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Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population.

ABSTRACT: OBJECTIVE:The causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome's role in RA pathology by a comprehensive metagenome-wide association study (MWAS). METHODS:We conducted MWAS of the RA gut microbiome in the Japanese population (n case=82, n control=42) by using whole-genome shotgun sequencing of high depth (average 13?Gb per sample). Our MWAS consisted of three major bioinformatic analytic pipelines (phylogenetic analysis, functional gene analysis and pathway analysis). RESULTS:Phylogenetic case-control association tests showed high abundance of multiple species belonging to the genus Prevotella (e.g., Prevotella denticola) in the RA case metagenome. The non-linear machine learning method efficiently deconvoluted the case-control phylogenetic discrepancy. Gene functional assessments showed that the abundance of one redox reaction-related gene (R6FCZ7) was significantly decreased in the RA metagenome compared with controls. A variety of biological pathways including those related to metabolism (e.g., fatty acid biosynthesis and glycosaminoglycan degradation) were enriched in the case-control comparison. A population-specific link between the metagenome and host genome was identified by comparing biological pathway enrichment between the RA metagenome and the RA genome-wide association study results. No apparent discrepancy in alpha or beta diversities of metagenome was found between RA cases and controls. CONCLUSION:Our shotgun sequencing-based MWAS highlights a novel link among the gut microbiome, host genome and pathology of RA, which contributes to our understanding of the microbiome's role in RA aetiology.

SUBMITTER: Kishikawa T

PROVIDER: S-EPMC6937407 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population.

Kishikawa Toshihiro T Maeda Yuichi Y Nii Takuro T Motooka Daisuke D Matsumoto Yuki Y Matsushita Masato M Matsuoka Hidetoshi H Yoshimura Maiko M Kawada Shoji S Teshigawara Satoru S Oguro Eri E Okita Yasutaka Y Kawamoto Keisuke K Higa Shinji S Hirano Toru T Narazaki Masashi M Ogata Atsushi A Saeki Yukihiko Y Nakamura Shota S Inohara Hidenori H Kumanogoh Atsushi A Takeda Kiyoshi K Okada Yukinori Y

Annals of the rheumatic diseases 20191107 1

<h4>Objective</h4>The causality and pathogenic mechanism of microbiome composition remain elusive in many diseases, including autoimmune diseases such as rheumatoid arthritis (RA). This study aimed to elucidate gut microbiome's role in RA pathology by a comprehensive metagenome-wide association study (MWAS).<h4>Methods</h4>We conducted MWAS of the RA gut microbiome in the Japanese population (<i>n</i><sub>case</sub>=82, <i>n</i><sub>control</sub>=42) by using whole-genome shotgun sequencing of h ...[more]

PMID: 31699813

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Project description:ObjectiveRheumatoid arthritis (RA) is a chronic inflammatory joint disease, which is associated with progressive disability, systemic complications, and early death. But its etiology and pathogenesis are not fully understood. We aimed to investigate the alterations in plasma metabolite profiles, gut bacteria, and fungi and their role of them in the pathogenesis of RA.MethodsMetabolomics profiling of plasma from 363 participants including RA (n = 244), systemic lupus erythematosus (SLE, n = 50), and healthy control (HC, n = 69) were performed using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The differentially expressed metabolites were selected among groups and used to explore important metabolic pathways. Gut microbial diversity analysis was performed by 16S rRNA sequencing and ITS sequencing (RA = 195, HC = 269), and the specific microbial floras were identified afterward. The diagnosis models were established based on significant differential metabolites and microbial floras, respectively.ResultsThere were 63 differential metabolites discovered between RA and HC groups, mainly significantly enriched in the arginine and proline metabolism, glycine, serine, and threonine metabolism, and glycerophospholipid metabolism between RA and HC groups. The core differential metabolites included L-arginine, creatine, D-proline, ornithine, choline, betaine, L-threonine, LysoPC (18:0), phosphorylcholine, and glycerophosphocholine. The L-arginine and phosphorylcholine were increased in the RA group. The AUC of the predictive model was 0.992, based on the combination of the 10 differential metabolites. Compared with the SLE group, 23 metabolites increased and 61 metabolites decreased in the RA group. However, no significant metabolic pathways were enriched between RA and SLE groups. On the genus level, a total of 117 differential bacteria genera and 531 differential fungal genera were identified between RA and HC groups. The results indicated that three bacteria genera (Eubacterium_hallii_group, Escherichia-Shigella, Streptococcus) and two fungal genera (Candida and Debaryomyces) significantly increased in RA patients. The AUC was 0.80 based on a combination of six differential bacterial genera and the AUC was 0.812 based on a combination of seven differential fungal genera. Functional predictive analysis displayed that differential bacterial and differential fungus both were associated with KEGG pathways involving superpathway of L-serine and glycine biosynthesis I, arginine, ornithine, and proline interconversion.ConclusionThe plasma metabolism profile and gut microbe profile changed markedly in RA. The glycine, serine, and threonine metabolism and arginine and proline metabolism played an important role in RA.

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Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population.

Publications

Metagenome-wide association study of gut microbiome revealed novel aetiology of rheumatoid arthritis in the Japanese population.

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