Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
Int J Mol Sci. 2022 Dec 8;23(24):15578. doi: 10.3390/ijms232415578.
High-fat exposure leads to impaired intestinal barrier function by disrupting the function of intestinal stem cells (ISCs); however, the exact mechanism of this phenomenon is still not known. We hypothesize that high concentrations of deoxycholic acid (DCA) in response to a high-fat diet (HFD) affect aryl hydrocarbon receptor (AHR) signalling in ISCs and the intestinal barrier. For this purpose, C57BL/6J mice feeding on a low-fat diet (LFD), an HFD, an HFD with the bile acid binder cholestyramine, and a LFD with the DCA were studied. We found that high-fat feeding induced an increase in faecal DCA concentrations. An HFD or DCA diet disrupted the differentiation function of ISCs by downregulating AHR signalling, which resulted in decreased goblet cells (GCs) and MUC2, and these changes were reversed by cholestyramine. In vitro experiments showed that DCA downregulated the differentiation function of ISCs, which was reversed by the AHR agonist 6-formylindolo [3,2-b]carbazole (FICZ). Mechanistically, DCA caused a reduction in indoleamine 2,3-dioxygenase 1 (IDO1) in Paneth cells, resulting in paracrine deficiency of the AHR ligand kynurenine in crypts. We demonstrated for the first time that DCA disrupts intestinal mucosal barrier function by interfering with AHR signalling in ISCs. Supplementation with AHR ligands may be a new therapeutic target for HFD-related impaired intestinal barrier function.
高脂肪暴露通过破坏肠干细胞（ISCs）的功能导致肠道屏障功能受损；然而，这种现象的确切机制尚不清楚。我们假设高脂肪饮食（HFD）中高浓度的脱氧胆酸（DCA）会影响 ISCs 中的芳烃受体（AHR）信号和肠道屏障。为此，我们研究了 C57BL/6J 小鼠在低脂饮食（LFD）、HFD、HFD 加胆酸结合剂考来烯胺和 LFD 加 DCA 喂养下的情况。我们发现高脂肪喂养会导致粪便 DCA 浓度升高。HFD 或 DCA 饮食通过下调 AHR 信号而破坏 ISC 的分化功能，导致杯状细胞（GCs）和 MUC2 减少，这些变化可被考来烯胺逆转。体外实验表明，DCA 下调 ISC 的分化功能，而 AHR 激动剂 6-甲氧基吲哚并[3,2-b]咔唑（FICZ）可逆转这种作用。在机制上，DCA 导致潘氏细胞中色氨酸 2,3-双加氧酶 1（IDO1）减少，导致隐窝中 AHR 配体犬尿氨酸的旁分泌不足。我们首次证明，DCA 通过干扰 ISCs 中的 AHR 信号破坏肠道黏膜屏障功能。补充 AHR 配体可能是治疗与 HFD 相关的肠道屏障功能受损的新靶点。
