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Dietary suppression of MHC-II expression in intestinal epithelial cells enhances intestinal tumorigenesis

ABSTRACT: Little is known about how interactions between diet, intestinal stem cells (ISCs) and immune cells impact the early steps of intestinal tumorigenesis. Here, we show that a high fat diet (HFD) reduces the expression of the major histocompatibility complex II (MHC-II) genes in intestinal epithelial cells including ISCs. This decline in epithelial MHC-II expression in a HFD correlates with reduced diversity of the intestinal microbiome and is recapitulated in antibiotic treated and germ-free mice on a control diet. Mechanistically, pattern recognition receptor (PRR) and IFN g signaling regulate epithelial MHC-II expression where genetic ablation of these signaling pathways dampen MHC-II epithelial expression. Interestingly, upon loss of the tumor suppressor gene Apc in a HFD, MHC-II- ISCs harbor greater in vivo tumor-initiating capacity than their MHC-II+ counterparts when transplanted into immune-component hosts but not immune-deficient hosts, thus implicating a role for epithelial MHC-II-mediated immune surveillance in suppressing tumorigenesis. Finally, ISC-specific genetic ablation of MHC-II in engineered Apc-mediated intestinal tumor models increases tumor burden in a cell autonomous manner. These findings highlight how a HFD perturbs a microbiome – stem cell – immune cell crosstalk in the intestine and contributes to tumor initiation through the dampening of MHC-II expression in pre-malignant ISCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE180949 | GEO | 2021/08/16

REPOSITORIES: GEO

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