Bile salt hydrolases (BSH) are microbial enzymes that deconjugate primary bile acids.[1] They catalyze the first step of bile acid metabolism and maintain the bile acid pool for further modification by the microbiota.[1][2] BSH enzymes play a role in a range of host and microbe functions including host physiology, immunity, and protection from pathogens.[3][4]

Structure

Bile salt hydrolases are members of the N-terminal nucleophilic hydrolase family, characterized by autocatalytic activation by an N-terminal nucleophile and subsequent amide bond cleavage.[2][5] The majority of BSH enzymes are composed of homotetramers, although they have been known to assume other forms including homodimers and heterotrimers.[2] All BSHs contain a catalytic Cys2 nucleophile residue, which is located at the N-terminus of the enzyme.[2] While BSH structure may vary, other amino acids have been shown to be conserved across BSH-carrying bacteria. These include Arg18, Asp21, Asn82, and Arg228.[6]

Bile acid metabolism

Deconjugation

Substrate properties and specificity

In humans, primary bile acids are synthesized from cholesterol in the liver to form either cholic acid (CA), chenodeoxycholic acid or chenodeoxycholic acid (CDCA).[7] These primary bile acids are then conjugated to the amino acids glycine or taurine and stored in the gallbladder.[7] During digestion, they are released and their detergent properties aid in the breakdown of dietary lipids.[8] While the majority of primary bile acids are recirculated back to the liver via enterohepatic circulation, a small portion remain in the gastrointestinal tract, where they are modified by bacteria carrying BSH enzymes.[7]

BSH specificity is thought to be determined by enzymatic structural differences and slight variations in amino acid composition.[6] In general, more BSHs are thought to have a preference for glycine-conjugated bile acids, although the extent of their specificity may not yet be understood.[9]

Mechanism

Deconjugation begins with the recognition of the substrate, which consists of a steroid core and a glyco- or tauro- amino acid.[2] While the precise mechanism of recognition is unknown, it has been hypothesized that BSHs recognize the substrate by their conjugated amino acid.[2] Upon recognition by the BSH, deconjugation begins with a nucleophilic attack by Cys2 on the amide bond of the target bile acid.[6] Subsequently, a tetrahedral intermediate is formed and stabilized by Asn82 and Asn173 while Arg18 stabilizes a negatively-charged sulfhydryl on the N-terminus of Cys2.[2] The negative charge on Cys2 is resolved by deacylation with water to finally produce a deconjugated primary bile acid.[6]

Microbial conjugated bile acids

BSHs have also been found to perform a novel function: reconjugation.[10] Unlike deconjugation, bile acid reconjugation involves the addition of amino acids to an unconjugated bile acid.[7] Additionally, microbial bile acid conjugation is not limited to glycine or taurine. Instead, most amino acids can be conjugated to an unconjugated backbone.[7] Microbial conjugation of bile acids has been hypothesized to either increase or decrease the antimicrobial properties of certain bile acids and their abundance may be altered in certain gastrointestinal diseases, although their exact roles in the gut have not been fully elucidated.[11]

Effects on human physiology and immunity

Physiology

One consequence of bile acid metabolism is the variety of effects on the host. In the case of BSHs, deconjugated bile acids can interact with host cellular receptors, thus altering aspects of host physiology.[1][12] A key human cellular receptor is the farnesoid X receptor (FXR), a bile acid-activated transcription factor, which regulates bile acid synthesis and transport.[13][14] Upon activation, FXR can repress bile acid synthesis and alter the bile acid pool.[14] Bacteria that possess a BSH are associated with lower human cholesterol levels because the secondary bile acids they produce act as FXR agonists and promote cholesterol excretion.[15][16] BSHs also have an effect on host glucose metabolism, energy, and lipid absorption.[17] Through TGR-5, BSHs can regulate host glucose metabolism and have been shown to beneficially regulate insulin levels in diabetics.[12]

