Mucus Sialylation Maintains the Peace in Intestinal Host Microbe Relations

Yao Y, Kim G, Shafe S, et al. Mucus sialylation determines intestinal host-commensal homeostasis. Cell 2022;185:1172–1188. Increasing evidence suggests that the alterations in the intestinal mucus barrier contribute to inflammatory bowel disease. Mucus represents a critical component in maintaining tissue homeostasis in the gastrointestinal tract by providing a physical barrier against noxious agents or microorganisms, and also by delivering immunoregulatory signals and immunologic tolerance, sources of nutrients and energy, as well as molecular scaffolding between luminal contents and the epithelial barrier. The viscoelastic and protective properties of intestinal mucus are provided mainly by a dense network of high-molecular-weight proteins (mucins) with a variety of O- and N-linked glycosylation. Terminal sialylation of glycans is a critical process in the biosynthesis of mucins; however, the regulatory mechanisms of maintaining intestinal mucus barrier integrity remain elusive. In the featured article, Yao et al demonstrated that the sialyltransferase ST6GALNAC1 (ST6) in goblet cells is essential for controlling mucus barrier integrity by protecting excessive bacterial proteolytic degradation of mucins through catalyzation of the terminal sialylation of glycans. Ultimately, the authors provided evidence for the functional relevance of ST6-mediated sialylation by the identification of biallelic loss-of-function germline mutations in 3 patients with very-early-onset inflammatory bowel disease. Functional experiments employing sophisticated human disease models (genetically engineered colorectal adenocarcinoma cell lines and induced pluripotent stem cell–derived intestinal organoids) demonstrated that patient-specific mutations cause compromised subcellular Golgi localization and post-translational modification (glycosylation and sialylation) of ST6, resulting in impaired enzyme activity. Using a mouse model with knock-in of a patient-specific mutation, the authors showed that ST6 deficiency leads to enhanced severity of experimental colitis associated with increased invasion of the colonic mucus by microbiota, reduced bacterial diversity, and excessive production of bacterial-derived short-chain fatty acids. Remarkably, experimental colitis could be ameliorated by treatment with orally administered sialylated mucins and antibiotic cocktails, or by targeting of microbial metabolites. Taken together, this article highlights the critical importance of microbe-associated molecular pattern–induced mucin sialylation in determining the biochemical composition of the intestinal mucus barrier. This elaborate study starts with basic laboratory findings on ST6 expression and function, followed by the description of the first patients with ST6 deficiency, the assessment of underlying disease mechanisms, and the testing of targeted treatments in state-of-the-art preclinical models. The therapeutic strategy to improve epithelial wound healing by targeting of the sialic acid catabolism and microbial commensalism opens innovative perspectives for the treatment of intestinal inflammation. Further studies are required to evaluate the relevance of ST6 in the cohort of common inflammatory bowel disease, elucidate the role of other sialyltransferases or mucins, and explore the mechanisms of microbial dysbiosis in the context of sialyltransferase deficiencies. This knowledge will be critical to further advance the proposed therapeutic implications for inflammatory bowel disease.