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Antibiotics-mediated intestinal microbiome perturbation aggravates tacrolimus-induced glucose disorders in mice

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Abstract

Both immunosuppressants and antibiotics (ABX) are indispensable for transplant patients. However, the former increases the risk of new-onset diabetes, whereas the latter impacts intestinal microbiota (IM). It is still unclear whether and how the interaction between immunosuppressants and ABX alters the IM and thus leads to glucose metabolism disorders. This study examined the alterations of glucose and lipid metabolism and IM in mice exposed to tacrolimus (TAC) with or without ABX. We found that ABX further aggravated TAC-induced glucose tolerance and increased insulin secretion. Combined treatment resulted in exacerbated lipid accumulation in the liver. TAC-altered microbial community was further amplified by ABX administration, as characterized by reductions in phylum Firmicutes, family Lachnospiraceae, and genus Coprococcus. Analyses based on the metagenomic profiles revealed that ABX augmented the effect of TAC on microbial metabolic function mostly related to lipid metabolism. The altered components of gut microbiome and predicted microbial functional profiles showed significant correlation with hepatic lipid accumulation and glucose disorders. In conclusion, ABX aggravated the effect of TAC on the microbiome and its metabolic capacities, which might contribute to hepatic lipid accumulation and glucose disorders. These findings suggest that the ABX-altered microbiome can amplify the diabetogenic effect of TAC and could be a novel therapeutic target for patients.

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References

  1. Valderhaug TG, Hjelmesaeth J, Jenssen T, Roislien J, Leivestad T, Hartmann A. Early posttransplantation hyperglycemia in kidney transplant recipients is associated with overall long-term graft losses. Transplantation 2012; 94(7): 714–720

    Article  CAS  Google Scholar 

  2. Valderhaug TG, Hjelmesaeth J, Hartmann A, Roislien J, Bergrem HA, Leivestad T, Line PD, Jenssen T. The association of early post-transplant glucose levels with long-term mortality. Diabetologia 2011; 54(6): 1341–1349

    Article  CAS  Google Scholar 

  3. 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

    Article  Google Scholar 

  4. Lankarani KB, Eshraghian A, Nikeghbalian S, Janghorban P, Malek-Hosseini SA. New onset diabetes and impaired fasting glucose after liver transplant: risk analysis and the impact of tacrolimus dose. Exp Clin Transplant 2014; 12(1): 46–51

    Article  Google Scholar 

  5. Ling Q, Xu X, Wang B, Li L, Zheng S. The origin of new-onset diabetes after liver transplantation: liver, islets, or gut? Transplantation 2016; 100(4): 808–813

    Article  CAS  Google Scholar 

  6. Bhat M, Pasini E, Copeland J, Angeli M, Husain S, Kumar D, Renner E, Teterina A, Allard J, Guttman DS, Humar A. Impact of immunosuppression on the metagenomic composition of the intestinal microbiome: a systems biology approach to post-transplant diabetes. Sci Rep 2017; 7(1): 10277

    Article  CAS  Google Scholar 

  7. Candon S, Perez-Arroyo A, Marquet C, Valette F, Foray AP, Pelletier B, Milani C, Ventura M, Bach JF, Chatenoud L. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes. PLoS One 2015; 10(5): e0125448

    Article  Google Scholar 

  8. Kawecki D, Pacholczyk M, Lagiewska B, Sawicka-Grzelak A, Durlik M, Mlynarczyk G, Chmura A. Bacterial and fungal infections in the early post-transplantation period after liver transplantation: etiologic agents and their susceptibility. Transplant Proc 2014; 46 (8): 2777–2781

    Article  CAS  Google Scholar 

  9. Yousuf T, Kramer J, Kopiec A, Jones B, Iskandar J, Ahmad K, Keshmiri H, Dia M. In search for equilibrium: immunosuppression versus opportunistic infection. J Clin Med Res 2016; 8(2): 175–177

    Article  Google Scholar 

  10. Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield GM, Hold G, Quraishi MN, Kinross J, Smidt H, Tuohy KM, Thomas LV, Zoetendal EG, Hart A. The gut microbiota and host health: a new clinical frontier. Gut 2016; 65(2): 330–339

