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Alterations of host-gut microbiome interactions in multiple sclerosis


Summary

Background

Multiple sclerosis (MS) has a complex genetic, immune and metabolic pathophysiology. Recent studies implicated the gut microbiome in MS pathogenesis. However, interactions between the microbiome and host immune system, metabolism and diet have not been studied over time in this disorder.

Methods

We performed a six-month longitudinal multi-omics study of 49 participants (24 untreated relapse remitting MS patients and 25 age, sex, race matched healthy control individuals. Gut microbiome composition and function were characterized using 16S and metagenomic shotgun sequencing. Flow cytometry was used to characterize blood immune cell populations and cytokine profiles. Circulating metabolites were profiled by untargeted UPLC-MS. A four-day food diary was recorded to capture the habitual dietary pattern of study participants.

Findings

Together with changes in blood immune cells, metagenomic analysis identified a number of gut microbiota decreased in MS patients compared to healthy controls, and microbiota positively or negatively correlated with degree of disability in MS patients. MS patients demonstrated perturbations of their blood metabolome, such as linoleate metabolic pathway, fatty acid biosynthesis, chalcone, dihydrochalcone, 4-nitrocatechol and methionine. Global correlations between multi-omics demonstrated a disrupted immune-microbiome relationship and a positive blood metabolome-microbiome correlation in MS. Specific feature association analysis identified a potential correlation network linking meat servings with decreased gut microbe B. thetaiotaomicron, increased Th17 cell and greater abundance of meat-associated blood metabolites. The microbiome and metabolome profiles remained stable over six months in MS and control individuals.

Interpretation

Our study identified multi-system alterations in gut microbiota, immune and blood metabolome of MS patients at global and individual feature level. Multi-OMICS data integration deciphered a potential important biological network that links meat intakes with increased meat-associated blood metabolite, decreased polysaccharides digesting bacteria, and increased circulating proinflammatory marker.

Funding

This work was supported by the Washington University in St. Louis Institute of Clinical and Translational Sciences , funded, in part, by Grant Number # UL1 TR000448 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Zhou Y, Piccio, L, Lovett-Racke A and Tarr PI); R01 NS10263304 (Zhou Y, Piccio L); the Leon and Harriet Felman Fund for Human MS Research (Piccio L and Cross AH). Cantoni C. was supported by the National MS Society Career Transition Fellowship ( TA-180531003 ) and by donations from Whitelaw Terry, Jr. / Valerie Terry Fund. Ghezzi L. was supported by the Italian Multiple Sclerosis Society research fellowship ( FISM 2018/B/1 ) and the National Multiple Sclerosis Society Post-Doctoral Fellowship ( FG-190734474 ). Anne Cross was supported by The Manny & Rosalyn Rosenthal-Dr. John L. Trotter MS Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Methods

 Ethics

The study was approved by the Human Research Protection Office at Washington University in St. Louis School of Medicine (WUSM) (approval number: 201,502,105). All patients gave informed consent to participation.

 Study participants

This is a matched case and control longitudinal study. MS patients were recruited at the John L. Trotter MS Center of WUSM from 2015–2018. Inclusion criteria for MS patients were: (1) diagnosis of MS using the 2010 revision of the McDonald criteria;

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Diagnostic criteria for multiple sclerosis–2010 revisions to the McDonald criteria.