A Metagenome-Wide Association Study of Gut Microbiome in Patients With Multiple Sclerosis Revealed Novel Disease Pathology

<jats:p>While microbiome plays key roles in the etiology of multiple sclerosis (MS), its mechanism remains elusive. Here, we conducted a comprehensive metagenome-wide association study (MWAS) of the relapsing-remitting MS gut microbiome (<jats:italic>n</jats:italic><jats:sub>case</jats:sub> = 26, <jats:italic>n</jats:italic><jats:sub>control</jats:sub> = 77) in the Japanese population, by using whole-genome shotgun sequencing. Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis, and pathway analysis). Phylogenetic case-control association tests showed discrepancies of eight clades, most of which were related to the immune system (false discovery rate [FDR] &lt; 0.10; e.g., <jats:italic>Erysipelatoclostridium_sp</jats:italic>. and <jats:italic>Gemella morbillorum</jats:italic>). Gene association tests found an increased abundance of one putative dehydrogenase gene (Clo1100_2356) and one ABC transporter related gene (Mahau_1952) in the MS metagenome compared with controls (FDR &lt; 0.1). Molecular pathway analysis of the microbiome gene case-control comparisons identified enrichment of multiple Gene Ontology terms, with the most significant enrichment on cell outer membrane (<jats:italic>P</jats:italic> = 1.5 × 10<jats:sup>−7</jats:sup>). Interaction between the metagenome and host genome was identified by comparing biological pathway enrichment between the MS MWAS and the MS genome-wide association study (GWAS) results (i.e., MWAS-GWAS interaction). No apparent discrepancies in alpha or beta diversities of metagenome were found between MS cases and controls. Our shotgun sequencing-based MWAS highlights novel characteristics of the MS gut microbiome and its interaction with host genome, which contributes to our understanding of the microbiome’s role in MS pathophysiology.</jats:p>