Immunity

Bile acid metabolism, and by association BSHs, influences the immune system by shaping the gut microbiota and bile acid pool.[18] BSHs shape the microbiota by altering the bile acid pool and creating substrates for further modification by other gut bacteria. Because they act as gatekeepers for further bile acid modification, BSHs play an important role in the production of deconjugated bile acids that can be modified into secondary bile acids.[1] Secondary bile acids can influence innate immunity through their interactions with the bile acid receptors mentioned above, FXR and TGR-5.[19] FXR and TGR-5 are expressed by intestinal immune cells such as macrophages, as well as NKT cells and dendritic cells.[19] FXR has been shown to play a role with TLR-9 in inhibiting inflammation.[19] TGR-5 interactions with the secondary bile acids DCA and LCA can prevent inflammation, and loss of this bile acid receptor is associated with an inflamed state in the gut.[19]

In autoimmune disorders such as type 1 diabetes, the microbiome is perturbed. Due to this imbalance, a diseased state of the gut is associated with changes to the bile acid pool and different BSH phylotypes. Specifically, BSHs with high activity are associated with diseases while intermediate activity BSHs are associated with healthy individuals.[17]

Effects on the gut microbiota

BSHs are critical for secondary bile acid transformations, which are performed by different members of the gut microbiota. The composition of the gut microbiome is shaped in part by the deconjugated primary bile acids made available by BSHs.[1] The modification of the primary bile acid end-product of BSHs to secondary bile acids produces several potent antimicrobials, which can protect the gut microbiota from pathogens.[7] Secondary bile acids act as detergents and disrupt the microbial membrane, with some bile acids targeting specific types of bacteria such as Gram positives.[20][21] Indirectly, bile acids shape the gut microbiota by regulating the innate immune system or activating cellular signaling machinery that excludes certain bacteria from the gut.[19][21]

Diversity

BSHs are commonly found in a variety of genera such as Lactobacillus, Enterococcus, and Bacteroides.[17] Recent advances relating to the Human Microbiome Project have allowed for the identification of variants in BSHs found in the human gut.[17] There are currently eight known phylotypes of BSH, with certain phylotypes being found in a single bacterial genus.[17] The BSHs found in different genera of bacteria may have different substrate specificity, which can be an important influence on the bile acid pool and gut microbiota.[9]

Probiotics

As both probiotics and live biotherapeutics become more advanced, strain selection is becoming more essential for good product design. BSHs are often found in candidate probiotic organisms due to their myriad effects on both human health and the gut microbiota. Bifidobacteria and Lactobacilli are two popular probiotic organisms, both of which carry a BSH.[17] BSHs play roles in reducing cholesterol levels and detoxifying bile acids that may damage the gut in high concentrations.[3] Current issues with use of BSH-containing bacteria in probiotics include bioavailability and further modification of deconjugated bile acids to potentially toxic secondary bile acids.[3]

