Benedikt Simbrunner, Benedikt S Hofer, Philipp Schwabl, Kerstin Zinober, Oleksandr Petrenko, Claudia Fuchs, Georg Semmler, Rodrig Marculescu, Mattias Mandorfer, Christian Datz, Michael Trauner, Thomas Reiberger
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引用次数: 0
Abstract
Background and aims: Experimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut-liver axis and their link to disease severity in patients with cirrhosis.
Methods: Patients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured.
Results: Systemic BA and FGF19 levels correlated significantly (r = 0.461; p < 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p < 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 (r = -0.512, p < 0.001) and BA (r = -0.487, p < 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls.
Conclusions: FXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut-liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis.
背景和目的：实验研究发现，法尼类固醇X受体（FXR）-成纤维细胞生长因子19（FGF19）信号传导功能障碍与肝病有关。本研究调查了 FXR-FGF19 通路沿肠道-肝脏轴线的关键交叉点及其与肝硬化患者疾病严重程度的联系：方法：纳入接受肝静脉压力梯度测量的肝硬化患者（队列 I n = 107，包括同时接受肝活检的 n = 53；健康对照组 n = 5）或接受回肠活检的结肠镜检查的肝硬化患者（队列 II n = 37；对照组 n = 6）。对反映 FXR 激活和肠屏障完整性的肝脏和肠道基因表达进行了评估。测量了全身胆汁酸（BA）和 FGF19 水平：结果：全身胆汁酸和 FGF19 水平有显著相关性（r = 0.461; p 结论：FXR-FGF19 信号与 FGF19 水平有显著相关性：肝硬化患者肠肝轴线上的重要分子交叉点上FXR-FGF19信号传导失调。回肠粘膜中 FXR 活性的降低与肠道屏障蛋白表达的减少有关。这些人体数据呼吁进一步开展机理研究，针对肝硬化患者的 FXR-FGF19 通路进行干预：临床试验编号：NCT03267615。
期刊介绍：
Hepatology International is the official journal of the Asian Pacific Association for the Study of the Liver (APASL). This is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal will focus mainly on new and emerging technologies, cutting-edge science and advances in liver and biliary disorders.
Types of articles published:
-Original Research Articles related to clinical care and basic research
-Review Articles
-Consensus guidelines for diagnosis and treatment
-Clinical cases, images
-Selected Author Summaries
-Video Submissions
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