Copyright
©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
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
Processing time: 85 Days and 13.8 Hours
AIM
To study the influence of different doses of tacrolimus (FK506) on gut microbiota after liver transplantation (LT) in rats.
METHODS
Specific pathogen-free Brown Norway (BN) rats and Lewis rats were separated into five groups: (1) Tolerance group (BN-BN LT, n = 8); (2) rejection group (Lewis-BN LT, n = 8); (3) high dosage FK506 (FK506-H) group (Lewis-BN LT, n = 8); (4) middle dosage FK506 (FK506-M) group (Lewis-BN LT, n = 8); and (5) low dosage FK506 (FK506-L) group (Lewis-BN LT, n = 8). FK506 was administered to recipients at a dose of 1.0 mg/kg, 0.5 mg/kg, and 0.1 mg/kg body weight for 29 d after LT to the FK506-H, FK506-M, and FK506-L groups, respectively. On the 30th day after LT, all rats were sampled and euthanized. Blood samples were harvested for liver function and plasma endotoxin testing. Hepatic graft and ileocecal tissues were collected for histopathology observation. Ileocecal contents were used for DNA extraction, Real-time quantitative polymerase chain reaction (RT-PCR) and digital processing of denaturing gradient gel electrophoresis (DGGE) profiles and analysis.
RESULTS
Compared to the FK506-H and FK506-L groups, FK506-M was optimal for maintaining immunosuppression and inducing normal graft function; the FK506-M maintained gut barrier integrity and low plasma endotoxin levels; furthermore, DGGE results showed that FK506-M induced stable gut microbiota. Diversity analysis indicated that FK506-M increased species richness and rare species abundance, and cluster analysis confirmed the stable gut microbiota induced by FK506-M. Phylogenetic tree analysis identified crucial bacteria associated with FK506-M; seven of the nine bacteria that were decreased corresponded to Bacteroidetes, while increased bacteria were of the Bifidobacterium species. FK506-M increased Faecalibacterium prausnitzii and Bifidobacterium spp. and decreased Bacteroides-Prevotella and Enterobacteriaceae, as assessed by RT-PCR, which confirmed the crucial bacterial alterations identified through DGGE.
CONCLUSION
Compared to the low or high dosage of FK506, an optimal dosage of FK506 induced immunosuppression, normal graft function and stable gut microbiota following LT in rats. The stable gut microbiota presented increased probiotics and decreased potential pathogenic endotoxin-producing bacteria. These findings provide a novel strategy based on gut microbiota for immunosuppressive dosage assessment for recipients following LT.
Core tip: This is the first study to illustrate the effects of different dosages of Tacrolimus (FK506) on gut microbiota following liver transplantation (LT) and indicates that an optimal dosage of FK506 induces effective immunosupression, good graft function and stable gut microbiota after LT in rats. Based on the relationship between gut microbiota and the immunosuppressive dosage in this study, we can not only illustrate precise changes of gut microbiota given by different dosages of FK-506 following LT, but we also provide a novel monitoring strategy based on changes in gut microbiota for immunosuppressive dosage assessment in patients following LT.
