The relationship between bacteria, cognitive function and obesity is well established, yet the role of archaeal species remains underexplored. We used shotgun metagenomics and neuropsychological tests to identify microbial species associated with cognition in a discovery cohort (IRONMET, n = 125). Interestingly, methanogen archaeas exhibited the strongest positive associations with cognition, particularly Methanobrevibacter smithii (M. smithii). Stratifying individuals by median-centered log ratios (CLR) of M. smithii (low and high M. smithii groups: LMs and HMs) revealed that HMs exhibited better cognition and distinct gut bacterial profiles (PERMANOVA p = 0.001), characterized by increased levels of Verrucomicrobia, Synergistetes and Lentisphaerae species and reduced levels of Bacteroidetes and Proteobacteria. Several of these species were linked to the cognitive test scores. These findings were replicated in a large-scale validation cohort (Aging Imageomics, n = 942). Functional analyses revealed an enrichment of energy, butyrate, and bile acid metabolism in HMs in both cohorts. Global plasma metabolomics by CIL LC-MS in IRONMET identified an enrichment of methylhistidine, phenylacetate, alpha-linolenic and linoleic acid, and secondary bile acid metabolism associated with increased levels of 3-methylhistidine, phenylacetylgluamine, adrenic acid, and isolithocholic acid in the HMs group. Phenylacetate and linoleic acid metabolism also emerged in the Aging Imageomics cohort performing untargeted HPLC-ESI-MS/MS metabolic profiling, while a targeted bile acid profiling identified again isolithocholic acid as one of the most significant bile acid increased in the HMs. 3-Methylhistidine levels were also associated with intense physical activity in a second validation cohort (IRONMET-CGM, n = 116). Finally, FMT from HMs donors improved cognitive flexibility, reduced weight, and altered SCFAs, histidine-, linoleic acid- and phenylalanine-related metabolites in the dorsal striatum of recipient mice. M. smithii seems to interact with the bacterial ecosystem affecting butyrate, histidine, phenylalanine, and linoleic acid metabolism with a positive impact on cognition, constituting a promising therapeutic target to enhance cognitive performance, especially in subjects with obesity.

Multiple sclerosis (MS) is defined as an inflammatory disorder that chronically affects the central nervous system of young people mostly and is distributed globally. It is associated with degeneration and demyelination of the myelin sheath around the nerves, resulting in multiple neurological disability symptoms ranging from mild to severe cases that end with paralysis sometimes. MS is one of the rising diseases globally that is unfortunately associated with reduced quality of life and adding national economic burdens. The definite MS mechanism is not clearly defined; however, all the previous researches confirm the role of the immune system as the master contributor in the pathogenesis. Innate and adaptive immune cells are activated peripherally then attracted toward the central nervous system (CNS) due to the breakdown of the blood-brain barrier. Recently, the gut-brain axis was shown to depend on gut metabolites that are produced by different microorganisms in the colon. The difference in microbiota composition between individuals is responsible for diversity in secreted metabolites that affect immune responses locally in the gut or systemically when reach blood circulation to the brain. It may enhance or suppress immune responses in the central nervous system (CNS) (repeated short forms); consequently, it may exacerbate or ameliorate MS symptoms. Recent data showed that some metabolites can be used as adjuvant therapy in MS and other inflammatory diseases. This review sheds light on the nature of MS and the possible interaction between gut microbiota and immune system regulation through the gut-brain axis, hence contributing to MS pathogenesis.

Multiple sclerosis (MS) is the most common demyelinating disease caused by a multifaceted interplay of genetic predispositions and environmental factors. Most patients initially experience the relapsing-remitting form of the disease (RRMS), which is characterized by episodes of neurological deficits followed by periods of symptom resolution. However, over time, many individuals with RRMS advance to a progressive form of the disease, known as secondary progressive MS (SPMS), marked by a gradual worsening of symptoms without periods of remission. The mechanisms underlying this transition remain largely unclear, and current disease-modifying therapies (DMTs) are partially effective in treating SPMS. Age is widely acknowledged as a risk factor for the transition from RRMS to SPMS. One factor associated with aging that may influence the progression of MS is gut dysbiosis. This review discusses how aging and age-related gut dysbiosis affect the progression of MS.

Modulation of the gut microbiota composition has been suggested as a potential disease modifying therapy in immune-mediated diseases such as multiple sclerosis (MS). However, a conclusive mechanism linking gut microbiota modulation to peripheral immune responses has remained elusive so far.

In this exploratory cohort study, people with MS (pwMS) and healthy controls (HC) supplemented a lactobacilli-rich probiotic for two or six weeks and were additionally investigated six weeks after the last intake. Immune cell phenotyping was performed in blood samples, complemented by mRNA expression analysis, serum cytokine measurements, and Treg suppression assays. Besides gut microbiota composition analysis, metabolite production was investigated in stool and serum. Links between metabolites and peripheral immune system were investigated in in vitro T cell differentiation assays.

In peripheral blood, Treg cells increased in both groups, while Th1 cells were significantly reduced in pwMS. This promotion of a regulatory immunophenotype was complemented by increased concentrations of IL-10 in serum and higher expression of IL10 and CTLA4. Functional assays revealed an enhanced suppressive capacity of Treg cells due to the probiotic intervention. The tryptophan metabolite indole-3-acetate (IAA) increased in stool and serum samples of pwMS during the probiotic intake. In vitro, IAA specifically enhanced the formation of IL-10 secreting T cells together with CYP1a1 expression. This effect was blocked by addition of an aryl hydrocarbon receptor (AHR) inhibitor.

A lactobacilli-enriched probiotic promotes a regulatory immunophenotype in pwMS, probably by enhancing AHR agonists in the gut. It may be of interest as add-on therapy in immune-mediated diseases such as MS.

This study has in part been funded by Novartis Pharma GmbH and BMBF grant no. 01EJ2202B.

The gut microbiome is altered in MS and may contribute to disease by disrupting the intestinal barrier. The colonic mucus barrier, which is primarily composed of mucin protein 2 (MUC2), plays a crucial role in providing a barrier between colonic epithelial cells and the microbiome. Disruption of intestinal epithelial and mucus barriers has been reported in inflammatory bowel disease (IBD) and Parkinson's disease (PD) but has not been studied in the context of the microbiome in multiple sclerosis (MS).

