Review: Microbiome in Inflammatory Arthritis and Human Rheumatic Diseases

Ever since its modern conception as a medical discipline, the study of microorganisms has paralleled the many technological advances in microbiology. In the 17th century, the inventor of the microscope, Antony van Leeuwenhoek, was also the first to describe—in the plaque of his own gums—the millions of microorganisms (or “animalcules”) that reside within us. It is that multitude of microbes populating most human body cavities and surfaces, including its genetic and enzymatic composition, that defines our microbiome (1). For centuries, the role of the microbiome as a potential determinant to health and disease has been rather ignored. This has been true in most fields of human research, but particularly so in autoimmune and rheumatic conditions. The reasons are multifactorial. Chief among those was the advent of Koch’s postulates in the late 1800s, which exerted a profound influence on how investigators thought about causality in medicine (2). Unknown at the time, however, were the facts that asymptomatic carriers are a common feature of many infectious diseases and that several microorganisms are fastidious in nature, with complex nutritional requirements for growth. The latter fundamentally prevented the study of bacteria within the context of a dynamic biologic community, the role of commensal taxa, the downstream molecular events, and the resulting immune interactions between microorganisms and their host. Consequently, only the prevalent microbiologic techniques in the past were used to characterize unique agents capable of triggering clinical rheumatic syndromes. Over time, the search led to correlative studies of specific bacteria and viruses in the etiopathogenesis of these disorders, most notably rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease (IBD), and the related spondyloarthritides (SpA), including ankylosing spondylitis (AS) and reactive arthritis (ReA). The revolution of culture-independent, highthroughput microbial DNA sequencing, in parallel with the resurgence of interest in and further understanding of mucosal immunity, has exponentially advanced our knowledge of the interplay between our microbes and ourselves. That profound, bidirectional interaction and its consequences in physiology and disease have led to a whole new field of research. Despite the relative novelty of the human microbiome as a discipline, a substantial body of evidence has accumulated addressing its potential involvement in the pathogenesis of rheumatic disease (3). In this article, we will critically review the available data from animal and human studies, focusing on the role of the intestinal microbiome in RA, psoriatic arthritis (PsA), and SpA. The role of the microbiome in autoimmunity and in other rheumatic diseases has been reviewed elsewhere (4,5) and is beyond the scope of this article. We include a description of the prospects of microbiome manipulation for therapeutic purposes and conclude by delineating challenges and opportunities in the field. Supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases grants K23-AR-064318 to Dr. Scher and RC2-AR-058986 through the American Recovery and Reinvestment Act of 2009 to Drs. Littman and Abramson), the Judith and Stewart Colton Center for Autoimmunity, and the Riley Family Foundation. Jose U. Scher, MD, Steven B. Abramson, MD: New York University School of Medicine and New York University Hospital for Joint Diseases, New York, New York; Dan R. Littman, MD, PhD: Kimmel Center for Biology and Medicine of the Skirball Institute and New York University School of Medicine, New York, New York. Drs. Scher, Littman, and Abramson have a patent application pending on microbiota and byproducts for diagnostics and therapeutics in rheumatic disease. Address correspondence to Jose U. Scher, MD, Division of Rheumatology, New York University Hospital for Joint Diseases, 301 East 17th Street, Room 1608, New York, NY 10003. E-mail: Jose.Scher@nyumc.org. Submitted for publication March 10, 2015; accepted in revised form June 23, 2015.