Impact of Immunosuppression on the Metagenomic Composition of the Intestinal Microbiome: a Systems Biology Approach to Post-Transplant Diabetes.

ABSTRACT

Solid organ transplantation (SOT) outcomes have continued to improve, although long-term use of immunosuppressants can lead to complications such as diabetes, compromising post-transplant outcomes. In this study, we have characterized the intestinal microbiome (IM) composition at the metagenomic level in the context of hyperglycemia induced by immunosuppressants. Sprague-Dawley rats were subjected to doses of tacrolimus and sirolimus that reliably induce hyperglycemia and an insulin-resistant state. Subsequent exposure to probiotics resulted in reversal of hyperglycemia. 16S rRNA and metagenomic sequencing of stool were done to identify the bacterial genes and pathways enriched in immunosuppression. Bacterial diversity was significantly decreased in sirolimus-treated rats, with 9 taxa significantly less present in both immunosuppression groups Roseburia, Oscillospira, Mollicutes, Rothia, Micrococcaceae, Actinomycetales and Staphylococcus. Following probiotics, these changes were reversed to baseline. At the metagenomic level, the balance of metabolism was shifted towards the catabolic side with an increase of genes involved in sucrose degradation, similar to diabetes. Conversely, the control rats had greater abundance of anabolic processes and genes involved in starch degradation. Immunosuppression leads to a more catabolic microbial profile, which may influence development of diabetes after SOT. Modulation of the microbiome with probiotics may help in minimizing adverse long-term effects of immunosuppression.