We investigated the epithelial tight junction protein zonulin occludins 1 (ZO-1), mucus protein MUC2, inflammatory stool markers (calprotectin), and gut microbiota composition in a cohort of subjects with relapsing and progressive MS.

MUC2 was decreased in stool of subjects with both relapsing and progressive MS. ZO-1 was elevated in the serum of subjects with progressive MS but was not altered in the stool. Inflammatory markers typically elevated in IBD and PD, including calprotectin, were not altered in MS stool, suggesting disease specificity of altered gut physiology in MS. Microbiota with known mucus degrading capacity were elevated in the stool of subjects with MS and negatively correlated with mucus protein levels.

Taken together, these findings suggest reduced gut barrier function in MS which is linked to increased mucin degrading bacteria.

This work was supported by grants from the National MS Society, the NIH/NINDS, the Nancy Davis Race to Erase MS Young Investigator Award, the Water Cove Charitable Foundation, and the Clara E. and John H. Ware Jr.

There is strong interest in using the gut microbiome for Parkinson's disease (PD) diagnosis and treatment. However, a consensus on PD-associated microbiome features and a multi-study assessment of their diagnostic value is lacking. Here, we present a machine learning meta-analysis of PD microbiome studies of unprecedented scale (4489 samples). Within most studies, microbiome-based machine learning models accurately classify PD patients (average AUC 71.9%). However, these models are study-specific and do not generalise well across other studies (average AUC 61%). Training models on multiple datasets improves their generalizability (average LOSO AUC 68%) and disease specificity as assessed against microbiomes from other neurodegenerative diseases. Moreover, meta-analysis of shotgun metagenomes delineates PD-associated microbial pathways potentially contributing to gut health deterioration and favouring the translocation of pathogenic molecules along the gut-brain axis. Strikingly, microbial pathways for solvent and pesticide biotransformation are enriched in PD. These results align with epidemiological evidence that exposure to these molecules increases PD risk and raise the question of whether gut microbes modulate their toxicity. Here, we offer the most comprehensive overview to date about the PD gut microbiome and provide future reference for its diagnostic and functional potential.

The importance of the microbiome, particularly the gut microbiota and its implications for health, is well established. However, an increasing number of studies further strengthen the link between an imbalanced gut microbiota and a greater predisposition to different diseases. The gut microbiota constitutes a fundamental ecosystem for maintaining human health. Its alteration, known as dysbiosis, is associated with a wide range of conditions, including intestinal, metabolic, immunological, or neurological pathologies, among others. In recent years, there has been a substantial increase in knowledge about probiotics-bacterial species that enhance health or address various diseases-with numerous studies reporting their benefits in preventing or improving these conditions. This review aims to analyze the most common pathologies resulting from an imbalance in the gut microbiota, as well as detail the most important and known gut probiotics, their functions, and mechanisms of action in relation to these conditions.

Gut commensals regulate neurological disorders through dynamic bidirectional communication along the gut-brain axis. Recent evidence has highlighted the well-documented beneficial role of the commensal gut bacterium Akkermansia muciniphila and its components in promoting host health. However, numerous clinical studies have demonstrated a paradoxical role of A. muciniphila in individuals with various neurological conditions. In this opinion article, we review the correlation between the prevalence of this gut commensal and the development of several disorders, including stroke, multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). We focus on the potential mechanisms by which A. muciniphila may contribute to these diseases. An in-depth understanding of these correlations and the underlying pathogenic mechanisms could shed new light on the mechanisms of disease pathogenesis and provide a logical rationale for developing new therapies for these neurological conditions.

This study aimed to determine the effects of the Mediterranean diet (MD) and lycopene on the development of EAE and on inflammatory markers. In the 43-day study, 72 female C57BL/6 mice were randomly divided into eight groups according to whether they were EAE or naive (control) mice, fed a Western diet or a MD, and whether they received lycopene. During the study, mice were fed ad libitum, and lycopene groups were given 10 mg/kg/day lycopene per mouse every other day for 28 days in oral gavage. The mice were scored for EAE, sacrificed and their spleen, lymph nodes, and spinal cords were removed. We observed slightly delayed EAE onset in the MD-Lyc group compared to the others, and the EAE clinical scores were also lower than in the other groups. T-cell counts in the spleen and lymph nodes of the MD-Lyc group were significantly lower than in other groups. The production of IFN-γ and IL-22 was higher than in the other groups. IL-17 A cytokine produced in the spleen was lower in the MD-Lyc group than in the other groups. In addition, the highest myelination score was seen in the MD-Lyc group. MD-Lyc group also had a unique microbiome profile compared with the remaining groups. In summary, MD and lycopene administration positively impacted EAE scores and myelination. However, more comprehensive studies at the in vitro and in vivo levels are needed to reveal the effect of this intervention on cell numbers in the CNS.

Helicobacter pylori (H. pylori) infection has the capacity to alter the gut microbiota composition. There is a significant correlation between H. pylori infection and type 2 diabetes mellitus (T2DM). Further research is necessary to explore whether gut microbiota plays a role in the relationship between H. pylori and T2DM.

Fecal samples were obtained from 44 patients with T2DM, including 20 who tested positive for H. pylori and 24 who tested negative. Intestinal microbiota composition was analyzed via 16S rRNA V3-V4 amplicon sequencing. Differences in microbial distribution and significant microbial biomarkers were identified between H. pylori positive and negative groups. A Spearman correlation analysis assessed the relationship between intestinal microbiota and glycemic parameters. Additionally, PICRUSt2 was used to predict intestinal bacterial functions.

Results indicate that in H. pylori (+) T2DM patients, HbA1c levels were significantly higher (8.9% vs. 8.1%, p = 0.021), while both the C-peptide peak (3.70 vs. 5.98 ng/mL, p = 0.040) and fasting C-peptide levels (1.42 vs. 2.31 ng/mL, p = 0.008) were significantly lower compared to H. pylori (-) T2DM groups. A total of 11 colonic phyla and 100 genera were identified in all fecal samples. In groups positive for H. pylori, there was a significant enrichment of the phylum Proteobacteria, while the genera Lactobacillus, Butyricimonas, and Akkermansia were significantly reduced (all p < 0.05). Correlation analysis showed that the abundance of the genera Butyricimonas (p = 0.01) and Akkermansia (p = 0.048) were negatively correlated with fasting plasma glucose. KEGG pathway analysis indicated a significant enrichment of methylmalonyl-CoA mutase and succinyl-CoA in H. pylori-infected T2DM patients.

