Ablation of Intestinal Epithelial Sialylation Predisposes to Acute and Chronic Intestinal Inflammation in Mice.

Abstract

Background & aims: Addition 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.

Methods: Mice 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 mutiomics studies.

Results: IEC Slc35a1^-/- mice developed mild spontaneous microbiota-dependent colitis. Additionally, 30% of IEC Slc35a1^-/- mice had spontaneous tumors in the rectum greater than the age of 12 months. TM-IEC Slc35a1^-/- mice were highly susceptible to acute inflammation induced by 1% dextran sulfate sodium versus control animals. 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 led to more severe small intestine mucositis in the IEC Slc35a1^-/- mice versus wild-type littermates, which was associated with reduced Lgr5⁺ cell representation in small intestinal crypts in IEC Slc35a1^-/-;Lgr5-GFP mice.

Conclusions: Loss of overall sialylation impairs mucus stability and the stem cell niche leading to microbiota-dependent spontaneous colitis and tumorigenesis.