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 Clostridium disporicum, which is associated a global reduction in the abundance of at least 10 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.