This study suggests that T2DM patients with H. pylori infection exhibit more impaired pancreatic islet function potentially due to H. pylori-induced alterations in the gut microbiota.

From a biological point of view, Diversity, Equity, and Inclusion (DEI) are important at multiple levels, which include our genetics, microbiomes, diets, and all organ system interactions. Considering only DEI's sociological aspects is equivalent to the error of "throwing out the baby with the bath water." Variances in microbial diversity within our microbiomes might affect our health through systemic interactions affecting metabolites, maintaining immune homeostasis, and wound healing of cellular damage from an infection, physical stress, or psychological trauma. An imbalance of our immune cell subsets, both innate and adaptive, and the microbes in any of our microbiomes might lead to more cellular damage from excessive inflammation and oxidative stress and less immune regulation. The immune dysregulation may occur due to the loss of endometrial barriers enabling the spread of microbes, environmental pollutants, and allergens. Heat waves, sleep deprivation, and increased prevalence of pollutants such as polychlorinated biphenyls, which weaken endothelial barriers, may be responsible for the enhanced prevalence of physical and psychological stresses. Leakage of our useful gut microbiota into the periphery might initiate inflammatory responses, and an altered gut microbiome might affect the gut-brain axis that influences physical and mental health.

Multiple sclerosis (MS) is a well-known, chronic autoimmune disorder of the central nervous system (CNS) involving demyelination and neurodegeneration. Research previously conducted in the area of the gut microbiome has highlighted it as a critical contributor to MS pathogenesis. Changes in the commensal microbiota, or dysbiosis, have been shown to affect immune homeostasis, leading to elevated levels of pro-inflammatory cytokines and disruption of the gut-brain axis. In this review, we provide a comprehensive overview of interactions between the gut microbiota and MS, especially focusing on the immunomodulatory actions of microbiota, such as influencing T-cell balance and control of metabolites, e.g., short-chain fatty acids. Various microbial taxa (e.g., Prevotella and Faecalibacterium) were suggested to lay protective roles, whereas Akkermansia muciniphila was associated with disease aggravation. Interventions focusing on microbiota, including probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary therapies to normalize gut microbial homeostasis, suppress inflammation and are proven to improve clinical benefits in MS patients. Alterations in gut microbiota represent opportunities for identifying biomarkers for early diagnosis, disease progression and treatment response monitoring. Further studies need to be conducted to potentially address the interplay between genetic predispositions, environmental cues, and microbiota composition to get the precise mechanisms of the gut-brain axis in MS. In conclusion, the gut microbiota plays a central role in MS pathogenesis and offers potential for novel therapeutic approaches, providing a promising avenue for improving clinical outcomes in MS management.

Progressive multiple sclerosis (MS) is a neurological disease with limited understanding of the biology associated with transition from relapsing to progressive disease. Intestinal microbes and metabolites are altered in MS, but relation to disease progression is largely unknown. We investigate microbiota and metabolites in subjects with stable MS, those who worsened, and in those with relapsing MS who became progressive over 2 years. We find that Eubacterium hallii, Butyricoccaceae, Blautia, and other short-chain fatty-acid-producing microbes have beneficial associations with worsening of disability, 3T magnetic resonance imaging (MRI) measures, cognition, and quality of life, while Alistipes is detrimentally associated. Global metabolomics identified serum and stool metabolites that are altered in progressive MS and in relapsing subjects who transitioned to progressive disease. Most fecal metabolites associated with disease progression are decreased, suggesting a deficiency of protective factors in the gut. Using a unique MS cohort, our findings identify gut microbiome and metabolite pathways influencing progressive MS.

The past 25 years have brought extraordinary advances in our understanding of MS pathogenesis and the subsequent development of effective therapies. Collaborative genetics efforts have uncovered the association of 236 common DNA variants with disease susceptibility and the first association with disease severity, paving the way to more effective therapies, particularly for progressive forms of the disease. In parallel, and in addition to established environmental disease triggers or modifiers, new collaborative work has revealed new associations with components of the gut microbiome. This research opened a new and exciting prospect for exploring the gut-brain axis, with the potential to also provide new pharmacologic targets and diet-based therapies. Finally, with the availability of massive amounts of information and unprecedented computer power, a new wave of artificial intelligence (AI)-based research is sprawling. These investigations will result in statistically powerful predictive models to identify individuals at risk even years before the disease is clinically apparent. Furthermore, using approaches like semantic representation and causal inference, some of these approaches will be explainable in biomedical terms, thus making them trusted and facilitating their implementation in the clinical setting. The common thread that characterizes all of these advances is multi-disciplinary collaboration among scientists in the form of formal consortia, working groups, or ad hoc partnerships. This may be the "secret sauce" of modern science and the best strategy to stop, restore, and end MS.

The role of the gut archaeal microbiome (archaeome) in health and disease remains poorly understood. Methanogenic archaea have been linked to multiple sclerosis (MS), but prior studies were limited by small cohorts and inconsistent methodologies. To address this, we re-evaluated the association between methanogenic archaea and MS using metagenomic data from the International Multiple Sclerosis Microbiome Study. We analyzed gut microbiome profiles from 115 MS patients and 115 healthy household controls across Buenos Aires (27.8%), Edinburgh (33.9%), New York (10.4%), and San Francisco (27.8%). Metagenomic sequences were taxonomically classified using kraken2/bracken and a curated profiling database to detect archaea, specifically Methanobrevibacter species. Most MS patients were female (80/115), aged 25-72 years (median: 44.5), and 70% were undergoing treatment, including dimethyl fumarate (n = 21), fingolimod (n = 20), glatiramer acetate (n = 14), interferon (n = 18), natalizumab (n = 6), or ocrelizumab/rituximab (n = 1). We found no significant differences in overall archaeome profiles between MS patients and controls. However, treated MS patients exhibited higher abundances of Methanobrevibacter smithii and M. sp900766745 compared to untreated patients. Notably, M. sp900766745 abundance correlated with lower disease severity scores in treated patients. Our results suggest that gut methanogens are not directly associated with MS onset or progression but may reflect microbiome health during treatment. These findings highlight potential roles for M. smithii and M. sp900766745 in modulating treatment outcomes, warranting further investigation into their relevance to gut microbiome function and MS management.IMPORTANCEMultiple sclerosis (MS) is a chronic neuroinflammatory disease affecting the central nervous system, with approximately 2.8 million people diagnosed worldwide, mainly young adults aged 20-30 years. While recent studies have focused on bacterial changes in the MS microbiome, the role of gut archaea has been less explored. Previous research suggested a potential link between methanogenic archaea and MS disease status, but these findings remained inconclusive. Our study addresses this gap by investigating the gut archaeal composition in MS patients and examining how it changes in response to treatment. By focusing on methanogens, we aim to uncover novel insights into their role in MS, potentially revealing new biomarkers or therapeutic targets. This research is crucial for enhancing our understanding of the gut microbiome's impact on MS and improving patient management.

