The «microbiome» of post-liver transplant complications

This paper reviews modern literature and presents a brief analysis of our own data on one of the most pressing issues in modern transplantology and, in particular, transplant hepatology – the role and place of gut-liver axis (GLA) in the early post-transplant period. Objective: to compare the correlation between gut microbiome palette and incidence of certain early postoperative complications in liver transplantation. Materials and methods. The study design is presented as a pilot, prospective, observational, double-blind study based on investigation of the composition of the microbiome residing in the large intestinal in patients that underwent orthotopic liver transplantation (OLTx). The primary cohort of patients consisted of 12 patients who underwent OLTx from a postmortem donor. To assess the gut microbiome palette, biomaterial was collected from all patients in the preand post-transplant period followed by next-generation sequencing. The study was conducted as primary study results registered under number NCT04281797. Results. In the preoperative period, differences close to statistically reliable in relation to Actinobacteria were observed in patients included in the liver transplant waiting list for cirrhosis (LC) and hepatocellular carcinoma (HCC) in cirrhosis. However, due to the pilot nature of the study, this study cohort was limited to an extremely small sample. In turn, in the post-transplant period, there was a statistically significant difference in the taxonomic range of Actinobacteria (p < 0.05) between the above groups, indicating a possible effect of liver transplantation on the gut microbiome. In addition, in the early post-transplant period, there was a marked difference in the microbiome palette between patients with and without acute cellular rejection. Conclusion. GLA and the gut microbiome play a critical role in many liver diseases, and may also have a significant impact on the post-transplant period. In this regard, further research in this direction will not only characterize the predictors and risk factors of bacterial infection and rejection episodes, but will also allow us to form a completely new approach to the treatment tactics for certain complications, including through formation of a microbiota-oriented pharmacotherapy.

1. Volta U, Bonazzi C, Bianchi FB, Baldoni AM, Zoli M, Pisi E. IgA antibodies to dietary antigens in liver cirrhosis. Ric Clin Lab. 1987 Jul-Sep; 17 (3): 235–242. doi: 10.1007/BF02912537. PMID: 3671996.

2. Milosevic I, Vujovic A, Barac A, Djelic M, Korac M, Radovanovic Spurnic A et al. Gut-Liver Axis, Gut Microbiota, and Its Modulation in the Management of Liver Diseases: A Review of the Literature. Int J Mol Sci. 2019 Jan 17; 20 (2): 395. doi: 10.3390/ijms20020395. PMID: 30658519; PMCID: PMC6358912.

3. Tilg H, Burcelin R, Tremaroli V. Liver tissue microbiome in NAFLD: next step in understanding the gut-liver axis? Gut. 2020 Aug; 69 (8): 1373–1374. doi: 10.1136/gutjnl-2019-320490. Epub 2020 Feb 14. PMID: 32060128.

4. Miele L, Marrone G, Lauritano C, Cefalo C, Gasbarrini A, Day C et al. Gut-liver axis and microbiota in NAFLD: insight pathophysiology for novel therapeutic target. Curr Pharm Des. 2013; 19 (29): 5314–5324. PMID: 23432669.

5. Solé C, Guilly S, Da Silva K, Llopis M, Le-Chatelier E, Huelin P et al. Alterations in Gut Microbiome in Cirrhosis as Assessed by Quantitative Metagenomics: Relationship with Acute-on-Chronic Liver Failure and Prognosis. Gastroenterology. 2021 Jan; 160 (1): 206–218. e13. doi: 10.1053/j.gastro.2020.08.054. Epub 2020 Sep 14. PMID: 32941879.

6. Lee GH. Hepatic encephalopathy in acute-on-chronic liver failure. Hepatol Int. 2015 Oct; 9 (4): 520–526. doi: 10.1007/s12072-015-9626-0. Epub 2015 May 28. PMID: 26016460.

