Publication

Biogeography and biochemistry of bile acid 7-dehydroxylation in the mammalian gut

Abstract

Bile acids (BAs) are small molecules synthesized by the host and chemically modified by the microorganisms inhabiting the intestinal tract. The microbial transformation of BAs in the gut is critical to BA-mediated signaling as it modifies their amount and affinity for specific BA receptors. Bile acid 7-dehydroxylating bacteria are intestinal commensals of particular importance as they catalyze the dehydroxylation of liver-derived (primary) bile acids at the C7 position (i.e., 7-dehydroxylation) and produce secondary bile acids. One of the major receptors for secondary BAs is Takeda G-protein receptor 5 (TGR5), and it is associated with regulation of energy expenditure and glucose management, protection from liver steatosis and inflammation. In addition, 7-dehydroxylated bile acids are also associated with protection from infection by specific intestinal pathogens (i.e., Clostridioides difficile). Thus, through their action on primary BAs, 7-dehydroxylating (7-DH-ing) bacteria play an important role in health promotion and in the functioning of major physiological processes in the body such as insulin secretion, thermogenesis and immune responses. Despite these potentially important roles in the mammalian host, bile acid 7-dehydroxylating bacteria are poorly studied and much remains to be deciphered regarding their metabolism, diversity, abundance in the gut, and colonization dynamics in the host. Here, we use Clostridium scindens, as model organism to study bile acid 7-dehydroxylation in vitro and in gnotobiotic mice. We found that C. scindens metabolize only human primary bile acids (CA and CDCA). We uncovered the formation of a novel intermediate during CA 7-dehydroxylation by C. scindens in vitro: 12-oxoLCA. In vivo, using NanoSIMS and metabolomic analysis, we demonstrated that the large intestine constitutes C. scindens primary ecological niche in gnotobiotic mice. Following up on the discovery of the 12oxoLCA, we hypothesized the existence of another 7-dehydroxylation pathway for cholic acid. We postulated that it may involve the B and C rings of the steroid structure and may entail the oxidation/reduction of the C12- hydroxyl group. Thus, it was dubbed the putative vertical pathway. Conducting in vitro enzymatic assays with purified enzymes, we confirmed the existence of this novel vertical biosynthetic 7-dehydroxylation pathway for cholic acid, the most abundant primary bile acid in humans, and identified the core of enzymes necessary and sufficient for CA 7-dehydroxylation. Furthermore, we used a coupled metabolomic and metaproteomic approach to probe in vivo activity of the gut microbial community in a gnotobiotic mouse model. Additionnally, we also considered the bile acid profile in mice with more complex microbiota or with no microbiota. By comparing the bile acid profile of the different mice models along with expression of key genes of bile acid synthesis, we emphasized the profound influence of the gut microbial community on BA pool homeostasis. Altogether, our data provides a significant contribution to our collective understanding of the microbiology of bile acid 7-dehydroxylating bacteria, a group of gut commensals highly relevant to host health but that remains poorly characterized. The discovery of a novel 7-dehydroxylation pathway is a major scientific achievement of this thesis.

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Related concepts (47)
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Primary bile acids are those synthesized by the liver. Secondary bile acids result from bacterial actions in the colon. In humans, taurocholic acid and glycocholic acid (derivatives of cholic acid) and taurochenodeoxycholic acid and glycochenodeoxycholic acid (derivatives of chenodeoxycholic acid) are the major bile salts.
Gut microbiota
Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut microbiota. The gut is the main location of the human microbiome. The gut microbiota has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut–brain axis.
Microbiome
A microbiome () is the community of microorganisms that can usually be found living together in any given habitat. It was defined more precisely in 1988 by Whipps et al. as "a characteristic microbial community occupying a reasonably well-defined habitat which has distinct physio-chemical properties. The term thus not only refers to the microorganisms involved but also encompasses their theatre of activity". In 2020, an international panel of experts published the outcome of their discussions on the definition of the microbiome.
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