Methotrexate-Induced Shifts in the Human Gut Microbiome Decrease Immune Activation
63 Pages Posted: 30 Apr 2020 Sneak Peek Status: Under ReviewMore...
Emerging evidence suggests that the use of non-antibiotic drugs can alter the human gut microbiota with unknown consequences for treatment outcomes. Here, we use a combination of in vitro, in vivo, and ex vivo methods to demonstrate that the first-line therapy for rheumatoid arthritis (RA), methotrexate (MTX), has off-target effects on the human gut microbiota, resulting in decreases in Bacteroidetes, which tend to be more sensitive. Longitudinal analyses of the gut microbiotas of RA patients revealed that MTX-induced shifts in bacterial relative abundance are associated with improved drug response and transplant experiments in gnotobiotic mice show that these shifts lead to reduced inflammation. Specific MTX-modulated taxa are associated with immune activation. Together, these results suggest that the mechanism-of-action of non-antibiotic drugs may be due in part to off-target effects on the gut microbiota, while providing a critical first step towards explaining long-standing differences in drug response between patients.
Keywords: rheumatoid arthritis, human gut microbiome, off-target effects, immune activation, methotrexate
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