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Clostridium scindens

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Clostridium scindens
Scientific classification Edit this classification
Domain: Bacteria
Phylum: Bacillota
Class: Clostridia
Order: Eubacteriales
Family: Clostridiaceae
Genus: Clostridium
Species:
C. scindens
Binomial name
Clostridium scindens
(Bokkenheuser et al. 1984)
Synonyms

Eubacterium sp. VPI12708

Clostridium scindens is a Gram-positive, obligate anaerobic, pleiomorphic, spore-forming bacterium belonging to the genus Clostridium.[1][2] C. scindens has been found in humans as a commensal colonizer of the colon.[1] Clostridium scindens is capable of converting primary bile acids to secondary bile acids, as well as converting glucocorticoids to androgens.[3] The presence of C. scindens in the human gut is associated resistance to Clostridioides difficile infection, due to the production of secondary bile acids which inhibit the growth of C. difficile.

Bile acid metabolism

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Bile Acids

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One of the key characteristics that distinguishes Clostridium scindens from other members of this genus is its ability to metabolize primary bile acids. Bile acids are cholesterol-based substrates formed in the liver, stored in the gallbladder, and released into the duodenum upon the entry of food to help facilitate the absorption of lipids and lipid-soluble vitamins.[4] Humans naturally produce conjugated primary bile acids, such as cholic acid and chenodeoxycholic acid, after which gut commensals like C. scindens convert them into unconjugated secondary bile acids, like deoxycholic acid and lithocholic acid respectively.[1] Primary bile acids are conjugated to either taurine or glycine by the enzyme N-acyltransferase to allow export from the liver.[5]

Bile Acid Inducible (bai) Operon

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A variety of different biochemical transformations can occur to convert primary bile acids into secondary bile acids, including deconjugation, dehydroxylation, oxidation, and epimerization.[6] Clostridium scindens in particular employs a mechanism called 7ɑ-dehydroxylation.[4] The process of 7ɑ-dehydroxylation is carried out by a gene cluster known as the bile acid-inducible (bai) operon.[4] The bai operon encodes the genes baiB, baiCD, baiE, baiA, baiF, baiG, baiH, and baiI, all of which play integral roles in transforming primary into secondary bile acids.

bai Operon Mechanism

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Deconjugation: Before primary bile acids reach the bai operon and undergo 7ɑ-dehydroxylation they must be deconjugated from taurine or glycine by a bile salt hydrolase enzyme.>[5]

baiG (H+-dependent bile acid transporter):[5] baiG encodes a bile acid transporter protein that allows bacteria to take up unconjugated bile acids for 7ɑ-dehydroxylation.[7]

baiB (bile-acid CoA ligase):[5] The first step of primary bile acid 7ɑ-dehydroxylation is carried out by baiB, which facilitates the formation of a bile acid-CoA thioester intermediate.[8] Simply put, this enzyme replaces a hydroxyl (-OH) group with a thioester-CoA (-SCoA) group. This reaction is ATP-dependent, also producing pyrophosphate and AMP as byproducts.[5] Previous research suggests that BaiB acts upon bile acids with a free C-24 group.[8] baiB shares amino acid homology with the Escherichia coli entE gene, coding for 2,3-dihydroxybenzoate-AMP ligase, and the Bifidobacterium brevis grsA and tycA genes, encoding Gramicidin S synthetase 1 and Tyrocidine synthetase 1 respectively.[8]

baiA2 (3-ɑ-hydroxysteroid dehydrogenase):[5] The next enzyme to act after baiB, baiA2 catalyzes the oxidation of the C-3 hydroxyl group into a carbonyl group.[5] This enzyme replaces the hydroxyl (-OH) group with a carbonyl (C=O) group. This enzyme is part of a short-chain dehydrogenase/reductase enzyme family that characteristically requires a NAD+/NADP+ cofactor for functionality.[5] Research into the cofactor binding site of baiA2 has revealed that it specifically uses NAD+ due to its structure.[9]

baiCD (NAD+-dependent-3-oxo-𝚫4-cholenoic acid oxidoreductase):[5] Located directly downstream of baiB on the bai operon, baiCD functions to catalyze C4-C5 oxidation, creating a 3-dehydro-Δ4-cholic-acid-CoA intermediate.[5] This enzyme performs a reduction that introduces a new double bond between C4-C5 in one of the bile acid’s aromatic rings. Along with baiA2, baiCD acts twice in the 7ɑ-dehydroxylation pathway, catalyzing the first and last two redox reactions.[10]

baiE (7-ɑ dehydratase):[5] Located directly downstream of baiCD, the baiE gene codes for a 7-ɑ dehydratase enzyme that performs a diaxial trans elimination of water from the baiCD-produced bile acid intermediate.[5] The mechanism for this transformation is not known, but previous research indicates that it is similar to that of the also elusive baiI, which may encode for 7-β dehydratase.[11] baiE and baiI are believed to likely have similar mechanisms due to their homologous amino acid sequences and apparent stereospecificity as well.[11]