B cell depletion is an efficacious therapy for multiple sclerosis, but its long-term safety profile in the gastrointestinal tract has not been specifically studied. This is of importance because the gut is the largest reservoir of IgA in the body, which maintains gut homeostasis in part by regulating the composition of the gut microbiota. This was addressed by development of a prolonged B cell depletion model using human CD20 transgenic mice and B cell depletion with the anti-human CD20 antibodies rituximab, a humanized mouse monoclonal, and 2H7, the mouse precursor to ocrelizumab. Both antibodies depleted B cells in the spleen, mesenteric lymph nodes, small intestine, and large intestine, with 2H7 being more efficient. Because gut IgA+ antibody secreting cells (ASC) are poorly defined a flow cytometry strategy was developed using differential expression of IgA and Ki-67 by Blimp1+ cells that identified four IgA-ASC subsets across a developmental spectrum. Neither antibody was efficacious in depleting of any IgA-ASC subset in the intestines. Consequently, fecal IgA levels and percentage of IgA-bound fecal microbes were unaltered. Cumulatively, these studies demonstrate that prolonged B cell-depletion did not substantially impact IgA levels nor overall gut health, providing important insight into the safety profile of B cell depletion drugs.

Microglia and astrocytes are the primary glial cells in the central nervous system (CNS) and their function is shaped by multiple factors. Regulation of CNS glia by the microbiota have been reported, although the role of specific bacteria has not been identified. We colonized germ-free mice with the type strain Akkermansia muciniphila (AmT) and a novel A. muciniphila strain BWH-H3 (Am-H3) isolated from a subject with multiple sclerosis and compared to mice colonized with Bacteroides cellulosilyticus strain BWH-E5 (Bc) isolated from a healthy control subject. We then investigated the effect of these bacteria on microglia and astrocyte gene expression by RNA sequencing. We found altered gene expression profiles in brain microglia, with Akkermansia downregulating genes related to antigen presentation and cell migration. Furthermore, we observed strain specific effects, with Akkermansia H3 upregulating histone and protein binding associated genes and downregulating channel and ion transport genes. Astrocyte pathways that were altered by Akkermansia H3 mono-colonization included upregulation of proliferation pathways and downregulation in cytoskeletal associated genes. Furthermore, animals colonized with type strain Akkermansia and strain H3 had effects on the immune system including elevated splenic γδ-T cells and increased IFNγ production in CD4 + T cells. We also measured intestinal short chain fatty acids and found that both A. muciniphila strains produced proprionate while B. cellulosilyticus produced acetate, proprionate, and isovalerate. Taken together, our study shows that specific members of the intestinal microbiota influence both microglial and astroyctes which may be mediated by changes in short chain fatty acids and peripheral immune signaling.

The intestinal flora (IF) has been linked to risks of non-communicable diseases, especially various cancers, stroke, and Alzheimer's disease. However, many uncertainties of these associations during different stages of growth, development, and aging still exist. Therefore, further in-depth explorations are warranted.

To explore the associations of the human IF with disease risks during different stages of growth, development, and aging to achieve more accurate and convincing conclusions.

Cohort, cross-sectional, case-control, and Mendelian randomization studies published in the PubMed and Web of Science databases until December 31, 2023 were systematically reviewed to clarify the associations of the IF at the genus level with the risks of various non-communicable diseases, which were grouped in accordance with the 10th revision of the International Classification of Diseases.

In total, 57 studies were included to quantitatively examine the influence of the IF on the risks of 30 non-communicable diseases during different stages of growth, development, and aging. Population studies and Mendelian randomization studies confirmed positive associations of the abundances of Bifidobacterium and Ruminococcus with multiple sclerosis.

These findings contribute to a deeper understanding of the roles of the IF and provide novel evidence for effective strategies for the prevention and treatment of non-communicable diseases. In the future, it will be necessary to explore a greater variety of research techniques to uncover the specific mechanisms by which gut microbiota trigger diseases and conduct in-depth studies on the temporal relationship between microbiota alterations and diseases, so as to clarify the causal relationship more accurately.

The microbiota-gut-brain axis has major implications for human health including gastrointestinal physiology, brain function, and behavior. The immune system represents a key pathway of communication along this axis with the microbiome implicated in neuroinflammation in health and disease. In this review, we discuss the mechanisms as to how the gut microbiota interacts with the brain, focusing on innate and adaptive immunity that are often disrupted in gut-brain axis disorders. We also consider the implications of these observations and how they can be advanced by interdisciplinary research. Leveraging an increased understanding of how these interactions regulate immunity has the potential to usher in a new era of precision neuropsychiatric clinical interventions for psychiatric, neurodevelopmental, and neurological disorders.

Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS.

Global metabolomics was performed in an observational cohort of people with MS, followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2 g/day) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory, and gut microbiome parameters.

In the observational cohort, higher primary bile acid levels at baseline predicted slower whole-brain atrophy, brain substructure atrophy, and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not differ significantly between arms (p = 0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naive cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted between the two groups.

Bile acid metabolism in MS is linked to brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable, and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.

National MS Society grant RG-1707-28601 to P.B., R01 NS082347 from the National Institute of Neurological Disorders and Stroke to P.A.C., and National MS Society grant RG-1606-08768 to S.S.

Accumulating evidence supports a role of the microbiota in health and disease, including in multiple sclerosis (MS). How MS drugs affect the microbiota and whether this is part of their mode of action is yet unknown.

