Metrnl is a newly identified secreted protein highly expressed in the intestinal epithelium. This study aimed to explore the role and mechanism of intestinal epithelial Metrnl in ulcerative colitis. Metrnl^−/− (intestinal epithelial cell-specific Metrnl knockout) mice did not display any phenotypes of colitis under basal conditions. However, under administration of 3% dextran sodium sulfate (DSS) drinking water, colitis was more severe in Metrnl^−/− mice than in WT mice, as indicated by comparisons of body weight loss, the presence of occult or gross blood per rectum, stool consistency, shrinkage in the colon, intestinal damage, and serum levels of inflammatory factors. DSS-induced colitis activated autophagy in the colon. This activation was partially inhibited by intestinal epithelial Metrnl deficiency, as indicated by a decrease in Beclin-1 and LC3-II/I and an increase in p62 in DSS-treated Metrnl^−/− mice compared with WT mice. These phenomena were further confirmed by observation of autophagosomes and immunofluorescence staining for LC3 in epithelial cells. The autophagy-related AMPK-mTOR-p70S6K pathway was also activated in DSS-induced colitis, and this pathway was partially blocked by intestinal epithelial Metrnl deficiency, as indicated by a decrease in AMPK phosphorylation and an increase in mTOR and p70S6K phosphorylation in DSS-treated Metrnl^−/− mice compared with WT mice. Therefore, Metrnl deficiency deteriorated ulcerative colitis at least partially through inhibition of autophagy via the AMPK-mTOR-p70S6K pathway, suggesting that Metrnl is a therapeutic target for ulcerative colitis.

Metrnl 是一种新发现的在肠上皮细胞中高度表达的分泌蛋白。本研究旨在探讨肠上皮Metrnl在溃疡性结肠炎中的作用及机制。Metrnl ^-/- (肠上皮细胞特异性 Metrnl 敲除) 小鼠在基础条件下未表现出任何结肠炎表型。然而，在饮用 3% 葡聚糖硫酸钠 (DSS) 的饮用水中，Metrnl 的结肠炎更为严重^-/-与 WT 小鼠相比，通过比较体重减轻、每个直肠是否存在隐血或总血、粪便稠度、结肠收缩、肠道​​损伤和血清炎症因子水平表明。DSS 诱导的结肠炎激活了结肠中的自噬。这种激活被肠上皮 Metrnl 缺乏部分抑制，如 Beclin-1 和 LC3-II/I 的减少以及 DSS 处理的 Metrnl 中 p62 的增加所示^-/-小鼠与 WT 小鼠相比。通过观察上皮细胞中的自噬体和 LC3 的免疫荧光染色进一步证实了这些现象。自噬相关的 AMPK-mTOR-p70S6K 通路也在 DSS 诱导的结肠炎中被激活，该通路被肠上皮 Metrnl 缺乏部分阻断，如 DSS-中 AMPK 磷酸化减少和 mTOR 和 p70S6K 磷酸化增加所示。与WT小鼠相比，处理过的Metrnl ^-/-小鼠。因此，Metrnl 缺乏至少部分地通过 AMPK-mTOR-p70S6K 通路抑制自噬使溃疡性结肠炎恶化，这表明 Metrnl 是溃疡性结肠炎的治疗靶点。