June 28, 2012 — The bridge between genetic susceptibility for rheumatoid arthritis (RA) and environmental triggers might be the bacteria in the digestive tract.
Research led by Mayo Clinic immunologist Veena Taneja, PhD, and published in the April 2012 issue of PloS ONE provides the first demonstration that HLA genes and the gut environment interact to affect arthritis susceptibility. The researchers suggest that the gut microbiome might be a useful biomarker in RA studies.
This study was conducted by Mayo Clinic and the University of Illinois at Urbana-Champaign researchers participating in the Mayo Illinois Alliance for Technology Based Healthcare.
Dr. Taneja told Medscape Medical News, "Our study brings to the fore that gut can change the immune system in diseases that do not actually involve gut. There is no single biomarker to define individuals at high risk for developing arthritis. Our study explains how host genetics may determine the bugs we carry and if together they can be used as biomarker. Further, it enhances our understanding that dysregulation of immune system in RA may also involve sites away from the actual affected tissues."
The researchers used humanized HLA transgenic mice that carried HLA-DR mutations making them either susceptible to arthritis (*0401 mice) or resistant to arthritis (*0402 mice) to determine whether genetic factors and gut flora would predict subsequent arthritis.
The analysis showed that the gut flora of the *401 arthritis-susceptible mice were dominated by a Clostridium-like bacterium, while those of the *0402 arthritis-resistant mice were enriched for Porphyromonadaceae species and for Bifidobacteria. The latter organism has been associated with anti-inflammatory response in the intestinal mucosal and peripheral immune systems via suppression of T-cell proliferation and production of pro-inflammatory cytokines, and inhibition of nuclear factor kappa B (NF-κB) activation, according to the researchers.
In addition, the resistant mice had a dynamic sex- and age-influenced gut microbiome, while the arthritis-susceptible mice did not show age and sex differences in gut flora, even though they did show altered gut permeability. Analysis of cytokine transcripts also showed different TH17 regulatory gene transcripts in the susceptible vs resistant mice.
Dr. Taneja said that the key finding was that HLA genes in association with the gut microbiome may both alter the immune environment and contribute to arthritis susceptibility. "We found higher concentrations of clostridium-like bacteria in the guts of genetically susceptible mice. This suggests that bacterial populations respond to the genetic environment of their host, which in this case is likely altering the immune environment and inducing autoimmune response. I think host genetics has a big role in determining gut flora. Gut flora does change with food and other environment, and that can alter immune response. Dependent on our study we can speculate that HLA genes in association with gut flora may have a role in determining susceptibility to arthritis," she said.
The researchers suspect that the Clostridia-like bacterium might disrupt the usual populations of nonpathogenic gut commensals. Coupled with the increased gut permeability, this raises the possibility that disease-causing bacteria such as Clostridia could produce a systemic immune response resulting in arthritis in those who are genetically susceptible. The researchers also point out that certain oral and gut commensal bacterial antigens have been found in synovial fluids of RA patients.
Dr. Taneja said, "Many have suspected that the gut microbiome plays a role in disease susceptibility. We were able to demonstrate a link between bacterial levels and disease onset in populations with a genetic predisposition. This shows, at the very least, that bacteria are indicators of rheumatoid arthritis. In all likelihood, bacteria can be manipulated to delay or stop disease onset and progression."
Dr. Taneja added, "The bacteria in our guts may make a minimally invasive biomarker for rheumatoid arthritis susceptibility, as well as a potential therapeutic target. We are now looking at whether manipulation of bacterial concentrations can slow disease progression or stop disease onset altogether. This study has raised a possible way that individualized medicine can be advanced. Although in humans, the immune system is more complicated, this study is a step closer to the concept that modulation of disease may be possible.”
Marianna M. Newkirk, PhD, associate professor of medicine at the McGill Centre for the Study of Host Resistance, McGill University Health Centre, Montreal, Quebec, reviewed the study for Medscape Medical News. Dr. Newkirk has studied the association of bacterial colonization patterns and rheumatoid factor status in RA patients.
Dr. Newkirk said, "There are some problems with the data presentation that make them less compelling to me. For the part of the paper where they present the data on the amounts/types of bacteria found in the males versus females of the two strains, unfortunately they are concluding that r values of less than 0.5 are meaningful based on a p value. The p value just indicates how close to the line the data points are and not that the r value is actually significant. I usually only assume that an r value is of meaning if it is at least 0.5 or greater and of course the closer to 1.0 it is the more I believe the data.... Their data though are clearly not normally distributed, so indeed non-parametric analyses were required.
"The cytokine data are much more solid and are clearly more compelling. The r values are above 0.5 (even up to almost 0.8, in the supplementary data). This information is less novel however, as we have known for a long time that targeting cytokines is a good therapeutic approach for the control and management of RA."
Dr. Newkirk concluded, "Since I am not totally convinced about their gut microbiome data, I would not be in a hurry to alter the diet of patients with rheumatoid arthritis. Thus from my perspective the jury is still out on this potential modifier of inflammation."
Drs. Taneja and Newkirk have disclosed no relevant financial relationships.
PloS ONE. 2012. Abstract
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Cite this: Gut Flora Might Trigger or Worsen RA - Medscape - Jun 28, 2012.
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