Altered Mucus Glycosylation in Core 1 O-Glycan-Deficient Mice Affects Microbiota Composition and Intestinal Architecture

A functional mucus layer is a key requirement for gastrointestinal health as it serves as a barrier against bacterial invasion and subsequent inflammation. Recent findings suggest that mucus composition may pose an important selection pressure on the gut microbiota and that altered mucus thickness or properties such as glycosylation lead to intestinal inflammation dependent on bacteria. Here we used TM-IEC C1galt-/- mice, which carry an inducible deficiency of core 1-derived O-glycans in intestinal epithelial cells, to investigate the effects of mucus glycosylation on susceptibility to intestinal inflammation, gut microbial ecology and host physiology. We found that TM-IEC C1galt-/- mice did not develop spontaneous colitis, but they were more susceptible to dextran sodium sulphate-induced colitis. Furthermore, loss of core 1-derived O-glycans induced inverse shifts in the abundance of the phyla Bacteroidetes and Firmicutes. We also found that mucus glycosylation impacts intestinal architecture as TM-IEC C1galt-/- mice had an elongated gastrointestinal tract with deeper ileal crypts, a small increase in the number of proliferative epithelial cells and thicker circular muscle layers in both the ileum and colon. Alterations in the length of the gastrointestinal tract were partly dependent on the microbiota. Thus, the mucus layer plays a role in the regulation of gut microbiota composition, balancing intestinal inflammation, and affects gut architecture.功能性黏液层是维系胃肠道健康的核心要素，其可作为屏障抵御细菌侵袭及后续引发的炎症反应。最新研究显示，黏液组成或会对肠道菌群施加重要的选择压力，而黏液厚度或糖基化等特性发生改变时，会引发依赖于细菌的肠道炎症。本研究使用TM-IEC C1galt-/-小鼠——该模型可在肠上皮细胞中诱导核心1衍生O-糖基化（core 1-derived O-glycans）缺失——来探究黏液糖基化对肠道炎症易感性、肠道微生物生态以及宿主生理状态的影响。研究结果显示，TM-IEC C1galt-/-小鼠不会自发罹患结肠炎，但对葡聚糖硫酸钠（dextran sodium sulphate）诱导的结肠炎易感性显著升高。此外，核心1衍生O-糖基化的缺失会导致拟杆菌门（Bacteroidetes）与厚壁菌门（Firmicutes）的丰度出现反向变化。本研究同时发现，黏液糖基化会影响肠道结构：TM-IEC C1galt-/-小鼠的胃肠道更长，回肠隐窝更深，增殖性上皮细胞数量小幅增加，回肠与结肠的环形肌层均更厚。胃肠道长度的改变部分依赖于肠道菌群。综上，黏液层可调控肠道菌群组成、平衡肠道炎症反应，并对肠道结构产生重要影响。