To assess how dimethyl fumarate (DMF) affects the gut microbiota and whether the microbiota is associated with clinical response or adverse events (AEs) to DMF or diet.

An observational cohort study, in which the microbiota from 45 patients with relapsing-remitting MS pre-DMF initiation and following 6 months of DMF therapy, and from 47 matched healthy controls, were compared, and associations with clinical and dietary data assessed.

Microbial DNA was sequenced and analyzed using MicrobiomeAnalyst. The clinical response was assessed after 1-year DMF therapy based upon evidence of disease activity (relapse, ΔEDSS increase >1, or MRI activity compared to pre-treatment). Dietary data were obtained by food questionnaires.

Alterations in relative abundance of several microbes were identified post 6-month DMF therapy compared to pre-treatment, including an increase in Firmicutes, Lachnospiraceae, and Ruminococcaceae, while reduction in Bacteroidetes and Proteobacteria. Patients who showed disease activity within 1 year from DMF initiation had pre-treatment higher abundance of Proteobacteria, Flavonifractor, and Acidaminococcaceae, while lower abundance of Firmicutes, Ruminococcaceae, Butyricicoccus, and Massiliprevotella massiliensis, compared to patients without disease activity. Patients who discontinued DMF therapy due to AEs had pre-treatment higher abundance of Proteobacteria, Bacteroidetes, Eggerthella, and Lachnoclostridium and lower abundance of Ruminococcaceae, Megamonas, and Holdemanella, among others. Differentially abundant microbes correlated with intake of several nutrients.

DMF immunotherapy is associated with modifications of the microbiota. The microbiota may affect the severity of AEs and the clinical response to DMF, and is potentially modulated by diet. Microbiota-based, personalized treatment approach, integrating pharmacotherapy with dietary components, carries potential to improved clinical outcome.

Gut microbiota dysbiosis is associated with multiple sclerosis (MS), but the causal relationship between specific gut bacteria and MS pathogenesis remains poorly understood. Therefore, we profiled the stool microbiome of people with MS (PwMS) and healthy controls (HC) using shotgun metagenomic sequencing. PwMS showed a distinct microbiome compared to HC, with Prevotella copri (PC) and Blautia species as drivers of microbial communities in HC and PwMS, respectively. Administration of MS-driving Blautia species (Blautia wexlerae; BW) to mice resulted in increased levels of gut inflammatory markers and altered microbiota with increased capacity to induce proinflammatory cytokines. Utilizing experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we identified a lower gut Bifidobacterium to Akkermansia ratio as a hallmark of the disease. BW-administered mice also showed a lower Bifidobacterium to Akkermansia ratio pre-EAE induction which correlated with increased disease severity post-EAE induction. The importance of the Bifidobacterium to Akkermansia ratio at the species level, lower Bifidobacterium adolescentis to Akkermansia muciniphila (BA:AM), was validated in our MS cohort and a large International Multiple Sclerosis Microbiome Study. Thus, our findings highlight the BA:AM ratio as a potential gut microbial marker in PwMS, opening avenues for microbiome-based diagnosis, prognosis, and therapy in MS.

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Amyloid-β (Aβ) accumulation and neurofibrillary tangles are two key histological features resulting in progressive and irreversible neuronal loss and cognitive decline. The macrophages of the central nervous system (CNS) belong to the innate immune system and comprise parenchymal microglia and CNS-associated macrophages (CAMs) at the CNS interfaces (leptomeninges, perivascular space and choroid plexus). Microglia and CAMs have received attention as they may play a key role in disease onset and progression e. g., by clearing amyloid beta (Aβ) through phagocytosis. Genome-wide association studies (GWAS) have revealed that human microglia and CAMs express numerous risk genes for AD, further highlighting their potentially critical role in AD pathogenesis. Microglia and CAMs are tightly controlled by environmental factors, such as the host microbiota. Notably, it was further reported that the composition of the gut microbiota differed between AD patients and healthy individuals. Hence, emerging studies have analyzed the impact of gut bacteria in different preclinical mouse models for AD as well as in clinical studies, potentially enabling promising new therapeutic options.

An alteration in the composition of the intestinal microbiota has been observed in patients with multiple sclerosis (pwMS) with respect to healthy controls (HC). Microorganism-derived metabolites such as short-chain fatty acids (SCFA) have been suggested to play a role in the disease. Thus, to analyze the association of SCFA with clinical and radiological parameters of the disease and with those related to the inflammatory response of the immune system.

Multicentric observational retrospective cross-sectional study. In addition 161 pwMS and 130 HC were included. The following plasma SCFA were analyzed using liquid chromatography coupled to mass spectrometry: acetate (AA), propionate (PA) and butyrate (BA). Blood cell subpopulations and cytokine expression were analyzed by flow cytometry.

Plasma PA and PA/AA ratio was lower in pwMS than in HC (P = 0.0001, and P = 0.00005, respectively). PA/AA and BA/AA ratios were lower in pwMS with higher disability (P = 0.001, and P = 0.001, respectively). T2 lesion load inversely correlated with PA/AA (r = -0.353; P = 0.002) and BA/AA (r = -0.322; P = 0.005) ratios. Plasma PA/AA and/or BA/AA ratios negatively correlated with the following pro-inflammatory cytokines producing cells: GM-CSF+CD4+T, GM-CSF+CD8+T, TNF-alpha+CD4+T, TNF-alpha+CD8+T, IFN-gamma+CD4+T, IFN-gamma+CD8+T, and TNF-alpha+B cells.

In MS, plasma PA/AA and BA/AA ratios are unbalanced, promoting an environment that could be boosting the mechanisms underlying the pathogenesis of the disease. Since we have found statistical significant associations with the EDSS and the number of T2 lesions, but not with the number of relapses or gadolinium enhancing lesions, PA/AA and BA/AA ratios could be more associated with those mechanisms of the disease related to the neurodegenerative processes than those related with the activity of the disease.

