Cover Page

Cite item


Traditionally, the biliary tract has been considered to be normally sterile, and the presence of microorganisms in bile is a marker of a pathological process. This assumption was confirmed by failure in allocation of bacterial strains from the normal bile duct. The paper provides rationale for a phenomenon of the normal biliary microbiota as a separate functional layer which protects a biliary tract from colonization by exogenous microorganisms. We revealed the potential of metagenomic data for prevention of infectious diseases, post-operative complications of reconstructive interventions including bile duct stenting and implantation the tissue-engineered structures exposed to the risks of colonization with pathogenic / exogenous microorganisms. The methods based on preserving homeostasis of normal biliary microbiota ecosystem can be used for prevention of hepatobiliary diseases and treatment of biliary tract inflammatory diseases.

About the authors

I. D. Klabukov

Sechenov First Moscow State Medical University, Institute for Regenerative Medicine

Author for correspondence.
ORCID iD: 0000-0002-2888-7999

Научный сотрудник отдела передовых клеточных технологий.

119991, Москва, ул. Трубецкая, д. 8, стр. 2, тел.: +7 (495) 609-14-00.

SPIN-код: 3388-8859

Russian Federation

A. V. Lyundup

Sechenov First Moscow State Medical University, Institute for Regenerative Medicine

ORCID iD: 0000-0002-0102-5491

Кандидат медицинских наук, заведующий отделом передовых клеточных технологий Института регенеративной медицины.

119991, Москва, ул. Трубецкая, д. 8, стр. 2, тел.: +7 (495) 609-14-00.

SPIN-код: 4954-3004

Russian Federation

T. G. Dyuzheva

Sechenov First Moscow State Medical University, Institute for Regenerative Medicine

ORCID iD: 0000-0003-0573-7573

Доктор медицинских наук, профессор, заведующая отделом регенеративной хирургии печени и поджелудочной железы.

119991, Москва, ул. Трубецкая, д. 8, стр. 2, тел.: +7 (495) 609-14-00.

