Purpose: Psoriasis is a chronic immune-mediated skin disease increasingly linked to skin and gut dysbiosis. Microbiota-derived tryptophan catabolites act as endogenous ligands of the aryl hydrocarbon receptor (AhR) and modulate inflammation, but their role in psoriasis remains incompletely defined. Here, we aimed to determine whether the microbiota-derived tryptophan metabolite indole-3-lactic acid (ILA) modulates psoriasiform inflammation and to define its underlying mechanisms and therapeutic potential. Methods: Using the imiquimod (IMQ)-induced mouse model of psoriasiform dermatitis (PsD), we profiled tryptophan metabolites by targeted LC-MS/MS in feces and serum. Mice received oral or topical ILA, with or without the AhR antagonist CH-223191. Ex vivo cervical lymph node (cLN) cells were stimulated with IL-23 + IL-1β to assess IL-17A production by γδ T cells. Separate cohorts received oral Lactobacillus reuteri supplementation. Public transcriptomic datasets were interrogated for cell type–specific AhR expression. Results: Targeted metabolomics revealed reduced ILA levels in both feces and serum of IMQ-treated mice. Oral or topical ILA attenuated disease severity, reduced epidermal proliferation and neutrophil infiltration, and suppressed the expression of inflammatory transcripts, including Il17a. Notably, topical ILA was superior to benvitimod, a synthetic AhR agonist approved for the treatment of psoriasis, in suppressing IMQ-induced PsD. The AhR antagonist CH-223191 partially abrogated the protective effects of oral ILA. Ex vivo, ILA selectively suppressed IL-17A production by γδ T cells, and this effect was reversed by AhR antagonism. Lactobacillus reuteri supplementation ameliorated PsD in an AhR-dependent manner, with fecal ILA levels inversely correlating with ear thickness and cutaneous neutrophil infiltration. Analysis of public datasets showed increased AhR expression in psoriatic T cells and a positive correlation of AhR and CYP1B1 with IL17A/IL17F. Conclusion: These findings identify a microbiota-derived ILA-AhR axis that limits γδT17/IL-17–driven skin inflammation, and support metabolite supplementation or probiotic augmentation as potential therapeutic strategies for psoriasis. Keywords: indole-3-lactic acid, psoriasis, aryl hydrocarbon receptor, IL-17A
Meng et al. (Sun,) studied this question.