomarkers of AD included cerebrospinal fluid (CSF) amyloid-beta 1-42 (amyloid) and phosphorylated tau (p-tau), and MRI visual scores (medial temporal atrophy, global cortical atrophy, white matter hyperintensities). Associations between gut microbiota composition and dichotomized AD biomarkers were assessed with machine learning classification models. The two models with the highest area under the curve (AUC) were selected for logistic regression, to assess associations between the 20 best predicting microbes and the outcome measures from these machine learning models while adjusting for age, sex, BMI, diabetes, medication use, and MMSE. The machine learning prediction for amyloid and p-tau from microbiota composition performed best with AUCs of 0.64 and 0.63. Highest ranked microbes included several short chain fatty acid (SCFA)-producing species. Higher abundance of Gut microbiota composition was associated with amyloid and p-tau status. We extend on recent studies that observed associations between SCFA levels and AD CSF biomarkers by showing that lower abundances of SCFA-producing microbes were associated with higher odds of positive amyloid and p-tau status.

Alzheimer's disease (AD) prevalence is increasing, but its etiology remains elusive. Gut microbes can contribute to AD pathology and may help identifying novel markers and therapies against AD. Herein, we examine how the gut microbiome differs in older adults with mild cognitive impairment compared to cognitively normal counterparts, and whether and how a modified Mediterranean-ketogenic diet (MMKD) alters the gut microbiome signature in association with cerebrospinal fluid (CSF) AD biomarkers. A randomized, double-blind, cross-over, single-center pilot study of MMKD versus American Heart Association Diet (AHAD) intervention is performed on 17 subjects (age: 64.6 ± 6.4 yr), of which 11 have mild cognitive impairment, while 6 are cognitively normal. Subjects undergo MMKD and AHAD intervention for 6-weeks separated by 6-weeks washout periods. Gut microbiome, fecal short-chain fatty acids (SCFAs), and markers of AD in CSF including amyloid β (Aβ)-40 and Aß-42, total tau, and phosphorylated tau-181 (tau-p181) are measured at before and after diet interventions. At baseline, subjects with normal vs. impaired cognition show no notable difference in microbiome diversity but several unique microbial signatures are detected in subjects with mild cognitive impairment. Proteobacteria correlate positively with Aβ-42: Aβ-40 while fecal propionate and butyrate correlates negatively with Aβ-42 in subjects with mild cognitive impairment. Several bacteria are differently affected by the two diets with distinct patterns between cognitively normal and impaired subjects. Notably, the abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae and Erysipelotriaceae increases while that of Bifidobacterium and Lachnobacterium reduces on MMKD, while AHAD increases Mollicutes. MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate. Conversely, AHAD increases acetate and propionate while reducing butyrate. The data suggest that specific gut microbial signatures may depict the mild cognitive impairment and that the MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers in CSF.

Alzheimer's disease (AD) is characterized by amyloid-β accumulation in the brain and hyperphosphorylated tau aggregation, as well as neuroinflammation. The gut-brain axis has emerged as a therapeutic target in neurodegenerative diseases by modulating metabolic activity, neuroimmune functions and sensory neuronal signaling. Here we investigate interactions between orally ingested chiral Au nanoparticles and the gut microbiota in AD mice. Oral administration of chiral Au nanoparticles restored cognitive abilities and ameliorated amyloid-β and hyperphosphorylated tau pathologies in AD mice via alterations in the gut microbiome composition and an increase in the gut metabolite, indole-3-acetic acid, which was lower in serum and cerebrospinal fluid of patients with AD compared with age-matched controls. Oral administration of indole-3-acetic acid was able to penetrate the blood-brain barrier and alleviated cognitive decline and pathology including neuroinflammation in AD mice. These findings provide a promising therapeutic target for the amelioration of neuroinflammation and treatment of neurodegenerative diseases.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive deficits and psychiatric symptoms. The gut microbiota-brain axis plays a pivotal role during AD development, which could target nutritional intervention. The prebiotic mannan oligosaccharide (MOS) has been reported to reshape the gut microbiome and enhanced the formation of the neuroprotective metabolites short-chain fatty acids (SCFAs). Here, we found that an 8-week treatment of MOS (0.12%, w/v in the drinking water) significantly improved cognitive function and spatial memory, accompanied by attenuated the anxiety- and obsessive-like behaviors in the 5xFAD transgenic AD mice model. MOS substantially reduced the Aβ accumulation in the cortex, hippocampus, and amygdala of the brain. Importantly, MOS treatment significantly balanced the brain redox status and suppressed the neuroinflammatory responses. Moreover, MOS also alleviated the HPA-axis disorders by decreasing the levels of hormones corticosterone (CORT) and corticotropin-releasing hormone (CRH) and upregulated the norepinephrine (NE) expressions. Notably, the gut barrier integrity damage and the LPS leak were prevented by the MOS treatment. MOS re-constructed the gut microbiota composition, including increasing the relative abundance of Lactobacillus and reducing the relative abundance of Helicobacter. MOS enhanced the butyrate formation and related microbes levels. The correlation analysis indicated that the reshaped gut microbiome and enhanced butyrate formation are highly associated with behavioral alteration and brain oxidative status. SCFAs supplementation experiment also attenuated the behavioral disorders and Aβ accumulation in the AD mice brain, accompanied by balanced HPA-axis and redox status. In conclusion, the present study indicated that MOS significantly attenuates the cognitive and mental deficits in the 5xFAD mice, which could be partly explained by the reshaped microbiome and enhanced SCFAs formation in the gut. MOS, as a prebiotics, can be translated into a novel microbiota-targeted approach for managing metabolic and neurodegenerative diseases.