Multiple sclerosis (MS) is a chronic central nervous system (CNS) neurodegenerative and neuroinflammatory disease marked by a host immune reaction that targets and destroys the neuronal myelin sheath. MS and correlating animal disease models show comorbidities, including intestinal barrier disruption and alterations of the commensal microbiome. It is accepted that diet plays a crucial role in shaping the microbiota composition and overall gastrointestinal (GI) tract health, suggesting an interplay between nutrition and neuroinflammation via the gut-brain axis. Unfortunately, poor host health and diet lead to microbiota modifications that could lead to significant responses in the host, including inflammation and neurobehavioral changes. Beneficial microbial metabolites are essential for host homeostasis and inflammation control. This review will highlight the importance of the gut microbiota in the context of host inflammatory responses in MS and MS animal models. Additionally, microbial community restoration and how it affects MS and GI barrier integrity will be discussed.

Gut microbial symbionts have been shown to influence the development of autoimmunity in multiple sclerosis (MS). Emerging research points to an important relationship between the microbial-IgA interface and MS pathophysiology. IgA-secreting B cells are observed in the MS brain, and shifts in gut bacteria-IgA binding have been described in some patients with MS. However, the relationships between the gut microbiome and the host immune response, particularly regarding B-cell-depleting immunomodulation, remain underexplored. This study aimed to evaluate the composition of the gut microbiome in patients with newly diagnosed MS at baseline and after B-cell depletion, using long-read sequencing for enhanced taxonomic resolution. We further aimed to investigate the host/microbiome interface by evaluating microbe/immunoglobulin A relationships.

We collected stool samples from 43 patients with newly diagnosed, untreated MS and 42 matched healthy controls. Nineteen patients with MS initiated anti-CD20 monoclonal antibody treatment and donated additional stool samples after 6 months of treatment. We evaluated the host-microbial interface using bacterial flow cytometry and long-read 16S rRNA gene amplicon sequencing. We used Immune Coating Scores to compare the proportions of bacteria identified in the IgA-coated vs IgA-uncoated bacterial fractions.

Patients with untreated, newly diagnosed MS showed significant reductions in IgA-bound fecal microbiota compared with controls. Using multiple linear regression models adjusted for potential confounders, we observed significant (p < 0.05) changes in the abundance and prevalence of various strain-level gut bacteria amplicon sequence variants (ASVs) within both total and IgA-coated bacterial fractions. Some changes (e.g., decreased relative abundance of a Faecalibacterium prausnitzii variant in MS) were consistent with previous reports, while others (e.g., increased relative abundance and prevalence of Monoglobus pectinyliticus in MS) were novel. Immune Coating Scores identified subsets of organisms for which normal IgA-coating patterns were disrupted at the onset of MS, as well as those (particularly Akkermansia muciniphila) whose IgA-coating became more aligned with controls after therapy.

This analysis of gut microbial ASVs reveals shifts in taxonomic strains induced by immune modulation in MS.

Multiple sclerosis (MS) is the most prevalent human inflammatory disease of the central nervous system with demyelination and glial scar formation as pathological hallmarks. Glial cells are key drivers of lesion progression in MS with roles in both tissue damage and repair depending on the surrounding microenvironment and the functional state of the individual glial subtype. In this review, we describe recent developments in the context of glial cell diversity in MS summarizing key findings with respect to pathological and maladaptive functions related to disease-associated glial subtypes. A particular focus is on the spatial and temporal dynamics of glial cells including subtypes of microglia, oligodendrocytes, and astrocytes. We contextualize recent high-dimensional findings suggesting that glial cells dynamically change with respect to epigenomic, transcriptomic, and metabolic features across the inflamed rim and during the progression of MS lesions. In summary, detailed knowledge of spatially restricted glial subtype functions is critical for a better understanding of MS pathology and its pathogenesis as well as the development of novel MS therapies targeting specific glial cell types.

Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), arise from complex interactions between genetic factors, environmental exposures, and aging. Additionally, gut dysbiosis has been linked to systemic inflammation and neurodegeneration. Advances in microbiome and metabolome profiling techniques have provided deeper insights into how alterations in gut microbiota and dietary patterns affect metabolic pathways and contribute to the progression of NDs. This review explores the profiles of gut microbiome and metabolome derived biomarkers and their roles in NDs. Across phyla, families, and genera, we identified 55 microbial alterations in PD, 24 in AD, 4 in ALS, and 17 in MS. Some notable results include an increase in Akkermansia in PD, AD, and MS and a decrease in short-chain fatty acids (SCFAs) in PD and AD. We examined the effects of probiotics, prebiotics, fecal microbiota transplants (FMT), sleep, exercise, and diet on the microbiota, all of which contributed to delayed onset and alleviation of symptoms. Further, artificial intelligence (AI) and machine learning (ML) algorithms applied to omics data have been crucial in identifying novel therapeutic targets, diagnosing and predicting prognosis, and enabling personalized medicine using microbiota-modulating therapies in NDs patients.

Cladribine tablets are an effective treatment for relapsing remitting multiple sclerosis (RRMS). However, almost half of the treated patients are not free of disease activity after two years. The aim of this study was to describe the changes that cladribine tablets effectuate in the gut and oral microbiota and the peripheral immunological profile between responders and non-responders.

In this pilot study of the multicenter, prospective, observational BIA (Brain-Immune-Intestine Axis) study, we included patients aged 18 to 55 years with RRMS who were scheduled to start treatment with cladribine tablets. We assessed the clinical status and the immunological and microbiological profile prior to the start of the treatment and after three and twelve months. At twelve months, we assessed the response status, based on clinical relapses, radiological activity and disability progression on the Expanded Disability Status Scale.

The first twenty-five patients of the BIA study were included in this analysis. Ten patients (40%) were responders twelve months after treatment. Three months after treatment we found a significant decline of naïve and transitional B cells and memory B cells, and of CD57+ CD56dim NK cells. After twelve months the values recovered to baseline levels, except for the memory B cells. We did not find significant changes of the microbiological profile over time, except for a decline of the phylum Bacteroidetes in the oral samples twelve months after treatment. Baseline values and changes over time did not significantly differ between responders and non-responders. However, several phyla, genera or species (Bacteroidetes, Prevotella, Faecalibacterium prausnitzii) showed a higher relative abundance, and several phyla, genera or species (Proteobacteria, Escherichia coli) had a lower relative abundance in responders compared to non-responders.

