The gut and liver communicate through the biliary tract, portal vein, and systemic circulation, with the gut-liver axis playing a critical role in regulating intestinal homeostasis. A study identifies pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, as a key regulator of intestinal stem cell (ISC) proliferation. PEDF suppresses the Wnt/β-catenin signaling pathway, which is essential for maintaining gut homeostasis. Intestinal inflammation can trigger microbial danger signals that are sensed by the liver, leading to the repression of PEDF production via peroxisome proliferator-activated receptor-α (PPARα). This repression allows ISC proliferation to accelerate tissue repair. Treatment with fenofibrate, a PPARα agonist, enhances colitis susceptibility due to PEDF activity. The study demonstrates that the gut-liver axis calibrates ISC expansion for intestinal homeostasis through reciprocal interactions. PEDF is primarily produced by the liver and plays a critical role in controlling ISC homeostasis. The liver senses microbial LPS during intestinal inflammation, which represses PEDF production via the PPARα signaling pathway. This mechanism promotes ISC proliferation for tissue repair. The study also shows that PPARα promotes liver PEDF production in response to microbial LPS. Fenofibrate enhances intestinal inflammation via PEDF, and neutralizing PEDF reduces colitis severity. Human studies confirm that PEDF is reduced during inflammatory bowel disease (IBD) development and represses ISC proliferation. The findings highlight the importance of the gut-liver axis in maintaining intestinal homeostasis and suggest PEDF as a potential therapeutic target for intestinal inflammation. The study provides insights into the molecular mechanisms underlying gut-liver communication and its role in intestinal physiology and disease.The gut and liver communicate through the biliary tract, portal vein, and systemic circulation, with the gut-liver axis playing a critical role in regulating intestinal homeostasis. A study identifies pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, as a key regulator of intestinal stem cell (ISC) proliferation. PEDF suppresses the Wnt/β-catenin signaling pathway, which is essential for maintaining gut homeostasis. Intestinal inflammation can trigger microbial danger signals that are sensed by the liver, leading to the repression of PEDF production via peroxisome proliferator-activated receptor-α (PPARα). This repression allows ISC proliferation to accelerate tissue repair. Treatment with fenofibrate, a PPARα agonist, enhances colitis susceptibility due to PEDF activity. The study demonstrates that the gut-liver axis calibrates ISC expansion for intestinal homeostasis through reciprocal interactions. PEDF is primarily produced by the liver and plays a critical role in controlling ISC homeostasis. The liver senses microbial LPS during intestinal inflammation, which represses PEDF production via the PPARα signaling pathway. This mechanism promotes ISC proliferation for tissue repair. The study also shows that PPARα promotes liver PEDF production in response to microbial LPS. Fenofibrate enhances intestinal inflammation via PEDF, and neutralizing PEDF reduces colitis severity. Human studies confirm that PEDF is reduced during inflammatory bowel disease (IBD) development and represses ISC proliferation. The findings highlight the importance of the gut-liver axis in maintaining intestinal homeostasis and suggest PEDF as a potential therapeutic target for intestinal inflammation. The study provides insights into the molecular mechanisms underlying gut-liver communication and its role in intestinal physiology and disease.