To visualize the idea of the 80 or so autoimmune diseases that afflict some 24 million people in the United States, consider a boxer bobbing and weaving in a ring. No visible opponent strides forth to land a blow, yet the boxer is engaged in a very real bout – with himself. He cannot emerge as a victor.
The reasons why the immune systems of people with various forms of arthritis, Type 1 diabetes, lupus, multiple sclerosis and many other diseases go awry and cause the body-as-boxer to attack itself remain murky and the subject of intense investigation. Genetics, individual biomarkers, environmental exposures, and lifestyle choices are among the factors. Now researchers at the University of Colorado – Anschutz Medical Campus have identified a new suspect: a strain of bacteria lurking in the gut that may be a trigger for rheumatoid arthritis (RA), an autoimmune disease that attacks the joints, causing often-severe pain and stiffness in about 1.5 million people in the U.S.
The findings, published in late October in Science Translational Medicine, focused on the moist inner lining of the intestine called the mucosa. There they searched for possible links between the jungle of gut microbes and antibodies found in people who have or are vulnerable to RA. They collected blood from people at risk for the disease and isolated the relevant disease-linked antibodies. In the lab, they demonstrated that the antibodies “cross-reacted” with bacteria from two families. That is, the antibodies bound to certain bacteria, creating an immune response.
Studying gut bacteria and rheumatoid arthritis
That finding spurred further investigations and a powerful discovery. After culling bacteria from stool samples of individuals at risk for RA, the researchers isolated a new strain of bacteria, Subdoligranulum didolesgii – more on that later – that the key antibodies targeted and bound to. Rather than eliminating the bacteria as an intruder, the antibodies launched an inflammatory attack by specific T cells, which normally help to protect the body from infections.
That work showed the bacteria triggered a strong immune response in the gut. But could the reaction invade the joints? To test that, the researchers gave the Subdoligranulum didolesgii strain orally to healthy mice. In short order, the rodents developed swollen and gnarled paws, reminiscent of the afflictions of human RA sufferers. Mice that did not receive that specific strain did not show these changes.
As part of her Ph.D. work, CU Medical Scientist Training Program student Dr. Meagan Chriswell was the lead author of the study. She cautioned that the findings, while promising, leave many questions yet to be answered about RA specifically and autoimmune disease in general. But the work sheds more light on the mysteries of the maladies, she added.
“There is no presupposition on our part that [this bacteria] is the sole cause of RA,” Chriswell said. “There are potentially other bacteria and other factors that could be happening biologically to drive it. However, this is the first time we have a discrete organism linked to the disease in this way. This is the beginning of a story, not the end.”
Others have taken note. Chriswell said she recently attended the annual meeting of the American College of Rheumatology conference in Philadelphia, which highlighted the study as important to basic science research. The work, which included contributions from 10 other CU School of Medicine faculty from the CU School of Medicine divisions of Rheumatology and Infectious Disease and the Department of Pathology, also drew attention from the school’s Dean, Dr. John J. Reilly.
Bacteria correlations in an autoimmune disease research chain
Far from being a stand-alone, the study is an extension of many years of work by specialists in the Division of Rheumatology on autoimmune diseases and how mucosal surfaces throughout the body – mouth, lungs, and gut among them – may be involved, said senior author and Division of Rheumatology head Dr. Kristi Kuhn. Kuhn is a researcher in RA and other forms of arthritis and autoimmune disease who also practices in the UCHealth Rheumatology Clinic – Anschutz Medical Campus.
Kuhn said research interest in the mucosa sprang in part from a connection between inflammatory bowel disease (IBD) and spondyloarthritis, which mainly attacks the spine but can also invade arm and leg joints, the skin and the intestines. Kuhn co-authored a 2021 article that summarized the long-running interest and research in links between the two conditions. The paper noted that “significant numbers” of patients with spondyloarthritis also have IBD and inflammation in the gut. Kuhn and her co-authors also pointed to the intestinal mucosa as an entry point for a possible “environmental trigger” for the arthritis in IBD patients.
