Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation.

Gut microbes, notably Clostridium asparagiforme, metabolize methotrexate via carboxypeptidase G2 (CPDG2) to produce deoxyaminopteroic acid (DAMPA), linked to host STAT3 signaling.

• Why it matters: MTX has mixed success in inflammatory bowel disease, but it is unclear how inflammation changes microbial MTX metabolism and how resulting metabolites affect host inflammatory control.
• What they did: The study identifies CPDG2-dependent DAMPA production by gut microbes, tests DAMPA in intestinal epithelial cells for STAT3 signaling, mitochondrial health, and mitophagy, and administers DAMPA in vivo.
• The result: DAMPA administration attenuates intestinal inflammation in mouse IBD models and remodels colonic mitochondrial pathways; IBD models and patients show reduced CPDG2 and DAMPA-associated mitochondrial pathway suppression.

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