7. Stoma IO. Mikrobiom cheloveka; Belorus. gos. med. un-t, Min. nauch.-prakt. centr hirurgii, transplantologii i gematologii. Minsk: Doktor Dizajn, 2018; 122.

8. Blesl A, Stadlbauer V. The Gut-Liver Axis in Cholestatic Liver Diseases. Nutrients. 2021 Mar 21; 13 (3): 1018. doi: 10.3390/nu13031018. PMID: 33801133; PMCID: PMC8004151.

9. Wang P, Chen K. Gut microbiota and hepatocellular carcinoma. Hepatobiliary Surg Nutr. 2020 Jun; 9 (3): 345–347. doi: 10.21037/hbsn.2019.10.34. PMID: 32509825; PMCID: PMC7262609.

10. Xie Y, Luo Z, Li Z, Deng M, Liu H, Zhu B et al. Structural shifts of fecal microbial communities in rats with acute rejection after liver transplantation. Microb Ecol. 2012 Aug; 64 (2): 546–554. doi: 10.1007/s00248-012-0030-1. Epub 2012 Mar 21. PMID: 22430504.

11. Ancona G, Alagna L, Lombardi A, Palomba E, Castelli V, Renisi G et al. The Interplay between Gut Microbiota and the Immune System in Liver Transplant Recipients and Its Role in Infections. Infect Immun. 2021 Oct 15; 89 (11): e0037621. doi: 10.1128/IAI.00376-21.

12. Albillos A, Gottardi A, Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy. J Hepatol. 2020 Mar; 72 (3): 558–577. doi: 10.1016/j.jhep.2019.10.003.

13. Kim S-I. Bacterial infection after liver transplantation. World J Gastroenterol. 2014 May 28; 20 (20): 6211–6220. doi: 10.3748/wjg.v20.i20.6211. PMID: 24876741; PMCID: PMC4033458.

14. Singh N, Paterson DL, Chang FY, Gayowski T, Squier C, Wagener MM et al. Methicillin-resistant Staphylococcus aureus: the other emerging resistant gram-positive coccus among liver transplant recipients. Clin Infect Dis. 2000; 30: 322–327.

15. Lin M, Mah A, Wright A. Infectious complications of liver transplantation. AME Medical Journal. 2018; 3 (1). Retrieved from https://amj.amegroups.com/article/view/4228.

16. Hlebnikova EP, Chzhao AV. Infekcionnye oslozhnenija u pacientov, podvergshihsja peresadke pecheni. Transplantologiya. The Russian Journal of Transplantation. 2011; (2–3): 57–62. (In Russ.).

17. Camus C. Complications infectieuses chez le transplanté hépatique. Réanimation. 2014; 23: 317–326. doi:10.1007/s13546-014-0888-7.

18. Pedersen MR, Choi M, Brink JA, Seetharam AB. Pretransplant factors and & associations with postoperative respiratory failure, ICU length of stay, and short-term survival after liver transplantation in a high MELD population. J Transplant. 2016; 2016: 6787854.

19. Petrowsky H, Rana A, Kaldas FM, Sharma A, Hong JC, Agopian VG et al. Liver transplantation in highest acuity recipients: identifying factors to avoid futility. Ann Surg. 2014; 259: 1186–1194.

20. Chen C, Yang D, Gao S, Zhang Y, Chen L, Wang B et al. Development and performance assessment of novel machine learning models to predict pneumonia after liver transplantation. Respir Res. 2021 Mar 31; 22 (1): 94. doi: 10.1186/s12931-021-01690-3. PMID: 33789673; PMCID: PMC8011203.

21. Savier E, Lim C, Rayar M, Orlando F, Boudjema K, Mohkam K et al. Favorable Outcomes of Liver Transplantation from Controlled Circulatory Death Donors Using Normothermic Regional Perfusion Compared to Brain Death Donors. Transplantation. 2020 Sep; 104 (9): 1943–1951. doi: 10.1097/TP.0000000000003372.

22. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020 Jun; 30 (6): 492–506. doi: 10.1038/s41422-020-0332-7. Epub 2020 May 20. PMID: 32433595; PMCID: PMC7264227.

23. Yang X, Lu D, Zhuo J, Lin Z, Yang M, Xu X. The Gutliver Axis in Immune Remodeling: New insight into Liver Diseases. Int J Biol Sci. 2020; 16 (13): 2357–2366. Published 2020 Jun 23. doi: 10.7150/ijbs.46405.

24. Ait Faqih S, Guebre-Egziabher F. Microbiote en transplantation d’organe solide. Le Courrier de la Transplantation. 2016 avril-mai-juin; XVI (2): 66–69.

25. Acharya C, Sahingur SE. Microbiota, cirrhosis, and the emerging oral-gut-liver axis. JCI Insight. 2017 Oct 5; 2 (19): e94416. doi: 10.1172/jci.insight.94416. PMID: 28978799; PMCID: PMC5841881.

26. Arab JP, Martin-Mateos RM, Shah VH. Gut-liver axis, cirrhosis, and portal hypertension: the chicken and the egg. Hepatol Int. 2018 Feb; 12 (Suppl 1): 24–33. doi: 10.1007/s12072-017-9798-x. Epub 2017 May 26. PMID: 28550391; PMCID: PMC6876989.

27. Hackstein CP, Assmus LM, Welz M, Klein S, Schwandt T, Schultze J et al. Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis. Gut. 2017; 66: 507–518. https://doi.org/10.1136/gutjnl-2015-311224.

28. Zigmond E, Bernshtein B, Friedlander G, Walker CR, Yona S, Kim KW et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity. 2014 May 15; 40 (5): 720–733. doi: 10.1016/j.immuni.2014.03.012. Epub 2014 May 1. PMID: 24792913.

29. Zhang Y, Xie B, Chen X, Zhang J, Yuan S. A key role of gut microbiota-vagus nerve/spleen axis in sleep deprivation-mediated aggravation of systemic inflammation after LPS administration. Life Sci. 2021 Jan 15; 265: 118736. doi: 10.1016/j.lfs.2020.118736. Epub 2020 Nov 8. PMID: 33176177.

30. Wu Y, Wang M, Zhu Y, Lin S. Serum interleukin-6 in the diagnosis of bacterial infection in cirrhotic patients: A meta-analysis. Medicine (Baltimore). 2016 Oct; 95 (41): e5127. doi: 10.1097/MD.0000000000005127. PMID: 27741137; PMCID: PMC5072964.

31. Kato K, Nagao M, Miyamoto K, Oka K, Takahashi M, Yamamoto M. Longitudinal Analysis of the Intestinal Microbiota in Liver Transplantation. Transplant Direct. 2017 Mar 10; 3 (4): e144. doi: 10.1097/TXD.0000000000000661. PMID: 28405600; PMCID: PMC5381737.

32. Schwenger KJ, Clermont-Dejean N, Allard JP. The role of the gut microbiome in chronic liver disease: the clinical evidence revised. JHEP Rep. 2019 Jul 31; 1 (3): 214–226. doi: 10.1016/j.jhepr.2019.04.004. PMID: 32039372; PMCID: PMC7001555.

33. Brandl K, Kumar V, Eckmann L. Gut-liver axis at the frontier of host-microbial interactions. Am J Physiol Gastrointest Liver Physiol. 2017 May 1; 312 (5): G413–G419. doi: 10.1152/ajpgi.00361.2016. Epub 2017 Feb 23. PMID: 28232456; PMCID: PMC5451561.

34. Bawa M, Saraswat VA. Gut-liver axis: role of inflammasomes. J Clin Exp Hepatol. 2013 Jun; 3 (2): 141–149. doi: 10.1016/j.jceh.2013.03.225. Epub 2013 Apr 15. PMID: 25755488; PMCID: PMC4216435.

