Depletion of the microbiome using broad-spectrum antibiotic cocktail improves the psoriasiform phenotype via attenuation of TNF alpha and IL-23-IL-17A in three psoriasis mouse models

The gut microbiome plays a critical role in immune development and can impact inflammation in distant organs in rheumatoid arthritis, uveitis and alopecia areata. The potential contributions of the microbiota to psoriasis remains unclear. To test the hypothesis that the microbiota contributes to psoriasiform skin inflammation, we treated KC-Tie2, IL-17C+ and KLK6+ psoriasiform mouse models with a broad-spectrum antibiotic cocktail (ampicillin, neomycin, vancomycin). 5-week old psoriasis mice (n=6-14/grp) were exposed to either regular drinking water or the antibiotic cocktail for ∼ 6 weeks, and then the skin examined. IL-17C+ and KLK6+ mice each had a 41% decrease in epidermal thickness (acanthosis; P<0.001), whereas KC-Tie2 mice showed no improvement. Interestingly, despite the lack of improvement in acanthosis, antibiotic treatment of KC-Tie2 mice lengthened the time to thrombus formation by 75% in an experimental arterial thrombosis assay, a comorbidity previously shown to be skin inflammation-dependent. Quantitative RT-PCR of signature psoriasis transcripts revealed model-specific decreases in TNFα, IL-23 and IL-17A in response to the antibiotic cocktail. Antibiotic-treatment of KLK6+ mice decreased TNFα (75%, P=0.02) and IL-23 (59%, P=0.004); antibiotic treatment of IL-17C+ mice decreased IL-17A to undetectable levels (P<0.001); and KC-Tie2 mice exposed to the cocktail had 33%, 41% and 51% decreases in TNFα (P=0.05), IL-23 (P=0.05) and IL-17A (P=0.07), despite a lack of improvement in acanthosis. These decreases across all three models aligned with decreases in skin CD4 and CD8+ T cells and CD11c+ and F4/80+ myeloid cells. Together, our findings point to a key role for the microbiome in modulating the TNFα-IL-23-IL-17A pathway in psoriasis. Further studies are ongoing to identify the specific gut microbes and mechanisms of modulation whereby the gut microbiome can influence distant skin inflammation.