Intestinal HIF-1α deletion exacerbates alcoholic liver disease by inducing intestinal dysbiosis and barrier dysfunction.
Intestinal HIF-1α deletion exacerbates alcoholic liver disease by inducing intestinal dysbiosis and barrier dysfunction.
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肠道 HIF-1α 缺失通过诱导肠道菌群失调和屏障功能障碍加剧酒精性肝病
DOI：
10.1016/j.jhep.2018.05.021
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发表时间：
2018-10
影响因子：
25.7
通讯作者：
Feng W
中科院分区：
文献类型：
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作者：
Shao T;Zhao C;Li F;Gu Z;Liu L;Zhang L;Wang Y;He L;Liu Y;Liu Q;Chen Y;Donde H;Wang R;Jala VR;Barve S;Chen SY;Zhang X;Chen Y;McClain CJ;Feng W
酒精性肝病(ALD)的特点是肠道生物失调和肠道通透性增加。缺氧诱导因子1α(HIF-1α)参与了肠道屏障完整性和炎症的转录调控。我们的目的是验证这一假设，即缺氧诱导因子-1的α在肠道微生物区系的动态平衡和维持肠道屏障完整性方面发挥关键作用。将野生型(WT)和肠上皮特异性HIF-1α基因敲除小鼠(IEHIF-1α−/−)配对喂养含5%(w/v)酒精或等热量麦芽糖糊精的改良Lieber-DeCarli液体饲料24天。测定血清丙氨酸氨基转移酶和内毒素。对粪便微生物区系进行评估。评估肝脏脂肪变性和损伤，以及肠道屏障的完整性。酒精灌胃可增加WT小鼠血清ALT和内毒素水平、肝脏甘油三酯浓度和肝损伤。这些有害影响在IEHIF-1α−/−小鼠身上被夸大了。酒精暴露导致IEHIF-1α−/−小鼠肠上皮紧密连接蛋白Claudin-1和occludin的表达显著降低。此外，酒精还可进一步降低IEHIF-1α−/−小鼠肠道三叶因子和肠毒素相关抗菌肽的含量。代谢组学分析显示，与酒精暴露的WT小鼠相比，IEHIF-1α−/−小鼠的肠道代谢失调加剧，固形物/类杆菌比率显著降低。在IEHIF-1α−/−小鼠中观察到阿克曼氏菌丰度增加，乳杆菌水平降低。非可吸收抗生素治疗逆转了WT和IEHIF-1α−/−小鼠的肝脏脂肪变性。肠道缺氧诱导因子-1α对于酒精暴露引起的肠道微生物区系和屏障功能的改变以及与内毒素血症和肝脏脂肪变性和损伤相关的适应反应是必不可少的。示意图说明了肠道缺氧诱导因子-1α耗竭加重酒精性肝病的拟议机制。AMP：抗菌肽，Cld1：claudin-1，ITF：肠三叶因子，p-gp：P-糖蛋白，B.P.：细菌产物酒精摄入改变肠道微生物区系和受肠道缺氧诱导因子1α(HIF-1α)调节的多种肠道屏障保护因子。肠道缺氧诱导因子-1α的缺失加剧了肠道渗漏，导致细菌和细菌产物移位到肝脏，从而导致酒精性肝病。肠道特异性上调缺氧诱导因子-1α有望成为治疗酒精性肝病的新途径
Alcoholic liver disease (ALD) is characterized by gut dysbiosis and increased gut permeability. Hypoxia Induced Factor 1α (HIF-1α) has been implicated in transcriptional regulation of intestinal barrier integrity and inflammation. We aimed to test the hypothesis that HIF-1α plays a critical role in gut microbiota homeostasis and the maintenance of intestinal barrier integrity in a mouse model of ALD. Wide type (WT) and intestinal epithelial-specific HIF-1α knockout mice (IEhif-1α−/−) were pair-fed modified Lieber-DeCarli liquid diet containing 5% (w/v) alcohol or isocaloric maltose dextrin for 24 days. Serum levels of ALT and endotoxin were determined. Fecal microbiota were assessed. Liver steatosis and injury, and intestinal barrier integrity were evaluated. Alcohol feeding increased serum levels of ALT and LPS, hepatic triglyceride concentration, and liver injury in the WT mice. These deleterious effects were exaggerated in IEhif-1α−/− mice. Alcohol exposure resulted in greater reduction of the expression of intestinal epithelial tight junction proteins, claudin-1 and occludin, in IEhif-1α−/− mice. In addition, cathelicidin-related antimicrobial peptide (CRAMP) and intestinal trefoil factor (ITF) were further decreased by alcohol in IEhif-1α−/− mice. Metagenomic analysis showed an increased gut dysbiosis with a significantly decreased firmicutes/bacteroidetes ratio in IEhif-1α−/− mice compared to the WT mice exposed to alcohol. An increased abundance of Akkermansia and a decreased level of Lactobacillus in IEhif-1α−/− mice were observed. Non-absorbable antibiotics treatment reversed the liver steatosis in both WT and IEhif-1α−/− mice. Intestinal HIF-1α is essential for the adaptation response to alcohol exposure-induced changes in intestinal microbiota and barrier function associated with elevated endotoxemia and hepatic steatosis and injury. A schematic diagram illustrating the proposed mechanism by which intestinal HIF-1α depletion exacerbates alcoholic liver disease. AMP: antimicrobial peptide, CLD1: claudin-1, ITF: intestinal trefoil factor, p-GP: p-glycoprotein, B.P.: bacterial products Alcohol consumption alters gut microbiota and multiple intestinal barrier protecting factors that are regulated by intestinal hypoxia inducible factor 1α (HIF-1α). Absence of intestinal HIF-1α exacerbates gut leakiness leading to an increased translocation of bacteria and bacterial products into liver, and consequently causes alcoholic liver disease (ALD). Intestinal specific upregulation of HIF-1α could be developed as a novel approach for the treatment of ALD
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影响因子：
29.4
作者：
Chen P;Torralba M;Tan J;Embree M;Zengler K;Stärkel P;van Pijkeren JP;DePew J;Loomba R;Ho SB;Bajaj JS;Mutlu EA;Keshavarzian A;Tsukamoto H;Nelson KE;Fouts DE;Schnabl B
通讯作者：
Schnabl B
影响因子：
32.4
作者：
Campbell EL;Bruyninckx WJ;Kelly CJ;Glover LE;McNamee EN;Bowers BE;Bayless AJ;Scully M;Saeedi BJ;Golden-Mason L;Ehrentraut SF;Curtis VF;Burgess A;Garvey JF;Sorensen A;Nemenoff R;Jedlicka P;Taylor CT;Kominsky DJ;Colgan SP
通讯作者：
Colgan SP
影响因子：
8
作者：
Flueck, K.;Breves, G.;Winning, S.
通讯作者：
Winning, S.
影响因子：
30.3
作者：
Kelly CJ;Zheng L;Campbell EL;Saeedi B;Scholz CC;Bayless AJ;Wilson KE;Glover LE;Kominsky DJ;Magnuson A;Weir TL;Ehrentraut SF;Pickel C;Kuhn KA;Lanis JM;Nguyen V;Taylor CT;Colgan SP
通讯作者：
Colgan SP
DOI：
10.1038/nrgastro.2010.39
发表时间：
2010-05
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
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