Ablation of intestinal epithelial sialylation predisposes to acute and chronic intestinal inflammation in mice

Abstract

BACKGROUND & AIMSAddition of sialic acids (sialylation) to glycoconjugates is a common capping step of glycosylation. Our study aims to determine the roles of the overall sialylation in intestinal mucosal homeostasis. METHODSMice with constitutive deletion of intestinal epithelial sialylation (IEC Slc35a1–/– mice) and mice with inducible deletion of sialylation in intestinal epithelium (TM-IEC Slc35a1–/– mice) were generated, which were used to determine the roles of overall sialylation in intestinal mucosal homeostasis by ex vivo and muti-omics studies. RESULTSIEC Slc35a1–/– mice developed mild spontaneous microbiota-dependent colitis. Additionally, 30% of IEC Slc35a1–/– mice had spontaneous tumors in the rectum over the age of 12 months. TM-IEC Slc35a1–/– mice were highly susceptible to acute inflammation induced by 1% DSS vs controls. Loss of total sialylation was associated with reduced mucus thickness on fecal sections and within colon tissues. TM-IEC Slc35a1–/– mice showed altered microbiota with an increase in Clostridia disporicum, which is associated a global reduction in the abundance of at least 20 unique taxa; however, metabolomic analysis did not show any significant differences in short-chain fatty acid levels. Treatment with 5-fluorouracil (5-FU) led to more severe small intestine mucositis in the IEC Slc35a1–/– mice vs. WT littermates, which was associated with reduced Lgr5+ cell representation in small intestinal crypts in IEC Slc35a1-/-;Lgr5-GFP mice. CONCLUSIONSLoss of overall sialylation impairs mucus stability and the stem cell niche leading to microbiota-dependent spontaneous colitis and tumorigenesis.