The commensal gut bacteria orchestrates I3S-Th17 axis and exacerbates chronic inflammatory skin disease

The maintenance of tissue-specific chronic inflammation may be of the concerted actions of genetic and unknown environmental factors. Here we describe an immunoregulatory function of the environmentally driven gut microbiota in psoriasis-like inflammation, which show varied disease severities in different environments. Using microbial sequencing, we show that skin chronic inflammatory condition modulates composition of gut microbiota, while microbiota depletion by antibiotics leads to alleviated disease conditions. We further identify a commensal gut bacteria Lactobacillus johnsonii and its bacteriogenic host-metabolite, indoxyl sulfate (I3S), as drivers of psoriatic inflammation. Mechanistically, I3S amplifies skin type 3 inflammation by promoting skin Th17 cell expansion via AHR signaling. In a human cohort, we observe a significant correlation between the level of I3S in the serum and PASI (psoriasis area and severity index). In summary, our study uncovers a mechanistic link between gut microbiota and skin type 3 inflammation, which suggests therapeutic strategies targeting gut commensal microbiota to diminish tissue-specific chronic inflammation.