Published online Sep 14, 2018. doi: 10.3748/wjg.v24.i34.3871
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
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.
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.
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.
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.
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.
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.
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.