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

The maintenance of tissue-specific chronic inflammation results from the interplay of genetic and unidentified environmental factors. Here, we describe an immunoregulatory role for an environmentally driven microbial metabolite in Card14E138A/+-induced spontaneous psoriasis. Through metabolite screening, we demonstrate chronic skin inflammation is accompanied by alterations microbial metabolite. Notably, depletion of gut, not skin, microbes alleviates disease symptoms. We further identify indoxyl sulfate (I3S), a bacteriogenic metabolite, as a key driver of psoriatic inflammation and confirm that gut-resident indole-producing microbiota mediate this process. Mechanistically, indole-producing microbiota promote host I3S biothsynthesis via a metabolic relay, and I3S potentiates skin inflammation by reshaping chromatin accessibility in skin Th17 cells through AHR signaling. In human psoriasis cohorts, serum I3S levels correlate with disease severit. In summary, our study uncovers a mechanistic link between gut microbial factors and type 3 skin inflammation, highlighting targeting gut microbiota as a strategy for mitigating skin inflammation.