SPIN-код: 7325-2086

Russian Federation

A. V. Tyakht

Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency

ORCID iD: 0000-0002-7358-2537
Moscow Russian Federation


  1. Keplinger KM, Bloomston M. Anatomy and embryology of the biliary tract. Surg Clin North Am. 2014;94(2):203–217. doi: 10.1016/j.suc.2014.01.001.
  2. Лоранская И.Д., Ракитская Л.Г., Малахова Е.В., Мамедова Л.Д. Лечение хронических холециститов // Лечащий врач. ― 2006. ― №6 ― С. 12–17. [Loranskaya ID, Rakitskaya LG, Malakhova EV, Mamedova LD. Management of chronic cholecystits. Practitioner. 2006;(6):12−17. (In Russ).]
  3. Merritt ME, Donaldson JR. Effect of bile salts on the DNA and membrane integrity of enteric bacteria. J Med Microbiol. 2009;58(12):1533–1541. doi: 10.1099/jmm.0.014092-0.
  4. Ljungh A, Wadstrom T. The role of microorganisms in biliary tract disease. Curr Gastroenterol Rep. 2002;4(2):167–171. doi: 10.1007/s11894-002-0055-6.
  5. Csendes A, Burdiles P, Maluenda F, et al. Simultaneous bacteriologic assessment of bile from gallbladder and common bile duct in control subjects and patients with gallstones and common duct stones. Arch Surg. 1996;131(4):389–394. doi: 10.1001/archsurg.1996.01430160047008.
  6. Hardy J, Francis KP, DeBoer M, et al. Extracellular replication of Listeria monocytogenes in the murine gall bladder. Science. 2004;303(5659):851–853. doi: 10.1126/science.1092712.
  7. Wu T, Zhang Z, Liu B, et al. Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study. BMC Genomics. 2013;14:669. doi: 10.1186/1471-2164-14-669.
  8. Liang T, Su W, Zhang Q, et al. Roles of sphincter of oddi laxity in bile duct microenvironment in patients with cholangiolithiasis: from the perspective of the microbiome and metabolome. J Am Coll Surg. 2016;222(3):269–280 e210. doi: 10.1016/j.jamcollsurg.2015.12.009.
  9. Jeffery IB, Claesson MJ, O’Toole PW, Shanahan F. Categorization of the gut microbiota: enterotypes or gradients? Nat Rev Microbiol. 2012;10(9):591–592. doi: 10.1038/nrmicro2859.
  10. Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nature Reviews Immunology. 2014;14(10):667–685.
  11. Verdier J, Luedde T, Sellge G. Biliary mucosal barrier and microbiome. Viszeralmedizin. 2015;31(3):156–161. doi: 10.1159/000431071.
  12. Hazrah P, Oahn KT, Tewari M, et al. The frequency of live bacteria in gallstones. HPB (Oxford). 2004;6(1):28–32. doi: 10.1080/13651820310025192.
  13. Manichanh C, Borruel N, Casellas F, Guarner F. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol. 2012;9(10):599–608. doi: 10.1038/nrgastro.2012.152.
  14. Zhao LP. The gut microbiota and obesity: from correlation to causality. Nature Reviews Microbiology. 2013;11(9):639–647. doi: 10.1038/nrmicro3089.
  15. Sekirov I, Russell SL, Antunes LCM, Finlay BB. Gut microbiota in health and disease. Physiol Rev. 2010;90(3):859–904. doi: 10.1152/physrev.00045.2009.
  16. Zeller G, Tap J, Voigt AY, et al. Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol. 2014;10(11):766. doi: 10.15252/msb.20145645.
  17. Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell. 2012;148(6):1258–1270. doi: 10.1016/j.cell.2012.01.035.
  18. Lu LJ, Liu J. Human microbiota and ophthalmic disease. Yale J Biol Med. 2016;89(3):325–330.
  19. Josefowicz SZ, Niec RE, Kim HY, et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature. 2012;482(7385):395–399. doi: 10.1038/nature10772.
  20. Zhang FM, Yu CH, Chen HT, et al. Helicobacter pylori infection is associated with gallstones: epidemiological survey in China. World J Gastroenterol. 2015;21(29):8912-8919. doi: 10.3748/wjg.v21.i29.8912.
  21. Marieb EN, Hoehn K. Human anatomy and physiology. 7th ed. Pearson; 2007. P. 498–499.
  22. Balemba OB, Salter MJ, Mawe GM. Innervation of the extrahepatic biliary tract. Anat Rec A Discov Mol Cell Evol Biol. 2004;280(1):836–847. doi: 10.1002/ar.a.20089.
  23. Hendrickx AP, Top J, Bayjanov JR, et al. Antibiotic-driven dysbiosis mediates intraluminal agglutination and alternative segregation of Enterococcus faecium from the intestinal epithelium. MBio. 2015;6(6):e01346–01315. doi: 10.1128/mBio.01346-15.
  24. Li H, Limenitakis JP, Fuhrer T, et al. The outer mucus layer hosts a distinct intestinal microbial niche. Nat Commun. 2015;6:8292. doi: 10.1038/ncomms9292.
  25. Savage DC, Dubos R, Schaedler RW. The gastrointestinal epithelium and its autochthonous bacterial flora. J Exp Med. 1968;127(1):67–76. doi: 10.1084/jem.127.1.67.
  26. McFarland LV. Update on the changing epidemiology of Clostridium difficile-associated disease. Nat Clin Pract Gastroenterol Hepatol. 2008;5(1):40–48. doi: 10.1038/ncpgasthep1029.
