Dietary choline prevents colitis-driven carcinogenesis via SLC5A7-dependent Notch1 degradation and goblet cell reprogramming.

Abstract

Chronic inflammation is a major driver of colorectal tumorigenesis, with patients suffering from inflammatory bowel disease (IBD) exhibiting a significantly elevated risk of developing colitis-associated cancer (CAC). Although epidemiological studies link dietary choline to reduced colorectal cancer (CRC) risk, its mechanism in inflammation-driven carcinogenesis remains unclear. Here, we demonstrate that the high-affinity choline transporter SLC5A7 mediates the protective effects of choline against intestinal inflammation and tumor development. Using intestinal epithelial-specific SLC5A7 knockout mice, we found that SLC5A7 deficiency exacerbated dextran sulfate sodium (DSS)-induced colitis and enhanced azoxymethane (AOM)/DSS-driven tumorigenesis. Single-cell RNA sequencing revealed that SLC5A7 loss led to marked goblet cell depletion, impaired mucosal barrier integrity, and increased bacterial invasion. Mechanistically, SLC5A7 directly bound to Notch1 and promoted its proteasomal degradation, thereby relieving Notch1-mediated suppression of goblet cell differentiation. Furthermore, choline supplementation upregulated SLC5A7 expression and inhibited Notch1 signaling in human colonic epithelial cells and intestinal organoids. Critically, all protective effects of dietary choline were abolished in SLC5A7-deficient mice. Our study defines a previously unrecognized pathway-from nutrient intake to epithelial defense-wherein choline activates SLC5A7 to degrade Notch1, promote goblet cell differentiation, and enhance barrier function, thereby suppressing colitis and associated carcinogenesis. These findings establish SLC5A7 as a key nutrient-sensitive regulator of intestinal homeostasis and provide a mechanistic basis for choline-based strategies to prevent IBD and CAC.