Researchers working to expand role of microbiome in rheumatic diseases

A growing body of research is beginning to harness the microbiota communities that live on our exposed surfaces, from the gut to the skin and eyes. Imbalances in microbiota communities, or dysbiosis, can trigger pathogenic inflammatory and autoimmune pathways in some hosts. And some microbiota can affect drug metabolism, suggesting new approaches to predicting drug response and disease modification.

“Microbiota can control the development and function of the immune system with effects on infection, vaccine response, immunotherapy, allergies, autoimmunity, and inflammatory disorders,” said Yasmine Belkaid, PhD, Chief of Metaorganism Immunity at the National Institute of Allergy and Infectious Diseases. “Microbiota play roles in the tissue threshold of activation, affecting pathogen control and immunopathology.”

In the session Expanding Role of Microbiome in Rheumatic Diseases, Dr. Belkaid provided an update on interactions between endogenous retroviruses (ERV) — remnants of viral encounters earlier in human evolution — and T cells specific to the skin microbiome that can promote antimicrobial defense and tissue repair. The session, which was originally presented Tuesday, Nov. 9, can be viewed on demand by registered meeting participants through March 11, 2022.

S. epidermidis, and likely other skin microbiota, can promote discrete ERV transcription by keratinocytes via the cGAS/STING pathway to produce a noninflammatory antiviral type I interferon response, Dr. Belkaid explained. Agents that impair or block STING signaling, such as antiretroviral agents, can affect T-cell responses and homeostatic immunity.

ERVs can also promote inflammation via the microbiota. A high-fat diet, for example, promotes inflammatory responses to S. epidermidis, in part by changing ERV expression, which can alter tissue activation thresholds.

“Just two weeks on a high-fat diet can change the skin immune response,” Dr. Belkaid said.

Diet can also affect variation in drug response by altering the gut microbiota. The gut microbiome — the combination of gut microbiota and the genes they encode — are known to affect HIV prophylaxis in women and immunotherapy in melanoma patients. The gut microbiome also affects methotrexate response in both mice and humans.

Patient gut microbiome can accurately predict response to methotrexate, said Renuka Nayak, MD, PhD, Assistant Professor of Medicine at the University of California, San Francisco. And methotrexate treatment may exert evolutionary pressure favoring the expansion of microbiota species that metabolize methotrexate. That microbiome change could play a role in the development of methotrexate resistance in patients who initially responded well to the agent.

“Variation in drug response is a major problem for us in rheumatology,” Dr. Nayak said. “The gut microbiome has 150-fold more genes than the human genome. The microbiome can convert prodrugs into active metabolites, inactivate active metabolites, and metabolize active drug into toxic metabolites, and it is an important immunomodulator.”

The gut microbiome in rheumatoid arthritis patients is very different from the microbiome of non-RA controls, Dr. Nayak explained. Short-chain fatty acids (SCFAs) produced by different microbial species are associated with variations in drug response. Some human gut bacteria actively metabolize methotrexate, which alters clinical response.

Methotrexate may also affect the microbiome more directly. Some species, notably E. coli, have multidrug efflux pumps that make them resistant. Clostridium asparagiforme is resistant to methotrexate, while multiple Bacteroides species are more susceptible.

“In addition to genetic and social determinants, microbiome determinants can affect methotrexate activity in RA patients,” Dr. Nayak said. “We may be able to alter the microbiome to affect treatment outcomes.”

Specific microbiota trigger arthritis, spondyloarthritis (SpA), and psoriasis in SKG mice, and dysbiosis plays a role in human immune-mediated inflammatory disease, said Jose U. Scher, MD, Associate Professor of Medicine and Director of the Psoriatic Arthritis Center and NYU MiCRA, New York University Grossman School of Medicine. The decreased gut microbiome diversity in psoriatic arthritis (PsA) patients resembles the dysbiosis seen in inflammatory bowel disease (IBD), he added. Clostridia, Ruminococcus, and other beneficial commensals are absent in PsA and IBD patients and correlate with decreased levels of protective SCFAs.

These SFCAs are bacterial metabolites and expand Treg cells in the gut to prevent IBD by suppressing proinflammatory Th17 cells. SCFAs and a high-fiber diet can ameliorate inflammatory arthritis phenotypes in mouse models, Dr. Scher added.

It is possible to alter the gut microbiome in both humans and in mice using a variety of methods: fecal microbial transplant (FMT), an undefined transplant of hundreds of different strains; a consortium of specific strains such as lactate producers; a single strain, such as L. rhamnosus; or a bioactive molecule produced by a strain that mediates a desired host effect.

A high-fiber diet increases SCFAs and lowers pro-arthritogenic cytokines, Dr. Scher said. FMT was superior to placebo (RR=3.6, p=0.021) for clinical and endoscopic remission of ulcerative colitis in a randomized controlled trial, and multiple case reports suggest benefit in PsA for patients who received FMT for Clostridium difficile infection.

“Emerging data implicate the microbiome as a determinant of pathogenesis is psoriatic disease, and microbiome-modulating therapies are being studied in oncology, IBD, and PsA,” Dr. Scher said. “FMT works in IBD research — the question is how to make it practical in the clinical world. Maybe we can modify the microbiome using other tools like a high-fiber diet.”