Baat Gene Knockout Alters Post-Natal Development, the Gut Microbiome, and Reveals Unusual Bile Acids in Mice

Neugebauer, Kerri A.; Okros, Maxwell; Guzior, Douglas V.; Feiner, Jeremiah; Chargo, Nicholas J.; Rzepka, Madison; Schilmiller, Anthony L.; O’Reilly, Sandra; Jones, A. Daniel; Watson, Victoria E.; Luyendyk, James P.; McCabe, Laura R.; Quinn, Robert A.

doi:10.1016/j.jlr.2022.100297

Cited by 16 publications

(22 citation statements)

References 35 publications

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“…Gut microbial BA deconjugation, catalyzed by BSHs, is critical for secondary BA metabolism in the intestines. Recent studies identified BA conjugation, which was previously thought to only occur via host-encoded enzymes, as a widespread transformation mediated by the gut microbiota to produce MCBAs. − To understand the role of BSH in the deconjugation of MCBAs, we biochemically characterized the substrate preference of two representative BSHs, L. plantarum BSH1 and C.…”

Section: Discussionmentioning

confidence: 99%

“…5−11 As BSH activity is thought to precede all subsequent BA transformations, this enzyme has been termed the "gatekeeper" enzyme of secondary BA metabolism. 2,7 Previous work has shown that BSHs have distinct substrate specificities, determined by both the identity of the conjugated amino acid 12,13 and the steroid core of the bile acid. 2,14,15 A recent report by Theriot and co-workers demonstrated that BSH side chain preference for the host-conjugated BAs is determined by a selectivity loop containing a three amino acid motif.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Gut microbial enzymes can then further metabolize unconjugated BAs through epimerization and redox modifications to produce secondary BAs . Recent work demonstrated that unconjugated BAs can also be reconjugated to a wide variety of many amino acids, including tyrosine, phenylalanine, and leucine, by microbial enzymes to produce microbially conjugated bile acids (MCBAs, Figure a). − As BSH activity is thought to precede all subsequent BA transformations, this enzyme has been termed the “gatekeeper” enzyme of secondary BA metabolism. , …”

Section: Introductionmentioning

confidence: 99%

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Electrostatic Interactions Dictate Bile Salt Hydrolase Substrate Preference

Malarney,

Chang

2023

Biochemistry

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The human intestines are colonized by trillions of microbes, comprising the gut microbiota, which produce diverse small molecule metabolites and modify host metabolites, such as bile acids, that regulate host physiology. Biosynthesized in the liver, bile acids are conjugated with glycine or taurine and secreted into the intestines, where gut microbial bile salt hydrolases (BSHs) deconjugate the amino acid to produce unconjugated bile acids that serve as precursors for secondary bile acid metabolites. Among these include a recently discovered class of microbially conjugated bile acids (MCBAs), wherein alternative amino acids are conjugated onto bile acids. To elucidate the metabolic potential of MCBAs, we performed detailed kinetic studies to investigate the preference of BSHs for host-conjugated bile acids and MCBAs. We identified a BSH that exhibits positive cooperativity uniquely for MCBAs containing an aromatic side chain. Further molecular modeling and phylogenetic analyses indicated that the BSH preference for aromatic MCBAs is due to a substrate-specific cation−π interaction and is predicted to be widespread among human gut microbial BSHs.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Electrostatic Interactions Dictate Bile Salt Hydrolase Substrate Preference

Malarney,

Chang

2023

Biochemistry

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“…1a). [5][6][7][8][9][10][11] As BSH activity is thought to precede all subsequent BA transformations, this enzyme has been termed the "gatekeeper" enzyme of secondary BA metabolism. 2,7 Previous work has shown that BSHs have distinct substrate specificities, determined by both the identity of the conjugated amino acid 12,13 and the steroid core of the bile acid.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7][8][9][10][11] As BSH activity is thought to precede all subsequent BA transformations, this enzyme has been termed the "gatekeeper" enzyme of secondary BA metabolism. 2,7 Previous work has shown that BSHs have distinct substrate specificities, determined by both the identity of the conjugated amino acid 12,13 and the steroid core of the bile acid. 2,14,15 A recent report by Theriot and co-workers demonstrated that BSH side chain preference for the hostconjugated BAs is determined by a selectivity loop containing a three amino acid motif.…”

Section: Introductionmentioning

confidence: 99%

Electrostatic Interactions Dictate Bile Salt Hydrolase Substrate Preference

Malarney,

Chang

2023

Preprint

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The human intestines are colonized by trillions of microbes, comprising the gut microbiota, which produce diverse small molecule metabolites and modify host metabolites, such as bile acids, that regulate host physiology. Biosynthesized in the liver, bile acids are conjugated with glycine or taurine and secreted into the intestines, where gut microbial bile salt hydrolases (BSHs) deconjugate the amino acid to produce unconjugated bile acids that serve as precursors for secondary bile acid metabolites. Among these include a recently discovered class of microbially-conjugated bile acids (MCBAs), wherein alternative amino acids are conjugated onto bile acids. To elucidate the metabolic potential of MCBAs, we performed detailed kinetic studies to investigate the preference of BSHs for host- and microbially-conjugated bile acids. We identified a BSH that exhibits positive cooperativity uniquely for MCBAs containing an aromatic sidechain. Further molecular modeling and phylogenetic analyses indicated that BSH preference for aromatic MCBAs is due to a substrate-specific cation-pi interaction and is predicted to be widespread among human gut microbial BSHs.

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Bile Salt Hydrolase Activity‐Based Probes for Monitoring Gut Microbial Bile Acid Metabolism

Han,

Xu,

Conwell

et al. 2024

ChemBioChem

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Bile acids are bioactive metabolites that are biotransformed into secondary bile acids by the gut microbiota, a vast consortium of microbes that inhabit the intestines. The first step in intestinal secondary bile acid metabolism is carried out by a critical enzyme, bile salt hydrolase (BSH), that catalyzes the gateway reaction that precedes all subsequent microbial metabolism of these important metabolites. As gut microbial metabolic activity is difficult to probe due to the complex nature of the gut microbiome, approaches are needed to profile gut microbiota‐associated enzymes such as BSH. Here, we develop a panel of BSH activity‐based probes (ABPs) to determine how changes in diurnal rhythmicity of gut microbiota‐associated metabolism affects BSH activity and substrate preference. This panel of covalent probes enables determination of BSH activity and substrate specificity from multiple gut anerobic bacteria derived from the human and mouse gut microbiome. We found that both gut microbiota‐associated BSH activity and substrate preference is rhythmic, likely due to feeding patterns of the mice. These results indicate that this ABP‐based approach can be used to profile changes in BSH activity in physiological and disease states that are regulated by circadian rhythms.

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Baat Gene Knockout Alters Post-Natal Development, the Gut Microbiome, and Reveals Unusual Bile Acids in Mice

Cited by 16 publications

References 35 publications

Electrostatic Interactions Dictate Bile Salt Hydrolase Substrate Preference

Electrostatic Interactions Dictate Bile Salt Hydrolase Substrate Preference

Electrostatic Interactions Dictate Bile Salt Hydrolase Substrate Preference

Bile Salt Hydrolase Activity‐Based Probes for Monitoring Gut Microbial Bile Acid Metabolism

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