Deconstructing the microbiota-gut-brain axis in multiple sclerosis: from a barrier-immune-metabolic framework to...

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by progressive neuroinflammation and demyelination. Increasing evidence suggests that the gut microbiota contributes to MS pathogenesis through bidirectional gut-brain interactions; however, the underlying mechanistic framework remains incompletely defined.

We performed a narrative synthesis of literature published from March 2010 to March 2026 using PubMed, Web of Science, the Cochrane Library, CNKI, and Wanfang Data. Relevant studies were critically evaluated to integrate current mechanistic and translational evidence regarding gut microbiota involvement in MS.

Gut microbial dysbiosis in MS is associated with impaired intestinal barrier function, immune dysregulation, and altered host metabolic signaling. Emerging evidence further suggests that other microbial niches, including the oral microbiome, may contribute to systemic immune activation through microbial translocation and inflammatory signaling. Microbial metabolites, particularly short-chain fatty acids and tryptophan-related compounds, represent important molecular mediators within the gut-brain axis. Emerging multi-omics studies suggest potential regulatory roles of specific microbial communities, including ileal taxa, alongside core host signaling targets such as Caspase 3 (CASP3) and E1A binding protein p300 (EP300), although evidence remains largely associative.

The gut microbiota may influence MS pathophysiology through a coordinated barrier-immune-metabolic axis. Emerging evidence from additional microbial niches, including the oral microbiome, further supports a broader microbial ecosystem perspective on MS immunopathology, although causal relationships remain to be established. Although microbiome-targeted interventions show promising therapeutic potential, translation into clinical practice requires further mechanistic validation and well-controlled human studies.