Chen Peng, Stärkel Peter, Turner Jerrold R, Ho Samuel B, Schnabl Bernd
Department of Medicine, University of California San Diego, La Jolla, CA.
Hepatology. 2015 Mar;61(3):883-94. doi: 10.1002/hep.27489. Epub 2015 Jan 30.
Intestinal barrier dysfunction is an important contributor to alcoholic liver disease (ALD). Translocated microbial products trigger an inflammatory response in the liver and contribute to steatohepatitis. Our aim was to investigate mechanisms of barrier disruption after chronic alcohol feeding. A Lieber-DeCarli model was used to induce intestinal dysbiosis, increased intestinal permeability, and liver disease in mice. Alcohol feeding for 8 weeks induced intestinal inflammation in the jejunum, which is characterized by an increased number of tumor necrosis factor alpha (TNF-α)-producing monocytes and macrophages. These findings were confirmed in duodenal biopsies from patients with chronic alcohol abuse. Intestinal decontamination with nonabsorbable antibiotics restored eubiosis, decreased intestinal inflammation and permeability, and reduced ALD in mice. TNF-receptor I (TNFRI) mutant mice were protected from intestinal barrier dysfunction and ALD. To investigate whether TNFRI on intestinal epithelial cells mediates intestinal barrier dysfunction and ALD, we used TNFRI mutant mice carrying a conditional gain-of-function allele for this receptor. Reactivation of TNFRI on intestinal epithelial cells resulted in increased intestinal permeability and liver disease that is similar to wild-type mice after alcohol feeding, suggesting that enteric TNFRI promotes intestinal barrier dysfunction. Myosin light-chain kinase (MLCK) is a downstream target of TNF-α and was phosphorylated in intestinal epithelial cells after alcohol administration. Using MLCK-deficient mice, we further demonstrate a partial contribution of MLCK to intestinal barrier dysfunction and liver disease after chronic alcohol feeding.
Dysbiosis-induced intestinal inflammation and TNFRI signaling in intestinal epithelial cells mediate a disruption of the intestinal barrier. Therefore, intestinal TNFRI is a crucial mediator of ALD.
肠屏障功能障碍是酒精性肝病（ALD）的一个重要促成因素。易位的微生物产物会引发肝脏中的炎症反应，并导致脂肪性肝炎。我们的目的是研究慢性酒精喂养后屏障破坏的机制。采用Lieber-DeCarli模型诱导小鼠肠道菌群失调、肠道通透性增加和肝病。酒精喂养8周可诱导空肠发生肠道炎症，其特征是产生肿瘤坏死因子α（TNF-α）的单核细胞和巨噬细胞数量增加。这些发现已在慢性酒精滥用患者的十二指肠活检中得到证实。用不可吸收的抗生素进行肠道去污可恢复正常菌群，减轻肠道炎症和通透性，并减轻小鼠的ALD。TNF受体I（TNFRI）突变小鼠可免受肠屏障功能障碍和ALD的影响。为了研究肠上皮细胞上的TNFRI是否介导肠屏障功能障碍和ALD，我们使用了携带该受体条件性功能获得等位基因的TNFRI突变小鼠。肠上皮细胞上TNFRI的重新激活导致肠道通透性增加和肝病，类似于酒精喂养后的野生型小鼠，这表明肠道TNFRI促进肠屏障功能障碍。肌球蛋白轻链激酶（MLCK）是TNF-α的下游靶点，在给予酒精后在肠上皮细胞中被磷酸化。使用MLCK缺陷小鼠，我们进一步证明了MLCK在慢性酒精喂养后对肠屏障功能障碍和肝病有部分作用。
菌群失调诱导的肠道炎症和肠上皮细胞中的TNFRI信号传导介导了肠屏障的破坏。因此，肠道TNFRI是ALD的关键介质。
