Frontiers of Medicine

, Volume 12, Issue 2, pp 123–129 | Cite as

Gut microbial balance and liver transplantation: alteration, management, and prediction

  • Xinyao Tian
  • Zhe Yang
  • Fangzhou Luo
  • Shusen Zheng


Liver transplantation is a conventional treatment for terminal stage liver diseases. However, several complications still hinder the survival rate. Intestinal barrier destruction is widely observed among patients receiving liver transplant and suffering from ischemia–reperfusion or rejection injuries because of the relationship between the intestine and the liver, both in anatomy and function. Importantly, the resulting alteration of gut microbiota aggravates graft dysfunctions during the process. This article reviews the research progress for gut microbial alterations and liver transplantation. Especially, this work also evaluates research on the management of gut microbial alteration and the prediction of possible injuries utilizing microbial alteration during liver transplantation. In addition, we propose possible directions for research on gut microbial alteration during liver transplantation and offer a hypothesis on the utilization of microbial alteration in liver transplantation. The aim is not only to predict perioperative injuries but also to function as a method of treatment or even inhibit the rejection of liver transplantation.


gut microbial balance liver transplantation ischemia–reperfusion acute rejection 


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This work was supported by the Innovative Research Groups of National Natural Science Foundation of China (No. 81421062), Major Program of the National Natural Science Foundation of China (No. 91542205), Natural Science Foundation of Zhejiang Province (No. LQ13H160004), Zhejiang Medical and Health Technology Program (No. 201472813), and Independent Research Program of Zhejiang University (No. 2016FZA7012).