    Article  Google Scholar 

  11. Velagapudi VR, Hezaveh R, Reigstad CS, Gopalacharyulu P, Yetukuri L, Islam S, Felin J, Perkins R, Boren J, Oresic M, Backhed F. The gut microbiota modulates host energy and lipid metabolism in mice. J Lipid Res 2010; 51(5): 1101–1112

    Article  CAS  Google Scholar 

  12. Nieuwdorp M, Gilijamse PW, Pai N, Kaplan LM. Role of the microbiome in energy regulation and metabolism. Gastroenterology 2014; 146(6): 1525–1533

    Article  CAS  Google Scholar 

  13. Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, Al-Soud WA, Sorensen SJ, Hansen LH, Jakobsen M. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 2010; 5(2): e9085

    Article  Google Scholar 

  14. 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  CAS  Google Scholar 

  15. Tilg H, Moschen AR. Microbiota and diabetes: an evolving relationship. Gut 2014; 63(9): 1513–1521

    Article  CAS  Google Scholar 

  16. Wu ZW, Ling ZX, Lu HF, Zuo J, Sheng JF, Zheng SS, Li LJ. Changes of gut bacteria and immune parameters in liver transplant recipients. Hepatobiliary Pancreat Dis Int 2012; 11(1): 40–50

    Article  CAS  Google Scholar 

  17. Zhang X, Shen D, Fang Z, Jie Z, Qiu X, Zhang C, Chen Y, Ji L. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One 2013; 8(8): e71108

    Article  CAS  Google Scholar 

  18. Jakobsson HE, Rodriguez-Pineiro AM, Schutte A, Ermund A, Boysen P, Bemark M, Sommer F, Backhed F, Hansson GC, Johansson ME. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep 2015; 16(2): 164–177

    Article  CAS  Google Scholar 

  19. Cho I, Yamanishi S, Cox L, Methe BA, Zavadil J, Li K, Gao Z, Mahana D, Raju K, Teitler I, Li H, Alekseyenko AV, Blaser MJ. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012; 488(7413): 621–626

    Article  CAS  Google Scholar 

  20. Boj SF, van Es JH, Huch M, Li VS, Jose A, Hatzis P, Mokry M, Haegebarth A, van den Born M, Chambon P, Voshol P, Dor Y, Cuppen E, Fillat C, Clevers H. Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand. Cell 2012; 151(7): 1595–1607

    Article  CAS  Google Scholar 

  21. Wang B, Jiang X, Cao M, Ge J, Bao Q, Tang L, Chen Y, Li L. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease. Sci Rep 2016; 6(1): 32002

    Article  CAS  Google Scholar 

  22. 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. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010; 7(5): 335–336

    Article  CAS  Google Scholar 

  23. 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. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 2013; 31(9): 814–821

    Article  CAS  Google Scholar 

  24. Parks DH, Beiko RG. Identifying biologically relevant differences between metagenomic communities. Bioinformatics 2010; 26(6): 715–721

    Article  CAS  Google Scholar 

  25. Lozano I, Van der Werf R, Bietiger W, Seyfritz E, Peronet C, Pinget M, Jeandidier N, Maillard E, Marchioni E, Sigrist S, Dal S. High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Nutr Metab (Lond) 2016; 13(1): 15

    Article  Google Scholar 

  26. Bamgbola O. Metabolic consequences of modern immunosuppressive agents in solid organ transplantation. Ther Adv Endocrinol Metab 2016; 7(3): 110–127

    Article  CAS  Google Scholar 

  27. Ussar S, Griffin NW, Bezy O, Fujisaka S, Vienberg S, Softic S, Deng L, Bry L, Gordon JI, Kahn CR. Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. Cell Metab 2015; 22(3): 516–530

    Article  CAS  Google Scholar 

  28. Prokai A, Fekete A, Pasti K, Rusai K, Banki NF, Reusz G, Szabo AJ. The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. Pediatr Diabetes 2012; 13(1): 81–91

