Why every rheumatologist should understand the microbiome
Akkermansia muciniphila. Prevotella copri. Enterococcus gallinarum. Porphyromonas gingivalis. These bacteria were rarely the subject of lectures in medical schools prior to 2018, but might well revolutionize the practice of rheumatology in the next decade or two. In this editorial, we will explain why rheumatologists might need to learn a bit more about the microbiome, the collection of micro-organisms that cohabit in, and on, the human body.
How the gut microbiome interacts with the immune system
By some parameters the gut, home to trillions of bacteria, is the largest organ in the immune system. The immune system interacts with these bacteria and decides which bacteria are symbionts, and which could potentially cause disease. Lymphocytes that interact with bacteria in the intestine distribute themselves widely throughout the body [1–3]. Many gut bacteria influence the production of cytokines and various T-cell subsets (reviewed in ), and bacterial products can be detected in the blood , the joints , and elsewhere throughout the body.
Since the immune system is educated by intestinal bacteria, and since rheumatologic diseases are usually immune-mediated, it stands to reason that gut bacteria may have an influence on rheumatic diseases. Indeed, gut bacteria are altered in patients with rheumatoid arthritis , systemic lupus erythematosus , ankylosing spondylitis , reactive arthritis , psoriatic arthritis , juvenile onset arthritis , gout , and scleroderma . Bacteria in the intestine have a profound effect on diseases such as collagen-induced arthritis , murine lupus , and spondyloarthritis in either rats  or mice .
How the microbiome might induce rheumatic diseases
Specific bacteria are sometimes implicated in an immune-mediated disease. Beta hemolytic Streptococcus in rheumatic fever is a classic example. Additional examples include Campylobacter as a trigger for Guillain-Barré syndrome (reviewed in ) and Salmonella, Shigella, Yersinia or Campylobacter as triggers for reactive arthritis [20,21]. Some evidence suggests that Staphylococcus aureus could contribute to the causation of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [22–24]. But what if research fails to implicate a specific bacterium as the cause of, say, rheumatoid arthritis? Can the microbiome still have a therapeutic implication?
Altering the microbiome with antibiotics and fecal transplants
Antibiotics can dramatically alter the microbiome, and broad spectrum antibiotics can ameliorate disease in animal models of immune-mediated inflammation . Antibiotics have also demonstrated some benefit in selected patients with inflammatory bowel disease . However, the benefit from antibiotics is transient, and bacteria will ultimately develop resistance. While fecal transplants have shown therapeutic efficacy in pseudomembranous colitis  and in ulcerative colitis [28,29], we doubt that the ultimate strategy to exploit the microbiome will be via a technique as crude as fecal transplantation, which carries the risk of transplanting a pathogen along with therapeutic bacteria.
The effect of diet on the microbiome
The bacteria which coexist within the human body are dependent on the food substrates provided to them. Thus, diet has a huge influence on the microbiome . For many years, we and others had assumed that most claims of dietary benefit in a disease such as rheumatoid arthritis represented a placebo effect. After all, many more people claim to be gluten sensitive compared with the number of people who have documented celiac disease . But what if eliminating gluten alters the microbiome, resulting in a therapeutic effect even in those who do not have gluten sensitivity? Physicians have an impoverished understanding of the role of diet in health and disease because diet is immensely complex, and thus a major challenge to study. We predict that well-controlled studies on diet will eventually reveal strategies that could profoundly affect outcomes in immune-mediated diseases.
Altering the microbiome with medications
While diet and possibly probiotics could change the intestinal ecosystem, it might also be possible to alter the dynamic between gut bacteria and the immune system without knowing anything about the detailed populations in that ecosystem. For example, intestinal mucus is a major barrier that limits the interaction between intestinal bacteria and both immune and non-immune cells in the gut (reviewed in . A medication that increases mucus production in the intestine could therefore theoretically be used to treat rheumatic disease.
Sulfasalazine has some efficacy in treating the peripheral arthritis associated with spondyloarthritis . A portion of its benefit might be its ability to reduce the number of bacteria in the gut by 100-fold . Its efficacy might also relate to its ability to reduce gut permeability  such that bacterial products are less likely to distribute throughout the body from the intestine. Increased intestinal permeability is a feature of several rheumatic diseases including ankylosing spondylitis . Other medications which limit the permeability of the intestine are also under study . Assuming that the dispersion of bacterial products from the gut contributes to rheumatic disease, medications that affect the receptors, such as Toll-like receptors, which recognize these bacterial products could have a therapeutic niche in the rheumatologic armamentarium .
Many rheumatologists are old enough to have begun practicing medicine well before the emergence of biologics that could target a specific cytokine. The therapy of rheumatic diseases has been revolutionized by this approach. If we find that E. gallinarum is the cause of autoimmune hepatitis as is seen with lupus , or that P. gingivalis is causally related to rheumatoid arthritis (reviewed in [39–41]), we might advance to using vaccination against a specific organism; and thus we could experience a similar revolution. The ideal is to target a specific micro-organism, but even in the absence of this understanding of human disease, we anticipate that the microbiome will become a therapeutic target for many diseases that are mediated by the immune response.
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