Kuhn had already published widely on evidence supporting the connections between the mucosa and the development of RA and other kinds of arthritis. These included co-authored papers released in 2016, 2018 and 2019. The new study, with Chriswell and colleagues, focuses on the intestinal mucosa as a thriving home for both the antibodies linked to RA and microbes that might be their targets.
“We wanted to take these antibodies that have mucosal features and see if they start to [bind to] bacteria,” Kuhn said. “The gut is our largest exposure to microbes.”
A strain with a spiritual and scientific connection
What of this still mysterious bacterial strain, Subdoligranulum didolesgii? Its importance is not only scientific but also cultural. Chriswell said she proposed the name as a member of the Cherokee Nation. “Didolesgii” is the Cherokee word for arthritis or rheumatism. She noted that indigenous people carry a disproportionate risk for arthritis. At the same time, their scholarly and academic work has been “chronically underrepresented in the literature,” she added.
“The [Cherokee] name is in recognition of the disease burden and an acknowledgment of the contributions through history of indigenous scholars,” Chriswell said.
As for science and research, the RA-bacterial connection raises many questions while pointing the way toward additional study. For example, Chriswell said the research did not find Subdoligranulum didolesgii in the mucosa of healthy individuals, but the sample size was small and insufficient to prove its existence is unique to people at risk for RA.
“The preliminary evidence suggests that it is not in healthy people, but we need larger population studies,” she said.
Opportunities for further study
The nature of the new strain is also a candidate for further probing. Chriswell noted that researchers will need to “tease out” whether Subdoligranulum didolesgii is a “commensal” organism – one that naturally exists in people but “starts behaving badly” and triggering an autoimmune response – or a response-triggering pathogen that people catch.
“That is unclear and is another area of active research in the lab,” Chriswell said.
Kuhn said the study suggests other directions, including “drilling down to understand the mechanism of how bacteria go on to trigger the immune response.” For example, does it lead the immune system to target a healthy protein in the body that looks like an invader? This reaction, dubbed “molecular memory,” is the driver in patients with strep throat who contract rheumatic fever. In that disease, the immune system attacks a target that looks like the bacteria but instead interacts with a human protein in heart tissue and damages the valves. Could Subdoligranulum didolesgii drive a similar process, leading the immune system to attack joint tissue? Alternatively, she added, could the bacteria be “somehow training our immune response to be more likely to react against our own tissue?”
Another challenge is to define other risk factors that could spark the immune response, Kuhn said. As she put it, “How do you go from having the bacteria and being at risk to developing RA? Is it just having these bacteria or are there other environmental factors? How do we start to put these puzzle pieces together to understand the risk and the trigger point for developing the disease?” She added that she and her colleagues have not ruled out the role of other bacterial strains – not only in the gut, but also the mouth, lungs and other sites – as disease-spurring culprits.
A new ray of light on a mysterious process
What does the new work portend for patients who have or are at risk for RA? Kuhn said for now treatment will remain focused on helping patients stick to effective medication regimens and manage risk factors, such as smoking, stress and body mass index, that are within their control. But further research, she added, could identify pathways that might be modified once the disease is triggered.
“The study helps us get closer to diagnosing the disease, detecting it earlier and hopefully discovering how to modify it,” Kuhn said.
Chriswell added that while it is “hard to make specific claims” from the study, it did succeed in probing “the mixed community of organisms” that make up the microbiome and pulling out one “that appears to drive disease.” She hopes that spurs the scientific community to further expose the biologic machinery that underlies those misery-inducing changes.
Study co-author Dr. Kevin Deane, associate professor in the CU Division of Rheumatology, called the new findings “a major breakthrough in our understanding of how autoimmune disease develops.” He added that Chriswell’s and Kuhn’s “experimental approach to use antibodies derived from humans to identify a bacterial organism that drives arthritis in an animal model should serve as a model for future studies that can explore the role of additional organisms in triggering autoimmune diseases.”