Changes in the gut microbiome before the development of rheumatoid arthritis could offer an opportunity for preventative treatments, according to new research. Bacteria associated with inflammation are found in higher levels in the gut around ten months before patients develop clinical rheumatoid arthritis, according to a longitudinal study by researchers from Leeds.
How Rheumatoid Arthritis Can be Delayed or Even Prevented
Rheumatoid arthritis, which affects more than half a million people in the UK, is a chronic disease that causes swelling, pain and stiffness in the joints because the immune system mistakenly attacks the body’s healthy cells. Previous research has linked rheumatoid arthritis to the gut microbiome, the ecosystem of microbes in the gut. However, this new study, published in the Annals of the Rheumatic Diseases, highlights a potential target for intervention. Lead researcher Dr. Christopher Rooney, NIHR Academic Clinical Lecturer at the University of Leeds and Leeds Teaching Hospitals NHS Trust, said: “Patients at risk of rheumatoid arthritis are already experiencing symptoms such as fatigue and joint pain and may know someone in their family who has the condition. As there is no known cure, at-risk patients often feel hopeless or even avoid getting tested. This new study could provide a great opportunity to act earlier to prevent rheumatoid arthritis.
The longitudinal study, funded by Versus Arthritis, was conducted on 19 patients at risk of rheumatoid arthritis, with samples taken five times over a 15-month period. Five of these patients developed clinical arthritis. They were found to have intestinal instability with higher levels of bacteria, including Prevotella, which is associated with rheumatoid arthritis, about ten months before the disease progressed. The remaining 14, whose disease did not progress, had largely stable levels of bacteria in their gut. Potential treatments the researchers plan to test in the ten-month window include dietary changes such as eating more fiber, taking prebiotics or probiotics, and improving dental hygiene to keep harmful bacteria that cause periodontal disease out of the gut.
The exact link between gut inflammation and the development of rheumatoid arthritis is still unclear. In a small number of patients in the study, the changes in the gut occurred before a rheumatologist detected changes in the joints, but further research is needed to determine whether they interact. Although bacteria have been linked to rheumatoid arthritis, the researchers want to make it clear that there is no evidence that it is contagious. According to Lucy Donaldson, Director of Research and Health Information at Versus Arthritis, these findings offer doctors of the future a crucial opportunity to delay or even prevent the onset of rheumatoid arthritis.
Years of Work
The research was carried out in collaboration with the National Institute for Health Research Leeds Biomedical Research Centre as part of the Antimicrobial Resistance and Infection and Musculoskeletal Diseases research themes. The study initially included data from 124 people who had high levels of CCP+, an antibody that attacks healthy cells in the blood and indicates the risk of developing rheumatoid arthritis. The researchers compared their samples with 22 healthy individuals and seven individuals who had been newly diagnosed with rheumatoid arthritis.
The results of this larger group showed that the gut microbiome was less diverse in the at-risk group compared to the healthy control group. The longitudinal study, in which samples were taken from 19 patients over a 15-month period, showed the changes in bacteria ten months before progression to rheumatoid arthritis. The Leeds research team will now carry out an analysis of the treatments already tested to support future testing of treatments at this potential intervention point after ten months.
Dental Disease Closely Linked to the Onset and Exacerbation of Rheumatoid Arthritis
Periodontitis, which affects the gums and tissues around the teeth, is one of the most common dental diseases worldwide. Periodontitis is usually caused by the formation and accumulation of bacterial biofilm around the teeth and can eventually lead to tooth loss if left untreated. Interestingly, the inflammatory effects of periodontal bacteria can extend far beyond the mouth and lead to systemic effects. In recent decades, clinical studies have shown that the periodontal pathogen Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) is closely linked to the onset and exacerbation of rheumatoid arthritis. However, what is going on at the molecular level is largely unexplored and unclear.
In a recent study published online in the International Journal of Oral Science, a research team from Tokyo Medical and Dental University (TMDU) in Japan attempted to close this knowledge gap through detailed mechanistic studies in an animal model. First, the researchers conducted preliminary experiments to confirm whether infection with A. actinomycetemcomitans affects arthritis in mice. To this end, they used the collagen antibody-induced arthritis mouse model, an established experimental model that mimics several aspects of RA in humans. They found that infection with this specific bacterium led to increased limb swelling, cellular infiltration into the joint lining and higher levels of the inflammatory cytokine interleukin-1β (IL-1β) in the limbs.
Remarkably, these symptoms of worsening RA could be suppressed by administering a chemical called clodronate, which breaks down macrophages – a type of immune cell. This showed that macrophages were somehow involved in the exacerbation of RA caused by infection with A. actinomycetemcomitans. Further studies using macrophages from the bone marrow of mice showed that infection with A. actinomycetemcomitans increased the production of IL-1β. This in turn triggered the activation of a multiprotein complex known as the inflammasome, which plays a key role in triggering and modulating the body’s inflammatory response to infection. The researchers added another piece to this puzzle by using mice deficient in caspase-11. In these animals, activation of the inflammasome by A. actinomycetemcomitans was suppressed. Most importantly, there was less worsening of arthritis symptoms in mice lacking caspase-11, indicating the important role that caspase-11 plays in this context.
Future Treatment Strategies Not Only for Rheumatoid Arthritis, But Possibly also for Alzheimer’s Disease
According to Professor Toshihiko Suzuki, one of the lead authors of the studies, these research findings provide new insights into the link between periodontal pathogenic bacteria and the exacerbation of arthritis through activation of the inflammasome, and offer important information about the long-discussed relationship between periodontal disease and systemic disease.
With any luck, these efforts will contribute to the development of novel therapeutic strategies for the treatment of RA. According to the experts, the results of this research could pave the way for advances in the clinical treatment of RA caused by infection with A. actinomycetemcomitans. In addition, the outcome of this work could contribute to the development of treatment strategies not only for arthritis, but also for other systemic diseases such as Alzheimer’s disease, which is also associated with periodontopathogenic bacteria.