Abstract
Antibody-mediated rejection (AMR) has become the major challenge for kidney transplantation, and the efficacy of existing therapies was limited to prevent AMR. Increasing evidences have demonstrated the link between gut microbiota alterations and allograft outcome. However, there has been no comprehensive analysis to profile the gut microbiota associated with AMR after kidney transplantation. We performed this study to characterize the gut microbiota possibly associated with AMR. Fecal specimens were collected from 24 kidney transplantation recipients with AMR and 29 controls. DNA extracted from the specimens was processed for 16S rRNA gene sequencing using Illumina MiSeq. Gut microbial community of recipients with AMR was significantly different from that of controls based on unweighted (P = 0.001) and weighted (P = 0.02) UniFrac distances, and the bacterial richness (observed species: P = 0.0448; Chao1 index: P = 0.0450; ACE index: P = 0.0331) significantly decreased in the AMR group. LEfSe showed that 1 phylum, 5 classes, 7 families, and 10 genera were increased, whereas 1 class, 2 order, 3 families, and 4 genera were decreased in the AMR group. Specific taxa such as Clostridiales could be potentially used as biomarkers to distinguish the recipients with AMR from the controls (AUC = 0.77). PICRUSt analysis illustrated that 16 functional pathways were with significantly different abundances in the AMR and control groups. Our findings provide a foundation for further investigation on the role of gut microbiota in AMR after kidney transplantation, and potentially support novel diagnostic biomarkers and therapeutic options for AMR.
Key points
• Gut microbial community of kidney recipients with AMR was different from that of controls.
• Clostridiales is a potential marker to distinguish recipients with AMR from controls.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Ainsworth C (2017) Microbiome: a bag of surprises. Nature 551(7679):S40–S41. https://doi.org/10.1038/551S40a
Amore A (2015) Antibody-mediated rejection. Curr Opin Organ Transplant 20(5):536–542. https://doi.org/10.1097/MOT.0000000000000230
Antunes LC, Han J, Ferreira RB, Lolic P, Borchers CH, Finlay BB (2011) Effect of antibiotic treatment on the intestinal metabolome. Antimicrob Agents Chemother 55(4):1494–1503. https://doi.org/10.1128/AAC.01664-10
Baldwin WM 3rd, Valujskikh A, Fairchild RL (2016) Mechanisms of antibody-mediated acute and chronic rejection of kidney allografts. Curr Opin Organ Transplant 21(1):7–14. https://doi.org/10.1097/MOT.0000000000000262
Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Pena AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R (2010) QIIME allows analysis of high-throughput community sequencing data. Nat Methods 7(5):335–336. https://doi.org/10.1038/nmeth.f.303
Charlson ES, Diamond JM, Bittinger K, Fitzgerald AS, Yadav A, Haas AR, Bushman FD, Collman RG (2012) Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant. Am J Respir Crit Care Med 186(6):536–545. https://doi.org/10.1164/rccm.201204-0693OC
Chen H, Jiang W (2014) Application of high-throughput sequencing in understanding human oral microbiome related with health and disease. Front Microbiol 5:508. https://doi.org/10.3389/fmicb.2014.00508
de Castro CG Jr, Ganc AJ, Ganc RL, Petrolli MS, Hamerschlack N (2015) Fecal microbiota transplant after hematopoietic SCT: report of a successful case. Bone Marrow Transplant 50(1):145. https://doi.org/10.1038/bmt.2014.212
DeSantis TZ, Hugenholtz P, Larsen N, Rojas M, Brodie EL, Keller K, Huber T, Dalevi D, Hu P, Andersen GL (2006) Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microbiol 72(7):5069–5072. https://doi.org/10.1128/AEM.03006-05
