Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 14, 2018; 24(34): 3871-3883
Published online Sep 14, 2018. doi: 10.3748/wjg.v24.i34.3871
Optimal immunosuppressor induces stable gut microbiota after liver transplantation
Jian-Wen Jiang, Zhi-Gang Ren, Hai-Feng Lu, Hua Zhang, Ang Li, Guang-Ying Cui, Jun-Jun Jia, Hai-Yang Xie, Xin-Hua Chen, Yong He, Li Jiang, Lan-Juan Li
Jian-Wen Jiang, Zhi-Gang Ren, Jun-Jun Jia, Hai-Yang Xie, Xin-Hua Chen, Yong He, Li Jiang, Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310003, Zhejiang Province, China
Jian-Wen Jiang, Zhi-Gang Ren, Hai-Feng Lu, Hua Zhang, Ang Li, Guang-Ying Cui, Jun-Jun Jia, Hai-Yang Xie, Xin-Hua Chen, Lan-Juan Li, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Jian-Wen Jiang, Health Management Center, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Zhi-Gang Ren, Ang Li, Guang-Ying Cui, Department of Infectious Diseases, Precision Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Hai-Feng Lu, Hua Zhang, Ang Li, Lan-Juan Li, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Author contributions: Li LJ designed the experiments; Jiang JW, Ren ZG, Lu HF, Zhang H, Jia JJ, Xie HY, He Y, Jiang L performed the experiments; Lu HF, Ren ZG, Li A, Chen XH analyzed the data; Ren ZG, Jiang JW wrote the paper; All authors reviewed and approved the manuscript.
Supported by the National Natural Science Foundation of China, No. 81672422, No. 81600506, and No. 81702757; Open Project in State Key Laboratory for Diagnosis and Treatment of Infectious Disease, No. 2015KF03; National S&T Major Project of China, No. 2018ZX10301201; Natural Science Foundation of Zhejiang Province, No. LY15H160033; China Postdoctoral Science Foundation, No. 2017464; Zhejiang Province Health Department Program, No. 2014KYB081, and No. 2017KY322; Academician Jieshou Li Mucosal Barrier Fund, No. 201208.
Institutional animal care and use committee statement: This study was reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital, School of Medicine, Zhejiang University.
Conflict-of-interest statement: All authors declare no conflict of interest exists.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The ARRIVE Guidelines have been adopted.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Lan-Juan Li, MD, PhD, Academic Research, Doctor, Professor, Senior Researcher, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, School of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou 310003, Zhejiang Province, China. ljli@zju.edu.cn
Telephone: +86-571-87236466 Fax: +86-571-87236466
Received: June 21, 2018
Peer-review started: June 21, 2018
First decision: July 18, 2018
Revised: July 24, 2018
Accepted: August 1, 2018
Article in press: August 1, 2018
Published online: September 14, 2018
ARTICLE HIGHLIGHTS
Research background

Liver transplantation (LT) is the only definitive therapy for end-stage liver diseases. The optimal dosage of immunosuppressive medication is crucial to prevent rejection, lessen the side effects of immunosuppressors (IS) and treatment of patients following LT. The gut microbiota plays a crucial role in the development of obesity, diabetes, liver diseases and so on. Nevertheless, the influence of IS on gut microbiota following LT remains unclear, the association between the dosage of IS and gut microbial alterations requires urgent elucidation.

Research motivation

Acute rejection is still a leading cause of hepatic graft dysfunction following LT. Each recipient of LT must take IS to prevent acute rejection, but the effect of IS on gut microbiota remains unclear. Tacrolimus (FK506) is the main IS following LT, so we studied the influence of different dosages of FK506 on gut microbiota after LT in rat.

Research objectives

In this study, we studied the influence of different dosages of FK506 on hepatic graft function and gut microbiota following LT in rats. Furthermore, we will identify the precise changes of the gut microbiota given by different doses of FK-506 and provide a new monitoring strategy for IS dosage assessment in recipients after LT.

Research methods

We performed LT experiments in rats by taking different dosage of FK506 for 29 d, and on the 30th day after LT, all rats were sampled and then euthanized. We studied the hepatic graft function using serum alanine aminotransferase and aspartate aminotransferase examination and morphology change using histopathology and transmission electron microscopy evaluation. We also identified the gut microbial profile and crucial bacterial community constituents using digital processing of denaturing gradient gel electrophoresis (DGGE), and further verified the alterations of dominant gut bacterial populations with RT-PCR.

Research results

Compared to the FK506-H and FK506-L groups, FK506-M was optimal for maintaining immunosuppression and induced normal graft function; the FK506-M maintained the integrity of gut barrier and low plasma endotoxin levels. Furthermore, FK506-M induced stable gut microbiota, increased species richness and rare species abundance by DGGE and Cluster analysis. The FK506-M increased Faecalibacterium prausnitzii and Bifidobacterium spp. and decreased Bacteroides-Prevotella and Enterobacteriaceae by Phylogenetic tree analysis and RT-PCR verification.

Research conclusions

An optimal dosage of FK506 induces effective immunosuppression, normal graft function and stable gut microbiota after LT in rat. A stable gut microbiota resulted in increased probiotics and decreased potential pathogenic endotoxin-producing bacteria. These findings provide a novel strategy involving the use of the gut microbiota for the assessment of the dosage of immunosuppressive medications and their effects on recipients following LT.

Research perspectives

This study is the first to illustrate the effects of FK506 with different dosages on gut microbiota following LT and indicates that an optimal dosage of FK506 induces effective immunosuppression, good graft function and stable gut microbiota after LT in rats. Based on the relationship between gut microbiota and immunosuppressive dosage in this study, we can not only illustrate precise changes of gut microbiota given by FK-506 with different dosages following LT, but we also provide a novel monitoring strategy based on changes in gut microbiota for IS assessment in recipients following LT. With the improvement of metagenomics and metabolomics techniques, the integrative study can further reveal how the gut microbiota participates in the side effects of IS on recipients and gut microbiota may be a target to reduce side effects of IS. In addition, in order to further study the mechanism of the involvement of gut microbiota on the side effects of IS on recipients, it is essential to do clinical research.