Gut microbiota-derived histamine exacerbates psoriasis by promoting γδT17 cell differentiation via the Hrh1/Wnt Axis.

Psoriasis is associated with gut microbiota dysbiosis and aberrantly elevated histamine levels, yet the pathological role of microbiota-derived histamine remains unclear. In this study, colonization of mice with histamine-producing engineered E. coli (BL21_pET-17b_hdc) revealed that microbiota-derived histamine (non-dietary origin) significantly exacerbated skin inflammation in a psoriasis model and induced γδT17 cell expansion across multiple immune organs. These effects were abolished in γδT cell-deficient mice. RNA sequencing demonstrated that histamine exposure upregulated the histamine receptor gene Hrh1 and activated the Wnt signaling pathway via pathway enrichment analysis. Further in vitro experiments confirmed that histamine promoted γδT17 cell differentiation in an Hrh1 receptor-dependent manner, with this process being associated with Wnt pathway activity. Our findings elucidate that gut microbiota-derived histamine exacerbates psoriatic inflammation by coordinately regulating the Hrh1 receptor and Wnt signaling pathway to drive γδT17 cell differentiation, providing a theoretical foundation for therapeutic strategies targeting microbial metabolites.