The impact of the gut microbiome on rheumatoid arthritis treatment

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PROJECT ABSTRACT Rheumatoid arthritis (RA) is an inflammatory arthritis resulting in irreversible damage unless effective therapy is provided quickly. Oral methotrexate (MTX) is first-line therapy for RA but is inadequate in 50-70% of patients; clinicians currently employ a “trial and error” approach to treatment. While many have studied whether human genetics or environmental factors predict MTX response, none have examined the role of the gut microbiome. We recently showed that the gut microbiome of RA patients predicts MTX responsiveness. We further showed that RA patients harboring gut microbiota that quickly metabolized MTX were less likely to respond to MTX, suggesting gut microbial metabolism of MTX contributes to response. The genes responsible for metabolism and the causal impact of microbial metabolism on MTX pharmacology remains unknown. This knowledge could transform our understanding of modifiable factors that affect MTX response; they could provide a foundation for the design of therapies that modify or target the gut microbiota. Thus, we seek to test the hypothesis that gut bacterial metabolism of MTX interferes with RA treatment. Dr. Nayak and a trainee, supported by this administrative supplement, will investigate the following independent and complementary aims: (1) identify gut microbial genes responsible for MTX metabolism, (2) quantify the impact of the gut microbiome on MTX metabolism in vivo. The proposed studies will provide insight into the mechanisms by which the microbiome affects the treatment of rheumatologic disease. Defining these mechanisms will advance our knowledge of the role of the microbiome in precision medicine.