Immunosuppressive effect of the gut microbiome altered by high-dose tacrolimus in mice

Abstract

The alterations induced in gut microbiota by tacrolimus may affect immune function and organ transplantation. Mice were treated with high-dose tacrolimus for 14 days. The fecal microbiota were analyzed by pyrosequencing the 16S rRNA genes, and the effect on metabolism was predicted using the sequence data. The subgroups of T cells in the serum, gut-associated lymphoid tissue, and draining lymph nodes were determined by flow cytometry. Tacrolimus treatment significantly altered the relative abundance of Allobaculum, Bacteroides, and Lactobacillus and CD4 CD25 FoxP3 regulatory T cells in the colonic mucosa and the circulation. These were significantly increased after either tacrolimus treatment or treatment by fecal microbiota transfer from tacrolimus-treated donors. Further, treatment with low-dose tacrolimus plus fecal microbiota transfer from high-dose tacrolimus-altered mice increased skin allograft survival rate in a skin transplantation model. Thus, high-dose tacrolimus alters the compositions and taxa of the gut microbiota. Administration of these conditioned gut microbiota plus low-dose tacrolimus resulted in regulation of colonic and systemic immune responses and an increased allograft survival rate. This study demonstrated a new strategy for controlling allograft rejection by combining an immunosuppressive agent with gut microbiome transplantation.

Microbiota changes and intestinal microbiota transplantation in liver diseases and cirrhosis

“…79 Calcineurin inhibitors affect the intestinal microbiome and intestinal barrier. 80 Longitudinal analysis of gut microbiota pre-and post-LT showed improvement in diversity after 6 months. 81 Interestingly, the pace of resolution of pretransplant perturbations in microbiota composition was negatively correlated with the burden of multidrug resistant organisms.…”

Butyric acid normalizes hyperglycemia caused by the tacrolimus-induced gut microbiota

“…Therefore, the mechanism of PTDM development after tacrolimus therapy is partly related to the direct toxicity of tacrolimus 12 . On the other hand, in our previous study, we reported that tacrolimus altered the composition and taxa of the gut microbiota, which resulted in immunoregulatory functions of colonic and systemic immune responses and an increased allograft survival rate 13 . Whether the effect on the tacrolimus‐induced gut microbiota might cause a greater tendency to PTDM is currently unclear.…”

Harnessing the microbiota for therapeutic purposes

“…In the same study, the transfer of the commensal Bifidobacterium pseudolongum alone was sufficient to reduce cardiac graft inflammation and fibrosis . The potential of adjuvant approaches combining standard immunosuppression with microbiota‐targeted interventions was exemplified by an animal study, where the combination of the tacrolimus with FMT resulted in increased skin allograft survival …”