Download PDF
Z Gastroenterol 2021; 59(01): 63-68
DOI: 10.1055/a-1330-9644
Übersicht

Bile Acids in Control of the Gut-Liver-Axis

Gallensäuren steuern die Darm-Leber-Achse
Benedikt Hild 
  Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Munster, Germany
,
Hauke S. Heinzow
  Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Munster, Germany
,
Hartmut H. Schmidt
  Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Munster, Germany
,
Miriam Maschmeier
  Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), Universitätsklinikum Münster, Munster, Germany
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

The liver and gut share an intimate relationship whose communication relies heavily on metabolites, among which bile acids play a major role. Beyond their function as emulsifiers, bile acids have been recognized for their influence on metabolism of glucose and lipids as well as for their impact on immune responses. Therefore, changes to the composition of the bile acid pool can be consequential to liver and to gut physiology. By metabolizing primary bile acids to secondary bile acids, the bacterial gut microbiome modifies how bile acids exert influence. An altered ratio of secondary to primary bile acids is found to be substantial in many studies. Thus, disease pathogenesis and progression could be changed by gut microbiome modification which influences the bile acid pool.

Zusammenfassung

Leber und Darm sind sehr eng miteinander verbunden. Ihre Interaktion erfolgt dabei u. a. über Metaboliten, die maßgeblich über die Pfortader und den Gallengang ausgetauscht werden. Eine besondere Bedeutung kommt dabei Gallensäuren zu. Neben ihrer Funktion als Emulgatoren spielen Gallensäuren nicht nur im Glucose- und Lipidstoffwechsel eine wichtige Rolle, sondern nehmen auch Einfluss auf die Immunantwort. Veränderungen der Gallezusammensetzung können sich daher sowohl auf die Physiologie der Leber als auch des Darms auswirken. Darmbakterien wandeln primäre in sekundäre Gallensäuren um und können auf diese Art den Einfluss der Gallensäuren modifizieren. Zahlreiche Studien belegen die Bedeutung eines veränderten Verhältnisses von primären zu sekundären Gallensäuren. Durch eine Modifikation des Darm-Mikrobioms, die wiederum Einfluss auf den Gallensäuren-Pool ausübt, könnte so die Pathogenese und der Verlauf zahlreicher Krankheiten verändert werden.

Key words

FXR - secondary bile acids - bacterial microbiome - NASH - metabolism - liver cancer - IBD

Schlüsselwörter

FXR - sekundäre Gallensäuren - bakterielles Mikrobiom - NASH - Stoffwechsel - Leberkarzinom - IBD


