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

doi:10.1007/s11684-019-0686-8

Front. Med.

2019, Vol. 13

Issue (4) : 471-481 https://doi.org/10.1007/s11684-019-0686-8

RESEARCH ARTICLE

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

Yuqiu Han¹, Xiangyang Jiang¹, Qi Ling^1,², Li Wu¹, Pin Wu³, Ruiqi Tang¹, Xiaowei Xu¹, Meifang Yang¹, Lijiang Zhang⁴, Weiwei Zhu¹, Baohong Wang¹(

), Lanjuan Li¹

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
². Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
³. Division of Throat Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
⁴. Center of Safety Evaluation, Zhejiang Academy of Medical Sciences, Hangzhou 310053, China

Download: PDF(2357 KB) HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

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.

Keywords antibiotics tacrolimus glucose disorders microbiome

Corresponding Author(s): Baohong Wang

Just Accepted Date: 20 March 2019 Online First Date: 06 May 2019 Issue Date: 02 August 2019

Cite this article:

Yuqiu Han,Xiangyang Jiang,Qi Ling, et al. Antibiotics-mediated intestinal microbiome perturbation aggravates tacrolimus-induced glucose disorders in mice[J]. Front. Med., 2019, 13(4): 471-481.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0686-8
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I4/471

Fig.1 Impact of ABX and TAC on glucose disorders in mice. (A) Glucose tolerance test (GTT). (B) Area under the curve (AUC) for the GTT curves. (C) Insulin release test. (D) Triglyceride levels in the blood. (A and C) *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001 compared with the control group; ^#P<0.05, ^##P<0.01 and ^####P<0.0001 compared with the TAC group. (B and D) *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001. Data are expressed as mean±SEM, n = 10 mice/group. Groups: blank control, Control; tacrolimus (2 mg/kg bw per day), TAC; tacrolimus and antibiotics, TAC+ ABX.

Fig.2 Oral ABX augmented the effect of TAC on triglyceride accumulation in the liver of mice. Concentration of triglyceride in the liver. *P<0.05 and ***P<0.001. Data are expressed as median with interquartile range, n = 10 mice/group. Groups: blank control, Control; tacrolimus (2 mg/kg bw per day), TAC; tacrolimus and antibiotics, TAC+ ABX.

Fig.3 Impact of ABX and TAC on intestinal microbiome in mice. (A) PCoA plot of the IM based on unweighted UniFrac metric. Each spot represents one sample. (B) Relative abundance of bacteria at the phylum level. (C) LEfSe cladograms represented taxa enriched in each group. Rings from the inside out represented taxonomic levels from phylum to genus. Sizes of circles indicate relative abundance of the taxon. (D) Discriminative biomarkers with an LDA score>2. n = 5 mice/group. Groups: blank control, Control; tacrolimus (2 mg/kg/day), TAC; tacrolimus and antibiotics, TAC+ ABX.

Fig.4 Differing microbes among groups and its correlation with the parameters of glucose tolerance. (A) Ratio of Firmicutes to Bacteroidetes. Relative abundances of (B) Firmicutes and (C) Verrucomicrobia at the phylum level in each group. Relative abundances of (D) Lachnospiraceae and (E) Verrucomicrobiaceae at the family level in each group. Relative abundances of (F) Coprococcus and (G) Akkermansia at the genus level in each group. (H) Heatmaps of Pearson correlation analysis between the relative abundance of bacteria and AUC of GTT and lipid deposition in the liver. AUC of GTT indicates the value of the area under the curve in the glucose tolerance test. *P<0.05, **P<0.01, ***P<0.001, and ****P<0.0001. Date are expressed as mean±SEM, n = 5 mice/group. Groups: blank control, Control; tacrolimus (2 mg/kg bw per day), TAC; tacrolimus and antibiotics, TAC+ ABX.

Fig.5 Functional shifts of IM among groups and their relationship with the parameters of glucose tolerance. (A) KEGG pathway categories were inferred from 16S rRNA gene sequences using PICRUSt. Comparison of the KEGG functional categories for the case-enriched gene markers is shown by percentage. (B) Spearman correlation analysis between changed four functional categories and glycometabolism-related indices. *P<0.05; **P<0.01. n = 5 mice/group. Groups: blank control, Control; tacrolimus (2 mg/kg/day), TAC; tacrolimus and antibiotics, TAC+ ABX. GTT: glucose tolerance test; AUC: the value of the area under the curve in GTT.

