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

肠道菌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，它的许多成员的特征很差。Coriobacteriaceae家族的成员是这些未充分研究的优势肠道细菌中的一些，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）。最近在动物模型中的研究表明，分配给Coriobacteriaceae的16 S rRNA基因序列的流行率取决于宿主基因型，并与肝脏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，该家族的一个核心物种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在代谢紊乱中的特定作用。细菌对胆汁酸的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。类似地，肠细菌代谢皮质类固醇对脂质代谢的影响迄今为止是未知的。我们最近在小鼠中证明，肠道细菌对脂肪肝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，它似乎是至关重要的，以详细评估微生物/宿主相互作用的背景下，宿主脂质metabolis.In这种情况下，我们打算使用四个优势菌株Coriobacteriaceae特有的代谢特征，以评估细菌转化的胆固醇衍生化合物对宿主脂质代谢和肝脂肪变性的发展的影响。我们将研究这些Coriobacteriaceae型菌株在无菌小鼠中定植后的宿主反应（肠道和肝脏）。因此，我们将使用各种实验饮食作为工具来调节胆固醇衍生产物的代谢。我们还将使用元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。为了测试这些功能性靶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的原生Coriobacteriaceae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、血液和尿液进行靶向定量，研究已鉴定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，我们打算表征肠道Coriobacteriaceae的病理生理和生态重要性。

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.