L-Histidine alleviates tacrolimus-induced islet dysfunction via the gut-pancreas axis

Tacrolimus is widely used after organ transplantation but can impair pancreatic β-cell function and glucose homeostasis. Using rodent models, antibiotic-mediated microbiota depletion, fecal microbiota transplantation, 16S rRNA sequencing, metabolomic profiling, and MIN-6 cells, we examined whether microbiota-associated L-histidine contributes to β-cell protection. Tacrolimus altered gut microbial composition and increased histidine-associated microbial and metabolic signals. L-histidine supplementation improved glucose tolerance and insulin secretion, reduced β-cell apoptosis, and increased PI3K/Akt/mTOR/p70S6K signaling and PDX-1, NeuroD1, and MafA expression. Microbiota depletion attenuated several protective effects of L-histidine, supporting a contribution of the gut microbiota to this response. These findings connect a microbiota-associated amino acid with tacrolimus-related β-cell dysfunction and provide a framework for investigating microbiota-metabolite contributions to metabolic complications of immunosuppression.