References

  1. 1 2 3 4 5 Foley, Matthew H.; O’Flaherty, Sarah; Barrangou, Rodolphe; Theriot, Casey M. (2019-03-07). "Bile salt hydrolases: Gatekeepers of bile acid metabolism and host-microbiome crosstalk in the gastrointestinal tract". PLOS Pathogens. 15 (3): e1007581. doi:10.1371/journal.ppat.1007581. ISSN 1553-7374. PMC 6405046. PMID 30845232.
  2. 1 2 3 4 5 6 7 Dong, Zixing; Lee, Byong H. (October 2018). "Bile salt hydrolases: Structure and function, substrate preference, and inhibitor development: Structural Basis for Designing BSH Inhibitors". Protein Science. 27 (10): 1742–1754. doi:10.1002/pro.3484. PMC 6199152. PMID 30098054.
  3. 1 2 3 Begley, Máire; Hill, Colin; Gahan, Cormac G. M. (March 2006). "Bile Salt Hydrolase Activity in Probiotics". Applied and Environmental Microbiology. 72 (3): 1729–1738. Bibcode:2006ApEnM..72.1729B. doi:10.1128/AEM.72.3.1729-1738.2006. ISSN 0099-2240. PMC 1393245. PMID 16517616.
  4. ↑ Bustos, Ana Y.; Font de Valdez, Graciela; Fadda, Silvina; Taranto, María P. (2018-10-01). "New insights into bacterial bile resistance mechanisms: the role of bile salt hydrolase and its impact on human health". Food Research International. 112: 250–262. doi:10.1016/j.foodres.2018.06.035. ISSN 0963-9969. PMID 30131136. S2CID 52058868.
  5. ↑ Oinonen, C.; Rouvinen, J. (December 2000). "Structural comparison of Ntn-hydrolases". Protein Science. 9 (12): 2329–2337. doi:10.1110/ps.9.12.2329. ISSN 0961-8368. PMC 2144523. PMID 11206054.
  6. 1 2 3 4 Xu, Fuzhou; Hu, Xiao-Jian; Singh, Warispreet; Geng, Wenjing; Tikhonova, Irina G.; Lin, Jun (2019-08-27). "The complex structure of bile salt hydrolase from Lactobacillus salivarius reveals the structural basis of substrate specificity". Scientific Reports. 9 (1): 12438. Bibcode:2019NatSR...912438X. doi:10.1038/s41598-019-48850-6. ISSN 2045-2322. PMC 6711994. PMID 31455813.
  7. 1 2 3 4 5 6 Guzior, Douglas V.; Quinn, Robert A. (2021-06-14). "Review: microbial transformations of human bile acids". Microbiome. 9 (1): 140. doi:10.1186/s40168-021-01101-1. ISSN 2049-2618. PMC 8204491. PMID 34127070.
  8. ↑ Hofmann, Alan F. (1999-12-13). "The Continuing Importance of Bile Acids in Liver and Intestinal Disease". Archives of Internal Medicine. 159 (22): 2647–2658. doi:10.1001/archinte.159.22.2647. ISSN 0003-9926. PMID 10597755. S2CID 21211064.
  9. 1 2 Foley, Matthew H.; O'Flaherty, Sarah; Allen, Garrison; Rivera, Alissa J.; Stewart, Allison K.; Barrangou, Rodolphe; Theriot, Casey M. (2021-02-09). "Lactobacillus bile salt hydrolase substrate specificity governs bacterial fitness and host colonization". Proceedings of the National Academy of Sciences. 118 (6): e2017709118. Bibcode:2021PNAS..11817709F. doi:10.1073/pnas.2017709118. ISSN 0027-8424. PMC 8017965. PMID 33526676.
  10. ↑ Quinn, Robert A.; Melnik, Alexey V.; Vrbanac, Alison; Fu, Ting; Patras, Kathryn A.; Christy, Mitchell P.; Bodai, Zsolt; Belda-Ferre, Pedro; Tripathi, Anupriya; Chung, Lawton K.; Downes, Michael; Welch, Ryan D.; Quinn, Melissa; Humphrey, Greg; Panitchpakdi, Morgan (March 2020). "Global chemical effects of the microbiome include new bile-acid conjugations". Nature. 579 (7797): 123–129. Bibcode:2020Natur.579..123Q. doi:10.1038/s41586-020-2047-9. ISSN 1476-4687. PMC 7252668. PMID 32103176.
  11. ↑ "Exploring bile acids produced by gut microbes". {{cite journal}}: Cite journal requires |journal= (help)
