Immunosuppressant imprecision: multidirectional effects on metabolism and microbiome

SUMMARY Transplant recipients require lifelong, multimodal immunosuppression to prevent rejection by dampening alloreactive immunity. These treatments have long been known to lack antigen specificity. Despite empirically selected long-term immunosuppression regimens, most allografts succumb to alloimmune responses that result in chronic inflammation and scarring. Additionally, immunosuppressive medications themselves contribute to unintended intestinal dysbiosis and metabolic disorders. This review focuses on the effect of immunosuppressant treatments on alloimmunity, gut microbiome, and metabolism, with a particular emphasis on the effects on metabolic disorders. We also outline the shared and unique microbial and metabolic signatures produced by each immunosuppressant class, underlining their distinct impacts on immunity and metabolic homeostasis. These observations underscore the need for a holistic understanding of these drugs’ on- and off-target effects to refine therapeutic strategies, enhance immunosuppression efficacy, and ultimately enhance graft and patient survival. By characterizing these complex interactions, strategies informed by the gut microbiome and host metabolism may offer a promising adjunctive approach to optimizing immunosuppressive regimens and promoting sustained graft acceptance.