Abstract
Multiple sclerosis (MS) can present at different ages in adults, leading to severe and progressive disability. As such, understanding the risk factors for MS onset may support earlier risk stratification and monitoring. The gut microbiome, trillions of intestinal microorganisms that shape host metabolism and immune tone has been repeatedly linked to MS risk and clinical course. Yet, whether the gut microbiome is linked to onset age and disease severity remains unclear. In this study, we thus aimed to explore the association between gut microbiome composition, age of MS onset, and disease severity. Using 16S rRNA profiles from the International MS Microbiome Study (iMSMS), we analyzed patients with MS and stratified them into early (18–29 years old), mid (30–49 years old), and late (≥50 years old) onset groups. We then assessed alpha (Shannon, Faith’s phylogenetic diversity) and beta diversity (Bray-Curtis), then used indicator species analysis and DESeq2 to identify onset-linked taxa and shifts in abundance patterns. Finally, we tested whether these microbiome features relate to disease burden, measured by Multiple Sclerosis Severity Scores (MSSS and relapse counts. We trained a random-forest model to compare the predictive contribution of host clinical variables and microbial features for classifying onset groups. Overall, we found no difference in alpha and beta diversity across onset groups. Moreover, core microbiome analysis showed that MS onset age groups shared most of their core amplicon sequence variants, while only a small subset of genera differed between groups. Overall community composition (Bray-Curtis dissimilarities) explained a modest variation in MSSS and showed no association with relapse count. Together, these results suggest that while microbiome diversity is broadly conserved across MS onset age groups, taxa-specific differences exist, but their association with severity was small and relapse count showed no association.