Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease
Altered FXR signalling is associated with bile acid dysmetabolism in short bowel syndrome-associated liver disease
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DOI：
10.1016/j.jhep.2014.06.025
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发表时间：
2014-11-01
影响因子：
25.7
通讯作者：
Bines, Julie E.
中科院分区：
文献类型：
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作者：
Pereira-Fantini, Prue M.;Lapthorne, Susan;Bines, Julie E.
背景和目标：尽管在短肠综合征（SBS）患者中观察到与肝脏疾病相关的死亡率，但对SBS相关肝脏疾病（SBS-ALD）发生的机制了解甚少。本研究探讨细菌介导的胆汁酸（BA）代谢异常对法尼醇X受体（FXR）信号通路和临床结果的影响，在一个仔猪模型SBS-ALD.Methods：4周龄的仔猪进行75%小肠切除术（SBR）或假手术。检测肝脏组织学和肝脏炎症基因表达。测定BA生物转化细菌的浓度，代谢组学研究详细描述了粪便、门静脉血清和胆汁样品中BA组成的变化。结果：SBS-ALD的组织学表现包括肝胆管增生、肝细胞气球样变和纤维化。炎症基因表达增加。微生物群变化包括SBS-ALD仔猪中梭菌减少10倍，拟杆菌减少2倍。BA组成发生了变化，反映了一个主要的BA占主导地位的组成。肠道和肝脏调节的BA合成的特点是由一个钝的肠道FXR活化反应和失败的SHP抑制关键肝targets.Conclusions：我们提出了一个病理情况下，微生物菌群失调SBR后的结果显着BA代谢异常和随之而来的结果，包括脂肪溢，持续性腹泻和肝损伤。此外，BA组合物的改变可能导致观察到的FXR介导的信号传导途径的干扰。这些发现为SBS患者介导肝脏疾病发展的复杂机制提供了深入了解。版权所有（C）2014由Elsevier B. V.代表欧洲肝脏研究协会出版。All rights reserved.
Background & Aims: Despite the mortality associated with liver disease observed in patients with short bowel syndrome (SBS), mechanisms underlying the development of SBS-associated liver disease (SBS-ALD) are poorly understood. This study examines the impact of bacterially-mediated bile acid (BA) dysmetabolism on farnesoid X receptor (FXR) signalling pathways and clinical outcome in a piglet model of SBS-ALD.Methods: 4-week old piglets underwent 75% small bowel resection (SBR) or sham operation. Liver histology and hepatic inflammatory gene expression were examined. Abundance of BA biotransforming bacteria was determined and metabolomic studies detailed the alterations in BA composition of stool, portal serum and bile samples. Gene expression of intestinal and hepatic FXR target genes and small heterodimer partner (SHP) transrepression targets were assessed.Results: Histological evidence of SBS-ALD included liver bile duct proliferation, hepatocyte ballooning and fibrosis. Inflammatory gene expression was increased. Microbiota changes included a 10-fold decrease in Clostridium and a two-fold decrease in Bacteroides in SBS-ALD piglets. BA composition was altered and reflected a primary BA dominant composition. Intestinal and hepatic regulation of BA synthesis was characterised by a blunted intestinal FXR activation response and a failure of SHP to repress key hepatic targets.Conclusions: We propose a pathological scenario in which microbial dysbiosis following SBR results in significant BA dysmetabolism and consequent outcomes including steatorrhoea, persistent diarrhoea and liver damage. Furthermore alterations in BA composition may have contributed to the observed disturbance in FXR-mediated signalling pathways. These findings provide an insight into the complex mechanisms mediating the development of liver disease in patients with SBS. Crown copyright (C) 2014 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. All rights reserved.