Inflammatory Arthritis and the Gut Microbiome: Do Microbes Hold the Key to New Treatments?

During the last few decades, advances in sequencing and omics technologies have fueled studies focused on understanding the role of the human gut microbiome in health and disease.¹ Recent calculations point to a 1:1 ratio of bacteria to human cells in the human body, with a total mass of bacteria estimated at 0.2 kg.² Bacterial phyla dominating the human gut include Bacteroidetes, Actinobacteria, Firmicutes, Proteobacteria, Fusobacteria, and Verrucomicrobia.³

Research has shown that in healthy states, complex interactions among intestinal microbiota, their metabolic products, and the host modulate the host immune response to maintain homeostasis and prevent inflammation and disease.⁴ At the other end, a disturbance in this balance, or an alteration of commensal species, has been associated with adverse effects on host immunity, increased inflammation, and the onset of disease.⁵

To date, the gut microbiome has been primarily studied in Clostridium difficile infection⁶ and inflammatory bowel diseases⁷; however, new studies focusing on rheumatic diseases are emerging by the day. Recent research points to an association between the gut microbiome composition and various types of immune-mediated inflammatory arthritides.^8-10

In an interview with Rheumatology Advisor, James T. Rosenbaum, MD, head of the Division of Arthritis and Rheumatic Diseases at Oregon Health & Science University, Portland, and Maxime Breban, MD, PhD, professor of medicine at the University of Versailles Saint-Quentin and head of the Division of Rheumatology at Ambroise Paré Hospital, Boulogne-Billancourt, France, discussed the latest insights on this connection.

Rheumatology Advisor: What is the mechanism by which the microbiome influences the inflammatory response in the gut and, potentially, the onset of different types of inflammatory arthritis?

Dr Rosenbaum: We don’t know the exact answer to this question, as multiple potential mechanisms have been identified.

Essentially, the microbiome educates the immune response so that certain bacteria influence which cytokines and regulatory T (T_reg) cells are produced. It influences how the inflammatory “thermostat” is set, and in those conditions where the gut is permeable, such as in psoriatic arthritis, bacterial products can circulate in the blood and joints and, hypothetically, have an influence on joint inflammation.

Another potential mechanism involves a change in the balance of the immune system through changes in the concentration of T_reg or Th17 cells. The third possibility is the accumulation of lymphocytes that have been activated in the gut to another part of the body. The fourth potential mechanism involves mimicry, or the idea that a structural component of bacteria, viruses, or yeast may have antigenic stimulation effects and cause cross-reactivity with something that is already present in our bodies. This is how rheumatic fever develops after a streptococcal throat infection.

Rheumatology Advisor: What type of gut microbiome dysbiosis is typically seen in patients with inflammatory arthritis?

Dr Breban: Microbiota composition has now been studied by several teams in the context of a variety of inflammatory arthritic disorders, including rheumatoid arthritis (RA) and other connective tissue diseases, psoriatic arthritis (PsA), and spondyloarthritis (SpA). The majority of those studies concerned gut microbiota and revealed intestinal dysbiosis as a general feature of inflammatory arthritis. One recurrent finding is a reduction of microbiota richness that seems to correlate with disease activity.

However, when compared in the same study, the nature of dysbiosis was different between disorders; for instance, between RA and SpA or between RA and PsA.¹¹ Notably, enrichment or reduction of given taxa appears to diverge between diseases and studies.

Rheumatology Advisor: Have any specific bacterial strains been implicated in different types of inflammatory arthritis?

Dr Rosenbaum: Different studies have implicated different bacterial strains, and I do not think there is a definitive consensus about the involvement of specific bacterial strains in various type of inflammatory arthritis. The granularity of the studies is not very good, and in my opinion, there hasn’t been enough consistency among studies to pin down a specific bacterial strain.

This is an exciting area of research, and we’re getting proof-of-concept studies in related diseases, such as ulcerative colitis, for which fecal microbiome transplant (FMT) has been proven effective in a recent clinical study published in The Lancet.¹²

Dr Breban: In SpA, which was the main focus of my group, we observed a significant increase in the abundance of Ruminicoccus gnavus, a strictly anaerobic Gram + cocci, in the feces from patients with SpA as compared to healthy controls, including HLA-B27-positive siblings and patients with RA.¹⁰ Moreover, this increase was positively correlated with disease activity.

Rheumatology Advisor: What is the association between HLA-B27 status and various spondyloarthropathies? What is the mechanism behind this association?

Dr Breban: The positive association between HLA-B27 and SpA is one of the strongest between an HLA allele and a given disorder. The prevalence of HLA-B27 in the general Caucasian population is estimated at 8%, whereas it is 75% to 80% in SpA. Thus, the increased risk of developing SpA due to the presence of HLA-B27 is 40-fold, as we recently estimated.¹³

The mechanism underlying such a striking association discovered 45 years ago remains poorly understood. At the molecular level, several hypotheses have been proposed, such as the presentation of an “arthritogenic” peptide by HLA-B27, the formation of noncanonical homodimers of HLA-B27 heavy chains, or the induction of an endoplasmic reticulum stress response. Whatever the precise molecular mechanism, a possibility suggested by recent microbiota studies is that the presence of HLA-B27 results in gut dysbiosis that fosters an inflammatory response initiated in the gut mucosa that spreads to the joints.

Rheumatology Advisor: Is FMT being investigated as a potential treatment option for patients with inflammatory arthritis?

Dr Rosenbaum: My group has been interested in this topic for a while, but before conducting a study, we would first like to have a more precise characterization of specific bacterial strains that might be implicated. Another important consideration is the considerable variability of microbiomes deriving from different donors, which makes ensuring consistency of treatment a challenge.

Rheumatology Advisor: Are you aware of any European clinics performing FMT for treatment purposes, or is this treatment still considered exploratory in Europe?

Dr Breban: FMT is currently under evaluation in the context of inflammatory bowel disease, with several encouraging reports, but we’re still waiting for the outcomes of large controlled trials. These pioneering studies have set the path for similar studies in inflammatory arthritis. One such double-blind randomized placebo-controlled trial in PsA is already recruiting in Denmark (ClinicalTrials.gov identifier: NCT03058900).

Rheumatology Advisor: Which important considerations need to be taken into account when designing a clinical study that involves FMT as treatment?

Dr Rosenbaum: Ensuring that each new treatment goes through all phases of safety and toxicity testing is vitally important. This includes the testing of the preparation for bacterial, viral, or any other microbial pathogens. One should also keep in mind that a microbiome that alters the immune system might be beneficial for one disease, but at the same time, potentially provoke another immune-mediated condition.

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References

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11. Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife. 2013;2:e01202.
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13. Constantino F, Talpin A, Said-Nahal R, et al. Prevalence of spondyloarthritis in reference to HLA-B27 in the French population: results of the GAZEL cohort. Ann Rheum Dis. 2015;74(4):689-693.