Do Microbiome Changes Protect Against RA?

Janis C. Kelly

February 13, 2015

Infections have long been suspected of triggering rheumatoid arthritis (RA), but some types of infection were associated with a reduced risk for RA in a population-based case-control study reported by Maria E.C. Sandberg, MD, and colleagues from the Karolinska Institute, Stockholm, Sweden, in Annals of the Rheumatic Diseases. Recent gastroenteritis and/or urogenital infections were associated with a reduced risk for new-onset RA, but preceding prostatitis, sinusitis, tonsillitis, and pneumonia did not affect risk.

The authors write, "In this context, we note with interest that the sites of infections that conferred a decreased risk in this study are primarily infected with gram-negative bacteria, while the sites in which infections did not confer a decreased risk are primarily infected with gram-positive bacteria. Lending some support to this hypothesis is that both sulfa (sulfasalazine) and tetracycline drugs, used for gram-negative infections at these particular sites, have in double-blind randomised clinical trials published before the era of 'biologic' treatments in RA been shown to be effective against RA."

Simon Stebbings, MBBS, MmedSc, MRCP, who was not involved in the study, told Medscape Medical News, "As this is an epidemiological study based on self-reported infection I think it raises questions but does not provide any answers. Could GI [gastrointestinal] and UTIs [urinary tract infections] really 'protect' against autoimmune disease? Some parasitic infections such as hookworm certainly seem to have a protective effect against inflammatory bowel disease. There, though, the mechanism is more easily identified with the immune response to these organisms downgrading the potential for autoimmunity."

"The authors of this study make a large leap, I believe, in suggesting that GI infections may downgrade the autoimmune trigger in the gut for RA by altering the microbiome. They provide no evidence for this causal link and there is nothing of note in the literature to support such an idea. In general it has been proposed that GI infections promote autoimmunity by breaching the mucosal barrier and allowing elements of the host microbiome to prime T cells in the lamina propria and perhaps for antigens to be transported to distant sites, such as the joints. It is not clear how a pathogenic bacterial organism might actually diminish this possibility. Hence, I think the basic premise is poorly supported by evidence to date." Dr. Stebbings is associate professor and consultant rheumatologist, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. He recently coauthored a major review on the role of the microbiome in rheumatic diseases.

Dr. Sandberg and colleagues had asked whether recent infections affected the risk for RA. They addressed this question using the EIRA (Epidemiological Investigation of Rheumatoid Arthritis) population-based case-control study to examine associations between new-onset RA and infections during the 2 previous years. RA was diagnosed according to the 1987 American College of Rheumatology criteria. Patients with RA (n = 2831) and healthy controls (n = 3570) were matched for sex, age, calendar period, and area of residence. The average age at study entry was 52 years, and 72% of patients were women. The analysis included self-reported gastroenteritis, UTI, genital infection, prostatitis, sinusitis, tonsillitis, and pneumonia that occurred within 2 years before the study. The researchers calculated odds ratios (ORs) using conditional logistic regression adjusted for smoking and socioeconomic status.

The risk for RA was reduced by 29% (OR, 0.71; 95% confidence interval [CI], 0.63 - 0.80) in patients who reported a GI infection during the previous 2 years, by 22% (OR, 0.78; 95% CI, 0.68 - 0.90) in those who reported a UTI, by 20% (OR, 0.80; (95% CI, 0.64 - 1.00) in those who reported a genital infection, and by 50% (OR, 0.50; 95% CI, 0.32 - 0.79) in those who reported having had all three types of infection. Respiratory infections and pneumonia were not associated with any change in RA risk.

"We see several possible biological mechanisms underlying our results: a decreased prevalence of infections may indicate a strong capacity for immune activation in general at mucosal surfaces, which could, in some not yet understood way, be linked to protection against RA," the authors write.

"A second, and partly related, potential explanation would be that infections in the gut and urinary tract may change the composition of the microbiome and that such a change would influence the susceptibility to RA. Hypotheses on connections between inflammation and microbial composition in the gut and risk for RA have been raised and discussed for many years and recently reports from basic science suggest that changes in the gut microbiome may play a role in the pathogenesis of RA."

Dr Stebbings said that positive aspects of the study are its prospective nature, with identification of incident diagnoses of RA and then a record of prediagnosis infections, and that it is a population-based study. One concern he raised is that that participants might have remembered GI upset and UTI in preference to other listed infections. "This is in part suggested by the fact that there was little difference between the cases and controls in terms of percentage reporting of any of the infections. As the authors acknowledge, there was no medical confirmation of the infections assessed by questionnaire," he said.

Dr Stebbings noted that evidence to date also suggests that the host microbiome is fairly resistant to change and probably returns to normal after most mild GI infections. However, additional host and microbial factors almost certainly play roles, and individuals may respond differently, as seen in different locales where the initial host microbiome may vary depending on diet and prevalent community organisms.

"Our knowledge of the gut microbiome and how it interacts with the host immune system is still in its infancy," Dr Stebbings said. "With the Human Microbiome Project and advances in molecular microbiology and informatics, we are likely to gain a better insight into how the human microbiome is affected by disease states and perhaps whether changes in the microbiome may be causative or contribute to autoimmune disease. We can now look at not only which bacteria are present but also their relative abundances, which is a huge advance."

Dr Stebbings warned that current research is a long way from understanding how dietary changes or probiotics might influence disease processes in inflammatory arthritis by altering the host microbiome. "I hold some hope that there may be some developments in this area in the next 5 to 10 years, but it is a massive task. It is certainly something patients are interested in," he said.

This study was supported by grants from the Swedish Medical Research Council, the Swedish Research Council for Health, Working Life and Welfare, the AFA Foundation, Vinnova, King Gustaf V's 80-year Foundation, the Swedish Rheumatic Foundation, and the Swedish Foundation for Strategic Research. The authors and Dr Stebbings have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online February 4, 2015. Abstract

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