{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:39:38Z","timestamp":1792172378950,"version":"4.4.0"},"reference-count":132,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Multiple sclerosis is autoimmune disease of the central nervous system (CNS) in which myelin-reactive immune attack drives demyelination and subsequent disability. Various studies have documented elevated abundance of the commensal gut bacterium <jats:italic>Akkermansia muciniphila<\/jats:italic> (<jats:italic>A. muciniphila<\/jats:italic>) in people with multiple sclerosis compared to healthy control subjects, suggesting that its elevated abundance may be a risk factor for the development of CNS autoimmunity. However, <jats:italic>A. muciniphila<\/jats:italic> is considered beneficial in various other pathological contexts, and recent studies suggest that <jats:italic>A. muciniphila<\/jats:italic> may be paradoxically associated with reduced disability and progression in multiple sclerosis. Moreover, experimental modulation of <jats:italic>A. muciniphila<\/jats:italic> levels in experimental autoimmune encephalomyelitis (EAE), an autoimmune model of multiple sclerosis, has generated conflicting results, suggesting that the effects of this microbe on CNS autoimmunity could be context-dependent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To address this possibility, we generated two distinct microbiome models in C57BL\/6J mice, each stably colonized by <jats:italic>A. muciniphila<\/jats:italic> or <jats:italic>A. muciniphila<\/jats:italic>-free, providing divergent ecological contexts in which <jats:italic>A. muciniphila<\/jats:italic> may exert a differential impact. We used EAE, flow cytometry, full-length 16S DNA sequencing, and mass spectrometry to assess the impact of <jats:italic>A. muciniphila<\/jats:italic> colonization on neurological outcomes, immune responses, gut microbiome composition, and short-chain fatty acid (SCFA) production, respectively. Dietary intervention was used to assess the functional consequences of differences in gut microbiota metabolic capacity. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that <jats:italic>A. muciniphila<\/jats:italic> colonization increased EAE severity only in a specific microbiome context, in conjunction with increased Th17 responses and CNS-infiltrating immune cells. Profiling of gut microbiome composition revealed that <jats:italic>A. muciniphila<\/jats:italic> colonization drove a reduction of <jats:italic>Clostridia<\/jats:italic>, key producers of SCFAs, specifically in the microbiome model in which <jats:italic>A. muciniphila<\/jats:italic> exacerbates EAE. Inferred metagenomic analyses suggested reduced SCFA production in the presence of <jats:italic>A. muciniphila<\/jats:italic>, which was confirmed by mass spectrometry. Consistently, provision of high dietary fiber as a substrate for SCFA production suppressed EAE only in the context of the <jats:italic>Clostridia<\/jats:italic>-rich microbiome sensitive to <jats:italic>A. muciniphila<\/jats:italic> colonization. <\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Taken together, our data suggest that the effect of <jats:italic>A. muciniphila<\/jats:italic> on CNS autoimmunity is highly dependent on the overall composition of the gut microbiome and suggest that this microbe may contribute to decreased gut SCFA metabolism in multiple sclerosis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1655428","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:44:32Z","timestamp":1760366672000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Colonization by Akkermansia muciniphila modulates central nervous system autoimmunity 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