Limited Gut Microbiome Differences Between Relapsing–Remitting and Secondary Progressive Multiple Sclerosis: A Shotgun Metagenomic Study

The gut microbiome may contribute to multiple sclerosis (MS) pathophysiology, but its relationship with disease phenotype and progression remains unclear. To characterize taxonomic and functional gut microbiome differences between relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS) and their associations with neurological disability and circulating biomarkers. This cross-sectional study included 89 participants (30 healthy controls, 29 RRMS, and 30 SPMS). Shotgun metagenomic sequencing was used to assess microbial diversity, taxonomic profiles, and predefined short-chain fatty acid (SCFA)-related pathways, integrated with disability measures and serum GFAP, NfL, and S100B. SPMS participants were substantially older than those with RRMS (median 49.0 vs. 31.0 years), prompting age-adjusted analyses and an age-overlap sensitivity analysis. Alpha diversity and overall microbial community composition were similar across groups. SPMS showed greater interindividual microbial community dispersion than RRMS in the full cohort, with a similar direction and magnitude but attenuated statistical significance in the age-overlap sensitivity analysis. Exploratory taxonomic signals were not confirmed by FDR-controlled analyses. No robust phenotype-specific differences in predicted SCFA-related pathways or associations of taxonomic or functional features with disability or circulating biomarkers were identified. Greater microbial community dispersion in SPMS was observed in the full cohort, but this finding was attenuated in the age-overlap sensitivity analysis and should be considered preliminary. Overall, these findings do not support a distinct SPMS-associated gut microbiome signature, although potential phenotype-related differences cannot be excluded.