Dickson RP, Erb-Downward JR, Freeman CM, Walker N, Scales BS, Beck JM, Martinez FJ, Curtis JL, Lama VN, Huffnagle GB (2014) Changes in the lung microbiome following lung transplantation include the emergence of two distinct Pseudomonas species with distinct clinical associations. PLoS One 9(5):e97214. https://doi.org/10.1371/journal.pone.0097214
Edgar RC (2010) Search and clustering orders of magnitude faster than BLAST. Bioinformatics 26(19):2460–2461. https://doi.org/10.1093/bioinformatics/btq461
Fieten KB, Totte JEE, Levin E, Reyman M, Meijer Y, Knulst A, Schuren F, Pasmans S (2018) Fecal microbiome and food allergy in pediatric atopic dermatitis: a cross-sectional pilot study. Int Arch Allergy Immunol 175(1-2):77–84. https://doi.org/10.1159/000484897
Fricke WF, Bromberg JS (2017) Checks and balances-microbiota shifts in immunosuppressed mice. Transplantation 101(1):26–27. https://doi.org/10.1097/TP.0000000000001493
Fricke WF, Maddox C, Song Y, Bromberg JS (2014) Human microbiota characterization in the course of renal transplantation. Am J Transplant 14(2):416–427. https://doi.org/10.1111/ajt.12588
Gargari G, Taverniti V, Gardana C, Cremon C, Canducci F, Pagano I, Barbaro MR, Bellacosa L, Castellazzi AM, Valsecchi C, Tagliacarne SC, Bellini M, Bertani L, Gambaccini D, Marchi S, Cicala M, Germana B, Dal Pont E, Vecchi M, Ogliari C, Fiore W, Stanghellini V, Barbara G, Guglielmetti S (2018) Fecal Clostridiales distribution and short-chain fatty acids reflect bowel habits in irritable bowel syndrome. Environ Microbiol 20(9):3201–3213. https://doi.org/10.1111/1462-2920.14271
Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE (2006) Metagenomic analysis of the human distal gut microbiome. Science 312(5778):1355–1359. https://doi.org/10.1126/science.1124234
Haas M (2016) The Revised (2013) Banff classification for antibody-mediated rejection of renal allografts: update, difficulties, and future considerations. Am J Transplant 16(5):1352–1357. https://doi.org/10.1111/ajt.13661
Haller MC, Royuela A, Nagler EV, Pascual J, Webster AC (2016) Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev (8):CD005632 https://doi.org/10.1002/14651858.CD005632.pub3
Hartman AL, Lough DM, Barupal DK, Fiehn O, Fishbein T, Zasloff M, Eisen JA (2009) Human gut microbiome adopts an alternative state following small bowel transplantation. Proc Natl Acad Sci U S A 106(40):17187–17192. https://doi.org/10.1073/pnas.0904847106
Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K, Zhu W, Sporrer D, Hehlgans T, Kreutz M, Holler B, Wolff D, Edinger M, Andreesen R, Levine JE, Ferrara JL, Gessner A, Spang R, Oefner PJ (2014) Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant 20(5):640–645. https://doi.org/10.1016/j.bbmt.2014.01.030
Kim M, Martin ST, Townsend KR, Gabardi S (2014) Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options. Pharmacotherapy 34(7):733–744. https://doi.org/10.1002/phar.1426
Kolho KL, Korpela K, Jaakkola T, Pichai MV, Zoetendal EG, Salonen A, de Vos WM (2015) Fecal microbiota in pediatric inflammatory bowel disease and its relation to inflammation. Am J Gastroenterol 110(6):921–930. https://doi.org/10.1038/ajg.2015.149
Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, Clemente JC, Burkepile DE, Vega Thurber RL, Knight R, Beiko RG, Huttenhower C (2013) Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 31(9):814–821. https://doi.org/10.1038/nbt.2676
Lee JR, Magruder M, Zhang L, Westblade LF, Satlin MJ, Robertson A, Edusei E, Crawford C, Ling L, Taur Y, Schluter J, Lubetzky M, Dadhania D, Pamer E, Suthanthiran M (2019) Gut microbiota dysbiosis and diarrhea in kidney transplant recipients. Am J Transplant: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 19(2):488–500. https://doi.org/10.1111/ajt.14974
Lee JR, Muthukumar T, Dadhania D, Taur Y, Jenq RR, Toussaint NC, Ling L, Pamer E, Suthanthiran M (2015) Gut microbiota and tacrolimus dosing in kidney transplantation. PLoS One 10(3):e0122399. https://doi.org/10.1371/journal.pone.0122399