35. Hakansson A, Molin G. Gut microbiota and inflammation. Nutrients. 2011; 3: 637–682.

36. Palmblad J. The role of granulocytes in inflammation. Scand J Rheumatol. 1984; 13: 163–172.

37. Fujiwara N, Kobayashi K. Macrophages in inflammation. Curr Drug Targets Inflamm Allergy. 2005; 4: 281–286.

38. Anderson CF, Mosser DM. A novel phenotype for an activated macrophage: the type 2 activated macrophage. J Leukoc Biol. 2002; 72: 101–106.

39. Gordon S. Alternative activation of macrophages. Nat Rev. 2003; 3: 23–35.

40. Chen D, Le TH, Shahidipour H, Read SA, Ahlenstiel G. The Role of Gut-Derived Microbial Antigens on Liver Fibrosis Initiation and Progression. Cells. 2019; 8 (11): 1324. Published 2019 Oct 27. doi: 10.3390/cells8111324.

41. Stärkel P, De Saeger C, Strain AJ, Leclercq I, Horsmans Y. NFκB, cytokines, TLR3 and 7 expressions in human end-stage HCV and alcoholic liver disease. Eur J Clin Investig. 2010; 40: 575–584. doi: 10.1111/j.1365-2362.2010.02295.x.

42. Miao EA, Mao DP, Yudkosky N. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci USA. 2010; 107: 3076–3080.

43. Kubicek-Sutherland JZ, Vu DM, Noormohamed A, Mendez HM, Stromberg LR, Pedersen CA et al. Direct detection of bacteremia by exploiting host-pathogen interactions of lipoteichoic acid and lipopolysaccharide. Sci Rep. 2019 Apr 17; 9 (1): 6203. doi: 10.1038/s41598-019-42502-5. PMID: 30996333; PMCID: PMC6470174.

44. Byun JS, Suh YG, Yi HS, Lee YS, Jeong WI. Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice. J Hepatol. 2013 Feb; 58 (2): 342–349. doi: 10.1016/j.jhep.2012.09.016.

45. Aragonès G, Colom-Pellicer M, Aguilar C, Guiu-Jurado E, Martínez S, Sabench F et al. Circulating microbiota-derived metabolites: A «liquid biopsy? Int J Obes. 2020 Apr; 44 (4): 875–885. doi: 10.1038/s41366-019-0430-0.

46. Queck A, Carnevale R, Uschner FE, Schierwagen R, Klein S, Jansen C et al. Role of portal venous platelet activation in patients with decompensated cirrhosis and TIPS. Gut. 2020 Aug; 69 (8): 1535–1536.

47. Dattaroy D, Seth RK, Sarkar S, Kimono D, Albadrani M, Chandrashekaran V et al. Sparstolonin B (SSnB) attenuates liver fibrosis via a parallel conjugate pathway involving P53-P21 axis, TGF-beta signaling and focal adhesion that is TLR4 dependent. Eur J Pharmacol. 2018 Dec 15; 841: 33–48. doi: 10.1016/j.ejphar.2018.08.040.

48. Xiao Y, Liu F, Yang J, Zhong M, Zhang E, Li Y et al. Over-activation of TLR5 signaling by high-dose flagellin induces liver injury in mice. Cell Mol Immunol. 2015; 12: 729–742. doi: 10.1038/cmi.2014.110.

49. Massey VL, Qin L, Cabezas J, Caballeria J, SanchoBru P, Bataller R et al. TLR7-let-7 Signaling Contributes to Ethanol-Induced Hepatic Inflammatory Response in Mice and in Alcoholic Hepatitis. Alcohol Clin Exp Res. 2018 Nov; 42 (11): 2107–2122. doi: 10.1111/acer.13871.

50. Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020 MarApr; 34 (2): 327–331. doi: 10.23812/CONTI-E. PMID: 32171193.

51. Yahfoufi N, Alsadi N, Jambi M, Matar C. The Immunomodulatory and Anti-Inflammatory Role of Polyphenols. Nutrients. 2018 Nov 2; 10 (11): 1618. doi: 10.3390/nu10111618. PMID: 30400131; PMCID: PMC6266803.

