Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York, USA.
Nutrition Program, Hunter College, City University of New York, New York, New York, USA.
Pharmacology. 2022;107(7-8):406-416. doi: 10.1159/000524386. Epub 2022 May 12.
Alcohol-induced thickening of the gut mucosal layer and increased expression of goblet cell gel-forming mucins, such as mucin-2 (MUC2) are associated with disruptions to the gut barrier in alcoholic liver disease (ALD). Interest in drugs that can target gut mucins in ALD has grown; however to date, no studies have examined the properties of drugs on expression of gut mucins in models of ALD. We previously demonstrated that at 10 mg/kg/day, the drug fenretinide (N-[4-hydroxyphenyl] retinamide [Fen]), a synthetic retinoid, mitigates alcohol-associated damage to the gut barrier and liver injury in a murine model of ALD.
In this study, we specifically sought to examine the effects of Fen on gut goblet cells, and expression of mucins, including MUC2 using a 25-day Lieber-DeCarli model of chronic alcohol intake.
Our results show that chronic alcohol intake increased gut-mucosal thickening, goblet cell numbers, and mRNA and protein expression of MUC2 in both the ileum and colon. Alcohol intake was associated with marked decreases in ileal and colonic Notch signaling, levels of Notch ligands Dll1 and Dll4, and increases in the expression of Notch-associated genes indispensable for goblet cell specification, including Math1 and Spdef. Interestingly, ileal and colonic expression of KLF4, which is involved in terminal differentiation of goblet cells, was reduced in mice chronically fed alcohol. Coadministration of alcohol with Fen at 10 mg/kg/day significantly reduced alcohol-associated increases in ileal and colonic mucosal thickening, ileal Muc2, colonic Muc2, Muc5ac and Muc6 mRNAs, and goblet cell numbers. We also found that Fen strongly prevented alcohol-mediated suppression of the Notch ligand Dll1, Notch signaling, and alcohol-induced increases in expression of Notch-associated goblet cell specification genes in both the ileum and colon. In the absence of alcohol, Fen treatments alone at 10 mg/kg/day had no effects on any of the goblet cell-related endpoints.
These data show for the first time that the drug Fen possesses mucosal layer-modulating properties in response to chronic alcohol abuse. These data warrant further preclinical examination of Fen given the need for anti-ALD drugs and emerging evidence of a role for intestinal goblet cell mucins in the progression of ALD.
酒精引起的肠道黏膜层增厚和杯状细胞凝胶形成粘蛋白（如粘蛋白-2[MUC2]）表达增加与酒精性肝病（ALD）中的肠道屏障破坏有关。人们对能够靶向 ALD 中肠道粘蛋白的药物越来越感兴趣；然而，迄今为止，尚无研究在 ALD 模型中检查药物对肠道粘蛋白表达的特性。我们之前证明，在 10mg/kg/天的剂量下，药物芬维 A 酯（N-[4-羟基苯基]视黄酰胺[芬]），一种合成维甲酸，可以减轻酒精诱导的肠道屏障损伤和 ALD 小鼠模型中的肝损伤。
在这项研究中，我们特别寻求检查芬维 A 酯对肠道杯状细胞和粘蛋白（包括 MUC2）表达的影响，使用 25 天的 Lieber-DeCarli 慢性酒精摄入模型。
我们的结果表明，慢性酒精摄入增加了回肠和结肠的肠道黏膜增厚、杯状细胞数量以及 MUC2 的 mRNA 和蛋白表达。酒精摄入与回肠和结肠 Notch 信号的显著降低、Notch 配体 Dll1 和 Dll4 的水平以及参与杯状细胞特化的必不可少的 Notch 相关基因的表达增加有关，包括 Math1 和 Spdef。有趣的是，KLF4 的表达减少，KLF4 参与杯状细胞的终末分化，在慢性给予酒精的小鼠中减少。芬维 A 酯与酒精同时给药 10mg/kg/天可显著降低酒精引起的回肠和结肠黏膜增厚、回肠 MUC2、结肠 MUC2、Muc5ac 和 Muc6mRNA 以及杯状细胞数量的增加。我们还发现，芬维 A 酯强烈阻止了酒精介导的 Notch 配体 Dll1、Notch 信号的抑制以及酒精诱导的回肠和结肠中与 Notch 相关的杯状细胞特化基因表达的增加。在没有酒精的情况下，单独使用 10mg/kg/天的芬维 A 酯治疗对任何与杯状细胞相关的终点均无影响。
这些数据首次表明，药物芬维 A 酯具有响应慢性酒精滥用的黏膜层调节特性。鉴于对抗 ALD 药物的需求以及肠道杯状细胞粘蛋白在 ALD 进展中的作用的新证据，这些数据证明需要进一步进行芬维 A 酯的临床前检查。
