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New research from The University of Queensland team led by Prof Ranjeny Thomas, Dr Anne-Sophie Bergot and MD-PhD student Benjamin Cai suggests that ankylosing spondylitis may start when immune cells carry bacterial components from the gut to the joints in people who are genetically at risk. Traces of gut bacteria were found in the joints of disease-susceptible mice and patients. Supporting gut health and keeping macrophages quiet could create new routes to better manage AS.
Ankylosing spondylitis (AS) is a debilitating disease affecting 1 in 100 Australians. It first appears between ages 15–45 and is three times more common in men than in women. AS is an inherited autoimmune inflammatory disease of the axial skeleton, mainly affecting the spine and large joints, leading to hunched deformity. Entheses, the sites where tendons or ligaments attach to bone, become inflamed, limiting mobility. AS is often accompanied by extra-articular inflammation such as the eyes, skin, and heart, and 70% of AS patients have asymptomatic intestinal inflammation, pointing to a close relationship between the gut and the joints.
Treatments against autoimmune arthritis today focus on reducing pain and stiffness, slowing down joint damage, and preventing complications. They are lifelong and often involve biologic drugs, such as TNF blockers or IL-23, IL-17 inhibitors. While these therapies have helped many patients, they don’t work for everyone. Around 40% of people eventually stop treatment due to side effects or because the drugs lose their effectiveness.
Since there is no cure for AS, there is a pressing need to better understand the disease and find new treatments. This is not just a medical challenge — it’s also a significant social and economic issue, affecting patients in the prime of their lives.
The model: gut–joint connection in the mouse model
Our research, published in JCI Insight looked at how gut bacteria can trigger joint problems in SKG mice that are genetically prone to arthritis. We bred the mice in isolators free of all microbes, similar to living in a sterile bubble.
In these SKG mice colonised with a single gut bacterium, injection of an inflammatory microbial trigger set off gut inflammation, severe arthritis and inflammation of the entheses. Mice without the arthritis risk gene or SKG mice with no bacteria stayed healthy under the same conditions, showing that both microbiome and genetics play a big role. When mice were given a mix of different gut bacteria (instead of just one species), their gut stayed healthier and arthritis was less severe. This suggests that a balanced gut microbiome can help protect against autoimmune arthritis, while an imbalanced one (dysbiosis) can make things worse.
How can this be? In genetically susceptible SKG mice, the lining of the gut becomes leaky, opening the door to bacteria to enter the gut tissue. The immune system then jumps in and activates an “eat-me” immune response where macrophages — the scavengers — would clear these invaders. In these mice, these macrophages become overly aggressive. To our surprise, we discovered that these angry macrophages carried bacteria from the gut into the joints and sparked a strong IL-17–driven immune reaction, which then leads to arthritis.
What is striking is that bacterial DNA was also found in the synovial tissue from a patient with psoriatic arthritis and axial involvement, suggesting similar transmission of bacterial DNA from gut may occur in humans.
Importantly, treating SKG mice with the same anti-IL-23 blocking antibodies used to treat patients improved gut health and prevented arthritis but not enthesitis development. This result highlighted the known inability of this anti-IL-23 treatment to improve the spine in AS patients, and the need for additional curative options.
The big takeaway? The interplay between the immune system and gut bacteria is central in the development of arthritis in individuals genetically at-risk for AS and other spondyloarthropathies. This paves the way to new treatment approaches for AS and in people who are genetically predisposed through improving gut resilience, changing the gut microbiome, or calming macrophages.
Current understanding and emerging considerations
Our results therefore suggest that, in addition to standard treatments such as disease-modifying anti-rheumatic drugs (DMARDs) and recommendations for a better life-style (like physical activity, stress management strategies, and smoking cessation), gut health may play a role in inflammatory arthritis, particularly in individuals who also experience gastrointestinal symptoms. Diet patterns that support gut health—such as those rich in dietary fibre—are associated with a more balanced gut microbiome. A Mediterranean-style diet is reported to promote good bacteria that produce short-chain fatty acids like butyrate, which have been linked to reduced systemic inflammation and improved immune regulation and are soon to be trialled in Type 1 Diabetes.
What’s next for this research?
Prof Thomas’ team at UQ is running the RA-HEAL trial, which is comparing two different ways to improve lifestyle risk factors in people with recently-diagnosed rheumatoid arthritis. One is a structured program and the other is self-directed. Both programs focus on lifestyle and wellbeing, including exercise, healthy eating and emotional wellbeing. Referrals are welcome.
Prof Thomas has also developed a promising new approach to treat autoimmune diseases using tiny, lipid-based carriers called liposomes. These liposomes can deliver disease-related antigens and immune regulators, such as vitamin D3, directly to macrophages, dendritic cells and B cells to restore immune tolerance during the presentation of these disease antigens to the immune system. Prof Thomas’ team is trialling liposome-based immune tolerance in Type 1 Diabetes, and planning future clinical trials for Rheumatoid Arthritis-specific immune tolerance. Their work in mice provides momentum to develop immunotherapy for AS.
Conclusion
This study suggests that the gut and gut bacteria are integral to the development of spondyloarthropathies like AS, in patients who are genetically susceptible. If that’s the case, keeping the gut healthy and maintaining a balanced microbiome could play an important role in preventing disease and slowing disease progression and improving outcomes. It also points to macrophages as key effector cells — specifically, by encouraging a more “regulated” response rather than an overactive, inflammatory one. Altogether, these findings open the door to gut-focused strategies as part of a broader approach to managing and preventing AS.
Prof Ranjeny Thomas AM is The Arthritis Movement Chair of Rheumatology at the Frazer Institute, The University of Queensland and consultant rheumatologist at Princess Alexandra Hospital, Brisbane.
Dr Anne-Sophie Bergot is a senior research scientist at the Frazer Institute, The University of Queensland, leading work in AS pre-clinical models and human pelvic inflammatory disease. She conducted pre-clinical studies of liposome immune tolerance in Type 1 diabetes.
Mr Benjamin Cai is a MD-PhD student from the UQ Medical School Clinician-Scientist Training Program, and a third-year PhD student in Prof Thomas’ group at the Frazer Institute, The University of Queensland.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
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