The Microbiome’s Impact on Rheumatoid Arthritis & Drug Response

CHICAGO—During a session of ACR Convergence 2025, speakers discussed intriguing possibilities about the role of the gut microbiome in the development of rheumatoid arthritis (RA), as well as its potential impacts in treatment response to methotrexate.

The Microbiome’s Multifaceted Role

Researchers are actively exploring how the microbiome impacts such conditions as respiratory disease, diabetes, inflammatory bowel disease, heart disease, cancer, liver and kidney diseases, and brain disorders.¹ In rheumatology, scientists have identified modifications of the microbiome in conditions such as systemic lupus erythematosus, systemic sclerosis, Sjögren’s syndrome and RA, although the exact implications of these differences are a matter of ongoing research.²

One of the speakers was Christopher Rooney, MD, PhD, MRCP, a clinical lecturer in medical microbiology at the University of Leeds in England. He noted the human body is a complex ecosystem, with roughly 500–1,000 different species of bacterial cells existing in a roughly 1:1 ratio to human cells. The complete microbiome consists of a variety of bacteria, viruses, fungi and archaea, but bacteria in the gut are the largest and most metabolically active component, and they are the primary topic of current scientific investigations.³

Among different individuals, the microbiome is remarkably varied. Diet plays a major role in its composition, as do other elements, such as smoking and various diseases and medications. However, these known factors account for only a minority of this variability, noted Dr. Rooney.⁴

Finding ways to quantify patterns and differences in the microbiome is a major research challenge given the dynamic complexity of the environment, necessitating sophisticated statistical and computational analyses. Researchers can characterize the specific species present, their abundance, their genomics and their metabolic activity.³

The microbiome plays many important roles, such as aiding digestion and preventing infection, but for autoimmune conditions, its role in immune homeostasis may be key.

Another speaker, rheumatologist Renuka Nayak, MD, PhD, explained, “Our immune system relies on the microbiome for its own education on [self] tolerance, and for the development of a lot of immune cell populations.” Dr. Nayak is an assistant professor of medicine at the University of California, San Francisco.

“The gut microbiome is in constant conversation with the immune system,” agreed Dr. Rooney. “The breakdown of that dialogue can lead to the breakdown of immunological tolerance.”

The Gut & Methotrexate

The burgeoning field of pharmacomicrobiomics, which investigates the effects of the gut microbiome on drug metabolism, has led to important discoveries in HIV and cancer therapies. Dr. Nayak has added to this body of research through detailed work studying the impact of the microbiome on responsiveness to methotrexate in people with RA.^5-8

Although it is first-line treatment for RA, more than 50% of patients inadequately respond to oral methotrexate as monotherapy, noted Dr. Nayak, and no current biomarkers can reliably predict response.⁹ Current guidelines from the ACR recommend maximizing methotrexate before moving to other therapies for RA.¹⁰

“A current, unmet need is to quickly identify patients who are not going to be optimally responsive to methotrexate,” said Dr. Nayak. This would allow clinicians to escalate therapy and potentially control disease more quickly and perhaps more effectively long term.

Dr. Nayak found pretreatment gut microbiome diversity differed significantly in newly diagnosed RA patients who went on to become methotrexate responders compared to patients with inadequate response to the drug. Using a machine learning program, the research team could even predict treatment response in a majority of patients using their initial microbiome data, outperforming current clinical and pharmacogenetic markers.⁵

In ex vivo studies and mouse models, they also explored how microbiome bacteria from non-responders tend to metabolize more methotrexate and decrease levels of methotrexate more rapidly than responders. Methotrexate metabolites produced by gut microbial communities may also contribute to variation in treatment response, and these may prove useful tools in predicting who will respond to methotrexate therapy.^5-8

“If we understand these mechanisms and can shift the chemical equilibrium away from methotrexate metabolism, that may be another opportunity to maximize methotrexate efficacy and improve care for our patients,” said Dr. Nayak.

The Gut as a Trigger?

Much of Dr. Rooney’s research centers on the hypothesis that the gut microbiome is a potential trigger for the development of autoimmunity in RA, and thus potentially a modifiable risk factor.

Local changes in the gut mucosal level (e.g., via antigen presentation of molecules produced by bacteria) may cascade through the immune system and lead to systemic effects.³ Dr. Rooney and others have also shown certain microbiome changes may be associated with increased intestinal permeability and positivity for anti-citrullinated protein antibodies (ACPA), a major risk factor for RA.¹¹

The gut microbiome in established RA shows clear evidence of changes, Dr. Rooney said, but it’s less clear exactly what aspects of that microbiome might be pathogenic. He also acknowledged a tension that hasn’t fully been resolved: Elements of the gut microbiome might help drive autoimmunity, or changes in the microbiome might be due to local and systemic inflammation already present.

Dr. Rooney shared work from his lab on individuals at risk of full-blown RA due to their ACPA positivity or arthralgia symptoms (without clinical synovitis). These individuals displayed a distinct microbiome, with decreased diversity of microbiome species. This was true whether or not they eventually progressed to RA as defined by current clinical guidelines. For those who did progress, the gut environment became more unstable in the 10 months preceding full-blown RA, with increased numbers of some species, including certain strains of Prevotellaccae bacteria.^12-13

Such work might eventually lead to interventions in the microbiome to help prevent or delay RA onset in at-risk groups, such as specific dietary changes, prebiotics, probiotics or even fecal microbiota transplantation.¹⁴

Dr. Rooney also discussed a qualitative study that explored attitudes about preventative interventions in people at risk for RA. At present, established modifiable risk factors are somewhat scarce, primarily focused on increasing physical activity, reducing obesity and encouraging smoking cessation.¹⁵

“This gives a potential for a new modifiable risk factor, and it’s been met with great enthusiasm,” said Dr. Rooney.

Ruth Jessen Hickman, MD, a graduate of the Indiana University School of Medicine, is a medical and science writer in Bloomington, Ind.

References

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