Taxonomic Profiling and Populational Patterns of Bacterial Bile Salt Hydrolase (BSH) Genes on Worldwide Human Gut Microbiome

Li, Jing; Jin, Liang; Song, Ziwei; Cai, Yuanyuan; Wang, Xue; Lin, Xiaoxuan; Cui, Yingyun; Shang, Jing

doi:10.1101/260794

Cited by 54 publications

(79 citation statements)

References 40 publications

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“…While there is significant divergence in BSH protein sequence across gut strains, all BSHs possess a conserved active site that includes a catalytic cysteine (Cys2). 1,10 This residue performs the nucleophilic attack on the substrate carbonyl, resulting in amide bond cleavage (Fig. 1b).…”

Section: Resultsmentioning

confidence: 99%

“…A recent study identified BSHs in gut species from 117 genera and 12 phyla, including the two dominant gut phyla, Bacteroidetes and Firmicutes, as well as Actinobacteria and Proteobacteria. 10 A non-toxic, small molecule pan-inhibitor of gut bacterial BSHs would provide a powerful tool to study how bile acids affect host physiology. Such a compound should limit bile acid deconjugation across the vast majority of gut strains without significantly affecting the growth of these bacteria.…”

Section: Introductionmentioning

confidence: 99%

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Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

Adhikari

Seegar

Ficarro

et al. 2019

Preprint

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17Bile salt hydrolase (BSH) enzymes are widely expressed by human gut bacteria and catalyze the 18 gateway reaction leading to secondary bile acid formation. Bile acids regulate key metabolic and 19 immune processes by binding to host receptors. There is an unmet need for a potent tool to 20 inhibit BSHs across all gut bacteria in order to study the effects of bile acids on host physiology. 21Here, we report the development of a covalent pan-inhibitor of gut bacterial BSH. From a 22 rationally designed candidate library, we identified a lead compound bearing an alpha-23 fluoromethyl ketone warhead that modifies BSH at the catalytic cysteine residue. Strikingly, this 24 inhibitor abolished BSH activity in conventional mouse feces. Mice gavaged with a single dose 25 of this compound displayed decreased BSH activity and decreased deconjugated bile acid levels 26 in feces. Our studies demonstrate the potential of a covalent BSH inhibitor to modulate bile acid 27 composition in vivo. 28 29 performed exclusively by gut bacterial bile salt hydrolase (BSH) enzymes. 1 BSHs (EC 3.5.1.24) 54 are widespread in human gut bacteria. A recent study identified BSHs in gut species from 117 55 genera and 12 phyla, including the two dominant gut phyla, Bacteroidetes and Firmicutes, as 56 well as Actinobacteria and Proteobacteria. 10 A non-toxic, small molecule pan-inhibitor of gut 57 bacterial BSHs would provide a powerful tool to study how bile acids affect host physiology. 58Such a compound should limit bile acid deconjugation across the vast majority of gut strains 59 without significantly affecting the growth of these bacteria. The use of a pan-inhibitor in vivo 60 would significantly alter bile acid pool composition, shifting the pool toward conjuated bile acids 61 and away from deconjugated bile acids and secondary bile acids (Fig. 1a). This chemical tool 62 would thus allow researchers to investigate previously unanswered questions, including how 63 primary and secondary bile acids differentially affect physiology in a fully colonized host. 64Herein, we report the development of a covalent inhibitor of bacterial BSHs using a 65 rational design approach. Importantly, this compound completely inhibits BSH activity in 66 conventional mouse feces, demonstrating its potential utility as a pan-inhibitor of BSHs. 67 68Results 69 Rational design of covalent small molecule inhibitors of bile salt hydrolases 70In order to generate potent, long-lasting inhibitors of BSHs, we chose to develop covalent 71 inhibitors of these gut bacterial enzymes. Covalent inhibitors have gained renewed interest in the 72 field of drug discovery due to their ability to inactivate their protein target with a high degree of 73 potency and selectivity even in the presence of large concentrations of native substrate. 11 The 74 substrates for BSHs, conjugated bile acids, are found in high concentrations in the colon (1-10 75 mM), 12 suggesting that covalent inhibition could be an effective strategy for targeting these 76 enzymes. In addition, recently develop...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

Adhikari

Seegar

Ficarro

et al. 2019

Preprint

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“…500We found that the abundance of several Bacteroides, Bilophila and Lachnospiraceae 501 bacteria increase during tadpole development and metamorphosis. These bacteria are well-502 known to be abundant in the gastro-intestinal tracts of numerous vertebrates, including man, 503and characterized by their resistance to high concentrations of bile salts or their bile acid 504 hydrolase activities(Song et al, 2019). We therefore propose an interpretation of our findings 505 in light of bile acids being key molecular components regulating the gut microbiome 506 composition during amphibian development and metamorphosis.…”

mentioning

confidence: 77%

“…Bile acids can act directly on the gut microbiome 512 because they have intrinsic antimicrobial activity and indirectly because their host cellular 513 receptors regulate antimicrobial peptides genes. In turn, some bacteria encode bile hydrolases 514 that enable the production of secondary bile acids(Joyce et al, 2014;Song et al, 2019). 515 Therefore, we can consider bile acid composition as a trait of strong evolutionary significance 516 since it links nutrition, gut, liver and gill physiology, host genome evolution and the gut 517 microbiome composition(Reschly et al, 2008;Hofmann et al, 2010;Ridlon et al, 2014).…”

