Functional microbiome reprogramming links dietary interventions to neuroin ammatory outcomes in multiple sclerosis

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. While disease-modifying therapies can reduce relapse rates, their limitations have spurred interest in adjunctive approaches such as fasting and ketogenic diets (FD, KD). In a randomized controlled trial, participants with relapsing-remitting MS followed FD, KD, or a control diet for 9 months, with multi-omic and clinical assessments. KD primarily bene ted MS via direct modulation of gut microbial function, enriching propionate production and glycerol metabolism modules linked to lower lesion volume. Romboutsia timonensis, Roseburia intestinalis, and Bacteroides thetaiotaomicron emerged as contributors, while KD shifted tryptophan metabolism toward microbiome-derived indoles, indicating functional rerouting along the gut-brain axis. Stool propionate did not re ect metagenomic potential, underscoring host and ecosystem complexity. We demonstrate novel evidence that KD drives tryptophan metabolism rerouting and species-speci c functional reprogramming, mechanistically linking diet to neuroprotection and revealing new targets for microbiome-based MS therapies.