The microbiome and rheumatoid arthritis

Abstract

Humans are not (and have never been) alone. From the moment we are born, millions of micro-organisms populate our bodies and coexist with us rather peacefully for the rest of our lives. This microbiome represents the totality of micro-organisms (and their genomes) that we necessarily acquire from the environment. Micro-organisms living in or on us have evolved to extract the energy they require to survive, and in exchange they support the physiological, metabolic and immune capacities that have contributed to our evolutionary success. Although currently categorized as an autoimmune disorder and regarded as a complex genetic disease, the ultimate cause of rheumatoid arthritis (RA) remains elusive. It seems that interplay between predisposing genetic factors and environmental triggers is required for disease manifestation. New insights from DNA sequence-based analyses of gut microbial communities and a renewed interest in mucosal immunology suggest that the microbiome represents an important environmental factor that can influence autoimmune disease manifestation. This Review summarizes the historical clues that suggest a possible role for the microbiota in the pathogenesis of RA, and will focus on new technologies that might provide scientific evidence to support this hypothesis.

Figure 1

Historical, literary, artistic and paleopathological evidence of RA as a New World disease that has ‘spread’ to the rest of the world. Paleopathological evidence of RA exists only in skeletal remains from New World populations and RA was not documented in the Old World until the late 18^th century, whereas other rheumatic diseases have been well described in biblical and ancient texts. Although debated, RA is thought to have spread to Europe after the beginning of trading with the Americas. The first medical literary evidence comes from a paper from 1800 by Landré-Beauvais, who reported his findings in “La goutte asthénique primitive”. In 1859, Alfred Garrod coined the term ‘Rheumatoid Arthritis’. Rubens seems to be the first painter to depict what seems to be RA of the hands in the mid 17th century. Paintings such as The three graces and The miracle of St Ignatius, show ulnar deviation, buttoniere deformities and MCP swelling. Epidemiological evidence supports the notion that RA is a disease of the New World. Amerindians and Eskimos have the highest prevalence of RA, followed by white populations. In keeping with this theory, African and Far East populations, being the latest to be in contact with European conquistadors, have a strikingly low prevalence of RA. Abbreviations: MCP, metacarpophalangeal; RA, rheumatoid arthritis. Permission to use image ‘Sir Alfred Baring Garrod. Photograph by Elliot and Fry’ obtained from the Wellcome Library, London ©

Figure 2

Culture-independent genomic analysis of the human microbiome. Culture-independent techniques have advanced our capacity to survey complex microbial communities in human samples. Well-characterized individuals (healthy and diseased) are asked to donate samples for microbiome analyses. Two metagenomic sequencing approaches are utilized. Conserved and variable 16S rRNA genomic regions are amplified and subjected to pyrosequencing. The resulting sequences are then aligned, filtered and compared to publicly available databases of 16S rRNA sequences, enabling taxonomic classification of bacteria present or absent in a given sample. Whole genome shotgun sequencing provides information that enables identification of genes present and allows for subsequent comparison of enzymatic pathways and functions represented among different samples. Enzymatic databases are also available to assist in the identification of protein function, enabling the richness and diversity of functional capacities provided by the microbiome to be assessed. Abbreviations: PCR, polymerase chain reaction; rRNA, ribosomal RNA.

Figure 3

Host–microbiota interactions in health and inflammatory arthritis. a | In healthy individuals, a well balanced host–microbial cross-talk is essential for the maintenance of homeostasis. A thick mucus layer and epithelial cells prevent direct contact with the gut-associated immune cells, which constantly survey the contents of the intestinal lumen and eliminate undesired antigens. Commensal bacteria, such as Bacteroides fragilis, can activate pro-tolerogenic machinery. A specific cell wall component, PSA, is sufficient to induce T_REG-cell activation, IL-10 production and T_H17-cell repression to avoid uncontrolled inflammation. b | When either genetic or environmental factors alter the balance in the microbiota composition, dysbiosis ensues. Potentially harmful micro-organisms (such as SFB or Lactobacillus) predominate and local expansion of proinflammatory cells (T_H17 cells, T_H1 cells and others) occurs via different molecules (such as ATP, SAA or CCL5 signaling). These autoreactive T cells migrate to peripheral immune compartments and activate B cells to differentiate into autoantibody-producing plasma cells. These cells and antibodies then migrate to synovial tissue where the inflammatory cascade is amplified through the activation of effector components, including macrophages, fibroblasts, osteoclasts, cytokines and proteinases. If self-perpetuating, this process can lead to arthritis and pannus formation. Abbreviations: ATP, adenosine-5'-triphosphate; CCL5, CC-chemokine ligand 5; IFNγ, interferon γ; IL-17, interleukin-17; PSA, polysaccharide A; SAA, serum amyloid A; SFB, segmented filamentous bacteria; T_H1, type 1 T helper cell; T_H17, type 17 T helper cell; T_REG, regulatory T cell.

Figure 4

Multiple animal models of inflammatory arthritis have demonstrated that the gut microbiota is critical for the development of disease. The use of gnotobiotic experiments, in which animals are kept germ-free until specific microorganisms are introduced, have advanced our understanding of how local changes in the gut flora produce an imbalance in the proinflammatory and anti-inflammatory immune response and ultimately trigger autoimmunity at distal sites. SFB are sufficient to activate lamina propria T_H17 cells in the K/BxN model of inflammatory arthritis. These cells migrate to the periphery, produce IL-17 (their signature cytokine) and stimulate plasma cells to produce arthritogenic autoantibodies. However, when kept in germ-free conditions, these animals do not develop arthritis. Lactobacillus is also capable of arthritis-induction in the Il1rn^−/− model. Increase in T_H17 cell activity and decrease in T_REG cell function are key to the development of joint inflammation. Abbreviations: AA, adjuvant arthritis; CIA, collagen-induced arthritis; IL-17, interleukin-17; SFB, segmented filamentous bacteria; T_H1, type 1 T helper cell; T_H17, type 17 T helper cell; TLR, Toll-like receptor; T_REG, regulatory T cell.