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Gut microbial factors predict disease severity in a mouse model of multiple sclerosis.

ABSTRACT: Gut bacteria are linked to neurodegenerative diseases but the risk factors beyond microbiota composition are limited. Here we used a pre-clinical model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), to identify microbial risk factors. Mice with different genotypes and complex microbiotas or six combinations of a synthetic human microbiota were analysed, resulting in varying probabilities of severe neuroinflammation. However, the presence or relative abundances of suspected microbial risk factors failed to predict disease severity. Akkermansia muciniphila, often associated with MS, exhibited variable associations with EAE severity depending on the background microbiota. Significant inter-individual disease course variations were observed among mice harbouring the same microbiota. Evaluation of microbial functional characteristics and host immune responses demonstrated that the immunoglobulin A coating index of certain bacteria before disease onset is a robust individualized predictor of disease development. Our study highlights the need to consider microbial community networks and host-specific bidirectional interactions when aiming to predict severity of neuroinflammation.

SUBMITTER: Steimle A

PROVIDER: S-EPMC11371644 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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Gut microbial factors predict disease severity in a mouse model of multiple sclerosis.

Steimle Alex A Neumann Mareike M Grant Erica T ET Willieme Stéphanie S De Sciscio Alessandro A Parrish Amy A Ollert Markus M Miyauchi Eiji E Soga Tomoyoshi T Fukuda Shinji S Ohno Hiroshi H Desai Mahesh S MS

Nature microbiology 20240715 9

Gut bacteria are linked to neurodegenerative diseases but the risk factors beyond microbiota composition are limited. Here we used a pre-clinical model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), to identify microbial risk factors. Mice with different genotypes and complex microbiotas or six combinations of a synthetic human microbiota were analysed, resulting in varying probabilities of severe neuroinflammation. However, the presence or relative abundances of su ...[more]

PMID: 39009690

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Project description:BackgroundMultiple sclerosis (MS) is an inflammatory and demyelinating disease of the CNS. The etiology of MS is complex, and results from the interaction of multiple environmental and genetic factors. Although human leukocyte antigen-HLA alleles such as HLA-DR2 and -DR3 are considered the strongest genetic factors, the environmental factors responsible for disease predisposition are not well understood. Recently, diet and gut microbiota have emerged as an important environmental factors linked to the increased incidence of MS. Especially, western diets rich in protein and fat have been linked to the increased incidence of obesity. Numerous clinical data indicate a role of obesity and gut microbiota in MS; however, the mechanistic link between gut microbiota and obesity in the pathobiology of MS remains unclear. The present study determines the mechanisms driving MS severity in the context of obesity utilizing a high-fat diet (HFD) induced obese HLA-DR3 class-II transgenic mouse model of MS.MethodsHLA-DR3 transgenic mice were kept on a standard HFD diet or Normal Chow (NC) for eight weeks. Gut microbiota composition and functional analysis were performed from the fecal DNA of mice. Experimental autoimmune encephalomyelitis-EAE (an animal model of MS) was induced by immunization with the proteolipid protein-PLP91-110 peptide in complete Freud's Adjuvant (CFA) and pertussis toxin.ResultsWe observed that HFD-induced obesity caused gut dysbiosis and severe disease compared to mice on NC. Amelioration of disease severity in mice depleted of gut microbiota suggested an important role of gut bacteria in severe EAE in obese mice. Fecal microbiota analysis in HFD mice shows gut microbiota alterations with an increase in the abundance of Proteobacteria and Desulfovibrionaceae bacteria and modulation of various bacterial metabolic pathways including bacterial hydrogen sulfide biosynthetic pathways. Finally, mice on HFD showed increased gut permeability and systemic inflammation suggesting a role gut barrier modulation in obesity induced disease severity.ConclusionsThis study provides evidence for the involvement of the gut microbiome and associated metabolic pathways plus gut permeability in obesity-induced modulation of EAE disease severity. A better understanding of the same will be helpful to identify novel therapeutic targets to reduce disease severity in obese MS patients.

Project description:Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2 production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K2, and SCFAs are associated with progression, warranting future functional validation and mechanistic study.

Project description:BackgroundThe gut microbiome plays an important role in autoimmunity including multiple sclerosis and its mouse model called experimental autoimmune encephalomyelitis (EAE). Prior studies have demonstrated that the multiple sclerosis gut microbiota can contribute to disease, hence making it a potential therapeutic target. In addition, antibiotic treatment has been shown to ameliorate disease in the EAE mouse model of multiple sclerosis. Yet, to this date, the mechanisms mediating these antibiotic effects are not understood. Furthermore, there is no consensus on the gut-derived bacterial strains that drive neuroinflammation in multiple sclerosis.ResultsHere, we characterized the gut microbiome of untreated and vancomycin-treated EAE mice over time to identify bacteria with neuroimmunomodulatory potential. We observed alterations in the gut microbiota composition following EAE induction. We found that vancomycin treatment ameliorates EAE, and that this protective effect is mediated via the microbiota. Notably, we observed increased abundance of bacteria known to be strong inducers of regulatory T cells, including members of Clostridium clusters XIVa and XVIII in vancomycin-treated mice during the presymptomatic phase of EAE, as well as at disease peak. We identified 50 bacterial taxa that correlate with EAE severity. Interestingly, several of these taxa exist in the human gut, and some of them have been implicated in multiple sclerosis including Anaerotruncus colihominis, a butyrate producer, which had a positive correlation with disease severity. We found that Anaerotruncus colihominis ameliorates EAE, and this is associated with induction of RORγt+ regulatory T cells in the mesenteric lymph nodes.ConclusionsWe identified vancomycin as a potent modulator of the gut-brain axis by promoting the proliferation of bacterial species that induce regulatory T cells. In addition, our findings reveal 50 gut commensals as regulator of the gut-brain axis that can be used to further characterize pathogenic and beneficial host-microbiota interactions in multiple sclerosis patients. Our findings suggest that elevated Anaerotruncus colihominis in multiple sclerosis patients may represent a protective mechanism associated with recovery from the disease. Video Abstract.

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Gut microbial factors predict disease severity in a mouse model of multiple sclerosis.

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Gut microbial factors predict disease severity in a mouse model of multiple sclerosis.

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