Functional microbiome reprogramming links dietary interventions to neuroinflammatory outcomes in multiple sclerosis

Abstract 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