Publication History

Received: 01 November 2020

Accepted: 04 December 2020

Article published online:
11 January 2021

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Lozupone CA, Stombaugh JI, Gordon JI. et al Diversity, stability and resilience of the human gut microbiota. Nature 2012; 489: 220-230 . doi:10.1038/nature11550
    CrossrefPubMedSearch in Google Scholar
  • 2 Sonnenburg ED, Sonnenburg JL. The ancestral and industrialized gut microbiota and implications for human health. Nat Rev Microbiol 2019; 17: 383-390 . doi:10.1038/s41579-019-0191-8
    CrossrefPubMedSearch in Google Scholar
  • 3 Tripathi A, Debelius J, Brenner DA. et al The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 2018; 15: 397-411 . doi:10.1038/s41575-018-0011-z
    CrossrefPubMedSearch in Google Scholar
  • 4 Volta U, Bonazzi C, Bianchi FB. et al IgA antibodies to dietary antigens in liver cirrhosis. Ric Clin Lab 1987; 17: 235-242 . doi:10.1007/BF02912537
    CrossrefPubMedSearch in Google Scholar
  • 5 Chu H, Duan Y, Yang L. et al Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease. Gut 2019; 68: 359-370 . doi:10.1136/gutjnl-2018-316307
    CrossrefPubMedSearch in Google Scholar
  • 6 Macpherson AJ, Heikenwalder M, Ganal-Vonarburg SC. The Liver at the Nexus of Host-Microbial Interactions. Cell Host Microbe 2016; 20: 561-571 . doi:10.1016/j.chom.2016.10.016
    CrossrefPubMedSearch in Google Scholar
  • 7 Kirpich IA, Marsano LS, McClain CJ. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease. Clin Biochem 2015; 48: 923-930 . doi:10.1016/j.clinbiochem.2015.06.023
    CrossrefPubMedSearch in Google Scholar
  • 8 Ohtani N, Kawada N. Role of the Gut-Liver Axis in Liver Inflammation, Fibrosis, and Cancer: A Special Focus on the Gut Microbiota Relationship. Hepatol Commun 2019; 3: 456-470 . doi:10.1002/hep4.1331
    CrossrefPubMedSearch in Google Scholar
  • 9 Yang X, Lu D, Zhuo J. et al The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases. Int J Biol Sci 2020; 16: 2357-2366 . doi:10.7150/ijbs.46405
    CrossrefPubMedSearch in Google Scholar
  • 10 Hillman ET, Lu H, Yao T. et al Microbial Ecology along the Gastrointestinal Tract. Microbes Environ 2017; 32: 300-313 . doi:10.1264/jsme2.ME17017
    CrossrefPubMedSearch in Google Scholar
  • 11 Leone V, Gibbons SM, Martinez K. et al Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe 2015; 17: 681-689 . doi:10.1016/j.chom.2015.03.006
    CrossrefPubMedSearch in Google Scholar
  • 12 Nair S, Cope K, Risby TH. et al Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am J Gastroenterol 2001; 96: 1200-1204 . doi:10.1111/j.1572-0241.2001.03702.x
    CrossrefPubMedSearch in Google Scholar
  • 13 Yuan J, Chen C, Cui J. et al Fatty Liver Disease Caused by High-Alcohol-Producing Klebsiella pneumoniae. Cell Metab 2019; 30: 675-688 e677 . doi:10.1016/j.cmet.2019.08.018
    CrossrefPubMedSearch in Google Scholar
  • 14 Zeisel SH, da Costa KA. Choline: an essential nutrient for public health. Nutr Rev 2009; 67: 615-623 . doi:10.1111/j.1753-4887.2009.00246.x
    CrossrefPubMedSearch in Google Scholar
  • 15 Giuffre M, Campigotto M, Campisciano G. et al A story of liver and gut microbes: how does the intestinal flora affect liver disease? A review of the literature. Am J Physiol Gastrointest Liver Physiol 2020; 318: G889-G906 . doi:10.1152/ajpgi.00161.2019
    CrossrefPubMedSearch in Google Scholar
  • 16 Zhou H, Hylemon PB. Bile acids are nutrient signaling hormones. Steroids 2014; 86: 62-68 . doi:10.1016/j.steroids.2014.04.016
    CrossrefPubMedSearch in Google Scholar
  • 17 Hylemon PB, Zhou H, Pandak WM. et al Bile acids as regulatory molecules. J Lipid Res 2009; 50: 1509-1520 . doi:10.1194/jlr.R900007-JLR200
    CrossrefPubMedSearch in Google Scholar
  • 18 Wahlstrom A, Sayin SI, Marschall HU. et al Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism. Cell Metab 2016; 24: 41-50 . doi:10.1016/j.cmet.2016.05.005