52. Juhas U, Ryba-Stanisławowska M, Szargiej P, Myśliwska J. Different pathways of macrophage activation and polarization. Postepy Hig Med Dosw (Online). 2015 Apr 22; 69: 496–502. doi: 10.5604/17322693.1150133. PMID: 25983288.

53. Scheenstra MR, van Harten RM, Veldhuizen EJA, Haagsman HP, Coorens M. Cathelicidins Modulate TLR-Activation and Inflammation. Front Immunol. 2020 Jun 9; 11: 1137. doi: 10.3389/fimmu.2020.01137. PMID: 32582207; PMCID: PMC7296178.

54. Møller DL, Sørensen SS, Wareham NE, Rezahosseini O, Knudsen AD, Knudsen JD et al. Bacterial and fungal bloodstream infections in pediatric liver and kidney transplant recipients. BMC Infectious Diseases. 2021; 21: 541. https://doi.org/10.1186/s12879-021-06224-2.

55. 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 (4): 456–470. Published 2019 Mar 1. doi: 10.1002/hep4.1331.

56. Lee EY, Lee MW, Wong GCL. Modulation of toll-like receptor signaling by antimicrobial peptides. Semin Cell Dev Biol. 2019 Apr; 88: 173–184. doi: 10.1016/j.semcdb.2018.02.002. Epub 2018 Feb 12. PMID: 29432957; PMCID: PMC6087683.

57. De Muynck K, Vanderborght B, Van Vlierberghe H, Devisscher L. The Gut-Liver Axis in Chronic Liver Disease: A Macrophage Perspective. Cells. 2021 Oct 30; 10 (11): 2959. doi: 10.3390/cells10112959. PMID: 34831182; PMCID: PMC8616442.

58. Kronsten VT, Tranah TH, Pariante C, Shawcross DL. Gut-derived systemic inflammation as a driver of depression in chronic liver disease. J Hepatol. 2021 Nov 17: S0168-8278(21)02180-2. doi: 10.1016/j.jhep.2021.11.008. Epub ahead of print. PMID: 34800610.

59. Marra F, Svegliati-Baroni G. Lipotoxicity and the gutliver axis in NASH pathogenesis. J Hepatol. 2018 Feb; 68 (2): 280–295. doi: 10.1016/j.jhep.2017.11.014. Epub 2017 Nov 14. PMID: 29154964.

60. Robinson MW, Harmon C, O’Farrelly. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol. 2016 May; 13 (3): 267–276.

61. Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017; 14: 527–539.

62. Liu D, Cao S, Zhou Y, Xiong Y. J Recent advances in endotoxin tolerance. Cell Biochem. 2019 Jan; 120 (1): 56–70.

63. Milani C, Duranti S, Bottacini F, Casey E, Turroni F, Mahony J et al. The First Microbial Colonizers of the Human Gut: Composition, Activities, and Health Implications of the Infant Gut Microbiota. Microbiol Mol Biol Rev. 2017 Nov 8; 81 (4): e00036-17. doi: 10.1128/MMBR.00036-17. PMID: 29118049; PMCID: PMC5706746.

64. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M et al. Human Gut Microbiome Viewed Across Age and Geography. Nature. 2012; 486: 222–227. doi: 10.1038/nature11053.

65. Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018 Jul; 15 (7): 397–411. doi: 10.1038/s41575-018-0011-z. Erratum in: Nat Rev Gastroenterol Hepatol. 2018 May 21; PMID: 29748586; PMCID: PMC6319369.

66. Inamine T, Schnabl B. Immunoglobulin A and liver diseases. J Gastroenterol. 2018; 53 (6): 691–700. doi: 10.1007/s00535-017-1400-8.

