Microbial metabolites impacting the response to methotrexate in rheumatoid arthritis

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PROJECT SUMMARY / ABSTRACT Low-dose methotrexate (MTX) is a cost-effective, first-line therapy for millions of individuals with inflammatory arthritis or skin disease, but as many as 50-70% of patients do not adequately respond to MTX. Modifying factors that limit MTX response would enable more patients to benefit from this anchor drug that synergistically increases the efficacy of other anti-inflammatory drugs. We recently showed that the gut microbiome of rheumatoid arthritis (RA) patients predicts MTX responsiveness, raising the possibility that the gut microbiome contributes to MTX response. Unexpectedly, we found that MTX, originally designed to inhibit human folate enzymes, exerts growth- inhibitory effects on gut microbiota, and transplantation of MTX-exposed microbiotas into gnotobiotic mice led to decreased immune activation. These findings suggest that one mechanism by which MTX exerts its anti- inflammatory effects is via modulation of the gut microbiota. Thus, the gut microbiome may be a modifiable factor that can be targeted to enable more patients to benefit from MTX. What remains lacking, however, is knowledge of the mechanisms by which MTX-microbiota interactions shape host immunity. Such knowledge would enable us to specifically target these gut microbial mechanisms, which may lead to improved drug response in the host. There is, therefore, a critical need to identify mechanisms by which MTX affects the microbiota to shape host immunity. With this information, we can advance precision medicine for patients with autoimmune disease. The long-term goal of our lab is to identify the molecular mechanisms by which the human gut microbiome impacts the treatment of rheumatic and autoimmune diseases. The overall objectives of this application are to identify MTX-induced gut metabolomic changes in vivo and test the impact of microbial adenosine pathways in mediating MTX response. Here we test the hypothesis that MTX acts on the gut microbiota to increase extracellular adenosine and reduce inflammation in the host. Using an innovative combination of metabolomics, bacterial genetics, and pre-clinical models of arthritis, we will (1) evaluate the metabolic consequences of MTX on gut microbiota in vivo, and (2) test the impact of microbial adenosine metabolism on MTX response in vivo. We expect to identify microbial mechanisms that impact MTX response. This project is significant because MTX non- response affects a majority of MTX users and identifying microbial contributions to non-response has the potential to advance the field and clinical practice. It is innovative because it probes drug-microbiota interactions and how these contribute to MTX response in patients. The results may have a positive impact by laying the foundation for the development of microbially-directed therapies to improve MTX response, potentially enabling a greater number of patients to benefit from an anchor drug in rheumatology.