Rare Bacteria Found in Study of RA Patients
Researchers at the Mayo Clinic recently published a study in the Journal of Genome Medicine that may have isolated three specific microbes as contributors to Rheumatoid Arthritis. The genera Collinsella,Eggerthella, and Faecalibacterium, are intestinal microbes that were rare in the healthy individuals of the study, but much more abundant in those with RA.1
"For decades, an infectious cause of RA via bacteria has been proposed, but evidence has been lacking.2" The question of which microbes and how their presence leads to disease has never been answered.3 Further, treatment of RA patients with antibiotics has produced mixed results.4
The Mayo Clinic study examined the plausibility of the role of certain microbes in the disease pathway of genetically susceptible patients and model organisms.
In order to test this hypothesis, the Mayo Clinic researchers created two groups, one with RA, and a control group of first-degree relatives and matched peers. The RA group consisted of 40 individuals, 70% female, who are all rheumatoid factor positive, had an average disease duration of 81.6 months, and who met the inclusion and exclusion requirements for an RA diagnosis. 60% of this group has the HLA-DR4 gene, a known risk factor for RA. The control group consisted of 32 individuals, 81% female, who did not have RA or genetic and biological markers. From both groups they took fecal samples of 16s ribosomal DNA, which was analyzed to identify specific species of bacteria. They then compared the two groups.5
The results showed that, "Patients with RA exhibited a significant decrease in gut microbial diversity compared with healthy controls." They also identified rare taxa of gut microbes that were abundant only in the RA patients: Collinsella,Eggerthella, and Faecalibacterium.6
To answer whether or not these specific bacteria could be pathogenic, the researchers treated arthritis-susceptible mice (HLA-DQ8) with Collinsella. A group of ten mice received Collinsella, and a group of eight did not. 100% of the mice treated with Collinsella, and 62.5% of the untreated mice, developed arthritis, though the severity of the arthritis did not differ. In addition, they found that the mice precultured with the bacteria had a significant CD4 T-cell immune response compared to the untreated mice.7
Though ten out of ten mice treated with the bacteria developed arthritis, five out of eight untreated mice also developed the same symptoms. This may mean that the bacteria Collinsella plays a role in activating the immune system in genetically susceptible model organisms, though without the treatment of bacteria the same symptoms can still appear. This leaves many questions unanswered, and does not establish causation.
How then might the presence of specific bacteria lead to development of the disease? This is not directly known, however the authors hypothesize that "Collinsella increases gut permeability," which allows bacteria in the gut to interact with ethilial tissue (a tissue that lines blood vessels and organs throughout the body), and that an immune response may arise from this interaction.8 The study did not test this hypothesis, though there is some tentative auxiliary evidence to support its plausibility.9, 10, 11
The researchers point out some areas that will need to be addressed in future inquiries. "Restricting the sample of patients to those with healthy weight might have inappropriately limited the generalizability of our findings, though we cannot exclude the possibility of confounding by BMI (Body Mass Index) in this study."12 They also note that the healthy control group did not have enough males to determine sex-dependent differences in microbiota.13 They conclude by stating, "Although specific molecular mechanisms remain largely unexplored, the results of this study suggest that susceptibility to RA could be triggered by gut dysbiosis and alterations in pathways in which rare lineages are involved. However, the study needs to be confirmed with a larger patient and FDR (First Degree Relative) cohort."14
Speaking as someone with RA, my own stance is one of cautious hope. I am cautious, because though this is certainly interesting, there are many questions that are unaddressed, and many limitations mentioned by the researchers. As an infectious cause of RA has never been demonstrated despite decades of intensive research, evidence that contradicts that arouses my skepticism, and an attitude of "let's wait and see where this goes." I am and always will be hopeful that a cause of RA will be found, and that new and more effective treatments will come with it.
I look forward to seeing how this research progresses and what experts in the field have to say.
The full study, published in Genome Medicine on the 21st of April, can be found here.
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