Background: The cross-talk between the host and its microbiota plays a key role in the promotion of health. The production of metabolites such as polyamines by intestinal-resident bacteria is part of this symbiosis shaping host immunity. The polyamines putrescine, spermine, and spermidine are abundant within the gastrointestinal tract and might substantially contribute to gut immunity.Objective: We aimed to characterize the polyamine spermidine as a modulator of T-cell differentiation and function. Methods: Naive T cells were isolated from wild-type mice or cord blood from healthy donors and submitted to polarizing cytokines, with and without spermidine treatment, to evaluate CD4 1 T-cell differentiation in vitro. Moreover, mice were subjected to oral supplementation of spermidine, or its