Inflammatory Mediators and Gut Microbial Toxins Drive Colon Tumorigenesis by IL-23 Dependent Mechanism

SIMPLE SUMMARY: Western-style diet, rich in high fat, is the major cause of obesity and enhanced risk of colon cancer in the USA and worldwide. The inflammatory molecules are a well-established link between obesity and the modulation of colon tumorigenesis. In particular, IL-23 plays an important role in the impact of a western-style diet on obesity, the gut microbiome, and colon tumorigenesis. However, the underlying mechanism of IL-23 production for colon tumor progression and whether IL-23 can be a potential target is not clear. Our findings signify the role of pro-tumorigenic innate immune cells, including dendritic cells and macrophages in IL-23 production by bacterial toxins and eicosanoids. IL-23 knockdown in the tumorigenic dendritic cells and macrophages inhibited the colon tumor cell and organoids growth. Taken together, targeting IL-23 may be a promising option for the prevention and treatment of high-fat/obesity-associated colon cancer in clinical trials. ABSTRACT: Obesity-associated chronic inflammation predisposes colon cancer risk development. Interleukin-23 (IL-23) is a potential inflammatory mediator linking obesity to chronic colonic inflammation, altered gut microbiome, and colon carcinogenesis. We aimed to elucidate the role of pro-inflammatory eicosanoids and gut bacterial toxins in priming dendritic cells and macrophages for IL-23 secretion to promote colon tumor progression. To investigate the association of IL-23 with obesity and colon tumorigenesis, we utilized TCGA data set and colonic tumors from humans and preclinical models. To understand IL-23 production by inflammatory mediators and gut microbial toxins, we performed several in vitro mechanistic studies to mimic the tumor microenvironment. Colonic tumors were utilized to perform the ex vivo experiments. Our findings showed that IL-23 is elevated in obese individuals, colonic tumors and correlated with reduced disease-free survival. In vitro studies showed that IL-23 treatment increased the colon tumor cell self-renewal, migration, and invasion while disrupting epithelial barrier permeability. Co-culture experiments of educated dendritic cells/macrophages with colon cancer cells significantly increased the tumor aggression by increasing the secretory levels of IL-23, and these observations are further supported by ex vivo rat colonic tumor organotypic experiments. Our results demonstrate gut microbe toxins and eicosanoids facilitate IL-23 production, which plays an important role in obesity-associated colonic tumor progression. This newly identified nexus represents a potential target for the prevention and treatment of obesity-associated colon cancer.