MICROBIOME & BILE ACID METABOLISM

A major focus of the Sterolbiome laboratory is working out biochemical pathways in gut bacteria responsible for the diversification of only a few host-derived primary bile acids to many dozens of ‘secondary bile salts’. Bile acids are synthesized in the liver from cholesterol, stored in the gallbladder, and released into the small intestine after a meal is consumed. Bile salts function to emulsify dietary lipids and lipid soluble vitamins in the small intestine, and ~95% of bile salts are actively transported in the distal small intestine and returned to the liver through the portal circulation in a recycling process known as the enterohepatic circulation. Beyond mere detergents, bile salts are also potent nutrient signaling hormones that regulate glucose and lipid homeostasis, and regulate their own synthesis and transport through negative feedback between the ileum and the liver. Roughly 400-800 mg of bile salts escapes enterohepatic circulation and enter into the large intestine. The large intestine contains one of the most densely populated natural environments. Indeed, estimates suggest for every 1 vertebrate cell there is a microbial cell inhabiting the body. Roughly 99% of the functional genes in vertebrates are found in host-associated bacteria. So far, the function of only a third of these genes is known.

In this ‘microbial dark matter’ are genes that encode enzymes involved in the biotransformation of bile salts. Indeed, from only a handful of ‘primary’ bile acids produced by the liver, gut microbiota convert these into an estimated ~400 metabolites. Secondary bile salts have altered binding affinity to host nuclear and G-protein coupled receptors, and access to many cells to a significantly higher degree than primary bile acids due to the increased hydrophobicity of many secondary bile acids. Researchers across the world are currently measuring bile salt profiles in both healthy cohorts as well as cohorts at risk for or suffering from gastrointestinal cancers, type II diabetes, non-alcoholic fatty liver disease, Alzheimer’s disease, inflammatory bowel disease, cholesterol gallstone disease, and others. Identifying the microbial enzymes responsible for diversifying primary bile salts into a myriad of secondary bile acid metabolites, and the taxa encoding these enzymes, will be important in our ability to shift microbiome composition/function and thus the bile salt profile in individuals.

Recently, the Sterolbiome lab has reported discovery and characterization of pairs of hydroxysteroid dehydrogenase (HSDH) enzymes that reversibly oxidize and epimerize hydroxyl groups on the steroid rings of bile salts. These enzymes are important because they change the detergent nature of the bile salt, its antibacterial nature, and its signaling properties in host cells. We have identified these enzymes in diverse taxa including diverse strains of species in the genera Clostridium, Eggerthella, and Bacteroides. Our phylogenetic analysis further expanded currently known species capable of bile acid oxidation and epimerization.

PI Ridlon began studying the multi-step bile acid 7α-dehydroxylation pathway during his doctoral and postdoctoral training, and has continued to make advances in the understanding of this pathway at the University of Illinois. We recently characterized the first genome-wide transcriptomic analysis of Clostridium scindens ATCC 35704 both in vitro and in vivo. Indeed, we characterized bacterial cecal transcriptomic and bile acid metabolomic effects of the dietary compound, berberine. We have utilized transcriptome data to discover novel bile acid inducible (bai) genes. Current and future work in our lab aims to couple gnotobiotic animal models, engineered bacterial strains, and diet to shift bile acid profiles to promote human health, and growth in production animals.

