PDF(Pubmed)
Abstract：
Hepatic factors secreted by the liver promote homeostasis and are pivotal for maintaining the liver-gut axis. Bile acid metabolism is one such example wherein, bile acid synthesis occurs in the liver and its biotransformation happens in the intestine. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication. Indeed, aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remain obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specific Rela-Stat3 network as a promising therapeutic target.
摘要：
由肝脏分泌的肝脏因子促进体内平衡并且是维持肝肠轴的关键。胆汁酸代谢是一个这样的例子，其中，胆汁酸的合成发生在肝脏中，其生物转化发生在肠道中。肝脏和肠道之间的功能失调相互作用通过其双向门静脉通信刺激各种病理结果。的确,在炎症性肠病（IBD）中已经报道了异常的胆汁酸代谢。然而,这些使肠道通透性和炎症持续存在的交叉茎的分子机制仍然不清楚。这里,我们发现了一种由Rela和Stat3调控的新型肝脏基因程序,该程序在急性实验性结肠炎模型中加重了炎症.Rela和Stat3的肝细胞特异性消融可降低肝脏和肠道中初级胆汁酸的水平，并显示出限制性的致结肠表型。在补充鹅去氧胆酸（CDCA）时，敲除小鼠表现出增强的结肠炎诱导的改变。这项研究为治疗IBD的多器官策略的发展提供了有说服力的证据，并确定了肝细胞特异性Rela-Stat3网络作为有前途的治疗靶标。
