Gut-liver axis calibrates intestinal stem cell fitness via PEDF
The gut and liver are recognized to mutually communicate through the biliary tract, portal vein and systemic circulation, but it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy, transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, that restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/b-catenin signaling pathway. Further, we found that microbial danger signals occurring as a result of intestinal inflammation can be sensed by the liver to repress PEDF production via peroxisome proliferator-activated receptor-a (PPARa), liberating ISC proliferation to accelerate tissue repair in the gut. Finally, treatment of mice with fenofibrate, a clinical agent of PPARa agonist for hypolipidemia enhances the susceptibility of colitis via PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis via reciprocal interactions between the gut and liver. Overall design: Expression profiling by high throughput sequencing