Medical convention separates the care of our mouths from the rest of our anatomy, but within our bodies, there are no such divisions. Scientists have long puzzled over a surprising connection between our mouths and our joints. “People who have health problems with their gums have an increased risk of developing rheumatoid arthritis,” said William Robinson, an immunologist at Stanford University. But how and why patients with periodontitis (PD) suffer from rheumatoid arthritis (RA) with a greater frequency than the general population remained a mystery.
Robinson and his colleagues have now cracked the case: bacteria in the mouth can slip into the bloodstream due to gum inflammation and trigger an immune response, which then mistakenly targets the joints. They recently published their results in Science Translational Medicine.
People who have health problems with their gums have an increased risk of developing rheumatoid arthritis.
- William Robinson, Stanford University
Based on prior evidence, Robinson focused his investigation on gum bacteria, especially an anaerobic bacterium called Porphyromonas gingivalis, which carries an enzyme that swaps arginine with citrulline after a protein has been synthesized, creating citrullinated proteins. Antibodies against citrullinated proteins occur in approximately two out of three RA cases.
To determine the mechanism connecting oral bacteria with RA, Robinson and his team took advantage of blood samples from a cohort of five patients with RA who had their fingers pricked by coauthor Dana Orange, a rheumatologist at Rockefeller University, once a week for one to four years. “It’s a small sample size” of patients, said Jennifer Malcolm, a medical researcher at the University of Glasgow who was not involved with the study. “But they followed them longitudinally, and they had lots of samples to look at.”
By performing bulk RNA sequencing of the samples, Robinson and his colleagues showed that flare-ups of RA symptoms tended to occur alongside oral bacteria leaking into the bloodstream. He and his team detected the microbes in the blood “about one month before the RA patients had clinical arthritis flares,” said Robinson. There was no such correlation between flare-ups and bacteria from other sources, such as stool or genitals, getting into the blood. “The next step is seeing if it can be reproduced in a much larger population,” said Malcom.
Camille Brewer and her graduate advisor William Robinson showed that bacteria from the mouth can lead to RA flares.
credit: Orr Sharpe
To show that the immune system noticed these wayward microbes, the researchers cultured the implicated oral bacteria with antibodies from B cells of patients with RA and found that the antibodies bound to them. “It suggests that those breaches of bacteria are eliciting the anticitrulline autoimmune response” that is characteristic of RA, said Robinson. Citrullinated proteins are present in every cell, so why this response targets the joints remains a critical open question.
“For decades or longer, we’ve thought that microbes cause autoimmune disease, but we’ve had a really tough time proving it,” said Robinson. “This discovery shows that these oral bacteria,” he added, “are triggering rheumatoid arthritis.”
Robinson thinks that oral bacteria generate a meaningful fraction of RA cases, although he emphasized that they aren’t the only factor contributing to the development of RA. Jan Potempa, a biochemist at the University of Louisville who was not involved with the research, agreed that the study “finally proves the causative relation between PD, with its periodontal pathogens, and RA.”
Given that 40-45 percent of the population has some form of PD, better oral health could be critical to preventing RA, said Robinson. “I tell all my patients to brush your teeth twice a day, floss, go to the dentist frequently,” he said.
Malcolm agreed: “Oral health contributes to our general, overall health.”
Reference
Brewer, R. C. et al. Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis. Science Translational Medicine 15, (2023).
