Microbial Metabolite Deoxycholic Acid Promotes Vasculogenic Mimicry Formation in Intestinal Carcinogenesis

Background: High-fat diet (HFD) leads to exposure to gut microbial metabolite secondary bile acids such as deoxycholic acid (DCA) in the intestine, which is closely linked to colorectal cancer (CRC). Vasculogenic mimicry (VM) is a critical event for cancer malignant transformation. We aimed to investigate the crucial roles of DCA on VM and the intestinal carcinogenesis. Methods: The effects of HFD on VM formation and epithelial-mesenchymal transition (EMT) in human CRC tissues were investigated. The fecal DCA level was detected in the HFD treated- Apc min/+  mice. The four-week  Apc min/+  mice were treated with 0·2% DCA for 12 weeks. Intestinal tumor tissues were collected for detection of VM, EMT, and vascular endothelial growth factor receptor 2 (VEGFR2) signaling. The effects of DCA on tube formation, EMT, and VEGFR2 signaling of HCT-116 cells were evaluated. Findings: Compared with the normal diet, HFD exacerbated VM formation and EMT in CRC patients. HFD could significantly increase fecal DCA level in Apc min/+  mice. More importantly, DCA promoted tumor cell proliferation and EMT, and increased VM formation accompanied by VEGFR2 activation, which led to intestinal carcinogenesis. DCA enhanced proliferation and migration of HCT-116 cells, and induced EMT and vitro tube formation. Furthermore, the silence of VEGFR2 blunted DCA-induced EMT, VM formation, and migration. Interpretation: Microbial metabolite DCA promoted VM formation and EMT through VEGFR2 activation, which further exacerbated intestinal carcinogenesis. Funding: This study was supported by the National Natural Science Foundation of China and the Key Project of Science and Technology Pillar Program of Tianjin. Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: This study was approved by the Ethics Committee of General Hospital, Tianjin Medical University, China.