Peripheral β-amyloid (Aβ), including those contained in the gut, may contribute to the formation of Aβ plaques in the brain, and gut microbiota appears to exert an impact on Alzheimer's disease (AD) via the gut-brain axis, although detailed mechanisms are not clearly defined. The current study focused on uncovering the potential interactions among gut-derived Aβ in aging, gut microbiota, and AD pathogenesis. To achieve this goal, the expression levels of Aβ and several key proteins involved in Aβ metabolism were initially assessed in mouse gut, with key results confirmed in human tissue. The results demonstrated that a high level of Aβ was detected throughout the gut in both mice and human, and gut Aβ42 increased with age in wild type and mutant amyloid precursor protein/presenilin 1 (APP/PS1) mice. Next, the gut microbiome of mice was characterized by 16S rRNA sequencing, and we found the gut microbiome altered significantly in aged APP/PS1 mice and fecal microbiota transplantation (FMT) of aged APP/PS1 mice increased gut BACE1 and Aβ42 levels. Intra-intestinal injection of isotope or fluorescence labeled Aβ combined with vagotomy was also performed to investigate the transmission of Aβ from gut to brain. The data showed that, in aged mice, the gut Aβ42 was transported to the brain mainly via blood rather than the vagal nerve. Furthermore, FMT of APP/PS1 mice induced neuroinflammation, a phenotype that mimics early AD pathology. Taken together, this study suggests that the gut is likely a critical source of Aβ in the brain, and gut microbiota can further upregulate gut Aβ production, thereby potentially contributing to AD pathogenesis.

Numerous studies have described the notable impact of gut microbiota on the brain in Alzheimer's disease (AD) via the gut - brain axis. However, the molecular mechanisms underlying the involvement of gut microbiota in the development of AD are limited. This study aimed to explore the potential mechanisms of gut microbiota in AD by integrating multi-omics data. In this study, APP/PS1 and WT mice at nine months of age were used as study mouse model. Cognitive function was assessed using the Morris water maze test. The levels of Aβ plaque and neuroinflammation in the brain were detected using immunofluorescence and PET/CT. In addition, we not only used 16S rRNA gene sequencing and metabolomics to explore the variation characteristics of gut microbiota and serum metabolism abundance, but also combined spatial metabolomics and transcriptomics to explore the change in the brain and identify their potential correlation. APP/PS1 mice showed significant cognitive impairment and amyloid-β deposits in the brain. The abundance of gut microbiota was significantly changed in APP/PS1 mice, including decreased

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a decade-long preclinical pathological period that can be divided into several stages. Emerging evidence has revealed that the microbiota-gut-brain axis plays an important role in AD pathology. However, the role of gut microbiota in different AD stages has not been well characterized. In this study, we performed fecal shotgun metagenomic analysis on a Chinese cohort with 476 participants across five stages of AD pathology to characterize stage-specific alterations in gut microbiota and evaluate their diagnostic potential. We discovered extensive gut dysbiosis that is associated with neuroinflammation and neurotransmitter dysregulation, with over 10% of microbial species and gene families showing significant alterations during AD progression. Furthermore, we demonstrated that microbial gene families exhibited strong diagnostic capabilities, evidenced by an average AUC of 0.80 in cross-validation and 0.75 in independent external validation. In the optimal model, the most discriminant gene families are primarily involved in the metabolism of carbohydrates, amino acids, energy, glycan and vitamins. We found that stage-specific microbial gene families in AD pathology could be validated by an in vitro gut simulator and were associated with specific genera. We also observed that the gut microbiota could affect the progression of cognitive decline in 5xFAD mice through fecal microbiota transplantation, which could be used for early intervention of AD. Our multi-stage large cohort metagenomic analysis demonstrates that alterations in gut microbiota occur from the very early stages of AD pathology, offering important etiological and diagnostic insights.

Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer's disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive. Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLP Composition of the gut microbiota in ADLP These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLP