Twin Study Links Gut Microbiome & Metabolites to Rheumatoid Arthritis

Studies implicate both genetic and environmental factors in rheumatoid arthritis (RA), including evidence that patients with RA and other autoimmune diseases often have a disrupted gut microbiome with reduced bacterial diversity.

To better understand this microbial connection, NYU Langone Health rheumatologist Rebecca B. Blank, MD, PhD, is asking whether the gut microbiome plays a causal role in RA pathogenesis and treatment response. “If so, can we manipulate the gut microbiome as part of clinical management?” she says.

To zero in on the potential influence of gut microbes, Dr. Blank and colleagues studied eight sets of identical twins discordant for RA, comparing gut microbiomes, plasma proteomes, and RA-associated antibodies using a multiomics approach. Their 2025 study, published in Annals of the Rheumatic Diseases, revealed striking differences. “We found that, while overall microbial diversity did not differ, the unaffected twins had a relative abundance of microbes that produce short-chain fatty acids,” Dr. Blank says. “That was pretty exciting for us.”

Stool samples from the unaffected twins specifically showed higher levels of the short-chain fatty acids propionate and butyrate, known to support intestinal barrier integrity and promote tolerogenic immune responses.

If validated by larger studies, the results suggest that short-chain fatty acids could serve as disease biomarkers or even play a protective role.

Growing Focus on SCFAs

Short-chain fatty acids are generated when gut microbes ferment the nondigestible sugars and fibers in the diet. They fuel intestinal epithelial cells, strengthen tight junctions, and help maintain intestinal barrier integrity—reducing the translocation of inflammatory triggers.

The results from Dr. Blank and colleagues add to a growing body of evidence linking short-chain fatty acids to better RA outcomes. A European group reported that among individuals with a genetic predisposition for RA, higher levels of short-chain fatty acids in blood serum associated with reduced progression to disease.

“We have found in our own studies that the patients with RA who end up becoming methotrexate responders tend to have higher levels of fecal butyrate at baseline than non-responders,” Dr. Blank says.

In mouse models of rheumatoid arthritis, other studies have shown that butyrate supplementation can ameliorate disease severity by increasing regulatory T cell responses and promoting immune tolerance.

Early Promise for an Adjunctive Therapy

These results have informed another line of research in Dr. Blank’s effort to improve therapeutic responses in RA. In a new clinical study of patients beginning methotrexate monotherapy, she and colleagues are giving half the participants butyrate supplements in addition to methotrexate for up to four months and comparing their outcomes with those receiving methotrexate alone.

Given that roughly half of patients with RA fail to respond to methotrexate as a monotherapy, this novel study will test whether shifting the gut microbiome might be one way to meaningfully improve response rates.

“What we’re seeing so far is that butyrate increases gut bacterial diversity,” Dr. Blank says. “In addition, it specifically increases the abundance of short-chain fatty acid producers, leading to even more production.” Early data also show a trend toward increased regulatory T cell responses in patients taking the supplement.

“The goal is not to use butyrate as a substitute for methotrexate but as an adjunctive treatment,” Dr. Blank says.

Deeper Dive into Diets

As evidence grows linking short-chain fatty acids to RA risk and treatment response, Dr. Blank and colleagues are adding dietary questions to questionnaires completed by participants in the butyrate supplementation trial and the NYU Langone RA registry.

Among patients with RA taking methotrexate alone, early data suggest that high-quality diets emphasizing nutrient-dense foods do not significantly improve drug-response rates. The addition of butyrate to a high-quality diet, however, yields a significant increase in the ratio of methotrexate responders to non-responders.

If overall diet alone doesn’t play a major role, Dr. Blank says, the results suggest that specific nutritional components just might.