Intestinal epithelial Casd1 regulates mucus sialic acid O-acetylation and limits tissue damage from large-intestinal mucosal insults

Recent studies show that intestinal epithelial sialylation is essential for homeostasis, but whether this protection depends on sialic acid O -acetylation is unclear. CAS1 domain-containing protein 1 (Casd1) governs sialic acid O -acetylation, a natural inhibitor of sialidase activity. We hypothesized that epithelial mucin O -acetylation protects the colon by limiting sialidase-mediated mucus degradation and dysbiosis. Human MUC2 and murine Muc2 were richly O -acetylated, while intestinal epithelial-specific Casd1 deletion abolished mucin O -acetylation. Unexpectedly, intestinal epithelial cell (IEC) Casd1 −/− mice maintained normal mucus structure, barrier function, physiology, and overall Muc2 sialylation, with only subtle sex-specific microbiota changes. However, IEC Casd1 −/− mice developed significantly greater ulceration during dextran sulfate sodium colitis and increased cecal and distal colonic injury following Citrobacter rodentium infection despite equivalent pathogen burdens. Thus, epithelial sialic acid O -acetylation is dispensable for baseline mucus homeostasis but critically limits tissue damage during inflammatory and infectious insults.