Recent advancements suggest that in addition to its roles in developmental processes, transcription repressor hairy and enhancer of split 1 (Hes1) also acts as a key regulator of inflammatory responses. A healthy gut microbiota ecology is critical for establishment of tissue homeostasis. However, the role of epithelial Hes1 in regulating intestinal microbiota ecology and intestinal homeostasis remains unexplored. Here we show that epithelial Hes1 deficiency leads to intestinal microbial dysbiosis and disturbed homeostasis. Both inducible Hes1 deletion and intestinal epithelial cell (IEC)-intrinsic Hes1 deletion resulted in loss of Bacteroidetes in ileum and increase of Escherichia coli and Akkermansia muciniphila in colon. Loss of Bacteroidetes closely correlated with decreased expression of commensal-dependent antimicrobial genes, leading to impaired resistance against pathogenic bacterial colonization. Moreover, Hes1 deficiency enhanced susceptibility to Dextran sodium sulphate-induced intestinal inflammation. Of note, transfer of Hes1-deficient-mouse-derived fecal microbiota promoted intestinal inflammation. The increase of A. muciniphila in colon was associated with Hes1-deficiency-induced unbalanced mucosal microhabitats. Thus, our results support that IEC-intrinsic Hes1 maintains gut homeostasis by preventing microbial dysbiosis partially through regulating mucosal microhabitats.

中文翻译：

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上皮 Hes1 通过防止微生物失调来维持肠道稳态。

最近的进展表明，除了其在发育过程中的作用外，转录抑制因子毛发和分裂 1 (Hes1) 的增强子还充当炎症反应的关键调节因子。健康的肠道菌群生态对于建立组织稳态至关重要。然而，上皮 Hes1 在调节肠道微生物群生态学和肠道稳态​​中的作用仍未得到探索。在这里，我们表明上皮 Hes1 缺陷导致肠道微生物失调和体内平衡紊乱。可诱导的 Hes1 缺失和肠上皮细胞 (IEC) 固有的 Hes1 缺失均导致回肠中拟杆菌的丢失以及结肠中大肠杆菌和 Akkermansia muciniphila 的增加。拟杆菌的丧失与共生依赖性抗菌基因表达的减少密切相关，导致对病原菌定植的抵抗力受损。此外，Hes1 缺乏增强了对葡聚糖硫酸钠诱导的肠道炎症的易感性。值得注意的是，Hes1 缺陷小鼠粪便微生物群的转移促进了肠道炎症。结肠中 A. muciniphila 的增加与 Hes1 缺陷诱导的不平衡粘膜微生境有关。因此，我们的结果支持 IEC 固有的 Hes1 通过部分调节粘膜微生境来防止微生物失调来维持肠道稳态。结肠中的 muciniphila 与 Hes1 缺陷诱导的不平衡粘膜微生境有关。因此，我们的结果支持 IEC 固有的 Hes1 通过部分调节粘膜微生境来防止微生物失调来维持肠道稳态。结肠中的 muciniphila 与 Hes1 缺陷诱导的不平衡粘膜微生境有关。因此，我们的结果支持 IEC 固有的 Hes1 通过部分调节粘膜微生境来防止微生物失调来维持肠道稳态。