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.

中文翻译：

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肠道微生物组的宏基因组关联研究揭示了日本人群中类风湿关节炎的新病因

目的微生物组组成的因果关系和致病机制在许多疾病中仍然难以捉摸，包括类风湿性关节炎（RA）等自身免疫性疾病。本研究旨在通过全面的宏基因组关联研究 (MWAS) 阐明肠道微生物组在 RA 病理学中的作用。方法 我们通过使用高深度的全基因组鸟枪法测序（每个样本平均 13 Gb）对日本人群（n 例 = 82，n 对照 = 42）进行 RA 肠道微生物组的 MWAS。我们的 MWAS 由三个主要的生物信息学分析流程（系统发育分析、功能基因分析和通路分析）组成。结果 系统发育病例对照关联测试显示，RA 病例宏基因组中属于普氏菌属的多个物种（例如，牙菌普氏菌）的丰度很高。非线性机器学习方法有效地消除了病例对照系统发育差异。基因功能评估表明，与对照相比，RA 宏基因组中一种氧化还原反应相关基因（R6FCZ7）的丰度显着降低。在病例对照比较中丰富了多种生物学途径，包括与代谢相关的途径（例如，脂肪酸生物合成和糖胺聚糖降解）。通过比较 RA 宏基因组和 RA 全基因组关联研究结果之间的生物途径富集，确定了宏基因组和宿主基因组之间的群体特异性联系。在 RA 病例和对照之间未发现宏基因组的 α 或 β 多样性有明显差异。