Functional microbiome shifts are associated with neuroinflammatory outcomes under dietary interventions 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. Our secondary analysis revealed that KD was associated with distinct gut microbial functional profiles, including enrichment of carbohydrate metabolism modules that co-occurred with lower T2 lesion volume. Stool propionate levels, however, did not correspond to the abundance of the annotated propionate production II module. Key contributors included Romboutsia timonensis , Roseburia intestinalis , and Bacteroides thetaiotaomicron . These microbial changes coincided with diet-associated changes in circulating tryptophan and indole metabolites, suggesting a system-level co-occurrence of changes along the gut-brain axis. We present evidence that KD is associated with coordinated tryptophan-related metabolite changes and species-specific functional differences alongside T2 lesion metrics. These exploratory associations warrant validation and mechanistic investigation. Registry ClinicalTrials.gov, TRN: NCT03508414, Registration date: 25 April 2018.