  1. 1.
    Sayegh MH, Carpenter CB. Transplantation 50 years later—progress, challenges, and promises. N Engl J Med 2004; 351(26): 2761–2766CrossRefPubMedGoogle Scholar
  2. 2.
    Hübscher SG. What is the long-term outcome of the liver allograft? J Hepatol 2011; 55(3): 702–717CrossRefPubMedGoogle Scholar
  3. 3.
    Bartosch S, Fite A, Macfarlane GT,McMurdo MET. Characterization of bacterial communities in feces from healthy elderly volunteers and hospitalized elderly patients by using real-time PCR and effects of antibiotic treatment on the fecal microbiota. Appl Environ Microbiol 2004; 70(6): 3575–3581CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science 2005; 308(5728): 1635–1638CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, Huth M, Nikolaev A, Neufert C, Madison B, Gumucio D, Neurath MF, Pasparakis M. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 2007; 446(7135): 557–561CrossRefPubMedGoogle Scholar
  6. 6.
    Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 2009; 15(13): 1546–1558CrossRefPubMedGoogle Scholar
  7. 7.
    Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr 2002; 22:283–307CrossRefPubMedGoogle Scholar
  8. 8.
    Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Hostbacterial mutualism in the human intestine. Science 2005; 307 (5717): 1915–1920CrossRefPubMedGoogle Scholar
  9. 9.
    Cicalese L, Sileri P, Green M, Abu-Elmagd K, Kocoshis S, Reyes J. Bacterial translocation in clinical intestinal transplantation. Transplantation 2001; 71(10): 1414–1417CrossRefPubMedGoogle Scholar
  10. 10.
    Nishida S, Levi D, Kato T, Nery JR, Mittal N, Hadjis N, Madariaga J, Tzakis AG. Ninety-five cases of intestinal transplantation at the University of Miami. J Gastrointest Surg 2002; 6(2): 233–239CrossRefPubMedGoogle Scholar
  11. 11.
    Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003; 361(9356): 512–519CrossRefPubMedGoogle Scholar
  12. 12.
    Zoetendal EG, Collier CT, Koike S, Mackie RI, Gaskins HR. Molecular ecological analysis of the gastrointestinal microbiota: a review. J Nutr 2004; 134(2): 465–472CrossRefPubMedGoogle Scholar
  13. 13.
    Sheehy EC, Beighton D, Roberts GJ. The oral microbiota of children undergoing liver transplantation. Oral Microbiol Immunol 2000; 15(3): 203–210CrossRefPubMedGoogle Scholar
  14. 14.
    Kamada N, Calne RY. A surgical experience with five hundred thirty liver transplants in the rat. Surgery 1983; 93(1 Pt 1): 64–69PubMedGoogle Scholar
  15. 15.
    Muyzer G, de Waal EC, Uitterlinden AG. Profiling of complex microbial populations by denaturing gradient gel electrophoresis analysis of polymerase chain reaction-amplified genes coding for 16S rRNA. Appl Environ Microbiol 1993; 59(3): 695–700PubMedPubMedCentralGoogle Scholar
  16. 16.
    Xing HC, Li LJ, Xu KJ, Shen T, Chen YB, Sheng JF, Chen Y, Fu SZ, Chen CL, Wang JG, Yan D, Dai FW, Zheng SS. Protective role of supplement with foreign Bifidobacterium and Lactobacillus in experimental hepatic ischemia-reperfusion injury. J Gastroenterol Hepatol 2006; 21(4): 647–656CrossRefPubMedGoogle Scholar
  17. 17.
    Westad F, Martens H. Variable selection in near infrared spectroscopy based on significance testing in partial least squares regression. J Near Infrared Spectrosc 2000; 8(2): 117–124CrossRefGoogle Scholar
  18. 18.
    Barkholt L, Ericzon BG, Tollemar J, Malmborg AS, Ehrnst A, Wilczek H, Andersson J. Infections in human liver recipients: different patterns early and late after transplantation. Transpl Int 1993; 6(2): 77–84CrossRefPubMedGoogle Scholar
  19. 19.
    Thompson JR, Marcelino LA, Polz MF. Heteroduplexes in mixedtemplate amplifications: formation, consequence and elimination by ‘reconditioning PCR’. Nucleic Acids Res 2002; 30(9): 2083–2088CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lipp JS, Morono Y, Inagaki F, Hinrichs KU. Significant contribution of Archaea to extant biomass in marine subsurface sediments. Nature 2008; 454(7207): 991–994CrossRefPubMedGoogle Scholar
  21. 21.
    Heilig HG, Zoetendal EG, Vaughan EE, Marteau P, Akkermans ADL, de Vos WM. Molecular diversity of Lactobacillus spp. and other lactic acid bacteria in the human intestine as determined by specific amplification of 16S ribosomal DNA. Appl Environ Microbiol 2002; 68(1): 114–123CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wise MG, Siragusa GR. Quantitative analysis of the intestinal bacterial community in one- to three-week-old commercially reared broiler chickens fed conventional or antibiotic-free vegetable-based diets. J Appl Microbiol 2007; 102(4): 1138–1149PubMedGoogle Scholar
  23. 23.
    Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC. Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clin Ther 2015; 37(5): 984–995CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Vanhoutte T, Huys G, Brandt E, Swings J. Temporal stability analysis of the microbiota in human feces by denaturing gradient gel electrophoresis using universal and group-specific 16S rRNA gene primers. FEMS Microbiol Ecol 2004; 48(3): 437–446CrossRefPubMedGoogle Scholar
  25. 25.
