Serum and Stool Metabolites Are Associated with Transition from Relapsing-remitting to Progressive Multiple Sclerosis
Federico Montini1, Luke Schwerdtfeger1, Bonnie Glanz2, Tanuja Chitnis3, Laura Cox4, Howard Weiner2
1Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, 2Brigham and Women'S Hospital, 3Brigham and Women's Hospital, 4Harvard Medical School
Objective:
To investigate whether patients who transition from relapsing-remitting to progressive multiple sclerosis (MS) have alterations in serum and stool metabolites. Identifying patients who transition to progressive MS is crucial for understanding the biology of progressive MS.
Background:
Patients with secondary progressive MS (SPMS) have altered microbiota compared to patients with relapsing-remitting (RRMS) disease and controls (HC). Gut microbiota can influence the host through numerous means, including microbially derived metabolites with immunomodulatory capacity.
Design/Methods:
We performed liquid chromatography with tandem mass spectrometry (LC-MS/MS) for global metabolic profiling of serum and stool from 23 HC, 23 stable RRMS, 21 SPMS, and 21 RRMS who transitioned to SPMS at 2-year follow-up (RRMS->SPMS). ANCOVA was used to detect differences in metabolite levels between groups while adjusting for covariates.
Results:
Greater than 1000 metabolites were identified, of which 264 in serum and 132 in stool were different across disease status. SPMS and RRMSàSPMS shared similar metabolic profiles in stool and blood vs. HC. Palmitoleate was increased in patients with a relapse, associated with higher EDSS, and also elevated in SPMS and RRMS->SPMS compared to HC. Several microbially-derived metabolites including secondary bile acids were significantly decreased in SPMS and RRMS->SPMS, but not in RMS compared to HC, including ursodeoxycholate and isoursodeoxycholate.
Conclusions:
RRMS subjects who transition to SPMS have serum and stool metabolic alterations similar to SPMS. Secondary bile acids are potential beneficial metabolites which have shown efficacy in mouse models of MS and were reduced in SPMS and RRMS->SPMS in our study. This approach may identify both microbial mediators of disease progression and novel therapeutic targets to treat MS.