    CrossrefPubMedSearch in Google Scholar
  • 19 Hundt M, Basit H, John S. Physiology, Bile Secretion. In StatPearls. Treasure Island (FL): 2020
    Search in Google Scholar
  • 20 Liddle RA. Regulation of cholecystokinin secretion by intraluminal releasing factors. Am J Physiol 1995; 269: G319-G327 . doi:10.1152/ajpgi.1995.269.3.G319
    PubMedSearch in Google Scholar
  • 21 Inagaki T, Moschetta A, Lee YK. et al Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci U S A 2006; 103: 3920-3925 . doi:10.1073/pnas.0509592103
    CrossrefPubMedSearch in Google Scholar
  • 22 Islam KB, Fukiya S, Hagio M. et al Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 2011; 141: 1773-1781 . doi:10.1053/j.gastro.2011.07.046
    CrossrefPubMedSearch in Google Scholar
  • 23 Watanabe M, Fukiya S, Yokota A. Comprehensive evaluation of the bactericidal activities of free bile acids in the large intestine of humans and rodents. J Lipid Res 2017; 58: 1143-1152 . doi:10.1194/jlr.M075143
    CrossrefPubMedSearch in Google Scholar
  • 24 Chiang JY. Bile acids: regulation of synthesis. J Lipid Res 2009; 50: 1955-1966 . doi:10.1194/jlr.R900010-JLR200
    CrossrefPubMedSearch in Google Scholar
  • 25 Chiang JY. Bile acid metabolism and signaling. Compr Physiol 2013; 3: 1191-1212 . doi:10.1002/cphy.c120023
    CrossrefPubMedSearch in Google Scholar
  • 26 Lefebvre P, Cariou B, Lien F. et al Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 2009; 89: 147-191 . doi:10.1152/physrev.00010.2008
    CrossrefPubMedSearch in Google Scholar
  • 27 Kliewer SA, Mangelsdorf DJ. Bile Acids as Hormones: The FXR-FGF15/19 Pathway. Dig Dis 2015; 33: 327-331 . doi:10.1159/000371670
    CrossrefPubMedSearch in Google Scholar
  • 28 Li T, Chiang JY. Bile acid signaling in metabolic disease and drug therapy. Pharmacol Rev 2014; 66: 948-983 . doi:10.1124/pr.113.008201
    CrossrefPubMedSearch in Google Scholar
  • 29 Inagaki T, Choi M, Moschetta A. et al Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2005; 2: 217-225 . doi:10.1016/j.cmet.2005.09.001
    CrossrefPubMedSearch in Google Scholar
  • 30 Fiorucci S, Mencarelli A, Palladino G. et al Bile-acid-activated receptors: targeting TGR5 and farnesoid-X-receptor in lipid and glucose disorders. Trends Pharmacol Sci 2009; 30: 570-580 . doi:10.1016/j.tips.2009.08.001
    CrossrefPubMedSearch in Google Scholar
  • 31 Little R, Wine E, Kamath BM. et al Gut microbiome in primary sclerosing cholangitis: A review. World J Gastroenterol 2020; 26: 2768-2780 . doi:10.3748/wjg.v26.i21.2768
    CrossrefPubMedSearch in Google Scholar
  • 32 Kummen M, Hov JR. The gut microbial influence on cholestatic liver disease. Liver Int 2019; 39: 1186-1196 . doi:10.1111/liv.14153
    CrossrefPubMedSearch in Google Scholar
  • 33 Tierney BT, Yang Z, Luber JM. et al The Landscape of Genetic Content in the Gut and Oral Human Microbiome. Cell Host Microbe 2019; 26: 283-295 e288 . doi:10.1016/j.chom.2019.07.008
    CrossrefPubMedSearch in Google Scholar
  • 34 Wells JE, Berr F, Thomas LA. et al Isolation and characterization of cholic acid 7alpha-dehydroxylating fecal bacteria from cholesterol gallstone patients. J Hepatol 2000; 32: 4-10 . doi:10.1016/s0168-8278(00)80183-x
    CrossrefPubMedSearch in Google Scholar
  • 35 Funabashi M, Grove TL, Wang M. et al A metabolic pathway for bile acid dehydroxylation by the gut microbiome. Nature 2020; 582: 566-570 . doi:10.1038/s41586-020-2396-4
    CrossrefPubMedSearch in Google Scholar
  • 36 Ma C, Han M, Heinrich B. et al Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 2018; 360
    CrossrefPubMedSearch in Google Scholar
  • 37 Yoshimoto S, Loo TM, Atarashi K. et al Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013; 499: 97-101 . doi:10.1038/nature12347
    CrossrefPubMedSearch in Google Scholar
  • 38 Ou J, DeLany JP, Zhang M. et al Association between low colonic short-chain fatty acids and high bile acids in high colon cancer risk populations. Nutr Cancer 2012; 64: 34-40 . doi:10.1080/01635581.2012.630164
