Functional microbiome reprogramming links dietary interventions to neuroinflammatory 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 benefited 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 reflect metagenomic potential, underscoring host and ecosystem complexity. We demonstrate novel evidence that KD drives tryptophan metabolism rerouting and species-specific functional reprogramming, mechanistically linking diet to neuroprotection and revealing new targets for microbiome-based MS therapies.Registry: ClinicalTrials.gov, TRN: NCT03508414, Registration date: 25 April 2018