baiF (bile-acid CoA hydrolase):[5] Immediately downstream of baiA2, baiF codes for a bile-acid CoA hydrolase that removes the CoA group from bile acid intermediates.[5] One research study revealed that this removed CoA is transferred and conjugated to cholic acid.[12] The baiF gene product resembles carnitine dehydratase in Escherichia coli, which is classified as a thioesterase.[13] However, baiF does not resemble any known thioesterases, so some researchers propose that baiF encodes a novel family of thioesterases.[13]

baiH (7-β dehydratase):[5] Downstream of baiG, the baiH gene encodes a 7-β dehydratase that has NADH:flavin oxidoreductase activity.[5] This enzyme removes the carbon-carbon double bond introduced by baiCD. The connection between 7-β dehydratase and NADH was illuminated in a study that introduced a purified version of this protein into C. scindens, resulting in a decrease in the ratio of oxidized to reduced bile acid intermediates in the 7ɑ-dehydroxylation pathway.[14] Since NAD+/NADH are electron carriers, these researchers assumed that this change in oxidized:reduced intermediate ratio indicated that 7-β dehydratase affected NADH levels.[14]

baiI (Δ-ketosteroid isomerase/7-β dehydratase):[5] baiI, the furthest downstream gene of the bai operon, encodes for a protein that does not appear to be required for 7ɑ-dehydroxylation despite being highly conserved among different strains of Clostridium scindens.[10] The classification of this protein is also under scrutiny, as some researchers believe it to have Δ-ketosteroid isomerase functionality while others believe it is a 7-β dehydratase like baiH.[15] [16]

Other forms of metabolism

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Carbon metabolism

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Clostridium scindens can anaerobically ferment several different carbon sources, including monosaccharides (fructose, galactose, glucose, mannose, ribose, and xylose), a disaccharide (lactose), and a couple of 2-sugar alcohols (dulcitol and sorbitol).[17] Glucose metabolism takes the form of mixed acid fermentation, as the fermentation products include acetate, ethanol, and formate.[17] In defined and minimal media, the preferred glucose fermentation product for C. scindens is ethanol, while the production of hydrogen, acetate, and formate significantly decreases during growth in minimal media.[17]

Amino acid metabolism

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Clostridium scindens also has the genetic potential to perform Stickland fermentation, or the generation of ATP through the fermentation of amino acids.[17] C. scindens pairs amino acid fermentation with bile acid metabolism by using amino acids as electron donors and primary bile acids as acceptors.[17] The presence of glycine and proline reductase enzymes in the Clostridium scindens ATCC35704 genome indicates that glycine and proline may be commonly fermented amino acids by this organism.[17]

