Background: The gut microbiome is a potential therapeutic target for multiple sclerosis (MS), yet its association with disease activity remains unclear. We systematically reviewed the literature to investigate the relationship between the gut microbiome and MS disease activity, course, and disability progression.

Methods: We searched MEDLINE, EMBASE, Web of Science and Google Scholar (01/2011-02/2024) to identify relevant observational or interventional studies published in English. Case reports were ineligible. Outcomes included disease activity (e.g. relapses, MRI), course (e.g. relapsing-remitting/secondary-progressive [RR/SPMS]) and disability progression (e.g. using the Expanded Disability Status Scale [EDSS]). Study quality was evaluated using the Newcastle-Ottawa Scale.

Results: Four longitudinal and nineteen cross-sectional studies were included, totaling 1760 persons with MS. Most were female (1237/1760, 70 %) and had RRMS (1378/1760, 78 %). The majority of studies (67 %;10/15) examining gut diversity (alpha or beta) did not find an association with disease activity, course or progression. However, several gut taxa exhibited significant associations with study outcomes, including eight that varied in consistent directions: a higher abundance of Actinobacteria, Bacteroidota and Roseburia inulinivorans were associated with better MS outcomes (e.g. lower EDSS scores), while higher abundances of Streptococcus, Clostridium nexile, Clostridium scindens and Collinsella aerofaciens were associated with worse outcomes (e.g. higher MRI lesion volumes).

Conclusions: Gut diversity was not associated with MS-related outcomes in most studies whereas several gut taxa were, including higher abundances of short chain-fatty acid producers (e.g. Bacteroidota) showing associations with lower EDSS scores. Most studies were cross-sectional, limiting interpretation of findings; longitudinal studies are warranted.