    Article  CAS  Google Scholar 

  29. Santos L, Rodrigo E, Pinera C, Quintella E, Ruiz JC, Fernandez-Fresnedo G, Palomar R, Gomez-Alamillo C, de Francisco A, Arias M. New-onset diabetes after transplantation: drug-related risk factors. Transplant Proc 2012; 44(9): 2585–2587

    Article  CAS  Google Scholar 

  30. Ubeda C, Pamer EG. Antibiotics, microbiota, and immune defense. Trends Immunol 2012; 33(9): 459–466

    Article  CAS  Google Scholar 

  31. Million M, Thuny F, Angelakis E, Casalta JP, Giorgi R, Habib G, Raoult D. Lactobacillus reuteri and Escherichia coli in the human gut microbiota may predict weight gain associated with vancomycin treatment. Nutr Diabetes 2013; 3(9): e87

    Article  CAS  Google Scholar 

  32. Bailey LC, Forrest CB, Zhang P, Richards TM, Livshits A, DeRusso PA. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014; 168(11): 1063–1069

    Article  Google Scholar 

  33. Membrez M, Blancher F, Jaquet M, Bibiloni R, Cani PD, Burcelin RG, Corthesy I, Mace K, Chou CJ. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J 2008; 22(7): 2416–2426

    Article  CAS  Google Scholar 

  34. Carvalho BM, Guadagnini D, Tsukumo DM, Schenka AA, Latuf-Filho P, Vassallo J, Dias JC, Kubota LT, Carvalheira JB, Saad MJ. Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice. Diabetologia 2012; 55(10): 2823–2834

    Article  CAS  Google Scholar 

  35. Brown K, Godovannyi A, Ma C, Zhang Y, Ahmadi-Vand Z, Dai C, Gorzelak MA, Chan Y, Chan JM, Lochner A, Dutz JP, Vallance BA, Gibson DL. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice. ISME J 2016; 10(2): 321–332

    Article  CAS  Google Scholar 

  36. Livanos AE, Greiner TU, Vangay P, Pathmasiri W, Stewart D, McRitchie S, Li H, Chung J, Sohn J, Kim S, Gao Z, Barber C, Kim J, Ng S, Rogers AB, Sumner S, Zhang XS, Cadwell K, Knights D, Alekseyenko A, Backhed F, Blaser MJ. Antibiotic-mediated gut microbiome perturbation accelerates development oftype 1 diabetes in mice. Nat Microbiol 2016; 1(11): 16140

    Article  CAS  Google Scholar 

  37. Vrieze A, Out C, Fuentes S, Jonker L, Reuling I, Kootte RS, van Nood E, Holleman F, Knaapen M, Romijn JA, Soeters MR, Blaak EE, Dallinga-Thie GM, Reijnders D, Ackermans MT, Serlie MJ, Knop FK, Holst JJ, van der Ley C, Kema IP, Zoetendal EG, de Vos WM, Hoekstra JB, Stroes ES, Groen AK, Nieuwdorp M. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol 2014; 60(4): 824–831

    Article  CAS  Google Scholar 

  38. Romero FA, Razonable RR. Infections in liver transplant recipients. World J Hepatol 2011; 3(4): 83–92

    Article  Google Scholar 

  39. Li M, Wang B, Zhang M, Rantalainen M, Wang S, Zhou H, Zhang Y, Shen J, Pang X, Zhang M, Wei H, Chen Y, Lu H, Zuo J, Su M, Qiu Y, Jia W, Xiao C, Smith LM, Yang S, Holmes E, Tang H, Zhao G, Nicholson JK, Li L, Zhao L. Symbiotic gut microbes modulate human metabolic phenotypes. Proc Natl Acad Sci USA 2008; 105 (6): 2117–2122

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  41. Kittelmann S, Seedorf H, Walters WA, Clemente JC, Knight R, Gordon JI, Janssen PH. Simultaneous amplicon sequencing to explore co-occurrence patterns ofbacterial, archaeal and eukaryotic microorganisms in rumen microbial communities. PLoS One 2013; 8(2): e47879

    Article  CAS  Google Scholar 

  42. Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev 1990; 70(2): 567–590

    Article  CAS  Google Scholar 

  43. Wong JM, de Souza R, Kendall CW, Emam A, Jenkins DJ. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 2006; 40(3): 235–243

