Gut microbe-derived metabolites drive psoriatic inflammation via modulation of skin Th17 cells

The persistence of tissue-specific chronic inflammation results from an interplay of genetic and environmental factors. How these factors coordinate to sustain pathology in chronic conditions like psoriasis is not well resolved. Using a Card14^E138A/+ murine model of psoriasis, we found that spontaneous skin inflammation reshaped not only the immune architecture in the skin but also systemic metabolites. We identified indole-producing microbiota in the gut-but not the skin-as drivers of psoriatic inflammation. Mechanistically, indole-producing intestinal microbes promoted host indoxyl sulfate (I3S) biosynthesis via a metabolic relay. I3S signaled through the aryl hydrocarbon receptor (AHR) in skin T helper (Th) 17 cells to modulate chromatin accessibility, which potentiated skin inflammation. In human psoriasis cohorts, serum I3S levels correlated with disease severity. In summary, our study uncovers a mechanistic link between gut microbial factors and skin inflammation, highlighting microbiota and metabolites as potential therapeutic targets for psoriasis.