Intestinal Microbiome-Macrophage Crosstalk Contributes to Cholestatic Liver Disease by Promoting Intestinal Permeability in Mice.
Intestinal Microbiome-Macrophage Crosstalk Contributes to Cholestatic Liver Disease by Promoting Intestinal Permeability in Mice.
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DOI：
10.1002/hep.31228
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Beraza N
中科院分区：
文献类型：
--
作者：
Isaacs-Ten A;Echeandia M;Moreno-Gonzalez M;Brion A;Goldson A;Philo M;Patterson AM;Parker A;Galduroz M;Baker D;Rushbrook SM;Hildebrand F;Beraza N
越来越多的证据支持胆汁淤积性肝脏疾病与微生物组组成变化之间的联系。尽管如此，微生物组在这种疾病的发病机制中的作用在很大程度上仍然不确定。为了解决这个问题，我们使用了两种实验模型，给予α-萘基异氰酸酯或喂食0.1% 3，5-二乙氧基羰基-1，4-二氢可力丁饮食，以在无菌小鼠和无菌小鼠中诱导胆汁淤积性肝病，这些小鼠常规使用来自野生型、无特定病原体动物的微生物组。接下来，我们通过使用氯膦酸盐脂质体消耗这些细胞并使用NOD-，LRR-和pyrin结构域蛋白3的特异性抑制剂抑制炎性小体来抑制巨噬细胞活化。我们的研究结果表明，胆汁淤积，胆汁酸在肝脏中的积累，在体内微生物组不存在的情况下不能促进肝损伤。其他体外研究支持内毒素使肝细胞对胆汁酸诱导的细胞死亡敏感。我们还证明，在胆汁淤积期间，巨噬细胞有助于促进肠道通透性，并通过激活炎性小体改变微生物组组成，总体上导致内毒素流入胆汁淤积性肝脏的增加。我们证明，肠道微生物组通过涉及巨噬细胞中炎性小体激活的机制促进胆汁淤积介导的细胞死亡和炎症。
Mounting evidence supports an association between cholestatic liver disease and changes in the composition of the microbiome. Still, the role of the microbiome in the pathogenesis of this condition remains largely undefined. To address this, we have used two experimental models, administering alpha‐naphtylisocyanate or feeding a 0.1% 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine diet, to induce cholestatic liver disease in germ‐free mice and germ‐free mice conventionalized with the microbiome from wild‐type, specific pathogen‐free animals. Next, we have inhibited macrophage activation by depleting these cells using clodronate liposomes and inhibiting the inflammasome with a specific inhibitor of NOD‐, LRR‐, and pyrin domain‐containing protein 3. Our results demonstrate that cholestasis, the accumulation of bile acids in the liver, fails to promote liver injury in the absence of the microbiome in vivo. Additional in vitro studies supported that endotoxin sensitizes hepatocytes to bile‐acid–induced cell death. We also demonstrate that during cholestasis, macrophages contribute to promoting intestinal permeability and to altered microbiome composition through activation of the inflammasome, overall leading to increased endotoxin flux into the cholestatic liver. We demonstrate that the intestinal microbiome contributes to cholestasis‐mediated cell death and inflammation through mechanisms involving activation of the inflammasome in macrophages.
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影响因子：
3.4
作者：
Capaldo, Christopher T.;Nusrat, Asma
通讯作者：
Nusrat, Asma
DOI：
10.1056/nejmra1506330
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Lazaridis KN;LaRusso NF
通讯作者：
LaRusso NF
影响因子：
15.5
作者：
Langille MG;Meehan CJ;Koenig JE;Dhanani AS;Rose RA;Howlett SE;Beiko RG
通讯作者：
Beiko RG
影响因子：
6
作者：
Fickert, Peter;Stoeger, Ulrike;Trauner, Michael
通讯作者：
Trauner, Michael
DOI：
10.1097/01.meg.0000085466.12407.e9
发表时间：
2003-09-01
影响因子：
2.1
作者：
Di Leo, V;Venturi, C;Floreani, A
通讯作者：
Floreani, A