1	TG Valderhaug, J Hjelmesaeth, T Jenssen, J Roislien, T Leivestad, A Hartmann. Early posttransplantation hyperglycemia in kidney transplant recipients is associated with overall long-term graft losses. Transplantation 2012; 94(7): 714–720 https://doi.org/10.1097/TP.0b013e31825f4434
2	TG Valderhaug, J Hjelmesaeth, A Hartmann, J Roislien, HA Bergrem, T Leivestad, PD Line, T Jenssen. The association of early post-transplant glucose levels with long-term mortality. Diabetologia 2011; 54(6): 1341–1349 https://doi.org/10.1007/s00125-011-2105-9
3	G Zaza, A Dalla Gassa, G Felis, S Granata, S Torriani, A Lupo. 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 https://doi.org/10.1371/journal.pone.0178228
4	KB Lankarani, A Eshraghian, S Nikeghbalian, P Janghorban, SA Malek-Hosseini. 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 https://doi.org/10.6002/ect.2013.0047
5	Q Ling, X Xu, B Wang, L Li, S Zheng. The origin of new-onset diabetes after liver transplantation: liver, islets, or gut? Transplantation 2016; 100(4): 808–813 https://doi.org/10.1097/TP.0000000000001111
6	M Bhat, E Pasini, J Copeland, M Angeli, S Husain, D Kumar, E Renner, A Teterina, J Allard, DS Guttman, A Humar. 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 https://doi.org/10.1038/s41598-017-10471-2
7	S Candon, A Perez-Arroyo, C Marquet, F Valette, AP Foray, B Pelletier, C Milani, M Ventura, JF Bach, L Chatenoud. 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 https://doi.org/10.1371/journal.pone.0125448
8	D Kawecki, M Pacholczyk, B Lagiewska, A Sawicka-Grzelak, M Durlik, G Mlynarczyk, A Chmura. 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 https://doi.org/10.1016/j.transproceed.2014.08.031
9	T Yousuf, J Kramer, A Kopiec, B Jones, J Iskandar, K Ahmad, H Keshmiri, M Dia. In search for equilibrium: immunosuppression versus opportunistic infection. J Clin Med Res 2016; 8(2): 175–177 https://doi.org/10.14740/jocmr2439w
10	JR Marchesi, DH Adams, F Fava, GD Hermes, GM Hirschfield, G Hold, MN Quraishi, J Kinross, H Smidt, KM Tuohy, LV Thomas, EG Zoetendal, A Hart. The gut microbiota and host health: a new clinical frontier. Gut 2016; 65(2): 330–339 https://doi.org/10.1136/gutjnl-2015-309990
11	VR Velagapudi, R Hezaveh, CS Reigstad, P Gopalacharyulu, L Yetukuri, S Islam, J Felin, R Perkins, J Boren, M Oresic, F Backhed. The gut microbiota modulates host energy and lipid metabolism in mice. J Lipid Res 2010; 51(5): 1101–1112 https://doi.org/10.1194/jlr.M002774
12	M Nieuwdorp, PW Gilijamse, N Pai, LM Kaplan. Role of the microbiome in energy regulation and metabolism. Gastroenterology 2014; 146(6): 1525–1533 https://doi.org/10.1053/j.gastro.2014.02.008
13	N Larsen, FK Vogensen, FW van den Berg, DS Nielsen, AS Andreasen, BK Pedersen, WA Al-Soud, SJ Sorensen, LH Hansen, M Jakobsen. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 2010; 5(2): e9085 https://doi.org/10.1371/journal.pone.0009085
14	J Qin, Y Li, Z Cai, S Li, J Zhu, F Zhang, S Liang, W Zhang, Y Guan, D Shen, Y Peng, D Zhang, Z Jie, W Wu, Y Qin, W Xue, J Li, L Han, D Lu, P Wu, Y Dai, X Sun, Z Li, A Tang, S Zhong, X Li, W Chen, R Xu, M Wang, Q Feng, M Gong, J Yu, Y Zhang, M Zhang, T Hansen, G Sanchez, J Raes, G Falony, S Okuda, M Almeida, E LeChatelier, P Renault, N Pons, JM Batto, Z Zhang, H Chen, R Yang, W Zheng, S Li, H Yang, J Wang, SD Ehrlich, R Nielsen, O Pedersen, K Kristiansen, J Wang. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012; 490(7418): 55–60 https://doi.org/10.1038/nature11450
