A selective gut bacterial bile salt hydrolase alters host metabolism

Yao, Lina; Seaton, Sarah C.; Ndousse-Fetter, Sula; Adhikari, Arijit A.; DiBenedetto, Nicholas; Mina, Amir I.; Banks, Alexander S.; Bry, Lynn; Devlin, A. Sloan

doi:10.7554/elife.37182

Cited by 200 publications

(242 citation statements)

References 89 publications

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“…1). 16 These results suggest that the enzymatic selectivity observed in B. theta culture was due to inherent biochemical properties of the BSH, not to differences in transport or the accessibility of the substrates to the enzyme.…”

Section: Resultsmentioning

confidence: 78%

“…1a). 16 As our goal was to develop BSH inhibitors that target both Gram negative and Gram positive strains, we decided to utilize the steroidal portion of the human primary bile acid chenodeoxycholic acid (CDCA, C12 = H) as our scaffold.…”

Section: Resultsmentioning

confidence: 99%

“…We heterologously expressed and purified the selective BSH (BT2086) that we had previously identified in Bacteroides thetaiotaomicron VPI-5482 ( B. theta ). 16 We then established kinetic parameters for its hydrolysis of conjugated primary and secondary bile acids using a ninhydrin-based assay. 29 Consistent with our previous results from B. theta cultures, purified B. theta BSH displayed a preference for TDCA deconjugation and did not deconjugate TCA (Table 1 and Supplementary Fig.…”

Section: Resultsmentioning

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: 78%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

Adhikari

Seegar

Ficarro

et al. 2019

Preprint

Self Cite

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“…By contrast, the abundance of Ruminococcus_1, Rikenella, Bacteroides, Butyrivibrio and Alistipes was negatively correlated with serum triglyceride, total cholesterol and LDL levels but were positively correlated with HDL levels (Wan, et al , ). Gut colonization with bacteria of the phylum Bacteroidetes altered bile salt hydrolase features, leading to changes in the gut bile acid composition that affected host metabolism and gene expression (Yao, et al , ) (Fig. ).…”

Section: The Link Between the Gut Microbiota And Cvd‐related Risk Facmentioning

confidence: 99%

The gut microbiota and its interactions with cardiovascular disease

Wang

Feng

et al. 2020

Microbial Biotechnology

104

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Summary The intestine is colonized by a considerable community of microorganisms that cohabits within the host and plays a critical role in maintaining host homeostasis. Recently, accumulating evidence has revealed that the gut microbial ecology plays a pivotal role in the occurrence and development of cardiovascular disease (CVD). Moreover, the effects of imbalances in microbe–host interactions on homeostasis can lead to the progression of CVD. Alterations in the composition of gut flora and disruptions in gut microbial metabolism are implicated in the pathogenesis of CVD. Furthermore, the gut microbiota functions like an endocrine organ that produces bioactive metabolites, including trimethylamine/trimethylamine N‐oxide, short‐chain fatty acids and bile acids, which are also involved in host health and disease via numerous pathways. Thus, the gut microbiota and its metabolic pathways have attracted growing attention as a therapeutic target for CVD treatment. The fundamental purpose of this review was to summarize recent studies that have illustrated the complex interactions between the gut microbiota, their metabolites and the development of common CVD, as well as the effects of gut dysbiosis on CVD risk factors. Moreover, we systematically discuss the normal physiology of gut microbiota and potential therapeutic strategies targeting gut microbiota to prevent and treat CVD.

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“…While the function of the each bile acids as TGR5 agonists unclear, agonistic activity tends to be stronger with secondary bile acids than with primary bile acids 34 . B. uniformis is able to hydrolyse many conjugated bile acids 35 , therefore administration of the bacteria might promote changes in the composition of bile acids in the gut and bloodstream, resulting in changes in bile acid responses in muscles and thereby improving endurance.…”

Section: Discussionmentioning

confidence: 99%

Bacteroides uniformis enhances endurance exercise performance through gluconeogenesis

Morita¹,

Kano²,

Ishii

et al. 2020

Preprint

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Athletes require high levels of energy to exercise under extreme conditions. Gut microbiota supplies energy to the host; however, the mechanism how gut microbiota contribute in the athlete is unclear. In this study, we determined that gut microbiota of Japanese long-distance runners differed from that of non-athletes, and the Bacteroides uniformis cell number in the feces correlated with 3,000-m race time. Mice administrated with B. uniformis extended the swimming time to exhaustion. Furthermore, acetate and propionate concentrations in the cecum increased in B. uniformis-administered mice subjected to weekly exercise.Expression levels of carnitine palmitoyl transferase 1a and phosphoenolpyruvate carboxykinase genes were elevated in the liver, suggesting that acetate and propionate produced by B. uniformis improve endurance exercise performance, at least in part, through enhancing gluconeogenesis. In addition, α-cyclodextrin administration increased B. uniformis and improved the performance in humans and mice, thus it is a candidate substance enhancing exercise performance through modification of gut microbiota. INTRODUCTIONHuman exercise performance comprises a combination of physical strength (e.g., muscle and explosive strength, endurance, and flexibility) and the actions performed in a given exercise (e.g., throwing, kicking, and hitting). Exercise performance can be improved through training; however, other factors, such as genetic background, may affect it. Recently, several reports have demonstrated that the gut microbiota contributes to health, energy homeostasis, and glucose and lipid metabolisms 1-4 . Hsu et al. reported that the swimming endurance time of germ-free mice was shorter than that of specific-pathogen-free mice and Bacteroides fragilis-monoassociated mice, thus identifying gut microbiota as one of the factors associated with exercise performance 5 . Conversely, other studies have shown that exercise changes the gut microbiome profile in mice 6,7 . In humans, Clarke et al. reported that the gut microbiota of rugby players had high α diversity and relative abundance of the genera Prevotella, Succinivibrio, Bacteroides, and Lactobacillus, as a difference to those of non-rugby players 8 . Another study on the gut microbiota of cyclists showed that a high abundance ofPrevotella was correlated with weekly exercise time 9 . However, none of these studies demonstrated a causal relationship between exercise performance and characteristic genera in the gut microbiota of athletes. Recently, Veillonella atypica, isolated from the gut microbiota of marathon runners, was shown to produce propionate from exercise-induced lactate in the gut, improving endurance exercise performance in mice 10 . Only that report has demonstrated a causal relationship between exercise performances and the gut microbiota in mice, but 3 detailed relationship remains unclear. In the present study, we investigated the role of Bacteroides uniformis, identified in the microbiome analysis of Japanese long-distance runners, in the en...

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A selective gut bacterial bile salt hydrolase alters host metabolism

Cited by 200 publications

References 89 publications

Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

The gut microbiota and its interactions with cardiovascular disease

Bacteroides uniformis enhances endurance exercise performance through gluconeogenesis

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