High-fat diet-induced dysbiosis mediates MCP-1/CCR2 axis-dependent M2 macrophage polarization and promotes intestinal adenoma-adenocarcinoma sequence.

ABSTRACT

High-fat diet (HFD) is a well-known risk factor for gut microbiota dysbiosis and colorectal cancer (CRC). However, evidence relating HFD, gut microbiota and carcinogenesis is limited. Our study aimed to demonstrate that HFD-induced gut dysbiosis promoted intestinal adenoma-adenocarcinoma sequence. In clinical study, we found that HFD increased the incidence of advanced colorectal neoplasia (AN). The expression of monocyte chemoattractant protein 1 (MCP-1), CC chemokine receptor 2 (CCR2) and CD163 in CRC patients with HFD was significantly higher than that in CRC patients with normal diet. When it comes to the Apcmin/+ mice, HFD consumption could induce gut dysbiosis and promote intestinal carcinogenesis, accompanying with activation of MCP-1/CCR2 axis that recruited and polarized M2 tumour-associated macrophages. Interestingly, transfer of faecal microbiota from HFD-fed mice to another batch of Apcmin/+ mice in the absence of HFD could also enhance carcinogenesis without significant body weight gain and induced MCP-1/CCR2 axis activation. HFD-induced dysbiosis could also be transmitted. Meanwhile, antibiotics cocktail treatment was sufficient to inhibit HFD-induced carcinogenesis, indicating the vital role of dysbiosis in cancer development. Conclusively, these data indicated that HFD-induced dysbiosis accelerated intestinal adenoma-adenocarcinoma sequence through activation of MCP-1/CCR2 axis, which would provide new insight into better understanding of the mechanisms and prevention for HFD-related CRC.