Gut bacteria-derived Metabolites and their Impact on the Pathogenesis of Primary Sclerosing Cholangitis

肠道细菌来源的代谢物及其对原发性硬化性胆管炎发病机制的影响

• 批准号: 290523071
• 负责人: Professor Dr. Jörg Heeren
• 金额: --
• 依托单位: Institut für Biochemie und Molekulare Zellbiologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290523071?language=en
• 关键词: Gut; bacteria; derived; Metabolites; their

The relevance of the immuno-metabolic interplay for the pathogenesis of Primary Sclerosing Cholangitis (PSC) is not well understood. In the first funding period, we showed that cold exposure, feeding with cholesterol-enriched diet as well as inflammatory processes targeting biliary epithelial cells led to profound changes in bile acid and lipid metabolism that subsequently determined the composition of the gut microbiome. For the current project, we propose that known PSC-associated comorbidities including inflammatory bowel disease (IBD) and low bone mass result in distinctive serum lipid and bile acids signatures, reflecting altered metabolic processes in the liver, the vasculature and the gut of individual patients. By state of the art mass spectroscopy, we aim to identify subgroup specific metabolite signatures in PSC patients with high and low bone mass, as well as in PSC patients with and without concomitant IBD, respectively. Metabolites will be correlated by bioinformatics with the composition and/or metagenome of faecal and biliary microbiota, bone density, liver transcriptomics (if available) and clinical features of PSC such as IBD. To study the causal relationship between PSC-associated faecal dysbiosis and portal blood metabolites, we will quantify bile acids, short-chain fatty acids (SCFAs) and the lipidome in the caecum and portal blood of mice that were transplanted with faecal microbiota of healthy volunteers and PSC patients with or without concomitant IBD. Moreover, we will investigate whether bile acids and/or SCFAs influence the immune-modulatory functions of liver sinusoidal endothelial cells (LSECs). By the expression of typical and atypical adhesion molecules as well as cytokines, these liver cells regulate the recruitment of lymphocytes, their migration into the portal tract, and thus biliary inflammation. Here, we will investigate whether metabolite changes influence inflammatory signalling pathways that regulate the expression of adhesion molecules and cytokines in freshly isolated LSECs and in vivo PSC models. To define environmental factors that could contribute to PSC development, we will perform these studies in dependence on housing temperature, diet and the bacterial composition. Overall, these studies will show whether LSEC-dependent regulation of immune cell migration and portal tract inflammation observed in PSC patients is influenced by changes of gut-derived metabolites. To define the role of the G-protein coupled bile acid receptor 1 (GPBAR1, also known as TGR5) in this process, we will generate mice that lack TGR5 specifically in endothelial cells to test whether LSEC-dependent immune responses are altered by TGR5-dependent bile acid signalling. This broad experimental strategy will allow us to unravel whether e.g. by cold stress leading to increased energy expenditure modifies PSC and fibrosis.

免疫代谢相互作用与原发性硬化性胆管炎（PSC）的发病机理的相关性尚不清楚。在第一个融资期间，我们表明，富含胆固醇的饮食以及针对胆固醇上皮细胞的炎症过程，寒冷暴露导致胆汁酸和脂质代谢的深刻变化，随后确定了肠道微生物组的组成。对于当前的项目，我们建议已知的PSC相关合并症，包括炎症性肠病（IBD）和低骨量会导致独特的血清脂质和胆汁酸的特征，反映出肝脏中的代谢过程改变，血管和个体患者的肠道。根据最先进的质谱法，我们旨在鉴定高骨量和低骨骼质量和低骨质量的PSC患者以及具有IBD的PSC患者中的亚组特定代谢产物特征。代谢物将通过生物信息学与粪便和/或元素的组成和/或胆汁菌属的组成和/或元基因组相关，骨密度，肝脏转录组学（如果可用）以及PSC的临床特征（例如IBD）。为了研究与PSC相关的粪便障碍与门户血液代谢产物之间的因果关系，我们将在小鼠的盲肠和脂肪症患者中量化小鼠的CAECUM和脂质组中的胆汁酸，短链脂肪酸（SCFA）和脂肪组和脂肪组，这些小鼠的卵巢症和Pscl症患者的脂肪症患者和Pscs健康的患者均不受治疗。此外，我们将研究胆汁酸和/或SCFA是否影响肝窦内皮细胞（LSEC）的免疫调节功能。通过典型和非典型粘附分子以及细胞因子的表达，这些肝细胞调节淋巴细胞的募集，它们迁移到门户区域，从而迁移到门户炎症中，从而迁移到左侧炎症。在这里，我们将研究代谢物变化是否影响调节新鲜分离的LSEC和体内PSC模型中粘附分子和细胞因子表达的炎症信号通路。为了定义可能有助于PSC发展的环境因素，我们将对住房温度，饮食和细菌成分进行这些研究。总体而言，这些研究将表明在PSC患者中观察到的LSEC依赖性调节免疫细胞迁移和门静脉炎症是否受肠道衍生代谢产物的变化的影响。为了在此过程中定义G蛋白耦合胆汁酸受体1（GPBAR1，也称为TGR5）的作用，我们将生成在内皮细胞中缺乏TGR5的小鼠，以测试LSEC依赖性免疫反应是否因TGR5依赖性胆汁酸信号传递而改变。这种广泛的实验策略将使我们能够解开是否是否通过冷应力导致能量消耗增加会改变PSC和纤维化。