Microbiota-derived PPAR-γ signaling and risk of bacterial enteric infection: insight from thiazolidinedione users in a US population-based study
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The ongoing antimicrobial resistant crisis heralds the need for new therapeutics against enteric infection. In mouse models, colon epithelial peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling limits oxygen and nitrate luminal bioavailability, thereby preventing bacterial pathogen colonization. However, whether this mechanism operates similarly in humans remains uncertain. To investigate, we used the cloud-based TriNetX Analytics Platform which aggregates health records from 117 million patients across 66 US healthcare organizations, to assess the risk of bacterial enteric infection among diabetic patients prescribed thiazolidinediones, a class of PPAR-γ agonists. Among 85,117 thiazolidinedione users, we observed a 22-49% lower risk of bacterial enteric infections compared to users of other anti-diabetes medications. This reduction in risk was consistent across high-risk individuals, regardless of sex or age. Similar results were replicated in high-risk patients when thiazolidinedione users were directly compared to those on DPP-4 inhibitors. These findings support the potential protective role of PPAR-γ signaling against bacterial enteric infection and call for further clinical investigation.
