A tryptophan metabolite of the skin microbiota attenuates inflammation in patients with atopic dermatitis through the aryl hydrocarbon receptor - 21/01/19

Doi : 10.1016/j.jaci.2018.11.036

Jinlei Yu, MD ^a,^{∗
These authors contributed equally to this work.}, Yang Luo, MS ^b,^{∗
These authors contributed equally to this work.}, Zhenlai Zhu, MD ^a,^{∗
These authors contributed equally to this work.}, Yufeng Zhou, MD, PhD ^c,^{∗
These authors contributed equally to this work.}, Licheng Sun, MD ^c, Jixin Gao, MD, PhD ^a, Jinlv Sun, MD, PhD ^d, Gang Wang, MD, PhD ^a, Xu Yao, MD, PhD ^b,^⁎ , Wei Li, MD, PhD ^a,^e,^⁎
^a Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
^b Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
^c Children's Hospital and Institute of Biomedical Sciences, Shanghai, China
^e Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
^d Department of Allergy, Peking Union Hospital, Peking Union Medical College, Beijing, China

^∗Corresponding author: Wei Li, MD, PhD, Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China. Current affiliation: Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, 200040, China.Department of DermatologyXijing HospitalFourth Military Medical UniversityXi'an710032China^∗Xu Yao, MD, PhD, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, 12 Jiangwangmiao St, Nanjing 210042, China.Institute of DermatologyChinese Academy of Medical Sciences and Peking Union Medical College12 Jiangwangmiao StNanjing210042China

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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.

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Graphical abstract

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Key words : Atopic dermatitis, skin, microbiota, tryptophan, metabolites, indole-3-aldehyde, aryl hydrocarbon receptor, thymic stromal lymphopoietin

Abbreviations used : AD, AhR, AhRE, CHS, CYP1A1, DMSO, FACS, 5-HTP, IAA, IAId, IMQ, KYN, LC-MS/MS, OXA, SCFA, siRNA, Trp, TSLP

Plan

Methods

Subjects and sample collection

LC-MS/MS

Mice and treatment

Single-cell suspension preparation and flow cytometry

Quantitative real-time RT-PCR

Western blotting

Cell culture and treatment

Chromatin immunoprecipitation assay

Statistical analysis

Results

IAId levels were decreased in lesional and nonlesional skin of patients with AD

Topical IAId attenuated the MC903-induced AD-like dermatitis in mice

Topical IAId alleviated inflammatory cell infiltration in mice with MC903-induced dermatitis

AhR was required for the inhibitory effects of IAId

IAId inhibited TSLP production in keratinocytes through activation of AhR

Oral IAId alleviated skin inflammation in mice with MC903-induced AD-like dermatitis

Discussion

Supported by the National Natural Science Foundation of China (81573038, 91642116, 81573045, and 31400782), the CAMS Innovation Fund for Medical Sciences (2016-I2M-1-005), the Natural Science Foundation of Jiangsu Province (BK20151066 and BK20170162), and the Milstein Medical Asian American Partnership Foundation. W.L. was founded by a Municipal Human Resources Development Program for Outstanding Leaders in Medical Disciplines in Shanghai (2017BR039).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.