Integrated metabolomic and metagenomic profiling reveals distinct signatures in treatment-naïve multiple sclerosis patients

SUMMARY Imbalances in gut microbiota composition and microbiota-associated metabolites have been linked with several neurological diseases, including multiple sclerosis (MS). However, a comprehensive multi-biofluid approach remains lacking. Most studies on MS include patients already receiving treatment and often neglect to account for sex-related differences, which could serve as potential confounding factors. Moreover, they mostly investigate only stools or plasma metabolomics. In this study, we recruited 18 treatment-naïve neuroinflammatory patients at diagnosis and compared them with 20 healthy controls, matched for sex and age. We conducted multi-biofluids metabolomic analysis of urine, stool, serum, and cerebrospinal fluid, complemented by taxonomical and functional profiling of the gut microbiome using shotgun metagenomic sequencing. Our results show that MS patients exhibit distinct microbiome composition and urinary metabolomic profiles compared to healthy controls. Furthermore, neuroinflammation is associated with dysregulation of microbially-produced short-chain fatty acids, their intestinal absorption and systemic bioavailability, as illustrated by the altered plasma levels.