Gut-liver axis calibrates intestinal stem cell fitness

Cell. 2024 Feb 15;187(4):914-930.e20. doi: 10.1016/j.cell.2024.01.001. Epub 2024 Jan 26.


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.

Keywords: PEDF; PPARα; Wnt/β-catenin signal; fenofibrate; gut-liver axis; intestinal stem cells.

MeSH terms

  • Animals
  • Cell Proliferation
  • Intestines* / cytology
  • Intestines* / metabolism
  • Liver* / metabolism
  • Mice
  • PPAR alpha / metabolism
  • Proteomics
  • Stem Cells / metabolism
  • Wnt Signaling Pathway


  • PPAR alpha