  12. 1 2 Chand, Deepak; Avinash, Vellore Sunder; Yadav, Yashpal; Pundle, Archana Vishnu; Suresh, Cheravakattu Gopalan; Ramasamy, Sureshkumar (2017-01-01). "Molecular features of bile salt hydrolases and relevance in human health". Biochimica et Biophysica Acta (BBA) - General Subjects. 1861 (1, Part A): 2981–2991. doi:10.1016/j.bbagen.2016.09.024. ISSN 0304-4165. PMID 27681686.
  13. ↑ Schubert, Kristin; Olde Damink, Steven W.M.; von Bergen, Martin; Schaap, Frank G. (September 2017). "Interactions between bile salts, gut microbiota, and hepatic innate immunity". Immunological Reviews. 279 (1): 23–35. doi:10.1111/imr.12579. PMID 28856736. S2CID 9299665.
  14. 1 2 Claudel, Thierry; Staels, Bart; Kuipers, Folkert (2005-10-01). "The Farnesoid X Receptor". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (10): 2020–2030. doi:10.1161/01.ATV.0000178994.21828.a7. PMID 16037564.
  15. ↑ Bourgin, Mélanie; Kriaa, Aicha; Mkaouar, Héla; Mariaule, Vincent; Jablaoui, Amin; Maguin, Emmanuelle; Rhimi, Moez (2021-05-22). "Bile Salt Hydrolases: At the Crossroads of Microbiota and Human Health". Microorganisms. 9 (6): 1122. doi:10.3390/microorganisms9061122. ISSN 2076-2607. PMC 8224655. PMID 34067328.
  16. ↑ Xu, Yang; Li, Fei; Zalzala, Munaf; Xu, Jiesi; Gonzalez, Frank J; Adorini, Luciano; Lee, Yoon-Kwang; Yin, Liya; Zhang, Yanqiao (October 2016). "FXR Activation Increases Reverse Cholesterol Transport by Modulating Bile Acid Composition and Cholesterol Absorption". Hepatology. 64 (4): 1072–1085. doi:10.1002/hep.28712. ISSN 0270-9139. PMC 5033696. PMID 27359351.
  17. 1 2 3 4 5 6 Song, Ziwei; Cai, Yuanyuan; Lao, Xingzhen; Wang, Xue; Lin, Xiaoxuan; Cui, Yingyun; Kalavagunta, Praveen Kumar; Liao, Jun; Jin, Liang; Shang, Jing; Li, Jing (2019-01-23). "Taxonomic profiling and populational patterns of bacterial bile salt hydrolase (BSH) genes based on worldwide human gut microbiome". Microbiome. 7 (1): 9. doi:10.1186/s40168-019-0628-3. ISSN 2049-2618. PMC 6345003. PMID 30674356.
  18. ↑ Godlewska, Urszula; Bulanda, Edyta; Wypych, Tomasz P. (2022). "Bile acids in immunity: Bidirectional mediators between the host and the microbiota". Frontiers in Immunology. 13: 949033. doi:10.3389/fimmu.2022.949033. ISSN 1664-3224. PMC 9425027. PMID 36052074.
  19. 1 2 3 4 5 Fiorucci, Stefano; Biagioli, Michele; Zampella, Angela; Distrutti, Eleonora (2018-08-13). "Bile Acids Activated Receptors Regulate Innate Immunity". Frontiers in Immunology. 9: 1853. doi:10.3389/fimmu.2018.01853. ISSN 1664-3224. PMC 6099188. PMID 30150987.
  20. ↑ Sato, Yuko; Atarashi, Koji; Plichta, Damian R.; Arai, Yasumichi; Sasajima, Satoshi; Kearney, Sean M.; Suda, Wataru; Takeshita, Kozue; Sasaki, Takahiro; Okamoto, Shoki; Skelly, Ashwin N.; Okamura, Yuki; Vlamakis, Hera; Li, Youxian; Tanoue, Takeshi (November 2021). "Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians". Nature. 599 (7885): 458–464. Bibcode:2021Natur.599..458S. doi:10.1038/s41586-021-03832-5. ISSN 1476-4687. PMID 34325466. S2CID 236514774.
  21. 1 2 Nie, Yang-fan; Hu, Jun; Yan, Xiang-hua (2015-06-01). "Cross-talk between bile acids and intestinal microbiota in host metabolism and health". Journal of Zhejiang University Science B. 16 (6): 436–446. doi:10.1631/jzus.B1400327. ISSN 1862-1783. PMC 4471595. PMID 26055905.
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