67. Rayes N, Seehofer D, Theruvath T, Schiller RA, Langrehr JM, Jonas S et al. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation – a randomized, double-blind trial. Am J Transplant. 2005 Jan; 5 (1): 125–130. doi: 10.1111/j.1600-6143.2004.00649.x. PMID: 15636620.

68. Mirpuri J, Raetz M, Sturge CR, Wilhelm CL, Benson A, Savani RC et al. Proteobacteria-specific IgA regulates maturation of the intestinal microbiota. Gut Microbes. 2014; 5: 28–39. doi: 10.4161/gmic.26489.

69. Kabat AM, Srinivasan N, Maloy KJ. Modulation of immune development and function by intestinal microbiota. Trends in immunology. 2014; 35: 507–517.

70. Spencer SP, Fragiadakis GK, Sonnenburg JL. Pursuing Human-Relevant Gut Microbiota-Immune Interactions. Immunity. 2019; 51 (2): 225–239. doi: 10.1016/j.immuni.2019.08.002.

71. Chen WLK, Edington C, Suter E, Yu J, Velazquez JJ, Velazquez JG et al. Integrated gut/liver microphysiological systems elucidates inflammatory inter-tissue crosstalk. Biotechnol Bioeng. 2017 Nov; 114 (11): 2648–2659. doi: 10.1002/bit.26370. Epub 2017 Jul 27. PMID: 28667746; PMCID: PMC5614865.

72. Bozward AG, Ronca V, Osei-Bordom D, Oo YH. Gut-Liver Immune Traffic: Deciphering Immune-Pathogenesis to Underpin Translational Therapy. Front Immunol. 2021; 12: 711217. Published 2021 Aug 25. doi: 10.3389/fimmu.2021.711217.

73. Kriss M, Verna EC, Rosen HR, Lozupone CA. Functional Microbiomics in Liver Transplantation: Identifying Novel Targets for Improving Allograft Outcomes. Transplantation. 2019; 103 (4): 668–678. doi: 10.1097/TP.0000000000002568.

74. Shcherba AE, Korotkov SV, Minov AF, Slobodin YV, Savchuk MM, Dzyadzko AM et al. Impact of sevoflurane and acetylcysteine on ischemia-reperfusion injury of the liver from brain-dead donor. Russian Journal of Transplantology and Artificial Organs. 2013; 15 (1): 39–44. https://doi.org/10.15825/1995-1191-2013-1-39-44.

75. Rao J, Cheng F, Zhou H, Yang W, Qiu J, Yang C et al. Nogo-B is a key mediator of hepatic ischemia and reperfusion injury. Redox Biol. 2020 Oct; 37: 101745. doi: 10.1016/j.redox.2020.101745. Epub 2020 Oct 8. PMID: 33099216; PMCID: PMC7582106.

76. Romanque UP, Uribe MM, Videla LA. Mecanismos moleculares en el daño por isquemia-reperfusión hepática y en el preacondicionamiento isquémico [Molecular mechanisms in liver ischemic-reperfusion injury and ischemic preconditioning]. Rev Med Chil. 2005 Apr; 133 (4): 469–476. Spanish. doi: 10.4067/s0034-98872005000400012. Epub 2005 Jun 8. PMID: 15953956.

77. Nastos C, Kalimeris K, Papoutsidakis N, Tasoulis MK, Lykoudis PM, Theodoraki K et al. Global consequences of liver ischemia/reperfusion injury. Oxid Med Cell Longev. 2014; 2014: 906965. doi: 10.1155/2014/906965. Epub 2014 Apr 1. PMID: 24799983; PMCID: PMC3995148.

78. Zhou J, Chen J, Wei Q, Saeb-Parsy K, Xu X. The Role of Ischemia/Reperfusion Injury in Early Hepatic Allograft Dysfunction. Liver Transpl. 2020 Aug; 26 (8): 1034–1048. doi: 10.1002/lt.25779. PMID: 32294292.