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confidence: 99%

Gut microbial ecology of Xenopus tadpoles across life stages

Scalvenzi

Clavereau

Bourge

et al. 2020

Preprint

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350 words max) 18 Background: The microorganism world living in amphibians is still largely under-represented 19and under-studied in the literature. Among anuran amphibians, African clawed frogs of the 20 Xenopus genus stand as well-characterized models with an in-depth knowledge of their 21 developmental biological processes including their metamorphosis. We used different 22 approaches including flow cytometry, 16s rDNA gene metabarcoding, metagenomic and 23 metatranscriptomic to analyze the succession of microbial communities and their activities 24 across different body habitats of Xenopus tropicalis. 25Results: We analyzed the bacterial components of the Xenopus gut microbiota, the adult gut 26 biogeography, the succession of communities during ontogeny, the impact of the alimentation 27 in shaping the tadpole's gut bacterial communities, the transmission of skin and fecal bacteria 28 to the eggs. We also identified the most active gut bacteria and their metabolic contribution to 29 the tadpole physiology and showed the close resemblance between amphibian and mammalian 30 gut microbiomes. 31Our results show that in the growing tadpole, the same predominant bacterial phylum as in the 32 mammalian gut is present as a large fraction of the 82,679 genes identified in the Xenopus 33 tadpole's gut metagenome encode proteins sharing common functions with proteins found in 34 the human gut microbiome. 35 Conclusions:We present a comprehensive new microbiome dataset of a laboratory amphibian 36 model. Our data provide evidences that studies on the Xenopus tadpole model can shed light on 37 the interactions between a vertebrate host and its microbiome. We interpreted our findings in 38 light of bile acids being key molecular components regulating the gut microbiome composition 39 during amphibian development and metamorphosis. 40 41 Metatranscriptome 43 44 Background 45Metazoans are vehicles for microbial communities, also named microbiota. The microbiota 46 and its metazoan host have mutualistic interactions and are thought to adapt and evolve as 47 holobiont (Wilson and Sober, 1989;Gill et al., 2006; Zilber-Rosenberg and Rosenberg, 2008; 48 Bordenstein and Theis, 2015). Several studies have highlighted the importance of the 49 microbiota in the function and development of several organs such as the alimentary canal, the 50 nervous system and the tegument ...) (Sekirov et al., 2010;Sommer and Bäckhed, 2013; 51 Douglas, 2018). The dynamic interaction between a microbiota and its host is under intense 52 scrutiny especially for mammalian species and a handful of model organisms (Colston and 53 Jackson, 2016;Douglas, 2019). However, very little is currently known on the biotic and abiotic 54 interactions between the microbiota of even well-known and classic vertebrate model 55 organisms such as amphibians (Colston and Jackson, 2016;Douglas, 2019; Rebollar and Harris, 56 2019). 57The current paucity of knowledge on amphibian's microbiome is an historical thumb of 58 nose. Indeed in 1901, Olga Metchnikoff publ...

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“…The majority of our knowledge base for food, microbes and BA metabolism comes from rodents and their translation to humans, there are considerable knowledge gaps in animal husbandry 52,53 . There are many incidences where this work does not translate, due simply to copy number classes of enzymes, fundamental metabolic differences and to signaling.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of bile salt hydrolase inhibitor efficacy for modulating host bile profile and physiology using a chicken model system

Geng

Long

Chang

et al. 2020

Sci Rep

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Gut microbial enzymes, bile salt hydrolases (BSHs) are the gateway enzymes for bile acid (BA) modification in the gut. This activity is a promising target for developing innovative non-antibiotic growth promoters to enhance animal production and health. Compelling evidence has shown that inhibition of BSH activity should enhance weight gain by altering the BA pool, host signalling and lipid metabolism. We recently identified a panel of promising BSH inhibitors. Here, we address the potential of them as alternative, effective, non-antibiotic feed additives, for commercial application, to promote animal growth using a chicken model. In this study, the in vivo efficacy of three BSH inhibitors (caffeic acid phenethylester, riboflavin, carnosic acid) were evaluated. 7-day old chicks (10 birds/group) were either untreated or they received one of the specific BSH inhibitors (25 mg/kg body weight) via oral gavage for 17 days. The chicks in treatment groups consistently displayed higher body weight gain than the untreated chicks. Metabolomic analysis demonstrated that BSH inhibitor treatment led to significant changes in both circulating and intestinal BA signatures in support of blunted intestinal BSH activity. Consistent with this finding, liver and intestinal tissue RNA-Seq analysis showed that carnosic acid treatment significantly altered expression of genes involved in lipid and bile acid metabolism. Taken together, this study validates microbial BSH activity inhibition as an alternative target and strategy to antibiotic treatment for animal growth promotion.

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Taxonomic Profiling and Populational Patterns of Bacterial Bile Salt Hydrolase (BSH) Genes on Worldwide Human Gut Microbiome

Cited by 54 publications

References 40 publications

Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

Gut microbial ecology of Xenopus tadpoles across life stages

Evaluation of bile salt hydrolase inhibitor efficacy for modulating host bile profile and physiology using a chicken model system

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