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The gut and liver are recognized to mutually communicate through the biliary tract, portal vein, and systemic circulation. However, it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy and transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, which restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/β-catenin signaling pathway. Furthermore, we found that microbial danger signals resulting from intestinal inflammation can be sensed by the liver, leading to the repression of PEDF production through peroxisome proliferator-activated receptor-α (PPARα). This repression liberates ISC proliferation to accelerate tissue repair in the gut. Additionally, treating mice with fenofibrate, a clinical PPARα agonist used for hypolipidemia, enhances colitis susceptibility due to PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis through reciprocal interactions between the gut and liver.
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•Liver-derived PEDF restrains ISC proliferation•The gut-liver axis calibrates PEDF production for ISC homeostasis•Microbial LPS regulates PEDF production via liver-derived PPARα•Fenofibrate enhances the susceptibility of intestinal inflammation via PEDF
The gut and liver reciprocally communicate to control gut homeostasis and tissue repair during health and diseases. Kim et al. demonstrate that liver-derived soluble factor pigment epithelium-derived factor (PEDF) restrains intestinal stem cell (ISC) expansion, suggesting that the gut-liver axis calibrates ISC fitness for intestinal homeostasis.