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.

Keywords

antibiotics / tacrolimus / glucose disorders / microbiome

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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.

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.

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