Immunosuppressant-Induced Alteration of Gut Microbiota Causes Loss of Skeletal Muscle Mass: Evidence from Animal Experiments Using Mice and Observational Study on Humans

<b>Background/Objectives</b>: The number of older adults requiring a kidney transplant (KT) is increasing; hence, postoperative sarcopenia prevention is necessary. KT recipients require permanent oral immunosuppressants (ISs), and the gut microbiota (GM) plays a role in various systemic diseases. However, few studies have evaluated post-kidney transplantation frailty and the associations among ISs, GM, and muscle mass alterations. Therefore, we investigated the effects of ISs on GM and skeletal muscle mass in mice and human KT recipients. <b>Methods:</b> Mice were treated with six different ISs, and their skeletal muscle mass, GM diversity, and colonic mucosal function were assessed. Human KT recipients and donors were monitored before and after surgery for 1 year, and GM diversity was evaluated before and 1 month after surgery. <b>Results</b>: The abundance of <i>Akkermansia</i>, crypt depth, and mucin 2 expression were lower in tacrolimus- and prednisolone-treated mice. The psoas muscle volume changes at 1 month and 1 year after surgery were lower in KT recipients than in donors. Furthermore, the beta diversity was significantly different between the operative groups (<i>p</i> = 0.001), and the KT group showed the lowest Shannon index. <b>Conclusions</b>: The findings of this study indicate potential links among ISs, GM, and muscle mass decline. Further investigation is required to improve therapeutic strategies and patient outcomes.