Impact of calcineurin inhibitors on gut microbiota: Focus on tacrolimus with evidence from in vivo and clinical studies.

Calcineurin Inhibitors (CNIs), including tacrolimus and cyclosporine A, are the most widely used immunosuppressive drugs in solid organ transplantation. Those drugs play a pivotal role in preventing graft rejection and reducing autoimmunity. However, recent studies indicate that CNIs can disrupt the composition of gut microbiota or result in "gut dysbiosis". This dysbiosis has been shown to be a significant factor in reducing host immunity by decreasing innate immune cells and impairing metabolic regulation, leading to lipid and glucose accumulation. Several in vivo and clinical studies have demonstrated a mechanistic link between gut dysbiosis and the side effects of CNI. Those studies have unveiled that gut dysbiosis induced by CNIs contributes to adverse effects such as hyperglycemia, nephrotoxicity, and diarrhea. These adverse effects of the induced gut dysbiosis require interventions to restore microbial balance. Probiotics and dietary supplements have emerged as potential interventions to mitigate the side effects of gut dysbiosis caused by CNIs. In this complex relationship between CNI treatment, gut dysbiosis, and interventions, several types of gut microbiota and host immunity are involved. However, the mechanisms underlying these relationships remain elusive. Therefore, the aim of this review is to comprehensively summarize and discuss the major findings from in vivo and clinical data regarding the impact of treatment with CNIs on gut microbiota. This review also explores interventions to mitigate dysbiosis for therapeutic approaches of the side effects of CNIs. The possible underlying mechanisms of CNIs-induced gut dysbiosis with or without interventions are also presented and discussed.