Gut-derived gammadeltaT cells contribute to gut inflammation-induced mastitis in mice

Gut dysbiosis is closely associated with mastitis; however, the extent to which gut inflammation can induce mastitis and the specific mechanism involved have not been fully elucidated. Herein, we provide evidence that gut inflammation provoke mastitis by promoting the activation and proliferation of gammadeltaT cells. TCRdelta KO and antibiotic-treated mice were significantly protected from mastitis in the context of gut inflammation. Moreover, mice with mastitis had marked gut dysbiosis, characterized by reduced commensal L. johnsonii and decreased metabolite Indole-3-propionic acid. Supplement of mice with L. johnsonii and IPA distinctly alleviated gut inflammation-induced mastitis by inhibiting gammadeltaT cells expansion. Mechanistically, IPA reduced IL-1b and IL-23 production from M1 macrophages via activation of the Pregnane X receptor, thereby inhibiting activation and proliferation of gammadeltaT cells that induced IL-17 and subsequent other effector molecules to ameliorate mastitis caused by gut inflammation. This work underscores the pivotal role of gammadeltaT cells in this process and contribute to a better understanding of the mechanisms of gammadeltaT cells regulation of mastitis in the milieu of gut inflammation.