Lee JR, Muthukumar T, Dadhania D, Toussaint NC, Ling L, Pamer E, Suthanthiran M (2014) Gut microbial community structure and complications after kidney transplantation: a pilot study. Transplantation 98(7):697–705. https://doi.org/10.1097/TP.0000000000000370
Lorenz M, Sunder-Plassmann G (2004) Iron therapy in renal transplant recipients. Transplantation 78(8):1239–1240 author reply 1240
Lozupone C, Knight R (2005) UniFrac: a new phylogenetic method for comparing microbial communities. Appl Environ Microbiol 71(12):8228–8235. https://doi.org/10.1128/AEM.71.12.8228-8235.2005
Lu H, He J, Wu Z, Xu W, Zhang H, Ye P, Yang J, Zhen S, Li L (2013) Assessment of microbiome variation during the perioperative period in liver transplant patients: a retrospective analysis. Microb Ecol 65(3):781–791. https://doi.org/10.1007/s00248-013-0211-6
Lucas JG, Co JP, Nwaogwugwu UT, Dosani I, Sureshkumar KK (2011) Antibody-mediated rejection in kidney transplantation: an update. Expert Opin Pharmacother 12(4):579–592. https://doi.org/10.1517/14656566.2011.525219
Magoc T, Salzberg SL (2011) FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics 27(21):2957–2963. https://doi.org/10.1093/bioinformatics/btr507
Morozumi K, Takeda A, Otsuka Y, Horike K, Gotoh N, Narumi S, Watarai Y, Kobayashi T (2016) Reviewing the pathogenesis of antibody-mediated rejection and renal graft pathology after kidney transplantation. Nephrology 21(Suppl 1):4–8. https://doi.org/10.1111/nep.12777
Mudge DW, Atcheson B, Taylor PJ, Sturtevant JM, Hawley CM, Campbell SB, Isbel NM, Nicol DL, Pillans PI, Johnson DW (2004) The effect of oral iron admiinistration on mycophenolate mofetil absorption in renal transplant recipients: a randomized, controlled trial. Transplantation 77(2):206–209. https://doi.org/10.1097/01.TP.0000100446.44001.00
Oh PL, Martinez I, Sun Y, Walter J, Peterson DA, Mercer DF (2012) Characterization of the ileal microbiota in rejecting and nonrejecting recipients of small bowel transplants. Am J Transplant 12(3):753–762. https://doi.org/10.1111/j.1600-6143.2011.03860.x
Pantenburg B, Heinzel F, Das L, Heeger PS, Valujskikh A (2002) T cells primed by Leishmania major infection cross-react with alloantigens and alter the course of allograft rejection. J Immunol 169(7):3686–3693. https://doi.org/10.4049/jimmunol.169.7.3686
Qian Y, Yang X, Xu S, Wu C, Song Y, Qin N, Chen SD, Xiao Q (2018) Alteration of the fecal microbiota in Chinese patients with Parkinson’s disease. Brain Behav Immun 70:194–202. https://doi.org/10.1016/j.bbi.2018.02.016
Racusen LC, Colvin RB, Solez K, Mihatsch MJ, Halloran PF, Campbell PM, Cecka MJ, Cosyns JP, Demetris AJ, Fishbein MC, Fogo A, Furness P, Gibson IW, Glotz D, Hayry P, Hunsickern L, Kashgarian M, Kerman R, Magil AJ, Montgomery R, Morozumi K, Nickeleit V, Randhawa P, Regele H, Seron D, Seshan S, Sund S, Trpkov K (2003) Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 3(6):708–714
Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, Croker BP, Demetris AJ, Drachenberg CB, Fogo AB, Furness P, Gaber LW, Gibson IW, Glotz D, Goldberg JC, Grande J, Halloran PF, Hansen HE, Hartley B, Hayry PJ, Hill CM, Hoffman EO, Hunsicker LG, Lindblad AS, Marcussen N, Mihatsch MJ, Nadasdy T, Nickerson P, Olsen TS, Papadimitriou JC, Randhawa PS, Rayner DC, Roberts I, Rose S, Rush D, Alinas-Madrigal L, Salomon DR, Sund S, Taskinen E, Trpkov K, Yamaguchi Y (1999) The Banff 97 working classification of renal allograft pathology. Kidney Int 55(2):713–723. https://doi.org/10.1046/j.1523-1755.1999.00299.x
Ren Z, Jiang J, Lu H, Chen X, He Y, Zhang H, Xie H, Wang W, Zheng S, Zhou L (2014) Intestinal microbial variation may predict early acute rejection after liver transplantation in rats. Transplantation 98(8):844–852. https://doi.org/10.1097/TP.0000000000000334
Sandal S, Zand MS (2015) Rational clinical trial design for antibody mediated renal allograft injury. Front Biosci 20:743–762
