Microbial metabolites impacting the response to methotrexate in rheumatoid arthritis - 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.
