Abstract: 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, 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 resulting from intestinal inflammation can be sensed by the liver, leading to the repression of PEDF production through peroxisome proliferator-activated receptor-a (PPARa). This repression liberates ISC proliferation to accelerate tissue repair in the gut. Additionally, treating mice with fenofibrate, a clinical PPARa 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.

Speaker：Dr. Wu completed his M.D. at Shanghai Jiaotong University, School of Medicine. He further undertook his doctoral research training at Muenster University, Germany, focusing on T cell migration during inflammation and autoimmunity. Then, he did his post-doctoral training at Brigham and Women’s Hospital, Harvard Medical School, where he studied transcriptional regulation for T cell differentiation. In 2016, Dr. Wu joined the faculty at Brigham and Women’s Hospital, Harvard Medical School as an Assistant Professor and then moved to NCI in 2017 as an Earl Stadtman Investigator, where he re-directed his research to understand intercellular regulation on mucosal barrier integrity. His lab is utilizing interdisciplinary approaches to elucidate the crosstalk between the nervous system, microbial pathogens, and the immune system. As a corresponding author, he published his recent work in prestigious journals like  Cell, Immunity and Nature Immunology .