Jinlei Yu1, Yang Luo2, Zhenlai Zhu1, Yufeng Zhou3, Licheng Sun3, Jixin Gao1, Jinlv Sun4, Gang Wang1, Xu Yao5, Wei Li6. 1. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. 2. Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China. 3. Children's Hospital and Institute of Biomedical Sciences, Shanghai, China. 4. Department of Allergy, Peking Union Hospital, Peking Union Medical College, Beijing, China. 5. Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China. Electronic address: dryao_xu@126.com. 6. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: liweiderma@163.com.
Abstract
BACKGROUND: Previous studies have revealed significant alterations in the skin microbiota of patients with atopic dermatitis (AD) not only in diversity and composition but also in function, and the tryptophan (Trp) metabolic pathway is attenuated in the skin microbiota of patients with AD. OBJECTIVE: We sought to assess Trp metabolites on the skin surfaces of patients with AD and to explore the function of the microbial Trp metabolites in skin inflammation in patients with AD. METHODS: A gel-patch method was developed to collect metabolites on the skin surface, which were then assessed by using liquid chromatography-tandem mass spectrometry. A mouse model of calcipotriol (MC903)-induced AD-like dermatitis was used to evaluate the effects of microbial metabolites on AD, and aryl hydrocarbon receptor (AhR)-null mice and keratinocyte cultures were used to investigate the mechanism. RESULTS: Major microbial metabolites of Trp were detected on the skin surfaces of healthy subjects, and the level of indole-3-aldehyde (IAId), an indole derivative of Trp catabolism, was significantly lower in lesional and nonlesional skin of patients with AD than that of healthy subjects. IAId significantly attenuated skin inflammation in mice with MC903-induced AD-like dermatitis, and this effect was blocked by an AhR antagonist and abolished in AhR-null mice. Furthermore, IAId was found to inhibit the MC903-induced expression of thymic stromal lymphopoietin in keratinocytes in vivo and in vitro, which was mediated by binding of AhR to the thymic stromal lymphopoietin promoter. CONCLUSION: IAId, a skin microbiota-derived Trp metabolite, negatively regulated skin inflammation in patients with AD, revealing that skin microbiota play a significant functional role in the pathogenesis of AD.
BACKGROUND: Previous studies have revealed significant alterations in the skin microbiota of patients with atopic dermatitis (AD) not only in diversity and composition but also in function, and the tryptophan (Trp) metabolic pathway is attenuated in the skin microbiota of patients with AD. OBJECTIVE: We sought to assess Trp metabolites on the skin surfaces of patients with AD and to explore the function of the microbial Trp metabolites in skin inflammation in patients with AD. METHODS: A gel-patch method was developed to collect metabolites on the skin surface, which were then assessed by using liquid chromatography-tandem mass spectrometry. A mouse model of calcipotriol (MC903)-induced AD-like dermatitis was used to evaluate the effects of microbial metabolites on AD, and aryl hydrocarbon receptor (AhR)-null mice and keratinocyte cultures were used to investigate the mechanism. RESULTS: Major microbial metabolites of Trp were detected on the skin surfaces of healthy subjects, and the level of indole-3-aldehyde (IAId), an indole derivative of Trp catabolism, was significantly lower in lesional and nonlesional skin of patients with AD than that of healthy subjects. IAId significantly attenuated skin inflammation in mice with MC903-induced AD-like dermatitis, and this effect was blocked by an AhR antagonist and abolished in AhR-null mice. Furthermore, IAId was found to inhibit the MC903-induced expression of thymic stromal lymphopoietin in keratinocytes in vivo and in vitro, which was mediated by binding of AhR to the thymic stromal lymphopoietin promoter. CONCLUSION:IAId, a skin microbiota-derived Trp metabolite, negatively regulated skin inflammation in patients with AD, revealing that skin microbiota play a significant functional role in the pathogenesis of AD.
Authors: Aayushi Uberoi; Casey Bartow-McKenney; Qi Zheng; Laurice Flowers; Amy Campbell; Simon A B Knight; Neal Chan; Monica Wei; Victoria Lovins; Julia Bugayev; Joseph Horwinski; Charles Bradley; Jason Meyer; Debra Crumrine; Carrie Hayes Sutter; Peter Elias; Elizabeth Mauldin; Thomas R Sutter; Elizabeth A Grice Journal: Cell Host Microbe Date: 2021-07-01 Impact factor: 31.316