15	H Tilg, AR Moschen. Microbiota and diabetes: an evolving relationship. Gut 2014; 63(9): 1513–1521 https://doi.org/10.1136/gutjnl-2014-306928
16	ZW Wu, ZX Ling, HF Lu, J Zuo, JF Sheng, SS Zheng, LJ Li. Changes of gut bacteria and immune parameters in liver transplant recipients. Hepatobiliary Pancreat Dis Int 2012; 11(1): 40–50 https://doi.org/10.1016/S1499-3872(11)60124-0
17	X Zhang, D Shen, Z Fang, Z Jie, X Qiu, C Zhang, Y Chen, L Ji. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One 2013; 8(8): e71108 https://doi.org/10.1371/journal.pone.0071108
18	HE Jakobsson, AM Rodriguez-Pineiro, A Schutte, A Ermund, P Boysen, M Bemark, F Sommer, F Backhed, GC Hansson, ME Johansson. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep 2015; 16(2): 164–177 https://doi.org/10.15252/embr.201439263
19	I Cho, S Yamanishi, L Cox, BA Methe, J Zavadil, K Li, Z Gao, D Mahana, K Raju, I Teitler, H Li, AV Alekseyenko, MJ Blaser. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature 2012; 488(7413): 621–626 https://doi.org/10.1038/nature11400
20	SF Boj, JH van Es, M Huch, VS Li, A Jose, P Hatzis, M Mokry, A Haegebarth, M van den Born, P Chambon, P Voshol, Y Dor, E Cuppen, C Fillat, H Clevers. Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand. Cell 2012; 151(7): 1595–1607 https://doi.org/10.1016/j.cell.2012.10.053
21	B Wang, X Jiang, M Cao, J Ge, Q Bao, L Tang, Y Chen, L Li. Altered fecal microbiota correlates with liver biochemistry in nonobese patients with non-alcoholic fatty liver disease. Sci Rep 2016; 6(1): 32002 https://doi.org/10.1038/srep32002
22	JG Caporaso, J Kuczynski, J Stombaugh, K Bittinger, FD Bushman, EK Costello, N Fierer, AG Pena, JK Goodrich, JI Gordon, GA Huttley, ST Kelley, D Knights, JE Koenig, RE Ley, CA Lozupone, D McDonald, BD Muegge, M Pirrung, J Reeder, JR Sevinsky, PJ Turnbaugh, WA Walters, J Widmann, T Yatsunenko, J Zaneveld, R Knight. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010; 7(5): 335–336 https://doi.org/10.1038/nmeth.f.303
23	MG Langille, J Zaneveld, JG Caporaso, D McDonald, D Knights, JA Reyes, JC Clemente, DE Burkepile, RL Vega Thurber, R Knight, RG Beiko, C Huttenhower. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 2013; 31(9): 814–821 https://doi.org/10.1038/nbt.2676
24	DH Parks, RG Beiko. Identifying biologically relevant differences between metagenomic communities. Bioinformatics 2010; 26(6): 715–721 https://doi.org/10.1093/bioinformatics/btq041
25	I Lozano, R Van der Werf, W Bietiger, E Seyfritz, C Peronet, M Pinget, N Jeandidier, E Maillard, E Marchioni, S Sigrist, S Dal. 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 https://doi.org/10.1186/s12986-016-0074-1
26	O Bamgbola. Metabolic consequences of modern immunosuppressive agents in solid organ transplantation. Ther Adv Endocrinol Metab 2016; 7(3): 110–127 https://doi.org/10.1177/2042018816641580
27	S Ussar, NW Griffin, O Bezy, S Fujisaka, S Vienberg, S Softic, L Deng, L Bry, JI Gordon, CR Kahn. Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. Cell Metab 2015; 22(3): 516–530 https://doi.org/10.1016/j.cmet.2015.07.007
28	A Prokai, A Fekete, K Pasti, K Rusai, NF Banki, G Reusz, AJ Szabo. The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. Pediatr Diabetes 2012; 13(1): 81–91 https://doi.org/10.1111/j.1399-5448.2011.00782.x
