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Functions and metabolic adaptation of dominant gut bacteria of the family Coriobacteriaceae in the context of host lipid metabolism

红赭菌科优势肠道细菌在宿主脂质代谢背景下的功能和代谢适应

基本信息

批准号：
242504939
负责人：
Professor Dr. Thomas Clavel
金额：
--
依托单位：
Institut für Medizinische Mikrobiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/242504939?language=en
关键词：
Functions metabolic adaptation dominant gut

项目摘要

The intestinal microbiota is a complex ecosystem. Many of its members are poorly characterized due to our inability to culture them or to the lack of reference models to study them. Members of the family Coriobacteriaceae are some of these dominant gut bacteria that are understudied, although they carry important metabolic functions (conversion of bile acids, steroids or phytoestrogens). Recent studies in animal models have shown that the prevalence of 16S rRNA gene sequences assigned to the Coriobacteriaceae is dependent on host genotype and correlates positively with hepatic triglyceride levels or with plasma non-HDL cholesterol levels. Moreover, data from the MetaHIT consortium showed that one core species of the family, Eggerthella lenta, is linked to the occurrence of type-2 diabetes in human subjects, indicating the need to assess the specific role of Coriobacteriaceae in metabolic disorders. Bile acid metabolism by bacteria is considered as an important factor influencing host lipid metabolism, yet experimental evidence is sparse. Similarly, the impact of corticosteroid metabolism by intestinal bacteria on lipid metabolism is so far unknown. We have recently demonstrated in mice that gut bacteria are critical for the onset and maintenance of fatty liver disease, but our knowledge of underlying molecular mechanisms is still scant. Thus, it appears crucial to assess in detail microbe/host interactions in the context of host lipid metabolism.In this context, we intend to use four dominant strains of Coriobacteriaceae with peculiar metabolic traits to assess the impact of the bacterial conversion of cholesterol-derived compounds on host lipid metabolism and the development of hepatic steatosis. We will study host responses (gut and liver) after colonization of germfree mice by these Coriobacteriaceae type strains. Thereby, we will use various experimental diets as tools to modulate the metabolism of cholesterol-derived products. We will also study the functional adaptation of bacteria to dietary intervention using metatranscriptomic and metabolomic techniques, in order to identify bacterial targets of particular relevance. To test the importance of these functional targets in an ecological context, we will determine the impact of dietary interventions on native Coriobacteriaceae isolated by cell sorting from the gut content of specific pathogen-free mice. Finally, the relevance of identified bacterial genes or metabolites will be investigated by targeted quantification in feces, blood and urine from patients with non-alcoholic fatty liver disease vs. healthy control subjects. Hence, by combining the complementary expertise of research teams in Germany (culture-based microbiology, diversity analysis, mouse models and bioanalytics) and France (functional metagenomics, transcriptomic, bioinformatics, lipid and hepatic metabolism), we intend to characterize the patho-physiological and ecological importance of intestinal Coriobacteriaceae.

肠道微生物群是一个复杂的生态系统。由于我们无法培养它们或缺乏研究它们的参考模型，其许多成员的特征很差。红珊瑚科的成员是一些尚未得到充分研究的占优势的肠道细菌，尽管它们具有重要的代谢功能（胆汁酸、类固醇或植物雌激素的转化）。最近的动物模型研究表明，归属于蠹杆菌科的 16S rRNA 基因序列的流行程度取决于宿主基因型，并与肝甘油三酯水平或血浆非 HDL 胆固醇水平呈正相关。此外，来自 MetaHIT 联盟的数据显示，该科的一个核心物种，Eggerthella lenta，与人类受试者中 2 型糖尿病的发生有关，这表明需要评估 Coriobacteriaceae 在代谢紊乱中的具体作用。细菌的胆汁酸代谢被认为是影响宿主脂质代谢的重要因素，但实验证据很少。同样，肠道细菌代谢皮质类固醇对脂质代谢的影响目前尚不清楚。我们最近在小鼠身上证明，肠道细菌对于脂肪肝疾病的发生和维持至关重要，但我们对潜在分子机制的了解仍然很少。因此，在宿主脂质代谢的背景下详细评估微生物/宿主的相互作用似乎至关重要。在这种情况下，我们打算使用具有特殊代谢特征的四种主要红蠹杆菌菌株来评估胆固醇衍生化合物的细菌转化对宿主脂质代谢和肝脂肪变性发展的影响。我们将研究这些蠹杆菌科菌株定植于无菌小鼠后的宿主反应（肠道和肝脏）。因此，我们将使用各种实验饮食作为调节胆固醇衍生产品代谢的工具。我们还将利用宏转录组学和代谢组学技术研究细菌对饮食干预的功能适应，以确定特别相关的细菌靶标。为了测试这些功能目标在生态环境中的重要性，我们将确定饮食干预对通过细胞分选从特定无病原体小鼠的肠道内容物中分离出的天然红蝽科细菌的影响。最后，将通过对非酒精性脂肪肝患者与健康对照受试者的粪便、血液和尿液进行有针对性的定量来研究已鉴定的细菌基因或代谢物的相关性。因此，通过结合德国（基于培养的微生物学、多样性分析、小鼠模型和生物分析）和法国（功能宏基因组学、转录组学、生物信息学、脂质和肝脏代谢）研究团队的互补专业知识，我们打算描述肠道红杆菌科的病理生理和生态重要性。