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

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.

Key words： antibiotics; tacrolimus; glucose disorders; microbiome

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.

Compliance with ethics guidelines

Yuqiu Han, Xiangyang Jiang, Qi Ling, Li Wu, Ping Wu, Ruiqi Tang, Xiaowei Xu, Meifang Yang, Lijiang Zhang, Weiwei Zhu, Baohong Wang, and Lanjuan Li declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-019-0686-8 and is accessible for authorized users.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 of type 1 diabetes in mice. Nat Microbiol 2016; 1(11): 16140

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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