Metagenome-wide Association Studies Potentiate Precision Medicine for Rheumatoid Arthritis

An article recently published in Nature Medicine by the group led by Drs. Jun Wang and Yingrui Li from BGI-Shenzhen and Xuan Zhang from Beijing Union Medical College Hospital, Chinese Academy of Medical Sciences revealed the relationship between the human microbiome and rheumatoid arthritis (RA) [1]. Zhang et al. performed metagenomic shotgun sequencing and a metagenome-wide association study (MGWAS) on fecal, dental, and salivary samples from a large cohort of treatment-naı̈ve RA individuals and healthy controls. As a result, they found that the gut microbiome and the oral microbiome exhibited significant differences between RA patients and normal subjects. More importantly, the altered gut microbiome and oral microbiome of RA patients were partially corrected by disease-modifying antirheumatic drugs (DMARDs). Therefore, their findings suggest that the gut and oral microbiome composition of RA patients could be potentially used to stratify RA patients and facilitate disease diagnosis and prognosis. RA is a relatively common autoimmune disease with high morbidity and increasing mortality, but its etiology remains obscure [2,3]. Previous studies have shown that genetic predisposition partially contributes to the disease development and some susceptibility alleles have been identified by the genome-wide association studies (GWAS) [4]. However, genetic predisposition alone cannot fully explain RA’s etiology, and environmental factors are believed to play an important role as well [3,5]. Thanks to the rapid development of next-generation sequencing (NGS) technology, especially metagenomics, the important role of microbiome has been more and more appreciated. Many diseases, especially the chronic diseases including obesity [6], diabetes [7], and autism [8], have been reported to be associated with the microbiome—the so-called ‘‘second genome of human” [9]. Microbiome is also considered to be closely related to the human immune system [10,11]. The microbial communities on human body surface (skin or mucosa) interact with the host immune system, help its maturation and enhance its defenses against harmful microorganisms [10]. On the other hand, complicated microbial antigens and enormous amount of microbial metabolites may trigger autoimmune diseases [3]. For instance, previous studies have suggested that RA could be triggered by gut microbiome [3] and gut bacterial Prevotella copri was believed to enhance the susceptibility to RA [12]. To understand the potential influence of microbiome on the pathogenesis of RA and explore metagenomic markers for RA diagnosis and prognosis, Zhang et al. [1] collected 212 fecal, 105 dental, and 98 saliva samples from RA patients and controls (including healthy relatives and unrelated individuals), and used shotgun sequencing technique for characterizing the microbiome in these samples. Their data revealed a clear difference in microbiome composition between RA patients and healthy controls. In addition, they also detected