Schaefer B, Effenberger M, Zoller H (2014) Iron metabolism in transplantation. Transpl Int 27(11):1109–1117. https://doi.org/10.1111/tri.12374
Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C (2011) Metagenomic biomarker discovery and explanation. Genome Biol 12(6):R60. https://doi.org/10.1186/gb-2011-12-6-r60
Sudharshan S, Javaheri A (2018) Cholesterol efflux in the transplant patient. Curr Opin Endocrinol Diabetes Obes 25(2):143–146. https://doi.org/10.1097/MED.0000000000000390
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 (2014) The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 124(7):1174–1182. https://doi.org/10.1182/blood-2014-02-554725
Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J, Gobourne A, Lee YJ, Dubin KA, Socci ND, Viale A, Perales M-A, Jenq RR, van den Brink MRM, Pamer EG (2012) Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 55(7):905–914. https://doi.org/10.1093/cid/cis580
Tourret J, Willing BP, Dion S, MacPherson J, Denamur E, Finlay BB (2017) Immunosuppressive treatment alters secretion of ileal antimicrobial peptides and gut microbiota, and favors subsequent colonization by uropathogenic Escherichia coli. Transplantation 101(1):74–82. https://doi.org/10.1097/TP.0000000000001492
Vindigni SM, Surawicz CM (2015) The gut microbiome: a clinically significant player in transplantation? Expert Rev Clin Immunol 11(7):781–783. https://doi.org/10.1586/1744666X.2015.1043894
Wang F, Li Q, Wang C, Tang C, Li J (2012) Dynamic alteration of the colonic microbiota in intestinal ischemia-reperfusion injury. PLoS One 7(7):e42027. https://doi.org/10.1371/journal.pone.0042027
Willicombe M, Roufosse C, Brookes P, Galliford JW, McLean AG, Dorling A, Warrens AN, Cook TH, Cairns TD, Taube D (2011) Antibody-mediated rejection after alemtuzumab induction: incidence, risk factors, and predictors of poor outcome. Transplantation 92(2):176–182. https://doi.org/10.1097/TP.0b013e318222c9c6
Wu ZW, Ling ZX, Lu HF, Zuo J, Sheng JF, Zheng SS, Li LJ (2012) Changes of gut bacteria and immune parameters in liver transplant recipients. Hepatobiliary Pancreat Dis Int 11(1):40–50
Xie Y, Luo Z, Li Z, Deng M, Liu H, Zhu B, Ruan B, Li L (2012) Structural shifts of fecal microbial communities in rats with acute rejection after liver transplantation. Microb Ecol 64(2):546–554. https://doi.org/10.1007/s00248-012-0030-1
Funding
This research was supported by the National Natural Science Foundation of China (Grant No. 32000650), the Henan Provincial Scientific and Technological Research Project (Grant No. 192102310036), and Henan Provincial Medical Scientific and Technological Research Project (Grant No. 201702191). The sponsors had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
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Tianzhong Yan, Junpeng Wang, and Xin Li conceived and designed research. Junpeng Wang, Zhiwei Wang, and Chan Zhang conducted experiments. GR analyzed the data. Guanghui Cao and Shun Liu analyzed data. Xin Li wrote the manuscript. All authors read and approved the manuscript.
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All procedures performed in studies involving human participants were conducted in accordance with the ethical guideline based on the regulations of Henan Provincial People’s Hospital affiliated to Zhengzhou University federal regulations. Informed consent was obtained from all individual participants included in the study.
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Wang, J., Li, X., Wu, X. et al. Gut microbiota alterations associated with antibody-mediated rejection after kidney transplantation. Appl Microbiol Biotechnol 105, 2473–2484 (2021). https://doi.org/10.1007/s00253-020-11069-x
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DOI: https://doi.org/10.1007/s00253-020-11069-x