    Wu ZW, Ling ZX, Lu HF, Zuo J, Sheng JF, Zheng SS, Li LJ. Changes of gut bacteria and immune parameters in liver transplant recipients. Hepatobiliary Pancreat Dis Int 2012; 11(1): 40–50CrossRefPubMedGoogle Scholar
  26. 26.
    Wu ZW, Lu HF, Wu J, Zuo J, Chen P, Sheng JF, Zheng SS, Li LJ. Assessment of the fecal lactobacilli population in patients with hepatitis B virus-related decompensated cirrhosis and hepatitis B cirrhosis treated with liver transplant. Microb Ecol 2012; 63(4): 929–937CrossRefPubMedGoogle Scholar
  27. 27.
    Xing HC, Li LJ, Xu KJ, Shen T, Chen YB, Sheng JF, Yu YS, Chen YG. Intestinal microflora in rats with ischemia/reperfusion liver injury. J Zhejiang Univ Sci B 2005; 6(1): 14–21CrossRefPubMedGoogle Scholar
  28. 28.
    Xie Y, Luo Z, Li Z, Deng M, Liu H, Zhu B, Ruan B, Li L. Structural shifts of fecal microbial communities in rats with acute rejection after liver transplantation. Microb Ecol 2012; 64(2): 546–554CrossRefPubMedGoogle Scholar
  29. 29.
    Lu H, He J, Wu Z, Xu W, Zhang H, Ye P, Yang J, Zhen S, Li L. Assessment of microbiome variation during the perioperative period in liver transplant patients: a retrospective analysis. Microb Ecol 2013; 65(3): 781–791CrossRefPubMedGoogle Scholar
  30. 30.
    Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol 2009; 124(1): 3–20, quiz 21–22CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Jiang JW, Ren ZG, Chen LY, Jiang L, Xie HY, Zhou L, Zheng SS. Enteral supplementation with glycyl-glutamine improves intestinal barrier function after liver transplantation in rats. Hepatobiliary Pancreat Dis Int 2011; 10(4): 380–385CrossRefPubMedGoogle Scholar
  32. 32.
    Ren ZG, Liu H, Jiang JW, Jiang L, Chen H, Xie HY, Zhou L, Zheng SS. Protective effect of probiotics on intestinal barrier function in malnourished rats after liver transplantation. Hepatobiliary Pancreat Dis Int 2011; 10(5): 489–496CrossRefPubMedGoogle Scholar
  33. 33.
    Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2005; 2 (9): 416–422CrossRefPubMedGoogle Scholar
  34. 34.
    Baumgart DC, Dignass AU. Intestinal barrier function. Curr Opin Clin Nutr Metab Care 2002; 5(6): 685–694CrossRefPubMedGoogle Scholar
  35. 35.
    Tapuria N, Kumar Y, Habib MM,Abu Amara M, Seifalian AM, Davidson BR. Remote ischemic preconditioning: a novel protective method from ischemia reperfusion injury—a review. J Surg Res 2008; 150(2): 304–330CrossRefPubMedGoogle Scholar
  36. 36.
    Ren Z, Cui G, Lu H, Chen X, Jiang J, Liu H, He Y, Ding S, Hu Z, Wang W, Zheng S. Liver ischemic preconditioning (IPC) improves intestinal microbiota following liver transplantation in rats through 16s rDNA-based analysis of microbial structure shift. PLoS One 2013; 8(10): e75950CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Xie Y, Chen H, Zhu B, Qin N, Chen Y, Li Z, Deng M, Jiang H, Xu X, Yang J, Ruan B, Li L. Effect of intestinal microbiota alteration on hepatic damage in rats with acute rejection after liver transplantation. Microb Ecol 2014; 68(4): 871–880CrossRefPubMedGoogle Scholar
  38. 38.
    Suau A, Bonnet R, Sutren M, Godon JJ, Gibson GR, Collins MD, Doré J. Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut. Appl Environ Microbiol 1999; 65(11): 4799–4807PubMedPubMedCentralGoogle Scholar
  39. 39.
    Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol 2008; 26(10): 1135–1145CrossRefPubMedGoogle Scholar
  40. 40.
    Wang WL, Xu SY, Ren ZG, Tao L, Jiang JW, Zheng SS. Application of metagenomics in the human gut microbiome. World J Gastroenterol 2015; 21(3): 803–814CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Oh PL, Martínez I, Sun Y, Walter J, Peterson DA, Mercer DF. Characterization of the ileal microbiota in rejecting and nonrejecting recipients of small bowel transplants. Am J Transplant 2012; 12(3): 753–762CrossRefPubMedGoogle Scholar
  42. 42.
    Lee JR, Muthukumar T, Dadhania D, Toussaint NC, Ling L, Pamer E, Suthanthiran M. Gut microbial community structure and complications after kidney transplantation: a pilot study. Transplantation 2014; 98(7): 697–705CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R, Dudakov JA, Liu C, West ML, Singer NV, Equinda MJ, Gobourne A, Lipuma L, Young LF, Smith OM, Ghosh A, Hanash AM, Goldberg JD, Aoyama K, Blazar BR, Pamer EG, van den Brink MRM. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med 2012; 209(5): 903–911CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Ren Z, Jiang J, Lu H, Chen X, He Y, Zhang H, Xie H, Wang W, Zheng S, Zhou L. Intestinal microbial variation may predict early acute rejection after liver transplantation in rats. Transplantation 2014; 98(8): 844–852CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany 2018

Authors and Affiliations

  • Xinyao Tian
    • 1
    • 2
  • Zhe Yang
    • 1
    • 2
  • Fangzhou Luo
    • 1
    • 2
  • Shusen Zheng
    • 1
    • 2
  1. 1.Department of Hepatobiliary and Pancreatic Surgery, First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
  2. 2.Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated HospitalZhejiang University School of MedicineHangzhouChina

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