Structural shifts in the intestinal microbiota of rats treated with cyclosporine A after orthotropic liver transplantation

Abstract

Understanding the effect of immunosuppressive agents on intestinal microbiota is important to reduce the mortality and morbidity from orthotopic liver transplantation (OLT). We investigated the relationship between the commonly used immunosuppressive agent cyclosporine A (CSA) and the intestinal microbial variation in an OLT model. The rat samples were divided as follows: (1) N group (normal control); (2) I group (isograft LT, Brown Norway [BN] rat to BN); (3) R group (allograft LT, Lewis to BN rat); and (4) CSA group (R group treated with CSA). The intestinal microbiota was assayed by denaturing gradient gel electrophoresis profiles and by using real-time polymerase chain reaction. The liver histopathology and the alanine/aspartate aminotransferase ratio after LT were both ameliorated by CSA. In the CSA group, the numbers of rDNA gene copies of Clostridium cluster I, Clostridium cluster XIV, and Enterobacteriaceae decreased, whereas those of Faecalibacterium prausnitzii increased compared with the R group. Cluster analysis indicated that the samples from the N, I, and CSA groups were clustered, whereas the other clusters contained the samples from the R group. Hence, CSA ameliorates hepatic graft injury and partially restores gut microbiota following LT, and these may benefit hepatic graft rejection.

Keywords

microbial community / liver transplantation / immunosuppressive agents / cyclosporine A

References

[1] Cheng EY, Everly MJ. Trends of Immunosuppression and Outcomes Following Liver Transplantation: An Analysis of the United Network for Organ Sharing Registry. In: Everly MJ, Terasaki PI. Clinical Transplants 2014. LA: UCLA Immunogenetics Center, 2015: 13–26 (Chapter 2)

[2] 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): 77–84

[3] Tanaka K, Uemoto S, Egawa H, Takada Y, Ozawa K, Teramukai S, Kasahara M, Ogawa K, Ono M, Sato H, Takai K, Fukushima M, Inaba K. Cytotoxic T-cell-mediated defense against infections in human liver transplant recipients. Liver Transpl 2007; 13(2): 287–293

[4] Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr 2002; 22(1): 283–307

[5] Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science 2005; 307(5717): 1915–1920

[6] Guarner F, Malagelada JR. Gut flora in health and disease. Lancet 2003; 361(9356): 512–519

[7] Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, Wang Y, Zhu B, Li L. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011; 54(2): 562–572

[8] Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, Monteith P, Noble NA, Sikaroodi M, Gillevet PM. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 2012; 303(6): G675–G685

[9] Atarashi K, Honda K. Microbiota in autoimmunity and tolerance. Curr Opin Immunol 2011; 23(6): 761–768

[10] 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): 546–554

[11] Dong VM, Womer KL, Sayegh MH. Transplantation tolerance: the concept and its applicability. Pediatr Transplant 1999; 3(3): 181–192

[12] Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005; 56(1): 23–46

[13] Malinowski M, Martus P, Lock JF, Neuhaus P, Stockmann M. Systemic influence of immunosuppressive drugs on small and large bowel transport and barrier function. Transpl Int 2011; 24(2): 184–193

[14] Ferris MJ, Muyzer G, Ward DM. Denaturing gradient gel electrophoresis profiles of 16S rRNA-defined populations inhabiting a hot spring microbial mat community. Appl Environ Microbiol 1996; 62(2): 340–346

[15] Zoetendal EG, Collier CT, Koike S, Mackie RI, Gaskins HR. Molecular ecological analysis of the gastrointestinal microbiota: a review. J Nutr 2004; 134(2): 465–472

[16] Mai V, Morris JG Jr. Colonic bacterial flora: changing understandings in the molecular age. J Nutr 2004; 134(2): 459–464

[17] Tian X, Yang Z, Luo F , Zheng S. Gut microbial balance and liver transplantation: alteration, management, and prediction. Front Med 2018; 12 (2): 123–129

[18] Zaza G, Dalla Gassa A, Felis G, Granata S, Torriani S, Lupo A. Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: comparison between an everolimus- and a standard tacrolimus-based regimen. PLoS One 2017; 12(5): e0178228

[19] 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): e75950

[20] Lu H, Wu Z, Xu W, Yang J, Chen Y, Li L. Intestinal microbiota was assessed in cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of HBV cirrhotic patients. Microb Ecol 2011; 61(3): 693–703

[21] 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

[22] Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 2009; 15(13): 1546–1558

[23] Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE. Metagenomic analysis of the human distal gut microbiome. Science 2006; 312(5778): 1355–1359

[24] Ley RE, Peterson DA, Gordon JI. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006; 124(4): 837–848

[25] 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): 647–656

[26] Chassaing B, Etienne-Mesmin L, Gewirtz AT. Microbiota-liver axis in hepatic disease. Hepatology 2014; 59(1): 328–339

[27] Ren Z, Li A, Jiang J, Zhou L, Yu Z, Lu H, Xie H, Chen X, Shao L, Zhang R, Xu S, Zhang H, Cui G, Chen X, Sun R, Wen H, Lerut JP, Kan Q, Li L, Zheng S. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut 2018 Jul 25. [Epub ahead of print] doi: 10.1136/gutjnl-2017-315084

[28] 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): 781–791

[29] Müller A, Jungen H, Iwersen-Bergmann S, Sterneck M, Andresen-Streichert H. Analysis of cyclosporin A in hair samples from liver transplanted patients. Ther Drug Monit 2013; 35(4): 450–458

[30] Jeffery IB, O’Toole PW, Öhman L, Claesson MJ, Deane J, Quigley EM, Simrén M. An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 2012; 61(7): 997–1006

[31] Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, McFarland LV, Mellow M, Zuckerbraun BS. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol 2013; 108(4): 478–498, quiz 499

[32] Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology 2013; 145(5): 946–953

[33] 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

Acknowledgements

This work was supported by the China Postdoctoral Science Foundation (No. 2017M610374), Zhejiang Medical Health Technology Project (No. 2019313269), Innovative Research Groups of the National Natural Science Foundation of China (No. 81421062), National Natural Science Foundation of China (No. 81470891), and Science and Technology Bureau of Zhejiang Province, China (No. 2016C33145).

Compliance with ethics guidelines

Junjun Jia, Xinyao Tian, Jianwen Jiang, Zhigang Ren, Haifeng Lu, Ning He, Haiyang Xie, Lin Zhou, and Shusen Zheng declare that they have no conflicts of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

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