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Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome.

ABSTRACT: Bile salt hydrolases (BSHs) catalyze the "gateway" reaction in a wider pathway of bile acid modification by the gut microbiota. Because bile acids function as signaling molecules regulating their own biosynthesis, lipid absorption, cholesterol homeostasis, and local mucosal defenses in the intestine, microbial BSH activity has the potential to greatly influence host physiology. However, the function, distribution, and abundance of BSH enzymes in the gut community are unknown. Here, we show that BSH activity is a conserved microbial adaptation to the human gut environment with a high level of redundancy in this ecosystem. Through metagenomic analyses we identified functional BSH in all major bacterial divisions and archaeal species in the gut and demonstrate that BSH is enriched in the human gut microbiome. Phylogenetic analysis illustrates that selective pressure in the form of conjugated bile acid has driven the evolution of members of the Ntn_CGH-like family of proteins toward BSH activity in gut-associated species. Furthermore, we demonstrate that BSH mediates bile tolerance in vitro and enhances survival in the murine gut in vivo. Overall, we demonstrate the use of function-driven metagenomics to identify functional anchors in complex microbial communities, and dissect the gut microbiome according to activities relevant to survival in the mammalian gastrointestinal tract.

SUBMITTER: Jones BV

PROVIDER: S-EPMC2533232 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome.

Jones Brian V BV Begley Máire M Hill Colin C Gahan Cormac G M CG Marchesi Julian R JR

Proceedings of the National Academy of Sciences of the United States of America 20080829 36

Bile salt hydrolases (BSHs) catalyze the "gateway" reaction in a wider pathway of bile acid modification by the gut microbiota. Because bile acids function as signaling molecules regulating their own biosynthesis, lipid absorption, cholesterol homeostasis, and local mucosal defenses in the intestine, microbial BSH activity has the potential to greatly influence host physiology. However, the function, distribution, and abundance of BSH enzymes in the gut community are unknown. Here, we show that ...[more]

PMID: 18757757

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Project description:BackgroundBile salt hydrolase plays an important role in bile acid-mediated signaling pathways, which regulate lipid absorption, glucose metabolism, and energy homeostasis. Several reports suggest that changes in the composition of bile acids are found in many diseases caused by dysbacteriosis.ResultsHere, we present the taxonomic identification of bile salt hydrolase (BSH) in human microbiota and elucidate the abundance and activity differences of various bacterial BSH among 11 different populations from six continents. For the first time, we revealed that bile salt hydrolase protein sequences (BSHs) are distributed in 591 intestinal bacterial strains within 117 genera in human microbiota, and 27.52% of these bacterial strains containing BSH paralogs. Significant variations are observed in BSH distribution patterns among different populations. Based on phylogenetic analysis, we reclassified these BSHs into eight phylotypes and investigated the abundance patterns of these phylotypes among different populations. From the inspection of enzyme activity among different BSH phylotypes, BSH-T3 showed the highest enzyme activity and is only found in Lactobaclillus. The phylotypes of BSH-T5 and BSH-T6 mainly from Bacteroides with high percentage of paralogs exhibit different enzyme activity and deconjugation activity. Furthermore, we found that there were significant differences between healthy individuals and patients with atherosclerosis and diabetes in some phylotypes of BSHs though the correlations were pleiotropic.ConclusionThis study revealed the taxonomic and abundance profiling of BSH in human gut microbiome and provided a phylogenetic-based system to assess BSHs activity by classifying the target sequence into specific phylotype. Furthermore, the present work disclosed the variation patterns of BSHs among different populations of geographical regions and health/disease cohorts, which is essential to understand the role of BSH in the development and progression of related diseases.

Project description:Cholestasis refers to impaired bile flow from the liver to the intestine. In neonates, cholestasis causes poor growth and may progress to liver failure and death. Normal bile flow requires an intact liver-gut-microbiome axis, whereby liver-derived primary bile acids are transformed into secondary bile acids. Microbial bile salt hydrolase (BSH) enzymes are responsible for the first step, deconjugating glycine- and taurine-conjugated primary bile acids. Cholestatic neonates often are treated with the potent choleretic bile acid ursodeoxycholic acid (UDCA), although interactions between UDCA, gut microbes, and other bile acids are poorly understood. To gain insight into how the liver-gut-microbiome axis develops in extreme prematurity and how cholestasis alters this maturation, we conducted a nested case-control study collecting 124 stool samples longitudinally from 24 preterm infants born at mean 27.2 ± 1.8 weeks gestation and 946 ± 249.6 g, half of whom developed physiologic cholestasis. Samples were analyzed by whole metagenomic sequencing, in vitro BSH enzyme activity assays optimized for low biomass fecal samples, and quantitative mass spectrometry to measure the bile acid metabolome. In extremely preterm neonates, acquisition of the secondary bile acid biosynthesis pathway and BSH genes carried by Clostridium perfringens are the most prominent features of early microbiome development. Cholestasis interrupts this developmental pattern. BSH gene abundance and enzyme activity are profoundly reduced in cholestatic neonates, resulting in decreased quantities of unconjugated bile acids. UDCA restores total fecal bile acid levels in cholestatic neonates, but this is due to a 522-fold increase in fecal UDCA. A majority of bile acids in early development are atypical positional and stereo-isomers of bile acids. We report novel associations linking isomeric bile acids and BSH activity to neonatal growth trajectories. These data highlight deconjugation of bile acids as a key microbial function that is acquired in early neonatal development and impaired by cholestasis.

Dataset Information

Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome.

Publications

Functional and comparative metagenomic analysis of bile salt hydrolase activity in the human gut microbiome.

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