Gut microbiota and its implications in small bowel transplantation

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 SBT and 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.

Keywords

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

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

[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

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

[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

[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

[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

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

[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

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

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

[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

[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

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

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

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

[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

[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

[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

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

[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

[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

[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

[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

[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

[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

[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

[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

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

[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

[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

[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

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

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

[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

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

[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

[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

[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

[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

[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

[41] Staffas A, Burgos da Silva M, van den Brink MR. The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease. Blood 2017; 129(8): 927–933

[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

[43] Zeiser R, Socié G, Blazar BR. Pathogenesis of acute graft-versus-host disease: from intestinal microbiota alterations to donor T cell activation. Br J Haematol 2016; 175(2): 191–207

[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): 223–231PMID:22535662

[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

[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

[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

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

[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

[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

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

[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

[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

[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

[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

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

[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

[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

[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 steroid-resistant acute graft-versus-host disease of the gut. Blood 2016; 128(16): 2083–2088

[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

[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

[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

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).

Compliance with ethics guidelines

Chenyang Wang, Qiurong Li, and Jieshou Li declare no competing financial interests. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

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