Selected Publications

  1. Wolf PG, Byrd DA, Cares K, Dai H, Odoms-Young A, Gaskins HR, Ridlon JM, Tussing-Humphreys L. Bile Acids, Gut Microbes, and the Neighborhood Food Environment-a Potential Driver of Colorectal Cancer Health Disparities. mSystems. 2022 Feb 1:e0117421. doi: 10.1128/msystems.01174-21. Epub ahead of print. PMID: 35103491.
  2. Wen J, Mercado GP, Volland A, Doden HL, Lickwar CR, Crooks T, Kakiyama G, Kelly C, Cocchiaro JL, Ridlon JM, Rawls JF. Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine. Sci Adv. 2021 Jul 23;7(30):eabg1371. doi: 10.1126/sciadv.abg1371. PMID: 34301599; PMCID: PMC8302129.
  3. Doden HL, Wolf PG, Gaskins HR, Anantharaman K, Alves JMP, Ridlon JM. Completion of the gut microbial epi-bile acid pathway. Gut Microbes. 2021 Jan-Dec;13(1):1-20. doi: 10.1080/19490976.2021.1907271. PMID: 33938389; PMCID: PMC8096331.
  4. Doden HL, Ridlon JM. Microbial Hydroxysteroid Dehydrogenases: From Alpha to Omega. Microorganisms. 2021 Feb 24;9(3):469. doi: 10.3390/microorganisms9030469. PMID: 33668351; PMCID: PMC7996314.
  5. Wolf PG, Devendran S, Doden HL, Ly LK, Moore T, Takei H, Nittono H, Murai T, Kurosawa T, Chlipala GE, Green SJ, Kakiyama G, Kashyap P, McCracken VJ, Gaskins HR, Gillevet PM, Ridlon JM. Berberine alters gut microbial function through modulation of bile acids. BMC Microbiol. 2021 Jan 11;21(1):24. doi: 10.1186/s12866-020-02020-1. PMID: 33430766; PMCID: PMC7798349.
  6. Streidl T, Karkossa I, Segura Muñoz RR, Eberl C, Zaufel A, Plagge J, Schmaltz R, Schubert K, Basic M, Schneider KM, Afify M, Trautwein C, Tolba R, Stecher B, Doden HL, Ridlon JM, Ecker J, Moustafa T, von Bergen M, Ramer-Tait AE, Clavel T. The gut bacterium Extibacter muris produces secondary bile acids and influences liver physiology in gnotobiotic mice. Gut Microbes. 2021 Jan-Dec;13(1):1-21. doi: 10.1080/19490976.2020.1854008. PMID: 33382950; PMCID: PMC7781625.
  7. Wylensek D, Hitch TCA, Riedel T, Afrizal A, Kumar N, Wortmann E, Liu T, Devendran S, Lesker TR, Hernández SB, Heine V, Buhl EM, M D’Agostino P, Cumbo F, Fischöder T, Wyschkon M, Looft T, Parreira VR, Abt B, Doden HL, Ly L, Alves JMP, Reichlin M, Flisikowski K, Suarez LN, Neumann AP, Suen G, de Wouters T, Rohn S, Lagkouvardos I, Allen-Vercoe E, Spröer C, Bunk B, Taverne-Thiele AJ, Giesbers M, Wells JM, Neuhaus K, Schnieke A, Cava F, Segata N, Elling L, Strowig T, Ridlon JM, Gulder TAM, Overmann J, Clavel T. A collection of bacterial isolates from the pig intestine reveals functional and taxonomic diversity. Nat Commun. 2020 Dec 15;11(1):6389. doi: 10.1038/s41467-020-19929-w. PMID: 33319778; PMCID: PMC7738495.
  8. Ridlon JM. Conceptualizing the Vertebrate Sterolbiome. Appl Environ Microbiol. 2020 Aug 3;86(16):e00641-20. doi: 10.1128/AEM.00641-20. PMID: 32503912; PMCID: PMC7414951.
  9. Campbell DE, Ly LK, Ridlon JM, Hsiao A, Whitaker RJ, Degnan PH. Infection with Bacteroides Phage BV01 Alters the Host Transcriptome and Bile Acid Metabolism in a Common Human Gut Microbe. Cell Rep. 2020 Sep 15;32(11):108142. doi: 10.1016/j.celrep.2020.108142. PMID: 32937127; PMCID: PMC8354205.