79. Xia VW, Worapot A, Huang S, Dhillon A, Gudzenko V, Backon A et al. Postoperative atrial fibrillation in liver transplantation. Am J Transplant. 2015; 15: 687–694.

80. Pareja E, Cortes M, Hervás D, Mir J, Valdivieso A, Castell JV et al. A score model for the continuous grading of early allograft dysfunction severity. Liver Transpl. 2015; 21: 38–46.

81. Ali JM, Davies SE, Brais RJ, Randle LV, Klinck JR, Allison ME et al. Analysis of ischemia/reperfusion injury in time-zero biopsies predicts liver allograft outcomes. Liver Transpl. 2015 Apr; 21 (4): 487–499. doi: 10.1002/lt.24072. PMID: 25545865.

82. Lu L, Zhou H, Ni M, Wang X, Busuttil R, Kupiec-Weglinski J et al. Innate Immune Regulations and Liver Ischemia-Reperfusion Injury. Transplantation. 2016 Dec; 100 (12): 2601–2610. doi: 10.1097/TP.0000000000001411. PMID: 27861288; PMCID: PMC5141614.

83. Bajaj JS, Kakiyama G, Cox IJ, Nittono H, Takei H, White M et al. Alterations in gut microbial function following liver transplant. Liver Transpl. 2018 Jun; 24 (6): 752–761.

84. Xing HC, Li LJ, Xu KJ, Shen T, Chen YB, Sheng JF et al. Protective role of supplement with foreign Bifidobacterium and Lactobacillus in experimental hepatic ischemia-reperfusion injury. J Gastroenterol Hepatol. 2006 Apr; 21 (4): 647–656. doi: 10.1111/j.1440-1746.2006.04306.x. PMID: 16677148.

85. Xie Y, Chen H, Zhu B, Qin N, Chen Y, Li Z et al. Effect of intestinal microbiota alteration on hepatic damage in rats with acute rejection after liver transplantation. Microb Ecol. 2014 Nov; 68 (4): 871–880. doi: 10.1007/s00248-014-0452-z. Epub 2014 Jul 9. PMID: 25004996.

86. Xie Y, Luo Z, Li Z, Deng M, Liu H, Zhu B et al. Structural shifts of fecal microbial communities in rats with acute rejection after liver transplantation. Microb Ecol. 2012 Aug; 64 (2): 546–554. doi: 10.1007/s00248-012-0030-1. Epub 2012 Mar 21. PMID: 22430504.

87. Salminen S, Benno Y, de Vos W. Intestinal colonisation, microbiota and future probiotics? Asia Pac J Clin Nutr. 2006; 15 (4): 558–562. PMID: 17077076.

88. Ren Z, Jiang J, Lu H, Chen X, He Y, Zhang H et al. Intestinal microbial variation may predict early acute rejection after liver transplantation in rats. Transplantation. 2014 Oct 27; 98 (8): 844–852. doi: 10.1097/TP.0000000000000334. PMID: 25321166; PMCID: PMC4206351.

89. Sawas T, Al Halabi S, Hernaez R, Carey WD, Cho WK. Patients Receiving Prebiotics and Probiotics Before Liver Transplantation Develop Fewer Infections Than Controls: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2015 Sep; 13 (9): 1567-74. e3; quiz e143-4. doi: 10.1016/j.cgh.2015.05.027. Epub 2015 Jun 2. PMID: 26044318.

90. Rayes N, Seehofer D, Hansen S, Boucsein K, Müller AR, Serke S et al. Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation. 2002 Jul 15; 74 (1): 123–127. doi: 10.1097/00007890-200207150-00021. PMID: 12134110.

91. Okubo H, Kushiyama A, Nakatsu Y, Yamamotoya T, Matsunaga Y, Fujishiro M et al. Roles of Gut-Derived Secretory Factors in the Pathogenesis of Non-Alcoholic Fatty Liver Disease and Their Possible Clinical Applications. Int J Mol Sci. 2018 Oct 8; 19 (10): 3064. doi: 10.3390/ijms19103064. PMID: 30297626; PMCID: PMC6213237.

92. Aragonès G, González-García S, Aguilar C, Richart C, Auguet T. Gut Microbiota-Derived Mediators as Potential Markers in Nonalcoholic Fatty Liver Disease. Biomed Res Int. 2019 Jan 2; 2019: 8507583. doi: 10.1155/2019/8507583. PMID: 30719448; PMCID: PMC6334327.

93. Boursier J, Mueller O, Barret M, Machado M, Fizanne L, Araujo-Perez F et al. The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota. Hepatology. 2016 Mar; 63 (3): 764–775. doi: 10.1002/hep.28356. Epub 2016 Jan 13. PMID: 26600078; PM-CID: PMC4975935.

94. Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW et al. Plasma metabolomic profile in nonalcoholic fatty liver disease. Metabolism. 2011 Mar; 60 (3): 404–413. doi: 10.1016/j.metabol.2010.03.006. Epub 2010 Apr 27. PMID: 20423748; PMCID: PMC2950914.

95. Allen K, Jaeschke H, Copple BL. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. The American Journal of Pathology. 2011; 178 (1): 175–186. doi: 10.1016/j.ajpath.2010.11.026.

96. Svegliati-Baroni G, Ridolfi F, Hannivoort R, Saccomanno S, Homan M, De Minicis S et al. Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor. Gastroenterology. 2005 Apr; 128 (4): 1042–1055. doi: 10.1053/j.gastro.2005.01.007. PMID: 15825085.

97. Greenhalgh K, Meyer KM, Aagaard KM, Wilmes P. The human gut microbiome in health: establishment and resilience of microbiota over a lifetime. Environ Microbiol. 2016; 18: 2103–2116. https://doi.org/10.1111/1462-2920.13318.

98. Porras D, Nistal E, Martínez-Flórez S, Pisonero-Vaquero S, Olcoz JL, Jover R et al. Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation. Free Radic Biol Med. 2017 Jan; 102: 188–202. doi: 10.1016/j.freeradbiomed.2016.11.037. Epub 2016 Nov 25. PMID: 27890642.

99. Giorgio V, Miele L, Principessa L, Ferretti F, Villa MP, Negro V et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig Liver Dis. 2014 Jun; 46 (6): 556–560. doi: 10.1016/j.dld.2014.02.010. Epub 2014 Mar 12. PMID: 24631029.

100. Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA et al. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol. 2013 Sep; 31 (9): 814–821. doi: 10.1038/nbt.2676. Epub 2013 Aug 25. PMID: 23975157; PMCID: PMC3819121.

101. Børsting C, Morling N. Next generation sequencing and its applications in forensic genetics. Forensic Sci Int Genet. 2015 Sep; 18: 78–89. doi: 10.1016/j.fsigen.2015.02.002. Epub 2015 Feb 14. PMID: 25704953.

102. McGinn S, Gut IG. DNA sequencing – spanning the generations. N Biotechnol. 2013 May 25; 30 (4): 366–372. doi: 10.1016/j.nbt.2012.11.012. Epub 2012 Nov 16. PMID: 23165096.

103. Cullum R, Alder O, Hoodless PA. The next generation: using new sequencing technologies to analyse gene regulation. Respirology. 2011 Feb; 16 (2): 210–222. doi: 10.1111/j.1440-1843.2010.01899.x. PMID: 21077988.

104. Ruggles KV, Fenyö D. Next Generation Sequencing Data and Proteogenomics. Adv Exp Med Biol. 2016; 926: 11–19. doi: 10.1007/978-3-319-42316-6_2. PMID: 27686803.

105. Halperin RF, Hegde A, Lang JD, Raupach EA. Improved methods for RNAseq-based alternative splicing analysis. Sci Rep. 2021 May 24; 11 (1): 10740. doi: 10.1038/s41598-021-89938-2. PMID: 34031440; PM-CID: PMC8144374.