    Article  CAS  Google Scholar 

  44. Bohmig GA, Krieger PM, Saemann MD, Wenhardt C, Pohanka E, Zlabinger GJ. n-butyrate downregulates the stimulatory function of peripheral blood-derived antigen-presenting cells: a potential mechanism for modulating T-cell responses by short-chain fatty acids. Immunology 1997; 92(2): 234–243

    Article  CAS  Google Scholar 

  45. Noverr MC, Huffnagle GB. Does the microbiota regulate immune responses outside the gut? Trends Microbiol 2004; 12 (12): 562–568

    Article  CAS  Google Scholar 

  46. De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, Backhed F, Mithieux G. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014; 156(1–2): 84–96

    Article  CAS  Google Scholar 

  47. Peng L, He Z, Chen W, Holzman IR, Lin J. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatr Res 2007; 61(1): 37–41

    Article  CAS  Google Scholar 

  48. Suzuki T, Yoshida S, Hara H. Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability. Br J Nutr 2008; 100(02): 297–305

    Article  CAS  Google Scholar 

  49. Hansen CH, Krych L, Nielsen DS, Vogensen FK, Hansen LH, Sorensen SJ, Buschard K, Hansen AK. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia 2012; 55(8): 2285–2294

    Article  CAS  Google Scholar 

  50. Dubourg G, Lagier JC, Armougom F, Robert C, Audoly G, Papazian L, Raoult D. High-level colonisation of the human gut by Verrucomicrobia following broad-spectrum antibiotic treatment. Int J Antimicrob Agents 2013; 41(2): 149–155

    Article  CAS  Google Scholar 

  51. Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, Bae JW. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014; 63(5): 727–735

    Article  CAS  Google Scholar 

  52. Hänninen A, Toivonen R, Poysti S, Belzer C, Plovier H, Ouwerkerk JP, Emani R, Cani PD, De Vos WM. Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. Gut 2018; 67(8): 1445–1453

    Article  Google Scholar 

  53. Zhang AH, Qiu S, Xu HY, Sun H, Wang XJ. Metabolomics in diabetes. Clin Chim Acta 2014; 429: 106–110

    Article  CAS  Google Scholar 

  54. Menni C, Fauman E, Erte I, Perry JR, Kastenmuller G, Shin SY, Petersen AK, Hyde C, Psatha M, Ward KJ, Yuan W, Milburn M, Palmer CN, Frayling TM, Trimmer J, Bell JT, Gieger C, Mohney RP, Brosnan MJ, Suhre K, Soranzo N, Spector TD. Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach. Diabetes 2013; 62(12): 4270–4276

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the Science Fund for Distinguished Young Scholars of Zhejiang Provincial Natural Science Foundation of China (No. R16H260001) and Major Program of National Natural Science Foundation of China (Nos. 81790633 and 81790630). It also was supported by the Fundamental Research Funds for the Central Universities (No. 2018FZA7001). Lijiang Zhang received grants from the Science Technology Department of Zhejiang Province (No. 2014F30018). We thank Prof. Minli Chen and Mr. Lizong Zhang of Zhejiang Chinese Medical University for their help in the animal experiment and Dr. Honglei Weng of Heidelberg University for language improvement.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. National Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Yuqiu Han, Xiangyang Jiang, Qi Ling, Li Wu, Ruiqi Tang, Xiaowei Xu, Meifang Yang, Weiwei Zhu, Baohong Wang & Lanjuan Li

  2. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Qi Ling

  3. Division of Throat Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Pin Wu

  4. Center of Safety Evaluation, Zhejiang Academy of Medical Sciences, Hangzhou, 310053, China

    Lijiang Zhang

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  1. Yuqiu Han
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Correspondence to Baohong Wang.

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Han, Y., Jiang, X., Ling, Q. et al. Antibiotics-mediated intestinal microbiome perturbation aggravates tacrolimus-induced glucose disorders in mice. Front. Med. 13, 471–481 (2019). https://doi.org/10.1007/s11684-019-0686-8

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