Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice.
Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice.
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DOI：
10.1002/hep.29676
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发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
Schnabl B
中科院分区：
文献类型：
--
作者：
Hartmann P;Hochrath K;Horvath A;Chen P;Seebauer CT;Llorente C;Wang L;Alnouti Y;Fouts DE;Stärkel P;Loomba R;Coulter S;Liddle C;Yu RT;Ling L;Rossi SJ;DePaoli AM;Downes M;Evans RM;Brenner DA;Schnabl B
酒精性肝病与肠道微生物群的变化有关。酒精相关的生态失调的功能后果在很大程度上尚不清楚。本研究的目的是确定肠道微生物群的变化如何导致酒精性肝病的机制。肠道内容物的宏基因组测序表明，小鼠长期乙醇喂养与编码胆酰甘氨酸水解酶的细菌基因组 DNA 的过度表达有关，该酶可分解肠道中的胆汁酸。胆汁酸分析证实，施用乙醇后小肠中未结合胆汁酸的量增加。在肠细胞中法尼醇x受体（FXR）活性降低的介导下，成纤维细胞生长因子（FGF）-15蛋白分泌降低与肝细胞色素P450酶（Cyp）-7a1蛋白表达和循环胆汁酸水平增加相关。用不可吸收的抗生素消除共生微生物群会减弱小鼠肝脏 Cyp7a1 的表达并减少酒精性肝病，这表明胆汁酸合成的增加依赖于肠道细菌。为了恢复肠道 FXR 活性，我们使用肠道限制性 FXR 激动剂 fexaramine 进行药物干预，可保护小鼠免受乙醇引起的肝损伤。虽然胆汁酸代谢仅发生最小程度的改变，但 fexaramine 治疗稳定了肠道屏障并显着调节了参与脂质代谢的肝脏基因。为了将有益的代谢作用与 FGF15 联系起来，使用腺相关病毒在小鼠中过度表达非致瘤性 FGF19 变体（人类 FGF15 直系同源物）。 FGF19 治疗显示出类似的有益代谢作用并改善酒精性脂肪性肝炎。总而言之，与酒精相关的宏基因组变化会导致胆汁酸谱的改变。有针对性的干预措施通过调节肝脏 Cyp7a1 和脂质代谢来改善胆汁酸-FXR-FGF15 信号传导，并减少乙醇诱导的小鼠肝病。
Alcoholic liver disease is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to alcoholic liver disease. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an overrepresentation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid x receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)-7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with non-absorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced alcoholic liver disease in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine-restricted FXR agonist fexaramine, which protected mice from ethanol-induced liver injury. While bile acid metabolism was only minimally altered, fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial metabolic effect to FGF15, a non-tumorigenic FGF19 variant – a human FGF15 ortholog – was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid–FXR–FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol-induced liver disease in mice.
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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：
29.4
作者：
Betrapally NS;Gillevet PM;Bajaj JS
通讯作者：
Bajaj JS
影响因子：
13.5
作者：
Lu, Yongke;Zhuge, Jian;Cederbaum, Arthur I.
通讯作者：
Cederbaum, Arthur I.
肠道选择性法尼醇 X 受体抑制可改善肥胖相关的代谢功能障碍。
影响因子：
16.6
作者：
Jiang C;Xie C;Lv Y;Li J;Krausz KW;Shi J;Brocker CN;Desai D;Amin SG;Bisson WH;Liu Y;Gavrilova O;Patterson AD;Gonzalez FJ
通讯作者：
Gonzalez FJ
影响因子：
3.7
作者：
Lowe PP;Gyongyosi B;Satishchandran A;Iracheta-Vellve A;Ambade A;Kodys K;Catalano D;Ward DV;Szabo G
通讯作者：
Szabo G