The University of Queensland (UQ) research team, led by Professor Ranjeny Thomas, Dr. Anne-Sophie Bergot, and MD-PhD student Benjamin Cai, has proposed a groundbreaking theory: ankylosing spondylitis (AS) may begin when immune cells transport bacterial components from the gut to the joints in individuals with a genetic predisposition. Traces of gut bacteria were identified in the joints of both disease-susceptible mice and human patients.
This finding suggests that maintaining gut health and moderating macrophage activity could lead to new management strategies for AS.
Understanding Ankylosing Spondylitis
AS is a debilitating autoimmune inflammatory disease affecting approximately 1 in 100 Australians, predominantly men, typically appearing between ages 15–45. It primarily impacts the axial skeleton, including the spine and large joints, and can lead to hunched deformity and limited mobility due to inflammation at entheses (where tendons or ligaments attach to bone). The disease is often accompanied by extra-articular inflammation in the eyes, skin, and heart. Notably, 70% of AS patients experience asymptomatic intestinal inflammation, indicating a connection between gut and joint health.
Current treatments aim to reduce pain and stiffness, slow joint damage, and prevent complications. These are lifelong therapies, often involving biologic drugs like TNF blockers or IL-23/IL-17 inhibitors.
However, these treatments are not universally effective, with about 40% of patients discontinuing due to side effects or loss of efficacy. There is a need for new treatments and a deeper understanding of the disease.
The Gut-Joint Connection Model
The UQ research, published in JCI Insight, investigated this connection using SKG mice genetically prone to arthritis. When these mice, bred in sterile conditions and then colonized with a single gut bacterium, were exposed to an inflammatory microbial trigger, they developed gut inflammation, severe arthritis, and enthesitis. SKG mice without bacteria or mice lacking the arthritis risk gene remained healthy under the same conditions, highlighting the combined roles of the microbiome and genetics. Conversely, mice given a diverse mix of gut bacteria showed better gut health and less severe arthritis, suggesting a balanced microbiome may offer protection.
In genetically susceptible SKG mice, the gut lining can become permeable, allowing bacteria to enter gut tissue. The immune system responds by activating macrophages, which typically clear invaders. In these mice, macrophages become overactive and were observed transporting bacteria from the gut to the joints, triggering a strong IL-17-driven immune reaction that culminates in arthritis.
Bacterial DNA was also detected in the synovial tissue of a patient with psoriatic arthritis and axial involvement, suggesting a similar gut-to-joint bacterial transmission mechanism may occur in humans.
Treatment Implications and Future Research
Treating SKG mice with anti-IL-23 blocking antibodies, similar to those used in human patients, improved gut health and prevented arthritis but not enthesitis.
This result aligns with the known limitations of anti-IL-23 treatments in improving spinal symptoms in AS patients and underscores the need for additional therapeutic options.
The findings emphasize the critical role of the immune system and gut bacteria interaction in arthritis development for genetically at-risk individuals. This opens avenues for new AS treatments focusing on improving gut resilience, modifying the gut microbiome, or modulating macrophage activity.
Current considerations suggest that, alongside standard disease-modifying anti-rheumatic drugs (DMARDs) and lifestyle recommendations, gut health may be crucial for inflammatory arthritis patients, particularly those with gastrointestinal symptoms. Diets rich in dietary fiber, such as a Mediterranean-style diet, promote a balanced gut microbiome and the production of beneficial short-chain fatty acids like butyrate, which have been linked to reduced systemic inflammation.
Professor Thomas's team is currently conducting the RA-HEAL trial, which examines structured versus self-directed lifestyle improvement programs for people with recently diagnosed rheumatoid arthritis, focusing on exercise, healthy eating, and emotional wellbeing. The team is also developing liposome-based immunotherapies to restore immune tolerance in autoimmune diseases, with ongoing trials for Type 1 Diabetes and planned trials for Rheumatoid Arthritis and AS.
This study indicates that gut health and gut bacteria are integral to the development of spondyloarthropathies like AS in genetically susceptible patients.
Strategies that support gut health, maintain a balanced microbiome, and regulate macrophage responses could play a significant role in preventing disease, slowing progression, and improving patient outcomes.