29	L Santos, E Rodrigo, C Pinera, E Quintella, JC Ruiz, G Fernandez-Fresnedo, R Palomar, C Gomez-Alamillo, A de Francisco, M Arias. New-onset diabetes after transplantation: drug-related risk factors. Transplant Proc 2012; 44(9): 2585–2587 https://doi.org/10.1016/j.transproceed.2012.09.053
30	C Ubeda, EG Pamer. Antibiotics, microbiota, and immune defense. Trends Immunol 2012; 33(9): 459–466 https://doi.org/10.1016/j.it.2012.05.003
31	M Million, F Thuny, E Angelakis, JP Casalta, R Giorgi, G Habib, D Raoult. Lactobacillus reuteri and Escherichia coli in the human gut microbiota may predict weight gain associated with vancomycin treatment. Nutr Diabetes 2013; 3(9): e87 https://doi.org/10.1038/nutd.2013.28
32	LC Bailey, CB Forrest, P Zhang, TM Richards, A Livshits, PA DeRusso. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014; 168(11): 1063–1069 https://doi.org/10.1001/jamapediatrics.2014.1539
33	M Membrez, F Blancher, M Jaquet, R Bibiloni, PD Cani, RG Burcelin, I Corthesy, K Mace, CJ Chou. Gut microbiota modulation with norfloxacin and ampicillin enhances glucose tolerance in mice. FASEB J 2008; 22(7): 2416–2426 https://doi.org/10.1096/fj.07-102723
34	BM Carvalho, D Guadagnini, DM Tsukumo, AA Schenka, P Latuf-Filho, J Vassallo, JC Dias, LT Kubota, JB Carvalheira, MJ Saad. Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice. Diabetologia 2012; 55(10): 2823–2834 https://doi.org/10.1007/s00125-012-2648-4
35	K Brown, A Godovannyi, C Ma, Y Zhang, Z Ahmadi-Vand, C Dai, MA Gorzelak, Y Chan, JM Chan, A Lochner, JP Dutz, BA Vallance, DL Gibson. Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice. ISME J 2016; 10(2): 321–332 https://doi.org/10.1038/ismej.2015.114
36	AE Livanos, TU Greiner, P Vangay, W Pathmasiri, D Stewart, S McRitchie, H Li, J Chung, J Sohn, S Kim, Z Gao, C Barber, J Kim, S Ng, AB Rogers, S Sumner, XS Zhang, K Cadwell, D Knights, A Alekseyenko, F Backhed, MJ Blaser. Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nat Microbiol 2016; 1(11): 16140 https://doi.org/10.1038/nmicrobiol.2016.140
37	A Vrieze, C Out, S Fuentes, L Jonker, I Reuling, RS Kootte, E van Nood, F Holleman, M Knaapen, JA Romijn, MR Soeters, EE Blaak, GM Dallinga-Thie, D Reijnders, MT Ackermans, MJ Serlie, FK Knop, JJ Holst, C van der Ley, IP Kema, EG Zoetendal, WM de Vos, JB Hoekstra, ES Stroes, AK Groen, M Nieuwdorp. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol 2014; 60(4): 824–831 https://doi.org/10.1016/j.jhep.2013.11.034
38	FA Romero, RR Razonable. Infections in liver transplant recipients. World J Hepatol 2011; 3(4): 83–92 https://doi.org/10.4254/wjh.v3.i4.83
39	M Li, B Wang, M Zhang, M Rantalainen, S Wang, H Zhou, Y Zhang, J Shen, X Pang, M Zhang, H Wei, Y Chen, H Lu, J Zuo, M Su, Y Qiu, W Jia, C Xiao, LM Smith, S Yang, E Holmes, H Tang, G Zhao, JK Nicholson, L Li, L Zhao. Symbiotic gut microbes modulate human metabolic phenotypes. Proc Natl Acad Sci USA 2008; 105(6): 2117–2122 https://doi.org/10.1073/pnas.0712038105
40	RE Ley, PJ Turnbaugh, S Klein, JI Gordon. Microbial ecology: human gut microbes associated with obesity. Nature 2006; 444(7122): 1022–1023 https://doi.org/10.1038/4441022a
41	S Kittelmann, H Seedorf, WA Walters, JC Clemente, R Knight, JI Gordon, PH Janssen. Simultaneous amplicon sequencing to explore co-occurrence patterns of bacterial, archaeal and eukaryotic microorganisms in rumen microbial communities. PLoS One 2013; 8(2): e47879 https://doi.org/10.1371/journal.pone.0047879
