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

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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.