TARGETING RHEUMATOID ARTHRITIS
CU study identifies a bacterial strain as a disease trigger
By Tyler Smith
April 2023
Autoimmune diseases afflict some 24 million people in the United States, in various forms of arthritis, Type 1 diabetes, lupus, multiple sclerosis, and many other diseases.
To visualize the effect of those 80 or so autoimmune diseases, 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 and he cannot emerge as a victor.
The reasons why the immune systems of people with go awry and cause the body 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, often causing severe pain and stiffness in about 1.5 million people in the United States.
The findings, published last fall in Science Translational Medicine, focused on the moist inner lining of the intestine called the mucosa, where investigators 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 relevant disease-linked antibodies. Then, in the lab, they demonstrated that those antibodies “cross-reacted” with bacteria from two families. The antibodies were binding to certain bacteria, creating an immune response.
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 strain of bacteria, Subdoligranulum didolesgii, that the key antibodies targeted
and were binding 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 question, 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. The mice that did not receive that specific bacterial strain did not show these changes.
Meagan Chriswell, a student in the CU Medical Scientist Training Program for students pursuing joint MD and PhD degrees, was lead author of the study. She cautioned that the findings, while promising, leave many questions to be answered about RA specifically and autoimmune disease in general. But the work sheds more light on the maladies, she added.
Meagan Chriswell
“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 attended the annual meeting of the American College of Rheumatology conference in Philadelphia, which highlighted the study as important basic science research. The work included contributions from 10 other CU School of Medicine faculty from the Department of Medicine’s divisions of rheumatology and infectious diseases, as well as the Department of Pathology.
LEARNING FROM PREVIOUS STUDIES
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 Kristi Kuhn, MD, PhD, senior author and head of the division.
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 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. The new study, with Chriswell and their colleagues, focuses on the intestinal mucosa as a thriving home
for both the antibodies linked to RA and microbes that might be their targets.
Kristi Kuhn, MD, PhD
“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.”
SPIRITUAL AND SCIENTIFIC CONNECTION
So, what of this still mysterious bacterial strain, Subdoligranulum didolesgii? Its importance is not only scientific but also cultural. Chriswell, member of the Cherokee Nation, said she proposed the name. “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 questions that point 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.
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,” triggering an autoimmune response) or a pathogen that people catch, which in turn triggers a response.
For patients who have or are at risk for RA, treatment for now 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.
“The study helps us get closer to diagnosing the disease, detecting it earlier, and hopefully discovering how to modify it,” Kuhn said.
Study co-author Kevin Deane, MD, PhD, associate professor in the Division of Rheumatology, called the new findings “a major breakthrough in our understanding of how autoimmune disease develops.” He added that the “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.”
This article was first published in UCHealth Today in December 2022.