  10. Xavier JB, Young VB, Skufca J, Ginty F, Testerman T, Pearson AT, Macklin P, Mitchell A, Shmulevich I, Xie L, Caporaso JG, Crandall KA, Simone NL, Godoy-Vitorino F, Griffin TJ, Whiteson KL, Gustafson HH, Slade DJ, Schmidt TM, Walther-Antonio MRS, Korem T, Webb-Robertson BM, Styczynski MP, Johnson WE, Jobin C, Ridlon JM, Koh AY, Yu M, Kelly L, Wargo JA. The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View. Trends Cancer. 2020 Mar;6(3):192-204. doi: 10.1016/j.trecan.2020.01.004. Epub 2020 Feb 7. PMID: 32101723; PMCID: PMC7098063.
  11. Ridlon JM, Devendran S, Alves JM, Doden H, Wolf PG, Pereira GV, Ly L, Volland A, Takei H, Nittono H, Murai T, Kurosawa T, Chlipala GE, Green SJ, Hernandez AG, Fields CJ, Wright CL, Kakiyama G, Cann I, Kashyap P, McCracken V, Gaskins HR. 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. 2020 May 3;11(3):381-404. doi: 10.1080/19490976.2019.1618173. Epub 2019 Jun 9. PMID: 31177942; PMCID: PMC7524365.
  12. Harris SC, Devendran S, Méndez-García C, Mythen SM, Wright CL, Fields CJ, Hernandez AG, Cann I, Hylemon PB, Ridlon JM. Bile acid oxidation by Eggerthella lenta strains C592 and DSM 2243T. Gut Microbes. 2018 Nov 2;9(6):523-539. doi: 10.1080/19490976.2018.1458180. Epub 2018 May 24. PMID: 29617190; PMCID: PMC6287680.
  13. Mythen SM, Devendran S, Méndez-García C, Cann I, Ridlon JM. Targeted Synthesis and Characterization of a Gene Cluster Encoding NAD(P)H-Dependent 3α-, 3β-, and 12α-Hydroxysteroid Dehydrogenases from Eggerthella CAG:298, a Gut Metagenomic Sequence. Appl Environ Microbiol. 2018 Mar 19;84(7):e02475-17. doi: 10.1128/AEM.02475-17. PMID: 29330189; PMCID: PMC5861830.
  14. Harris SC, Devendran S, Alves JMP, Mythen SM, Hylemon PB, Ridlon JM. Identification of a gene encoding a flavoprotein involved in bile acid metabolism by the human gut bacterium Clostridium scindens ATCC 35704. Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Mar;1863(3):276-283. doi: 10.1016/j.bbalip.2017.12.001. Epub 2017 Dec 5. PMID: 29217478.
  15. Ridlon JM, Wolf PG, Gaskins HR. Taurocholic acid metabolism by gut microbes and colon cancer. Gut Microbes. 2016 May 3;7(3):201-15. doi: 10.1080/19490976.2016.1150414. Epub 2016 Mar 22. PMID: 27003186; PMCID: PMC4939921.
  16. Ridlon JM, Harris SC, Bhowmik S, Kang DJ, Hylemon PB. Consequences of bile salt biotransformations by intestinal bacteria. Gut Microbes. 2016;7(1):22-39. doi: 10.1080/19490976.2015.1127483. Erratum in: Gut Microbes. 2016 Jun 9;7(3):262. PMID: 26939849; PMCID: PMC4856454.
  17. Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014 May;30(3):332-8. doi: 10.1097/MOG.0000000000000057. PMID: 24625896; PMCID: PMC4215539.
  18. Ridlon JM, Alves JM, Hylemon PB, Bajaj JS. Cirrhosis, bile acids and gut microbiota: unraveling a complex relationship. Gut Microbes. 2013 Sep-Oct;4(5):382-7. doi: 10.4161/gmic.25723. Epub 2013 Jul 12. PMID: 23851335; PMCID: PMC3839982.
  19. Ridlon JM, Hylemon PB. Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium. J Lipid Res. 2012 Jan;53(1):66-76. doi: 10.1194/jlr.M020313. Epub 2011 Oct 20. PMID: 22021638; PMCID: PMC3243482.
  20. Kang DJ, Ridlon JM, Moore DR 2nd, Barnes S, Hylemon PB. Clostridium scindens baiCD and baiH genes encode stereo-specific 7alpha/7beta-hydroxy-3-oxo-delta4-cholenoic acid oxidoreductases. Biochim Biophys Acta. 2008 Jan-Feb;1781(1-2):16-25. doi: 10.1016/j.bbalip.2007.10.008. Epub 2007 Nov 7. PMID: 18047844; PMCID: PMC2275164.
  21. Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006 Feb;47(2):241-59. doi: 10.1194/jlr.R500013-JLR200. Epub 2005 Nov 18. PMID: 16299351.