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.