Hypernutrition and hyperlipidemia are well-established risk factors for colorectal carcinoma (CRC) progression and metastasis. However, beyond conventional lipids such as triglycerides and cholesterol, the mechanisms linking hypernutrition to CRC liver metastasis—the most frequent site of distant spread—remain poorly understood. Here, using a mouse cecum orthotopic CRC model combined with high fat diet (HFD) feeding, along with in vitro endothelia cell assays, we showed that elevated circulating blood lipids, particularly primary conjugated-BAs (C-BAs), induced by excessive dietary fat intake, promoted CRC metastasis to liver. This effect is associated with disruption of both intestinal epithelial barrier (IEB) and gut vascular barrier (GVB). HFD-induced hypernutrition disrupts bile acid homeostasis, leading to increased bile acid levels in the serum, colon, and ileum. Notably, four primary C-BAs were significantly elevated: taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), glycocholic acid (GCA), and glycochenodeoxycholic acid (GCDCA). Administration of individual BAs recapitulated the pro-metastatic effects of HFD in vivo. Mechanistically, these C-BAs impaired FXR-mediated feedback regulation of bile acid metabolism and activated oxidative stress and Ca²⁺–MLCK signaling, resulting in GVB disruption. This was accompanied by decreased expression of tight junction (TJ) proteins, Claudin, Occluding, and ZO-1, but increased VEGFA and PV-1 expression, resulting in the increased intestinal permeability and enhanced liver metastasis of CRC. Importantly, the FXR agonist obeticholic acid restored FXR signaling, reduced intestinal permeability, and attenuated HFD-driven CRC liver metastasis. Our findings uncover a mechanistic link between dietary hypernutrition and GVB dysfunction mediated by conjugated bile acids, highlighting FXR as a potential therapeutic target for preventing hypernutrition-associated CRC metastasis.

Professor Feng He is Director of the Center for Cancer Research at Shanghai University of Traditional Chinese Medicine. His research focuses on stress response mechanisms regulating immune and metabolic homeostasis in gastrointestinal cancers and metabolic diseases. He has published over 40 SCI-indexed papers, including 9 highly cited and 2 hot papers, in journals such as Cancer Cell, Journal of Hepatology, and PNAS, with over 6,000 citations. He is listed among the Stanford/Elsevier World’s Top 2% Scientists. Professor He has reviewed 400+ manuscripts for 70+ journals and serves on the editorial boards of BMC Biology, eGastroenterology, and MedMat.