Abstract
A high-fat diet (HFD) increases tumorigenicity by reducing MHC class II on intestinal stem cells (ISC).
Major Finding: A high-fat diet (HFD) increases tumorigenicity by reducing MHC class II on intestinal stem cells (ISC).
Mechanism: HFD-fed mice had reduced microbiome diversity leading to decreased MHC class II and immune recognition.
Impact: This work reveals how diet correlates with tumorigenesis through ISC–immune cell–microbiome interplay.
Diet has been determined to be a major factor in the development of multiple cancer types, including colorectal cancer. Intestinal stem cells (ISC) are known cells of origin for tumorigenesis and are also major responders to environmental stimuli in the intestine, including diet. This cell type also functions at the intersection between diet and immune cells within this space. As a Western or high-fat diet (HFD) has been implicated in the heightened development of intestinal tumorigenesis, the compounding role that ISCs and immune cells have along with diet in this process remains to be understood. Thus, Beyaz and colleagues investigated the relationship between HFD and these cell types and how tumor initiation and immune surveillance are subsequently altered. Lgr5+ ISCs from mice fed an HFD had significantly downregulated immunomodulatory genes, most notably those of the MHC class II complex. Additional experiments indicated that this was caused by a reduction in microbiome diversity brought about by HFD and was confirmed by treating mice with broad-spectrum antibiotics. One of the most prominently altered bacterial genera was Helicobacter, and its colonization was positively correlated with MHC class II present on ISCs. Furthermore, MHC class II gene expression was decreased on ISCs from HFD-fed mice through a reduction in both pattern recognition receptor and IFNγ signaling that was also associated with a drop in CD45+ immune infiltrates including CD3+, CD8+, and CD4+ T cells. A decrease in ISC MHC class II promoted tumorigenesis, but this induction was no longer present when the same experiment was performed in immune-deficient mice. This work, therefore, shows that an HFD can contribute to an increase in intestinal tumorigenesis by alterations to the microbiome and subsequent effects on immune recognition through a reduction in MHC class II on ISCs.
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