42	EN Bergman. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev 1990; 70(2): 567–590 https://doi.org/10.1152/physrev.1990.70.2.567
43	JM Wong, R de Souza, CW Kendall, A Emam, DJ Jenkins. Colonic health: fermentation and short chain fatty acids. J Clin Gastroenterol 2006; 40(3): 235–243 https://doi.org/10.1097/00004836-200603000-00015
44	GA Bohmig, PM Krieger, MD Saemann, C Wenhardt, E Pohanka, GJ Zlabinger. 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 https://doi.org/10.1046/j.1365-2567.1997.00337.x
45	MC Noverr, GB Huffnagle. Does the microbiota regulate immune responses outside the gut? Trends Microbiol 2004; 12(12): 562–568 https://doi.org/10.1016/j.tim.2004.10.008
46	F De Vadder, P Kovatcheva-Datchary, D Goncalves, J Vinera, C Zitoun, A Duchampt, F Backhed, G Mithieux. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014; 156(1-2): 84–96 https://doi.org/10.1016/j.cell.2013.12.016
47	L Peng, Z He, W Chen, IR Holzman, J Lin. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatr Res 2007; 61(1): 37–41 https://doi.org/10.1203/01.pdr.0000250014.92242.f3
48	T Suzuki, S Yoshida, H Hara. Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability. Br J Nutr 2008; 100(02): 297–305 https://doi.org/10.1017/S0007114508888733
49	CH Hansen, L Krych, DS Nielsen, FK Vogensen, LH Hansen, SJ Sorensen, K Buschard, AK Hansen. Early life treatment with vancomycin propagates Akkermansia muciniphila and reduces diabetes incidence in the NOD mouse. Diabetologia 2012; 55(8): 2285–2294 https://doi.org/10.1007/s00125-012-2564-7
50	G Dubourg, JC Lagier, F Armougom, C Robert, G Audoly, L Papazian, D Raoult. High-level colonisation of the human gut by Verrucomicrobia following broad-spectrum antibiotic treatment. Int J Antimicrob Agents 2013; 41(2): 149–155 https://doi.org/10.1016/j.ijantimicag.2012.10.012
51	NR Shin, JC Lee, HY Lee, MS Kim, TW Whon, MS Lee, JW Bae. 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 https://doi.org/10.1136/gutjnl-2012-303839
52	A Hänninen, R Toivonen, S Poysti, C Belzer, H Plovier, JP Ouwerkerk, R Emani, PD Cani, WM De Vos. Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. Gut 2018; 67(8): 1445–1453 https://doi.org/10.1136/gutjnl-2017-314508
53	AH Zhang, S Qiu, HY Xu, H Sun, XJ Wang. Metabolomics in diabetes. Clin Chim Acta 2014; 429: 106–110 https://doi.org/10.1016/j.cca.2013.11.037
54	C Menni, E Fauman, I Erte, JR Perry, G Kastenmuller, SY Shin, AK Petersen, C Hyde, M Psatha, KJ Ward, W Yuan, M Milburn, CN Palmer, TM Frayling, J Trimmer, JT Bell, C Gieger, RP Mohney, MJ Brosnan, K Suhre, N Soranzo, TD Spector. Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach. Diabetes 2013; 62(12): 4270–4276 https://doi.org/10.2337/db13-0570

[1]	Solmaz Ohadian Moghadam, Seyed Ali Momeni. Human microbiome and prostate cancer development: current insights into the prevention and treatment[J]. Front. Med., 2021, 15(1): 11-32.
[2]	Yongfei Hu, George F. Gao, Baoli Zhu. The antibiotic resistome: gene flow in environments, animals and human beings[J]. Front. Med., 2017, 11(2): 161-168.
[3]	Ying Ma,Nanxue Zhang,Shi Wu,Haihui Huang,Yanpei Cao. *Antimicrobial activity of topical agents against Propionibacterium acnes: an in vitro* study of clinical isolates from a hospital in Shanghai, China**[J]. Front. Med., 2016, 10(4): 517-521.

Viewed

Full text

Abstract

Cited

Shared

Discussed