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A promising line of inquiry at �ٺ���Ƶ Health’s Psoriatic Arthritis Center is aimed at uncovering whether and how gut microbiota can warn of autoimmune-linked alterations—and potentially improve patient response to therapeutic interventions.

“We’re interested in how to make good use of the microbiome as a tool for diagnostics and therapeutics, or what we call pharmacomicrobiomics,” says Jose U. Scher, MD, assistant professor of medicine and director of the Psoriatic Arthritis Center. One hypothesis suggests that prebiotics, such as medium-chain fatty acids, might sharpen that microbiomic tool by aiding the growth of beneficial gut microbes that can help improve the bioavailability of oral medications and patients’ response to them.

Prebiotics Appear to Enable Inflammation Reduction

Dr. Scher, in collaboration with , associate professor of pathology, found that a gain-of-function mutation introduced in the STAT3 gene of mouse T cells led to an overproduction of inflammation-promoting interleukin 17 (IL-17)—and the mice showed clear signs of psoriasis and psoriatic arthritis. When they fed the mice prebiotics, however, the researchers saw a noticeable shift toward more protective microbes. The same prebiotic intervention in wild-type mice led to an increase in the number of inflammation-fighting regulatory T cells.

The results from this promising animal model prompted a series of human studies. In one, administering medium-chain fatty acids as a prebiotic in healthy individuals appeared to diversify their gut microbiota and to expand the population of regulatory T cells in their blood. “We saw more bacteria overall, and in particular, more reportedly beneficial bacteria,” Dr. Scher says. “So now we have a proof of principle that a single modification correlates with an increase in your body’s inflammation regulators,” he says.

Dr. Scher’s group is asking the same question in patients with psoriatic arthritis. The next step, he says, will be to correlate that increase in beneficial microbes and regulatory T cells with an improvement in symptoms in patients with that condition.

Using Prebiotics to Improve Therapeutic Interventions

Follow-up research is asking whether modifying patients’ microbiota before treating them with methotrexate might improve their outcomes. With funding from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), Fardina Malik, MD, instructor of medicine, is leading a pilot study of 20 patients with psoriatic arthritis to explore whether a prebiotic rich in medium-chain fatty acids may modify patients’ gut microbes in a way that improves methotrexate’s efficacy.

“We believe that expansion of certain gut bacteria can alter methotrexate activation and hence improve absorption and efficacy,” Dr. Malik says. “Increase in blood T regulatory cells as a result of medium-chain fatty acid administration might act synergistically with anti-inflammatory action of methotrexate.”

In a related study of 40 patients, the researchers concluded that the baseline microbiota of people who have rheumatoid arthritis prior to methotrexate therapy could help predict their response to that therapy four months later. The findings revealed that if certain signatures are present in a patient’s microbes, response to methotrexate is significantly better than in patients who do not have those signatures.

“Biologic therapies are incredibly costly, so if we can conclude that prebiotics assist in the effectiveness of methotrexate and other oral anti-rheumatic drugs, that’s an invaluable amount of benefit for patients and cost savings for the entire healthcare system,” says Dr. Scher.

A Potential Explanation for IL-17i-Mediated Gut Inflammation

The same concept can be applied to other medications like the interleukin-17 inhibitor, or IL-17i. The drug class, commonly prescribed to patients with psoriatic arthritis and spondyloarthritis, has the well-known and seemingly paradoxical side effect of exacerbating Crohn’s disease in some patients.

At the gut level, research led by Julia Manasson, MD, post-doctoral T32 research fellow, and colleagues suggests significant shifts in the microbiota of patients with spondyloarthritis receiving IL-17i therapy, with some showing a significant increase in the abundance of Candida albicans yeast in the intestinal lumen. The same shift was not observed in patients receiving TNF blockade therapy. The increase, Dr. Scher says, may explain why certain patients who already have subclinical gut inflammation develop clinically overt inflammation and Crohn’s disease upon treatment with an IL-17 inhibitor.
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