References

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  1. ^ a b c Kang, D (2008). "Clostridium scindens baiCD and baiH genes encode stereo-specific 7α/7β-hydroxy-3-oxo-Δ4-cholenoic acid oxidoreductases☆". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1781 (1–2): 16–25. doi:10.1016/j.bbalip.2007.10.008. ISSN 1388-1981. PMC 2275164. PMID 18047844.
  2. ^ Morris, G. N.; Winter, J.; Cato, E. P.; Ritchie, A. E.; Bokkenheuser, V. D. (1985). "Clostridium scindens sp. nov., a Human Intestinal Bacterium with Desmolytic Activity on Corticoids". International Journal of Systematic and Evolutionary Microbiology. 35 (4): 478–481. doi:10.1099/00207713-35-4-478. ISSN 1466-5034.
  3. ^ Ridlon, Jason M.; Ikegawa, Shigeo; Alves, João M.P.; Zhou, Biao; Kobayashi, Akiko; Iida, Takashi; Mitamura, Kuniko; Tanabe, Genzoh; Serrano, Myrna; De Guzman, Ainee; Cooper, Patsy; Buck, Gregory A.; Hylemon, Phillip B. (2013). "Clostridium scindens: a human gut microbe with a high potential to convert glucocorticoids into androgens". Journal of Lipid Research. 54 (9): 2437–2449. doi:10.1194/jlr.M038869. PMC 3735941. PMID 23772041.
  4. ^ a b c Marion, Solenne; Studer, Nicolas; Desharnais, Lyne; Menin, Laure; Escrig, Stéphane; Meibom, Anders; Hapfelmeier, Siegfried; Bernier-Latmani, Rizlan (2019-07-04). "In vitro and in vivo characterization of Clostridium scindens bile acid transformations". Gut Microbes. 10 (4): 481–503. doi:10.1080/19490976.2018.1549420. ISSN 1949-0976. PMC 6748637. PMID 30589376.
  5. ^ a b c d e f g h i j k l m n o p q Wise, Journey L.; Cummings, Bethany P. (2023-01-09). "The 7-α-dehydroxylation pathway: An integral component of gut bacterial bile acid metabolism and potential therapeutic target". Frontiers in Microbiology. 13. doi:10.3389/fmicb.2022.1093420. ISSN 1664-302X. PMC 9868651. PMID 36699589.
  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.
  7. ^ Mallonee, D H; Hylemon, P B (1996). "Sequencing and expression of a gene encoding a bile acid transporter from Eubacterium sp. strain VPI 12708". Journal of Bacteriology. 178 (24): 7053–7058. doi:10.1128/jb.178.24.7053-7058.1996. ISSN 0021-9193. PMC 178615. PMID 8955384.
  8. ^ a b c Mallonee, D H; Adams, J L; Hylemon, P B (1992). "The bile acid-inducible baiB gene from Eubacterium sp. strain VPI 12708 encodes a bile acid-coenzyme A ligase". Journal of Bacteriology. 174 (7): 2065–2071. doi:10.1128/jb.174.7.2065-2071.1992. ISSN 0021-9193. PMC 205821. PMID 1551828.
  9. ^ Bhowmik, Shiva; Jones, David H.; Chiu, Hsien-Po; Park, In-Hee; Chiu, Hsiu-Ju; Axelrod, Herbert L.; Farr, Carol L.; Tien, Henry J.; Agarwalla, Sanjay; Lesley, Scott A. (2014). "Structural and functional characterization of BaiA, an enzyme involved in secondary bile acid synthesis in human gut microbe". Proteins: Structure, Function, and Bioinformatics. 82 (2): 216–229. doi:10.1002/prot.24353. ISSN 0887-3585. PMC 3992121. PMID 23836456.
  10. ^ a b Funabashi, Masanori; Grove, Tyler L.; Wang, Min; Varma, Yug; McFadden, Molly E.; Brown, Laura C.; Guo, Chunjun; Higginbottom, Steven; Almo, Steven C.; Fischbach, Michael A. (2020-06-25). "A metabolic pathway for bile acid dehydroxylation by the gut microbiome". Nature. 582 (7813): 566–570. doi:10.1038/s41586-020-2396-4. ISSN 0028-0836. PMC 7319900. PMID 32555455.
  11. ^ a b Ridlon, Jason M.; Devendran, Saravanan; Alves, João Mp; Doden, Heidi; Wolf, Patricia G.; Pereira, Gabriel V.; Ly, Lindsey; Volland, Alyssa; Takei, Hajime; Nittono, Hiroshi; Murai, Tsuyoshi; Kurosawa, Takao; Chlipala, George E.; Green, Stefan J.; Hernandez, Alvaro G. (2020-05-03). "The ' in vivo lifestyle' of bile acid 7α-dehydroxylating bacteria: comparative genomics, metatranscriptomic, and bile acid metabolomics analysis of a defined microbial community in gnotobiotic mice". Gut Microbes. 11 (3): 381–404. doi:10.1080/19490976.2019.1618173. ISSN 1949-0976. PMC 7524365. PMID 31177942.
  12. ^ Ridlon, Jason M.; Hylemon, Phillip B. (2012). "Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium". Journal of Lipid Research. 53 (1): 66–76. doi:10.1194/jlr.M020313. PMC 3243482. PMID 22021638.
  13. ^ a b Ye, Hua-Qing; Mallonee, Darrell H.; Wells, James E.; Björkhem, Ingemar; Hylemon, Phillip B. (1999). "The bile acid-inducible baiF gene from Eubacterium sp. strain VPI 12708 encodes a bile acid-coenzyme A hydrolase". Journal of Lipid Research. 40 (1): 17–23. doi:10.1016/S0022-2275(20)33335-6.
  14. ^ a b Franklund, C V; Baron, S F; Hylemon, P B (1993). "Characterization of the baiH gene encoding a bile acid-inducible NADH:flavin oxidoreductase from Eubacterium sp. strain VPI 12708". Journal of Bacteriology. 175 (10): 3002–3012. doi:10.1128/jb.175.10.3002-3012.1993. ISSN 0021-9193. PMC 204619. PMID 8491719.
  15. ^ Eisenstein, Michael (2020-01-30). "The hunt for a healthy microbiome". Nature. 577 (7792): S6–S8. doi:10.1038/d41586-020-00193-3. ISSN 0028-0836. PMID 31996823.
  16. ^ Kang, Dae-Joong; Ridlon, Jason M.; Moore, Doyle Ray; Barnes, Stephen; Hylemon, Phillip B. (2008-01-01). "Clostridium scindens baiCD and baiH genes encode stereo-specific 7α/7β-hydroxy-3-oxo-Δ4-cholenoic acid oxidoreductases". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1781 (1): 16–25. doi:10.1016/j.bbalip.2007.10.008. ISSN 1388-1981. PMC 2275164. PMID 18047844.
  17. ^ a b c d e f Devendran, Saravanan; Shrestha, Rachana; Alves, João M. P.; Wolf, Patricia G.; Ly, Lindsey; Hernandez, Alvaro G.; Méndez-García, Celia; Inboden, Ashley; Wiley, J'nai; Paul, Oindrila; Allen, Avery; Springer, Emily; Wright, Chris L.; Fields, Christopher J.; Daniel, Steven L. (2019). Müller, Volker (ed.). "Clostridium scindens ATCC 35704: Integration of Nutritional Requirements, the Complete Genome Sequence, and Global Transcriptional Responses to Bile Acids". Applied and Environmental Microbiology. 85 (7). doi:10.1128/AEM.00052-19. ISSN 0099-2240. PMC 6585500. PMID 30737348.
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