IDDF2019-ABS-0339 High-fat diet-induced gut microbiota dysbiosis activate MCP-1/CCR2 pathway and promote intestinal carcinogenesis

Abstract

Background High-fat diet (HFD) is an important risk factor for colorectal cancer (CRC). However, the mechanisms remain to be clarified. The potential pathway MCP-1/CCR2 activation can recruit and polarize M2 tumor-associated macrophages(TAMs). Here we aimed to investigate the effects and mechanisms of HFD on the gut microbiota and intestinal tumor development. Methods A retrospective cohort study was performed to investigate HFD in relation to advanced colorectal neoplasia (AN). 15 CRC patients from each group for IHC staining were selected to evaluate MCP-1/CCR2 expression. Four-week-old Apcmin/+ mice were randomly divided into HFD group and control group. Intestinal tumor development, cell proliferation and apoptosis, inflammation and MCP-1/CCR2 pathway were determined. Intestinal M2 TAMs were measured by immunofluorescence double staining. Fecal pellets were collected for microbiota and short-chain fatty acids (SCFA) analysis. Antibiotics cocktail was administered with HFD to investigate the effect of crosstalk between the HFD and gut microbiota. Fecal microbiota transplantation (FMT) was used in another batch of Apcmin/+mice to determine the causality between HFD-induced dysbiosis and carcinogenesis. Results Participants with HFD were more likely to develop AN, especially invasive carcinoma. The expression of MCP-1/CCR2 and CD163 in CRC patients with HFD was significantly higher. In the Apcmin/+ mice, the total number of intestinal adenoma of HFD group was significantly increased. Pathological analysis confirmed intestinal carcinogenesis in small intestine and colon in HFD group, while there were only adenomas in the control group. This was accompanied by promoting tumor cell proliferation and decreasing apoptosis. Moreover, HFD administration altered gut microbiota, with increased opportunistic pathogens and decreased SCFA producing bacteria. The dysbiosis up-regulated the expression of MCP-1 and CCR2. And an increased M2 TAMs was observed in HFD group. And the effects of intestinal carcinogenesis can be restored by antibiotics cocktail. The transfer of fecal microbiota from HFD-fed mice also increased the tumor multiplicity and promoted carcinogenesis, while the MCP-1/CCR2 axis was also activated. Conclusions HFD-induced dysbiosis promoted the intestinal carcinogenesis through activating the MCP-1/CCR2 axis.