After treatment with cladribine tablets, we found significant changes in the immunological landscape. Also, the microbiological profile showed several differences in microbes with known anti- or pro-inflammatory properties between responders and non-responders. Overall, we showed that we can measure a treatment effect from cladribine tablets with our analyses. Future research on data from the BIA study, with a larger sample size and extended follow-up, can possibly confirm the reliability of our findings.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by neurodegeneration, axonal damage, demyelination, and inflammation. Recently, gut dysbiosis has been linked to MS and other autoimmune conditions. Namely, gut microbiota has a vital role in regulating immune function by influencing immune cell development, cytokine production, and intestinal barrier integrity. While balanced microbiota fosters immune tolerance, dysbiosis disrupts immune regulation, damages intestinal permeability, and heightens the risk of autoimmune diseases. The critical factor in shaping the gut microbiota and modulating immune response is diet. Research shows that high-fat diets rich in saturated fats are associated with disease progression. Conversely, diets rich in fruits, yogurt, and legumes may lower the risk of MS onset and progression. Specific dietary interventions, such as the Mediterranean diet (MD) and ketogenic diet, have shown potential to reduce inflammation, support neuroprotection, and promote CNS repair. Probiotics, by restoring microbial balance, may also help mitigate immune dysfunction noted in MS. Personalized dietary strategies targeting the gut microbiota hold promise for managing MS by modulating immune responses and slowing disease progression. Optimizing nutrient intake and adopting anti-inflammatory diets could improve disease control and quality of life. Understanding gut-immune interactions is essential for developing tailored nutritional therapies for MS patients.

Intestinal bacteria form one of the most complex microbial communities in the human body, playing a crucial role in maintaining host health and contributing to the development of various diseases. Here, we provide a comprehensive overview of the composition and function of intestinal bacteria, the factors affecting their homeostasis, and their association and mechanisms with a range of diseases (e.g., inflammatory bowel diseases, colorectal cancer, metabolic diseases). Additionally, their advanced potential in disease diagnosis and treatment is highlighted. Therapies, such as chemotherapy, radiotherapy, and immunotherapy, are significantly impacted by intestinal bacteria, with research indicating that bacteria can enhance chemoimmunotherapy efficiency by affecting T cell recruitment and immune cell infiltration. Fecal microbiota transplantation has emerged as a promising option for treating recurrent Clostridium difficile infections and certain metabolic and neurological disorders. Gut bacteria-related serum metabolites serve as non-invasive indicators for diagnosing CRC, while fecal immunochemical tests offer promising applications in CRC screening. Future research is needed to better understand the causal relationships between intestinal bacteria and diseases, develop more precise diagnostic tools, and evaluate the effectiveness and safety of microbiome-targeted therapies in clinical treatment. This study provides deeper insights into the role of intestinal bacteria in human health and disease, providing a scientific basis for innovative therapeutic strategies that have the potential to transform the landscape of healthcare.

The human gut microbiota, a complex and diverse community of microorganisms, plays a crucial role in maintaining overall health by influencing various physiological processes, including digestion, immune function, and disease susceptibility. The balance between beneficial and harmful bacteria is essential for health, with dysbiosis - disruption of this balance - linked to numerous conditions such as metabolic disorders, autoimmune diseases, and cancers. This review highlights key genera such as Enterococcus, Ruminococcus, Bacteroides, Bifidobacterium, Escherichia coli, Akkermansia muciniphila, Firmicutes (including Clostridium and Lactobacillus), and Roseburia due to their well-established roles in immune regulation and metabolic processes, but other bacteria, including Clostridioides difficile, Salmonella, Helicobacter pylori, and Fusobacterium nucleatum, are also implicated in dysbiosis and various diseases. Pathogenic bacteria, including Escherichia coli and Bacteroides fragilis, contribute to inflammation and cancer progression by disrupting immune responses and damaging tissues. The potential for microbiota-based therapies, such as probiotics, prebiotics, fecal microbiota transplantation, and dietary interventions, to improve health outcomes is examined. Future research directions in the integration of multi-omics, the impact of diet and lifestyle on microbiota composition, and advancing microbiota engineering techniques are also discussed. Understanding the gut microbiota's role in health and disease is essential for formulating personalized, efficacious treatments and preventive strategies, thereby enhancing health outcomes and progressing microbiome research.

Studies suggest that gut dysbiosis occurs in autoimmune neurological diseases, but a comprehensive synthesis of the evidence is lacking. Our aim was to systematically review and meta-analyze the correlation between the gut microbiota and autoimmune neurological disorders to inform clinical diagnosis and therapeutic intervention. We searched the databases of PubMed, Embase, Web of Science, and the Cochrane Library until 1 March 2024 for research on the correlation between gut microbiota and autoimmune neurological disorders. A total of 62 studies provided data and were included in the analysis (n = 3,126 patients, n = 2,843 healthy individuals). Among the included studies, 42 studies provided data on α-diversity. Regarding α-diversity, except for Chao1, which showed a consistent small decrease (SMD = -0.26, 95% CI = -0.45 to -0.07, p < 0.01), other indices demonstrated no significant changes. While most studies reported significant differences in β-diversity, consistent differences were only observed in neuromyelitis optica spectrum disorders. A decrease in short-chain fatty acid (SCFA)-producing bacteria, including Faecalibacterium and Roseburia, was observed in individuals with autoimmune encephalitis, neuromyelitis optica spectrum disorders, myasthenia gravis, and multiple sclerosis. Conversely, an increase in pathogenic or opportunistic pathogens, including Streptococcus and Escherichia-Shigella, was observed in these patients. Subgroup analyses assessed the confounding effects of geography and immunotherapy use. These findings suggest that disturbances of the gut flora are associated with autoimmune neurological diseases, primarily manifesting as non-specific and shared microbial alterations, including a reduction in SCFA-producing bacteria and an increase in pathogenic or opportunistic pathogens.

https://www.crd.york.ac.uk/prospero/, identifier CRD42023410215.