    CrossrefPubMedSearch in Google Scholar
  • 39 Bernstein H, Bernstein C, Payne CM. et al Bile acids as carcinogens in human gastrointestinal cancers. Mutat Res 2005; 589: 47-65 . doi:10.1016/j.mrrev.2004.08.001
    CrossrefPubMedSearch in Google Scholar
  • 40 Dermadi D, Valo S, Ollila S. et al Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon. Cancer Res 2017; 77: 3352-3363 . doi:10.1158/0008-5472.CAN-16-2860
    CrossrefPubMedSearch in Google Scholar
  • 41 Bailey AM, Zhan L, Maru D. et al FXR silencing in human colon cancer by DNA methylation and KRAS signaling. Am J Physiol Gastrointest Liver Physiol 2014; 306: G48-G58 . doi:10.1152/ajpgi.00234.2013
    CrossrefPubMedSearch in Google Scholar
  • 42 Modica S, Murzilli S, Salvatore L. et al Nuclear bile acid receptor FXR protects against intestinal tumorigenesis. Cancer Res 2008; 68: 9589-9594 . doi:10.1158/0008-5472.CAN-08-1791
    CrossrefPubMedSearch in Google Scholar
  • 43 Nguyen TT, Lian S, Ung TT. et al Lithocholic Acid Stimulates IL-8 Expression in Human Colorectal Cancer Cells Via Activation of Erk1/2 MAPK and Suppression of STAT3 Activity. J Cell Biochem 2017; 118: 2958-2967 . doi:10.1002/jcb.25955
    CrossrefPubMedSearch in Google Scholar
  • 44 Raufman JP, Shant J, Guo CY. et al Deoxycholyltaurine rescues human colon cancer cells from apoptosis by activating EGFR-dependent PI3K/Akt signaling. J Cell Physiol 2008; 215: 538-549 . doi:10.1002/jcp.21332
    CrossrefPubMedSearch in Google Scholar
  • 45 Farhana L, Nangia-Makker P, Arbit E. et al Bile acid: a potential inducer of colon cancer stem cells. Stem Cell Res Ther 2016; 7: 181 . doi:10.1186/s13287-016-0439-4
    CrossrefPubMedSearch in Google Scholar
  • 46 Tung BY, Emond MJ, Haggitt RC. et al Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med 2001; 134: 89-95 . doi:10.7326/0003-4819-134-2-200101160-00008
    CrossrefPubMedSearch in Google Scholar
  • 47 Alberts DS, Martinez ME, Hess LM. et al Phase III trial of ursodeoxycholic acid to prevent colorectal adenoma recurrence. J Natl Cancer Inst 2005; 97: 846-853 . doi:10.1093/jnci/dji144
    CrossrefPubMedSearch in Google Scholar
  • 48 Tiratterra E, Franco P, Porru E. et al Role of bile acids in inflammatory bowel disease. Ann Gastroenterol 2018; 31: 266-272 . doi:10.20524/aog.2018.0239
    PubMedSearch in Google Scholar
  • 49 Gadaleta RM, van Erpecum KJ, Oldenburg B. et al Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut 2011; 60: 463-472 . doi:10.1136/gut.2010.212159
    CrossrefPubMedSearch in Google Scholar
  • 50 Gadaleta RM, Oldenburg B, Willemsen EC. et al Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-kappaB signaling in the intestine. Biochim Biophys Acta 2011; 1812: 851-858 . doi:10.1016/j.bbadis.2011.04.005
    CrossrefPubMedSearch in Google Scholar
  • 51 Vavassori P, Mencarelli A, Renga B. et al The bile acid receptor FXR is a modulator of intestinal innate immunity. J Immunol 2009; 183: 6251-6261 . doi:10.4049/jimmunol.0803978
    CrossrefPubMedSearch in Google Scholar
  • 52 Verbeke L, Farre R, Verbinnen B. et al The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol 2015; 185: 409-419 . doi:10.1016/j.ajpath.2014.10.009
    CrossrefPubMedSearch in Google Scholar
  • 53 Gnewuch C, Liebisch G, Langmann T. et al Serum bile acid profiling reflects enterohepatic detoxification state and intestinal barrier function in inflammatory bowel disease. World J Gastroenterol 2009; 15: 3134-3141 . doi:10.3748/wjg.15.3134
    CrossrefPubMedSearch in Google Scholar
  • 54 Sinha SR, Haileselassie Y, Nguyen LP. et al Dysbiosis-Induced Secondary Bile Acid Deficiency Promotes Intestinal Inflammation. Cell Host Microbe 2020; 27: 659-670 e655 . doi:10.1016/j.chom.2020.01.021
    CrossrefPubMedSearch in Google Scholar
  • 55 Cipriani S, Mencarelli A, Chini MG. et al The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One 2011; 6: e25637 . doi:10.1371/journal.pone.0025637
