AUTHOR=Kishikawa Toshihiro , Ogawa Kotaro , Motooka Daisuke , Hosokawa Akiko , Kinoshita Makoto , Suzuki Ken , Yamamoto Kenichi , Masuda Tatsuo , Matsumoto Yuki , Nii Takuro , Maeda Yuichi , Nakamura Shota , Inohara Hidenori , Mochizuki Hideki , Okuno Tatsusada , Okada Yukinori 

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2020.585973

DOI=10.3389/fcimb.2020.585973

ISSN=2235-2988

ABSTRACT=<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 (<italic>n</italic><sub>case</sub> = 26, <italic>n</italic><sub>control</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., <italic>Erysipelatoclostridium_sp</italic>. and <italic>Gemella morbillorum</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 (<italic>P</italic> = 1.5 × 10<sup>−7</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.</p>