Multiple Sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS). In this study, the concentration of heavy metals was measured in stool samples of MS patients by Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS) method and compared with healthy people. Also, another goal of this study is to investigate the alteration of the gut microbiome of MS patients by metagenomics technique based on the 16S rRNA gene sequencing. The IL-10 ELISA assay showed no significant differences between the serum level of the IL-10 in the patients and the control group (p = 0.510). Heavy metal measurement by ICP-MS showed significantly higher levels of arsenic (As, Mean = 32.77 μg/kg), nickel (Ni, Mean = 7.154 μg/kg), manganese (Mn, Mean = 3723 μg/kg), and zinc (Zn, Mean = 5508 μg/kg) in the stool samples of the MS group compared to the control group, while concentrations of iron (Fe, Mean = 9585 μg/kg), lead (Pb, Mean = 18.54 μg/kg), titanium (Ti, Mean = 69.69 μg/kg), and tin (Sn, Mean = 13.92 μg/kg) were significantly lower. The result of gut microbiome analysis showed an increase in the abundance of the Verrumicrobiaceae, Lachnospiraceae and Ruminococcaceae families was considerably increased in MS patients compared to the control group (p < 0.05). This study reports that high levels of heavy metals such as Ars, Ni, Mn, and Zn, deficiency of Fe, Pb, Ti, and Sn, and alteration of the gut microbiome are involved in the pathogenesis of MS. The novelty of this study lies in its multi-faceted approach to understanding MS by integrating the measurement of heavy metals in stool samples with the analysis of gut microbiome alterations, thereby providing comprehensive insights into heavy metals, the gut microbiome, and potential therapeutic avenues. This study suggests several potential applications and practical implications based on its findings regarding heavy metals, gut microbiome alterations, and IL-10 levels in MS. First, the identification of elevated levels of specific heavy metals and deficiencies in others may lead to targeted screening and monitoring, informing preventive strategies for MS patients. Additionally, the observed gut microbiome changes could facilitate the development of microbiome-based therapies, such as probiotics or dietary interventions, aimed at restoring microbial balance. Finally, exploring the interplay between heavy metals, gut microbiome, and immune response may guide the creation of novel therapeutic interventions, ultimately enhancing treatment efficacy and providing new avenues for managing MS, thereby alleviating the burden of this chronic condition.

Over the past several decades, high-resolution brain imaging, blood and cerebrospinal fluid analyses, and other advanced technologies have changed diagnosis from an exercise depending primarily on the history and physical examination to a computer- and online resource-aided process that relies on larger and larger quantities of data. In addition, randomized controlled trials (RCT) at a population level have led to many new drugs and devices to treat neurological disease, including disease-modifying therapies. We are now at a crossroads. Combinatorially profound increases in data about individuals has led to an alternative to population-based RCTs. Genotyping and comprehensive "deep" phenotyping can sort individuals into smaller groups, enabling precise medical decisions at a personal level. In neurology, precision medicine that includes prediction, prevention and personalization requires that genomic and phenomic information further incorporate imaging and behavioral data. In this article, we review the genomic, phenomic, and computational aspects of precision medicine for neurology. After defining biological markers, we discuss some applications of these "-omic" and neuroimaging measures, and then outline the role of computation and ultimately brain simulation. We conclude the article with a discussion of the relation between precision medicine and value-based care.

The cuprizone (CPZ) model of multiple sclerosis (MS) is excellent for studying the molecular differences behind the damage caused by poisoning. Metabolic differences in the kynurenine pathway (KP) of tryptophan (TRP) degradation are observed in both MS and a CPZ mouse model. Our goal was to analyze the kynurenine, serotonin, and indole pathways of TRP degradation on the periphery, in the neurodegenerative processes of inflammation. In our study, mice were fed with 0.2% CPZ toxin for 5 weeks. We examined the metabolites in the three pathways of TRP breakdown in urine, plasma, and relevant visceral organs with bioanalytical measurements. In our analyses, we found a significant increase in plasma TRP, 5-hydroxytryptophan (5-HTP), and indole-3-acetic acid (IAA) levels, while a decrease in the concentrations of 3-hydroxy-L-kynurenine (3-HK), xanthurenic acid (XA), kynurenic acid (KYNA), and quinaldic acid in the plasma of toxin-treated group was found. A marked decrease in the levels of 3-HK, XA, KYNA, quinaldic acid, and indole-3-lactic acid was also observed in the visceral organs by the end of the poisoning. Furthermore, we noticed a decrease in the urinary levels of the TRP, KYNA, and XA metabolites, while an increase in serotonin and 5-hydroxyindoleacetic acid in the CPZ group was noticed. The toxin treatment resulted in elevated tryptamine and indoxyl sulfate levels and reduced IAA concentration. Moreover, the urinary para-cresyl sulfate concentration also increased in the treated group. In the present study, we showed the differences in the three main metabolic pathways of TRP degradation in the CPZ model. We confirmed the relationship and correlation between the content of the kynurenine metabolites in the plasma and the tissues of the visceral organs. We emphasized the suppression of the KP and the activity of the serotonin and indole pathways with a particular regard to the involvement of the microbiome by the indole pathway. Consequently, this is the first study to analyze in detail the distribution of the kynurenine, serotonin, and indole pathways of TRP degradation in the periphery.

Microbiome abnormalities (dysbiosis) significantly contribute to the progression of Alzheimer's disease (AD). However, the therapeutic efficacy of microbiome modulators in protecting against these ailments remains poorly studied. Herein, we tested a cocktail of unique probiotics, including 5 Lactobacillus and 5 Enterococcus strains isolated from infant gut with proven microbiome modulating capabilities. We aimed to determine the probiotics cocktail's efficacy in ameliorating AD pathology in a humanized AD mouse model of APP/PS1 strains. Remarkably, feeding mice with 1 × 1011 CFU per day in drinking water for 16 weeks significantly reduced cognitive decline (measured by the Morris Water Maze test) and AD pathology markers, such as Aβ aggregation, microglia activation, neuroinflammation, and preserved blood-brain barrier (BBB) tight junctions. The beneficial effects were linked to a reduced inflammatory microbiome, leading to decreased gut permeability and inflammation in both systemic circulation and the brain. Although both male and female mice showed overall improvements in cognition and biological markers, females did not exhibit improvements in specific markers related to inflammation and barrier permeability, suggesting that the underlying mechanisms may differ depending on sex. In conclusion, our results suggest that this unique probiotics cocktail could serve as a prophylactic agent to reduce the progression of cognitive decline and AD pathology. This is achieved by beneficially modulating the microbiome, improving intestinal tight junction proteins, reducing permeability in both gut and BBB, and decreasing inflammation in the gut, blood circulation, and brain, ultimately mitigating AD pathology and cognitive decline.