  27. Cohen MB. Clostridium difficile infections: emerging epidemiology and new treatments. J Pediatr Gastroenterol Nutr. 2009;48 Suppl 2:S63–65. doi: 10.1097/MPG.0b013e3181a118c6.
  28. Swidsinski A, Loening-Baucke V, Lochs H, Hale LP. Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J Gastroenterol. 2005;11(8):1131–1140. doi: 10.3748/wjg.v11.i8.1131.
  29. Limoli DH, Jones CJ, Wozniak DJ. Bacterial extracellular polysaccharides in biofilm formation and function. Microbiol Spectr. 2015;3(3). doi: 10.1128/microbiolspec.MB-0011-2014.
  30. de Vos WM. Microbial biofilms and the human intestinal microbiome. NPJ Biofilms Microbiomes. 2015;1(1):15005. doi: 10.1038/npjbiofilms.2015.5.
  31. Chen WG, Liu FL, Ling ZX, et al. Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS One. 2012;7(6):e39743. doi: 10.1371/journal.pone.0039743.
  32. Swidsinski A, Loening-Baucke V. Functional structure of intestinal microbiota in health and disease. In: Fredricks DN, editor. Human microbiota: how microbial communities affect health and disease. Hoboken, New Jersey: John Wiley & Sons, Inc; 2013. P. 211–253. doi: 10.1002/9781118409855.
  33. Sung JY, Costerton JW, Shaffer EA. Defense system in the biliary tract against bacterial infection. Dig Dis Sci. 1992;37(5):689–696. doi: 10.1007/Bf01296423.
  34. Robinson CM, Pfeiffer JK. Viruses and the Microbiota. Annu Rev Virol. 2014;1:55–69. doi: 10.1146/annurev-virology-031413-085550.
  35. Mueller T, Beutler C, Pico AH, et al. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver Int. 2011;31(10):1574–1588. doi: 10.1111/j.1478-3231.2011.02635.x.
  36. Ye F, Shen H, Li Z, et al. Influence of the biliary system on biliary bacteria revealed by bacterial communities of the human biliary and upper digestive tracts. PLoS One. 2016;11(3):e0150519. doi: 10.1371/journal.pone.0150519.
  37. Gunn JS. Mechanisms of bacterial resistance and response to bile. Microbes Infect. 2000;2(8):907–913. doi: 10.1016/s1286-4579(00)00392-0.
  38. Giannelli V, Di Gregorio V, Iebba V, et al. Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol. 2014;20(45):16795–16810. doi: 10.3748/wjg.v20.i45.16795.
  39. Miyake Y, Yamamoto K. Role of gut microbiota in liver diseases. Hepatol Res. 2013;43(2):139–146. doi: 10.1111/j.1872-034X.2012.01088.x.
  40. Govorun VM, Momynaliev KT, Chelisheva VV, Isakov VA. Helicobacter spp. found in gallbladder stones. Gut. 2002;51(Suppl 2):A74.
  41. Gevers D, Kugathasan S, Denson LA, et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe. 2014;15(3):382–392. doi: 10.1016/j.chom.2014.02.005.
  42. Pflughoeft KJ, Versalovic J. Human microbiome in health and disease. Annu Rev Pathol. 2012;7:99–122. doi: 10.1146/annurev-pathol-011811-132421.
  43. Markland SM, LeStrange KJ, Sharma M, Kniel KE. Old friends in new places: exploring the role of extraintestinal E. coli in intestinal disease and foodborne illness. Zoonoses Public Health. 2015;62(7):491–496. doi: 10.1111/zph.12194.
  44. Lozupone CA, Li M, Campbell TB, et al. Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe. 2013;14(3):329–339. doi: 10.1016/j.chom.2013.08.006.
  45. Compare D, Coccoli P, Rocco A, et al. Gut-liver axis: The impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2012;22(6):471–476. doi: 10.1016/j.numecd.2012.02.007.
  46. Hoban A, Stilling R, Desbonnet L, et al. Regulation of myelination in the prefrontal cortex by the gut microbiota: implications for health and disease. FASEB J. 2015;29(1 Suppl):672.4.
  47. Backhed F, Fraser CM, Ringel Y, et al. Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. Cell Host Microbe. 2012;12(5):611–622. doi: 10.1016/j.chom.2012.10.012.
  48. Varyukhina S, Freitas M, Bardin S, et al. Glycan-modifying bacteria-derived soluble factors from Bacteroides thetaiotaomicron and Lactobacillus casei inhibit rotavirus infection in human intestinal cells. Microbes Infect. 2012;14(3):273–278. doi: 10.1016/j.micinf.2011.10.007.
  49. Kuss SK, Best GT, Etheredge CA, et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science. 2011;334(6053):249–252. doi: 10.1126/science.1211057.
  50. Гибадулина И.О., Гибадулин Н.В. Диагностические аспекты хронического холангита после холецистэктомии // Экспериментальная и клиническая гастроэнтерология. ― 2011. ― №6 ― С. 68–72. [Gibadulina IO, Gibadulin NV. Diagnostic aspects of chronic cholangitis after cholecystectomy. Eksp Klin Gastroenterol. 2011;(6):68−72. (In Russ).]
