Gut-derived genistein from Parabacteroides distasonis alleviates psoriatic inflammation via CD200-mediated NF-κB inhibition in mice.

The gut-skin axis plays a pivotal role in psoriasis pathogenesis, yet the precise metabolic crosstalk by which intestinal commensals regulate cutaneous immunity remains elusive. Here, we identify a functional "microbe-enzyme-metabolite-immune" axis that orchestrates skin homeostasis. Through multi-omics analyses of psoriatic patients and imiquimod-induced murine models, we reveal a significant depletion of the gut commensal Parabacteroides distasonis (P. distasonis) and its metabolite, genistein. We demonstrate that P. distasonis utilizes its inherent β-glucosidase activity to convert dietary genistin into bioactive genistein, a process we validated using an engineered β-glucosidase-expressing E. coli strain. Therapeutically, supplementation with P. distasonis or genistein significantly ameliorates psoriatic phenotypes, restores skin barrier integrity (filaggrin/loricrin), and suppresses IL-23/IL-17-mediated inflammation. Mechanistically, we uncovered that genistein enhanced CD200-CD200R signaling and suppressed macrophage activation. It effectively reactivates CD200 expression, thereby inhibiting the canonical NF-κB signaling pathway and blunting macrophage-driven inflammation. Notably, the therapeutic efficacy of this axis was abrogated by CD200 blockade, confirming its indispensability. Collectively, our findings elucidate a causal mechanism linking gut microbial enzyme activity to host skin immunity, highlighting P. distasonis-derived genistein as a promising precision intervention for psoriasis management.