    CrossrefPubMedSearch in Google Scholar
  • 56 Nijmeijer RM, Gadaleta RM, van Mil SW. et al Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease. PLoS One 2011; 6: e23745 . doi:10.1371/journal.pone.0023745
    CrossrefPubMedSearch in Google Scholar
  • 57 Chen ML, Takeda K, Sundrud MS. Emerging roles of bile acids in mucosal immunity and inflammation. Mucosal Immunol 2019; 12: 851-861 . doi:10.1038/s41385-019-0162-4
    CrossrefPubMedSearch in Google Scholar
  • 58 Kuno T, Hirayama-Kurogi M, Ito S. et al Reduction in hepatic secondary bile acids caused by short-term antibiotic-induced dysbiosis decreases mouse serum glucose and triglyceride levels. Sci Rep 2018; 8: 1253 . doi:10.1038/s41598-018-19545-1
    CrossrefPubMedSearch in Google Scholar
  • 59 Watanabe M, Houten SM, Wang L. et al Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 2004; 113: 1408-1418 . doi:10.1172/JCI21025
    CrossrefPubMedSearch in Google Scholar
  • 60 Kast HR, Nguyen CM, Sinal CJ. et al Farnesoid X-activated receptor induces apolipoprotein C-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol 2001; 15: 1720-1728 . doi:10.1210/mend.15.10.0712
    CrossrefPubMedSearch in Google Scholar
  • 61 Jiang C, Xie C, Li F. et al Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015; 125: 386-402 . doi:10.1172/JCI76738
    CrossrefPubMedSearch in Google Scholar
  • 62 Jiang C, Xie C, Lv Y. et al Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 2015; 6: 10166 . doi:10.1038/ncomms10166
    CrossrefPubMedSearch in Google Scholar
  • 63 Tomlinson E, Fu L, John L. et al Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 2002; 143: 1741-1747 . doi:10.1210/endo.143.5.8850
    CrossrefPubMedSearch in Google Scholar
  • 64 Zhang S, Wang J, Liu Q. et al Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J Hepatol 2009; 51: 380-388 . doi:10.1016/j.jhep.2009.03.025
    CrossrefPubMedSearch in Google Scholar
  • 65 Fang S, Suh JM, Reilly SM. et al Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015; 21: 159-165 . doi:10.1038/nm.3760
    CrossrefPubMedSearch in Google Scholar
  • 66 Xi Y, Li H. Role of farnesoid X receptor in hepatic steatosis in nonalcoholic fatty liver disease. Biomed Pharmacother 2020; 121: 109609 . doi:10.1016/j.biopha.2019.109609
    CrossrefPubMedSearch in Google Scholar
  • 67 Kakiyama G, Hylemon PB, Zhou H. et al Colonic inflammation and secondary bile acids in alcoholic cirrhosis. Am J Physiol Gastrointest Liver Physiol 2014; 306: G929-937 . doi:10.1152/ajpgi.00315.2013
    CrossrefPubMedSearch in Google Scholar
  • 68 Hartmann P, Hochrath K, Horvath A. et al Modulation of the intestinal bile acid/farnesoid X receptor/fibroblast growth factor 15 axis improves alcoholic liver disease in mice. Hepatology 2018; 67: 2150-2166 . doi:10.1002/hep.29676
    CrossrefPubMedSearch in Google Scholar
  • 69 Wu W, Zhu B, Peng X. et al Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease. Biochem Biophys Res Commun 2014; 443: 68-73 . doi:10.1016/j.bbrc.2013.11.057
    CrossrefPubMedSearch in Google Scholar
  • 70 David LA, Maurice CF, Carmody RN. et al Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505: 559-563 . doi:10.1038/nature12820
    CrossrefPubMedSearch in Google Scholar
  • 71 Wang S, Martins R, Sullivan MC. et al Diet-induced remission in chronic enteropathy is associated with altered microbial community structure and synthesis of secondary bile acids. Microbiome 2019; 7: 126 . doi:10.1186/s40168-019-0740-4
    CrossrefPubMedSearch in Google Scholar
  • 72 Devkota S, Wang Y, Musch MW. et al Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature 2012; 487: 104-108 . doi:10.1038/nature11225
    CrossrefPubMedSearch in Google Scholar
  • 73 Guo CJ, Allen BM, Hiam KJ. et al Depletion of microbiome-derived molecules in the host using Clostridium genetics. Science 2019; 366
    CrossrefPubMedSearch in Google Scholar