Influence of intestinal Coriobacteriia on host metabolism

The intestinal microbiota and their metabolites are known to influence host metabolism, but only few bacteria involved have been described. In studies with rodents and humans, alterations in host metabolism have been associated with the presence of Coriobacteriia, which can deconjugate and dehydrogenate bile acids (BAs) and express lipases. Gnotobiotic mouse experiments performed by a former PhD student from the lab showed that colonisation with four Coriobacteriia species resulted in increased plasma cholesterol levels. In addition, white adipose tissue (WAT) mass doubled in Coriobacteriia-colonised mice fed a diet supplemented with primary BAs. These results indicate that Coriobacteriia play a causal role in host metabolism, but it remains unclear how. The aim of this PhD thesis was to investigate whether and how Coriobacteriia, specifically Eggerthella lenta and Collinsella aerofaciens, mediate changes in host metabolism. In the first part of this work, the effects of colonising gnotobiotic OMM12 mice with E. lenta on the liver proteome and gut metabolome were investigated. E. lenta stably colonised the mouse intestine at high relative abundances. It had no significant effect on liver proteomes, whereas the colon metabolome differed significantly between colonisation groups. While creatine, sarcosine, N,N dimethylarginine, and N-Acetyl-DL-methionine were decreased in E. lenta-colonised mice, latifolicinin C acid was elevated. In the second part, the effects of colonising germfree (GF) mice with the four Coriobacteriia species Adlercreutzia mucosicola, C. aerofaciens, E. lenta, and Lancefieldella parvula (CORIO) in combination with diets differing in fat content and primary BAs on host metabolism were investigated. However, as the CORIO strains did not colonise, the GF and specific pathogen-free (SPF) mice fed the different diets were compared. Most interestingly, GF mice had a significantly elongated small intestine compared to SPF mice, regardless of diet. In the third part, C. aerofaciens was studied in more detail. A total of 14 strains, isolated from human faeces, were analysed and all exhibited a consistent cell-bound lipase activity. Gnotobiotic mouse experiments were performed with the C. aerofaciens type strain to investigate its effects on intestinal lipid absorption using stable isotope-labelled lipids. C. aerofaciens successfully colonised all regions of the gut, with higher cell densities in the caecum and colon. In mice fed chow supplemented with primary BAs (sampled one hour after gavage of the labelled lipids), and in mice fed chow high in fat (sampled six hours after gavage), levels of labelled fatty acids (FAs) in plasma were higher in the C. aerofaciens-monocolonised mice compared to GF and SPF controls. However, statistical significance was only reached for the C. aerofaciens-monocolonised mice fed the high-fat diet (HFD) and sampled six hours after gavage compared to corresponding SPF mice. In the last part, to assess the potential clinical relevance of bacterial lipase, the occurrence of dominant lipase-positive bacteria, including C. aerofaciens, in the stool microbiota of 338 participants from a human cohort (16S rRNA gene amplicon profiles) was analysed in relation to host body parameters. Regression analyses revealed a significant positive association between the cumulative relative abundance of lipase-positive bacteria and several host metabolic parameters, including higher body fat content and blood lipids. The results of this this PhD thesis provide further evidence for the role of Coriobacteriia in metabolic health. The identification of underlying molecular mechanisms require further investigations.