Gut microbiota and its implications in small bowel transplantation



The gut microbiota is mainly composed of a diverse population of commensal bacterial species and plays a pivotal role in the maintenance of intestinal homeostasis, immune modulation and metabolism. The influence of the gut microbiota on solid organ transplantation has recently been recognized. In fact, several studies indicated that acute and chronic allograft rejection in small bowel transplantation (SBT) is closely associated with the alterations in microbial patterns in the gut. In this review, we focused on the recent findings regarding alterations in the microbiota following SBTand the potential roles of these alterations in the development of acute and chronic allograft rejection. We also reviewed important advances with respect to the interplays between the microbiota and host immune systems in SBT. Furthermore, we explored the potential of the gut microbiota as a microbial marker and/or therapeutic target for the predication and intervention of allograft rejection and chronic dysfunction. Given that current research on the gut microbiota has become increasingly sophisticated and comprehensive, large cohort studies employing metagenomic analysis and multivariate linkage should be designed for the characterization of host–microbe interaction and causality between microbiota alterations and clinical outcomes in SBT. The findings are expected to provide valuable insights into the role of gut microbiota in the development of allograft rejection and other transplant-related complications and introduce novel therapeutic targets and treatment approaches in clinical practice.


gut microbiota small bowel transplantation acute rejection chronic rejection mucosal immunity biomarker microbiota-targeted therapy 


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This work was supported by the grants from the National Basic Research Program of China (973 Program, No. 2013CB531403) and National High-tech Research and Development Program of China (863 Program, No. 2012AA021007).


  1. 1.
    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
  2. 2.
    Ley RE, Hamady M, Lozupone C, Turnbaugh PJ, Ramey RR, Bircher JS, Schlegel ML, Tucker TA, Schrenzel MD, Knight R, Gordon JI. Evolution of mammals and their gut microbes. Science 2008; 320(5883): 1647–1651CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cox MJ, Cookson WO, Moffatt MF. Sequencing the human microbiome in health and disease. Hum Mol Genet 2013; 22(R1): R88–R94CrossRefPubMedGoogle Scholar
  4. 4.
    Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, Griffin NW, Lombard V, Henrissat B, Bain JR, Muehlbauer MJ, Ilkayeva O, Semenkovich CF, Funai K, Hayashi DK, Lyle BJ, Martini MC, Ursell LK, Clemente JC, Van Treuren W, Walters WA, Knight R, Newgard CB, Heath AC, Gordon JI. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 2013; 341(6150): 1241214CrossRefPubMedGoogle Scholar
  5. 5.
    Lepage P, Häsler R, Spehlmann ME, Rehman A, Zvirbliene A, Begun A, Ott S, Kupcinskas L, Doré J, Raedler A, Schreiber S. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 2011; 141(1): 227–236CrossRefPubMedGoogle Scholar
  6. 6.
    Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Li S, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K, Wang J. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490(7418): 55–60CrossRefPubMedGoogle Scholar
  7. 7.
    Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444 (7122): 1022–1023CrossRefPubMedGoogle Scholar
  8. 8.
    Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, Sitaraman SV, Knight R, Ley RE, Gewirtz AT. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010; 328(5975): 228–231CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Fishbein TM. Intestinal transplantation. N Engl J Med 2009; 361 (10): 998–1008CrossRefPubMedGoogle Scholar
  10. 10.
    Garg M, Jones RM, Vaughan RB, Testro AG. Intestinal transplantation: current status and future directions. J Gastroenterol Hepatol 2011; 26(8): 1221–1228CrossRefPubMedGoogle Scholar
  11. 11.
    Abu-Elmagd KM, Kosmach-Park B, Costa G, Zenati M, Martin L, Koritsky DA, Emerling M, Murase N, Bond GJ, Soltys K, Sogawa H, Lunz J, Al Samman M, Shaefer N, Sindhi R, Mazariegos GV. Long-term survival, nutritional autonomy, and quality of life after intestinal and multivisceral transplantation. Ann Surg 2012; 256(3): 494–508CrossRefPubMedGoogle Scholar
  12. 12.
    van der Hilst CS, Ijtsma AJ, Bottema JT, van Hoek B, Dubbeld J, Metselaar HJ, Kazemier G, van den Berg AP, Porte RJ, Slooff MJ. The price of donation after cardiac death in liver transplantation: a prospective cost-effectiveness study. Transpl Int 2013; 26(4): 411–418CrossRefPubMedGoogle Scholar
  13. 13.
    Cotter PD. Small intestine and microbiota. Curr Opin Gastroenterol 2011; 27(2): 99–105CrossRefPubMedGoogle Scholar
  14. 14.
    Andersen DA, Horslen S. An analysis of the long-term complications of intestine transplant recipients. Prog Transplant 2004; 14(4): 277–282CrossRefPubMedGoogle Scholar
  15. 15.
    Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 2012; 3(1): 4–14CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hartman AL, Lough DM, Barupal DK, Fiehn O, Fishbein T, Zasloff M, Eisen JA. Human gut microbiome adopts an alternative state following small bowel transplantation. Proc Natl Acad Sci USA 2009; 106(40): 17187–17192CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Fishbein TM, Florman S, Gondolesi G, Schiano T, LeLeiko N, Tschernia A, Kaufman S. Intestinal transplantation before and after the introduction of sirolimus. Transplantation 2002; 73(10): 1538–1542CrossRefPubMedGoogle Scholar
  18. 18.
    Fishbein TM, Kaufman SS, Florman SS, Gondolesi GE, Schiano T, Kim-Schluger L, Magid M, Harpaz N, Tschernia A, Leibowitz A, LeLeiko NS. Isolated intestinal transplantation: proof of clinical efficacy. Transplantation 2003; 76(4): 636–640CrossRefPubMedGoogle Scholar
  19. 19.
    Sudan DL. Treatment of intestinal failure: intestinal transplantation. Nat Clin Pract Gastroenterol Hepatol 2007; 4(9): 503–510CrossRefPubMedGoogle Scholar
  20. 20.
    Ishii T, Mazariegos GV, Bueno J, Ohwada S, Reyes J. Exfoliative rejection after intestinal transplantation in children. Pediatr Transplant 2003; 7(3): 185–191CrossRefPubMedGoogle Scholar
  21. 21.
    Guaraldi G, Cocchi S, Codeluppi M, Di Benedetto F, De Ruvo N, Masetti M, Venturelli C, Pecorari M, Pinna AD, Esposito R. Outcome, incidence, and timing of infectious complications in small bowel and multivisceral organ transplantation patients. Transplantation 2005; 80(12): 1742–1748CrossRefPubMedGoogle Scholar
  22. 22.
    Chen HX, Yin L, Peng CH, Zhou GW, Shen BY, Chen H, Shen C, Li HW. Abdominal cluster transplantation and management of perioperative hemodynamic changes. Hepatobiliary Pancreat Dis Int 2006; 5(1): 28–33PubMedGoogle Scholar
  23. 23.
    Fricke WF, Maddox C, Song Y, Bromberg JS. Human microbiota characterization in the course of renal transplantation. Am J Transplant 2014; 14(2): 416–427CrossRefPubMedGoogle Scholar
  24. 24.
    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
  25. 25.
    Krams SM, Wang M, Castillo RO, Ito T, Phillips L, Higgins J, Kambham N, Esquivel CO, Martinez OM. Toll-like receptor 4 contributes to small intestine allograft rejection. Transplantation 2010; 90(12): 1272–1277CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Orloff SL, Yin Q, Corless CL, Loomis CB, Rabkin JM, Wagner CR. A rat small bowel transplant model of chronic rejection: histopathologic characteristics. Transplantation 1999; 68(6): 766–779CrossRefPubMedGoogle Scholar
  27. 27.
    Li Q, Wang C, Zhang Q, Tang C, Li N, Li J. The reduction of allograft arteriosclerosis in intestinal transplant is associated with sphingosine kinase 1/sphingosine-1-phosphate signaling after fish oil treatment. Transplantation 2012; 93(10): 989–996CrossRefPubMedGoogle Scholar
  28. 28.
    Joosten SA, van Kooten C, Paul LC. Pathogenesis of chronic allograft rejection. Transpl Int 2003; 16(3): 137–145CrossRefPubMedGoogle Scholar
  29. 29.
    Chen Y, Li X, Tian L, Lui VCH, Dallman MJ, Lamb JR, Tam PKH. Inhibition of sonic hedgehog signaling reduces chronic rejection and prolongs allograft survival in a rat orthotopic small bowel transplantation model. Transplantation 2007; 83(10): 1351–1357CrossRefPubMedGoogle Scholar
  30. 30.
    Bromberg JS, Fricke WF, Brinkman CC, Simon T, Mongodin EF. Microbiota—implications for immunity and transplantation. Nat Rev Nephrol 2015; 11(6): 342–353CrossRefPubMedGoogle Scholar
  31. 31.
    Li Q, Zhang Q, Wang C, Tang C, Zhang Y, Li N, Li J. Fish oil enhances recovery of intestinal microbiota and epithelial integrity in chronic rejection of intestinal transplant. PLoS One 2011; 6(6): e20460CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012; 489(7415): 231–241CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014; 157(1): 121–141CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Surana NK, Kasper DL. Deciphering the tête-à-tête between the microbiota and the immune system. J Clin Invest 2014; 124(10): 4197–4203PubMedPubMedCentralGoogle Scholar
  35. 35.
    Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486 (7402): 207–214CrossRefGoogle Scholar
  36. 36.
    Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 2014; 146(6): 1489–1499CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    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 MR. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med 2012; 209(5): 903–911CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, No D, Gobourne A, Viale A, Dahi PB, Ponce DM, Barker JN, Giralt S, van den Brink M, Pamer EG. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 2014; 124(7): 1174–1182CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Weber D, Oefner PJ, Hiergeist A, Koestler J, Gessner A, Weber M, Hahn J, Wolff D, Stämmler F, Spang R, Herr W, Dettmer K, Holler E. Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood 2015; 126(14): 1723–1728CrossRefPubMedGoogle Scholar
  40. 40.
    Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, Slingerland AE, Smith OM, Young LF, Gupta J, Lieberman SR, Jay HV, Ahr KF, Porosnicu Rodriguez KA, Xu K, Calarfiore M, Poeck H, Caballero S, Devlin SM, Rapaport F, Dudakov JA, Hanash AM, Gyurkocza B, Murphy GF, Gomes C, Liu C, Moss EL, Falconer SB, Bhatt AS, Taur Y, Pamer EG, van den Brink MRM, Jenq RR. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci Transl Med 2016; 8(339): 339ra71CrossRefGoogle Scholar
  41. 41.
    Staffas A, Burgos da Silva M, van den Brink MR. The intestinal microbiota in allogeneic hematopoietic cell transplant and graftversus-host disease. Blood 2017; 129(8): 927–933CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Vossen JM, Guiot HF, Lankester AC, Vossen AC, Bredius RG, Wolterbeek R, Bakker HD, Heidt PJ. Complete suppression of the gut microbiome prevents acute graft-versus-host disease following allogeneic bone marrow transplantation. PLoS One 2014; 9(9): e105706CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zeiser R, Socié G, Blazar BR. Pathogenesis of acute graft-versushost disease: from intestinal microbiota alterations to donor T cell activation. Br J Haematol 2016; 175(2): 191–207CrossRefPubMedGoogle Scholar
  44. 44.
    Eriguchi Y, Takashima S, Oka H, Shimoji S, Nakamura K, Uryu H, Shimoda S, Iwasaki H, Shimono N, Ayabe T, Akashi K, Teshima T. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of a-defensins. Blood 2012; 120 (1): 223–231CrossRefPubMedGoogle Scholar
  45. 45.
    Li Q, Zhang Q, Wang C, Tang C, Zhang Y, Jiang S, Li N, Li J. Influence of alemtuzumab on the intestinal Paneth cells and microflora in macaques. Clin Immunol 2010; 136(3): 375–386CrossRefPubMedGoogle Scholar
  46. 46.
    Li QR, Wang CY, Tang C, He Q, Li N, Li JS. Reciprocal interaction between intestinal microbiota and mucosal lymphocyte in cynomolgus monkeys after alemtuzumab treatment. Am J Transplant 2013; 13(4): 899–910CrossRefPubMedGoogle Scholar
  47. 47.
    Li Q, Wang C, Tang C, He Q, Li J. Lymphocyte depletion after alemtuzumab induction disrupts intestinal fungal microbiota in cynomolgus monkeys. Transplantation 2014; 98(9): 951–959CrossRefPubMedGoogle Scholar
  48. 48.
    Sudan D. Small bowel transplantation: current status and new developments in allograftmonitoring. Curr Opin Organ Transplant 2005; 10(2): 124–127CrossRefGoogle Scholar
  49. 49.
    Gondolesi G, Ghirardo S, Raymond K, Hoppenhauer L, Surillo D, Rumbo C, Fishbein T, Sansaricq C, Sauter B. The value of plasma citrulline to predict mucosal injury in intestinal allografts. Am J Transplant 2006; 6(11): 2786–2790CrossRefPubMedGoogle Scholar
  50. 50.
    Sudan D, Vargas L, Sun Y, Bok L, Dijkstra G, Langnas A. Calprotectin: a novel noninvasive marker for intestinal allograft monitoring. Ann Surg 2007; 246(2): 311–315CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Zhao L. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol 2013; 11(9): 639–647CrossRefPubMedGoogle Scholar
  52. 52.
    Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, Almeida M, Arumugam M, Batto JM, Kennedy S, Leonard P, Li J, Burgdorf K, Grarup N, Jørgensen T, Brandslund I, Nielsen HB, Juncker AS, Bertalan M, Levenez F, Pons N, Rasmussen S, Sunagawa S, Tap J, Tims S, Zoetendal EG, Brunak S, Clément K, Doré J, Kleerebezem M, Kristiansen K, Renault P, Sicheritz-Ponten T, de Vos WM, Zucker JD, Raes J, Hansen T; MetaHIT consortium, Bork P, Wang J, Ehrlich SD, Pedersen O. Richness of human gut microbiome correlates with metabolic markers. Nature 2013; 500 (7464): 541–546CrossRefPubMedGoogle Scholar
  53. 53.
    Qin N, Yang F, Li A, Prifti E, Chen Y, Shao L, Guo J, Le Chatelier E, Yao J, Wu L, Zhou J, Ni S, Liu L, Pons N, Batto JM, Kennedy SP, Leonard P, Yuan C, Ding W, Chen Y, Hu X, Zheng B, Qian G, Xu W, Ehrlich SD, Zheng S, Li L. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014; 513(7516): 59–64CrossRefPubMedGoogle Scholar
  54. 54.
    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
  55. 55.
    van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013; 368(5): 407–415CrossRefPubMedGoogle Scholar
  56. 56.
    Ratner M. Microbial cocktails join fecal transplants in IBD treatment trials. Nat Biotechnol 2015; 33(8): 787–788CrossRefPubMedGoogle Scholar
  57. 57.
    Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van HylckamaVlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012; 143(4): 913–916.e7CrossRefPubMedGoogle Scholar
  58. 58.
    Friedman-Moraco RJ, Mehta AK, Lyon GM, Kraft CS. Fecal microbiota transplantation for refractory Clostridium difficile colitis in solid organ transplant recipients. Am J Transplant 2014; 14(2): 477–480CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Kakihana K, Fujioka Y, Suda W, Najima Y, Kuwata G, Sasajima S, Mimura I, Morita H, Sugiyama D, Nishikawa H, Hattori M, Hino Y, Ikegawa S, Yamamoto K, Toya T, Doki N, Koizumi K, Honda K, Ohashi K. Fecal microbiota transplantation for patients with steroidresistant acute graft-versus-host disease of the gut. Blood 2016; 128 (16): 2083–2088CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Andermann TM, Rezvani A, Bhatt AS. Microbiota manipulation with prebiotics and probiotics in patients undergoing stem cell transplantation. Curr Hematol Malig Rep 2016; 11(1): 19–28CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Li Q, Wang C, Tang C, He Q, Zhao X, Li N, Li J. Therapeutic modulation and reestablishment of the intestinal microbiota with fecal microbiota transplantation resolves sepsis and diarrhea in a patient. Am J Gastroenterol 2014; 109(11): 1832–1834CrossRefPubMedGoogle Scholar
  62. 62.
    Li Q, Wang C, Tang C, He Q, Zhao X, Li N, Li J. Successful treatment of severe sepsis and diarrhea after vagotomy utilizing fecal microbiota transplantation: a case report. Crit Care 2015; 19(1): 37CrossRefPubMedPubMedCentralGoogle Scholar

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© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Research Institute of General Surgery, Jinling Hospital, Medical SchoolNanjing UniversityNanjingChina

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