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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (4) : 471-481
Antibiotics-mediated intestinal microbiome perturbation aggravates tacrolimus-induced glucose disorders in mice
Yuqiu Han1, Xiangyang Jiang1, Qi Ling1,2, 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
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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 Authors: 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.
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.
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