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Gut microbiota and its implications in small bowel transplantation

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Abstract

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.

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References

  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): 1635–1638

    Article  PubMed  PubMed Central  Google Scholar 

  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): 1647–1651

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Cox MJ, Cookson WO, Moffatt MF. Sequencing the human microbiome in health and disease. Hum Mol Genet 2013; 22(R1): R88–R94

    Article  PubMed  CAS  Google Scholar 

  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): 1241214

    Article  PubMed  CAS  Google Scholar 

  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): 227–236

    Article  PubMed  Google Scholar 

  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): 55–60

    Article  PubMed  CAS  Google Scholar 

  7. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444 (7122): 1022–1023

    Article  PubMed  CAS  Google Scholar 

  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): 228–231

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Fishbein TM. Intestinal transplantation. N Engl J Med 2009; 361 (10): 998–1008

    Article  PubMed  CAS  Google Scholar 

  10. Garg M, Jones RM, Vaughan RB, Testro AG. Intestinal transplantation: current status and future directions. J Gastroenterol Hepatol 2011; 26(8): 1221–1228

    Article  PubMed  Google Scholar 

  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): 494–508

    Article  PubMed  Google Scholar 

  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): 411–418

    Article  PubMed  Google Scholar 

  13. Cotter PD. Small intestine and microbiota. Curr Opin Gastroenterol 2011; 27(2): 99–105

    Article  PubMed  Google Scholar 

  14. Andersen DA, Horslen S. An analysis of the long-term complications of intestine transplant recipients. Prog Transplant 2004; 14(4): 277–282

    Article  PubMed  Google Scholar 

  15. Wu HJ, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 2012; 3(1): 4–14

    Article  PubMed  PubMed Central  Google Scholar 

  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): 17187–17192

    Article  PubMed  PubMed Central  Google Scholar 

  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): 1538–1542

    Article  PubMed  CAS  Google Scholar 

  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): 636–640

    Article  PubMed  Google Scholar 

  19. Sudan DL. Treatment of intestinal failure: intestinal transplantation. Nat Clin Pract Gastroenterol Hepatol 2007; 4(9): 503–510

    Article  PubMed  Google Scholar 

  20. Ishii T, Mazariegos GV, Bueno J, Ohwada S, Reyes J. Exfoliative rejection after intestinal transplantation in children. Pediatr Transplant 2003; 7(3): 185–191

    Article  PubMed  Google Scholar 

  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): 1742–1748

    Article  PubMed  Google Scholar 

  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): 28–33

    PubMed  Google Scholar 

  23. Fricke WF, Maddox C, Song Y, Bromberg JS. Human microbiota characterization in the course of renal transplantation. Am J Transplant 2014; 14(2): 416–427

    Article  PubMed  CAS  Google Scholar 

  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): 753–762

    Article  PubMed  CAS  Google Scholar 

  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): 1272–1277

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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): 766–779

    Article  PubMed  CAS  Google Scholar 

  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): 989–996

    Article  PubMed  CAS  Google Scholar 

  28. Joosten SA, van Kooten C, Paul LC. Pathogenesis of chronic allograft rejection. Transpl Int 2003; 16(3): 137–145

    Article  PubMed  CAS  Google Scholar 

  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): 1351–1357

    Article  PubMed  CAS  Google Scholar 

  30. Bromberg JS, Fricke WF, Brinkman CC, Simon T, Mongodin EF. Microbiota—implications for immunity and transplantation. Nat Rev Nephrol 2015; 11(6): 342–353

    Article  PubMed  CAS  Google Scholar 

  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): e20460

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Maynard CL, Elson CO, Hatton RD, Weaver CT. Reciprocal interactions of the intestinal microbiota and immune system. Nature 2012; 489(7415): 231–241

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell 2014; 157(1): 121–141

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Surana NK, Kasper DL. Deciphering the tête-à-tête between the microbiota and the immune system. J Clin Invest 2014; 124(10): 4197–4203

    PubMed  PubMed Central  CAS  Google Scholar 

  35. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486 (7402): 207–214

    Article  CAS  Google Scholar 

  36. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 2014; 146(6): 1489–1499

    Article  PubMed  CAS  Google Scholar 

  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): 903–911

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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): 1174–1182

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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): 1723–1728

    Article  PubMed  CAS  Google Scholar 

  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): 339ra71

    Article  CAS  Google Scholar 

  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): 927–933

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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): e105706

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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): 191–207

    Article  PubMed  CAS  Google Scholar 

  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): 223–231

    Article  PubMed  CAS  Google Scholar 

  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): 375–386

    Article  PubMed  CAS  Google Scholar 

  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): 899–910

    Article  PubMed  CAS  Google Scholar 

  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): 951–959

    Article  PubMed  CAS  Google Scholar 

  48. Sudan D. Small bowel transplantation: current status and new developments in allograftmonitoring. Curr Opin Organ Transplant 2005; 10(2): 124–127

    Article  Google Scholar 

  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): 2786–2790

    Article  PubMed  CAS  Google Scholar 

  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): 311–315

    Article  PubMed  PubMed Central  Google Scholar 

  51. Zhao L. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol 2013; 11(9): 639–647

    Article  PubMed  CAS  Google Scholar 

  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): 541–546

    Article  PubMed  CAS  Google Scholar 

  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): 59–64

    Article  PubMed  CAS  Google Scholar 

  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): 844–852

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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): 407–415

    Article  PubMed  CAS  Google Scholar 

  56. Ratner M. Microbial cocktails join fecal transplants in IBD treatment trials. Nat Biotechnol 2015; 33(8): 787–788

    Article  PubMed  CAS  Google Scholar 

  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.e7

    Article  PubMed  CAS  Google Scholar 

  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): 477–480

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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): 2083–2088

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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): 19–28

    Article  PubMed  PubMed Central  Google Scholar 

  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): 1832–1834

    Article  PubMed  CAS  Google Scholar 

  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): 37

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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).

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Correspondence to Qiurong Li or Jieshou Li.

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Wang, C., Li, Q. & Li, J. Gut microbiota and its implications in small bowel transplantation. Front. Med. 12, 239–248 (2018). https://doi.org/10.1007/s11684-018-0617-0

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