  51. Shaffer EA. Epidemiology and risk factors for gallstone disease: has the paradigm changed in the 21st century? Curr Gastroenterol Rep. 2005;7(2):132–140. doi: 10.1007/s11894-005-0051-8.
  52. Nakanuma Y. Tutorial review for understanding of cholangiopathy. Int J Hepatol. 2012;2012:547840. doi: 10.1155/2012/547840.
  53. Welch RA, Burland V, Plunkett G 3rd, et al. Extensive mosaic structure revealed by the complete genome sequence of uropathogenic Escherichia coli. Proc Natl Acad Sci U S A. 2002;99(26):17020–17024. doi: 10.1073/pnas.252529799.
  54. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207–214. doi: 10.1038/nature11234.
  55. Simon C, Daniel R. Metagenomic analyses: past and future trends. Appl Environ Microbiol. 2011;77(4):1153–1161. doi: 10.1128/AEM.02345-10.
  56. Aagaard K, Petrosino J, Keitel W, et al. The Human Microbiome Project strategy for comprehensive sampling of the human microbiome and why it matters. FASEB J. 2013;27(3):1012–1022. doi: 10.1096/fj.12-220806.
  57. Dubinkina VB, Ischenko DS, Ulyantsev VI, et al. Assessment of k-mer spectrum applicability for metagenomic dissimilarity analysis. BMC Bioinformatics. 2016;17:38. doi: 10.1186/s12859-015-0875-7.
  58. Scott AJ, Khan GA. Origin of bacteria in bileduct bile. Lancet. 1967;2(7520):790–792. doi: 10.1016/S0140-6736(67)92231-3.
  59. Hov JR. The microbiome and human disease: a new organ of interest in biliary disease. In: Hirschfield G, Adams D, Liaskou E, editors. Biliary disease: from science to clinic. Cham: Springer International Publishing; 2017. Р. 85−96. doi: 10.1007/978-3-319-50168-0_5.
  60. Colman RJ, Rubin DT. Fecal microbiota transplantation as therapy for inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis. 2014;8(12):1569–1581. doi: 10.1016/j.crohns.2014.08.006.
  61. Bolan S, Seshadri B, Talley NJ, Naidu R. Bio-banking gut microbiome samples. EMBO Rep. 2016;17(7):929–930. doi: 10.15252/embr.201642572.
  62. Tabibian JH, O’Hara SP, Lindor KD. Primary sclerosing cholangitis and the microbiota: current knowledge and perspectives on etiopathogenesis and emerging therapies. Scand J Gastroenterol. 2014;49(8):901–908. doi: 10.3109/00365521.2014.913189.
  63. Mattner J. Impact of microbes on the pathogenesis of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Int J Mol Sci. 2016;17(11):1864. doi: 10.3390/ijms17111864.
  64. Vitek L, Carey MC. New pathophysiological concepts underlying pathogenesis of pigment gallstones. Clin Res Hepatol Gastroenterol. 2012;36(2):122–129. doi: 10.1016/j.clinre.2011.08.010.
  65. Stinton LM, Myers RP, Shaffer EA. Epidemiology of gallstones. Gastroenterol Clin North Am. 2010;39(2):157–169. doi: 10.1016/j.gtc.2010.02.003.
  66. Keren N, Konikoff FM, Paitan Y, et al. Interactions between the intestinal microbiota and bile acids in gallstones patients. Environ Microbiol Rep. 2015;7(6):874–880. doi: 10.1111/1758-2229.12319.
  67. Krastev Z, Vladimirov B, Mateva L, Alexiev A. Quantitative assessment of severity of biliary tract infection. Hepatogastroenterology. 1996;43(10):792−795.
  68. Darkahi B, Sandblom G, Liljeholm H, et al. Biliary microflora in patients undergoing cholecystectomy. Surg Infect (Larchmt). 2014;15(3):262–265. doi: 10.1089/sur.2012.125.
  69. Cotter PD, Stanton C, Ross RP, Hill C. The impact of antibiotics on the gut microbiota as revealed by high throughput DNA sequencing. Discov Med. 2012;13(70):193–199.
  70. Modi SR, Collins JJ, Relman DA. Antibiotics and the gut microbiota. J Clin Invest. 2014;124(10):4212–4218. doi: 10.1172/Jci72333.
  71. Ecological modeling from time-series inference: insight into dynamics and stability of intestinal microbiota. PLoS Comput Biol. 2013;9(12):e1003388. doi: 10.1371/journal.pcbi.1003388.
  72. Глебов К.Г., Котовский А.Е., Дюжева Т.Г. Критерии выбора конструкции эндопротеза для эндоскопического стентирования желчных протоков // Анналы хирургической гепатологии. ― 2014. ― T.19. ― №2 ― С. 55–65. [Glebov KG, Kotov-skiy AE, Dyuzheva TG. Criteria for the choice of construction of endoprosthesis for endoscopic biliary stenting. Annaly khirurgicheskoi gepatologii. 2014;19(2):55−65. (In Russ.)]
  73. Swidsinski A, Schlien P, Pernthaler A, et al. Bacterial biofilm within diseased pancreatic and biliary tracts. Gut. 2005;54(3):388–395. doi: 10.1136/gut.2004.043059.

Supplementary files

There are no supplementary files to display.

Comments on this article

View all comments

Copyright (c) 2017 "Paediatrician" Publishers LLC

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies