Modulating Gut Microbiota Prevents Anastomotic Leak to Reduce Local Implantation and Dissemination of Colorectal Cancer Cells after Surgery

Anastomotic leak (AL) is a major complication in colorectal cancer (CRC) surgery, and consists of the leakage of intestinal content through a poorly healed colonic wound. CRC recurrence after surgery is a major determinant of survival. We hypothesize that AL may allow cancer cells to escape the gut and lead to cancer recurrence, and that improving anastomotic healing may prevent local implantation and metastatic dissemination of cancer cells.We investigated the association between AL and postoperative outcomes in patients with CRC. Using mouse models of poor anastomotic healing, we assessed the processes of local implantation and dissemination of cancer cells. The effect of dietary supplementation with inulin and 5-ASA, which activate peroxisome proliferator-activated receptor gamma (PPAR-γ) in the gut, on local anastomotic tumors was assessed in mice undergoing colonic surgery. Inulin and 5-ASA were also assessed in a mouse model of liver metastasis.Patients experiencing AL displayed lower overall and oncological survival than non-AL patients. Poor anastomotic healing in mice led to larger anastomotic and peritoneal tumors. The microbiota of patients with AL displays a lower capacity to activate the antineoplastic PPAR-γ In the gut. Modulation of gut microbiota using dietary inulin and 5-ASA reinforced the gut barrier and prevented anastomotic tumors and metastatic spread in mice.Our findings reinforce the hypothesis that preventing AL is paramount to improving oncological outcomes after CRC surgery. Furthermore, they pave the way toward dietary targeting of PPAR-γ as a novel way to enhance healing and diminish cancer recurrence.