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Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa
Laure Guenin-Macé, … , James P. Di Santo, Caroline Demangel
Laure Guenin-Macé, … , James P. Di Santo, Caroline Demangel
Published September 24, 2020
Citation Information: JCI Insight. 2020;5(20):e140598. https://doi.org/10.1172/jci.insight.140598.
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Research Article Dermatology Inflammation

Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa

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Abstract

Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway–inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.

Authors

Laure Guenin-Macé, Jean-David Morel, Jean-Marc Doisne, Angèle Schiavo, Lysiane Boulet, Véronique Mayau, Pedro Goncalves, Sabine Duchatelet, Alain Hovnanian, Vincent Bondet, Darragh Duffy, Marie-Noëlle Ungeheuer, Maïa Delage, Aude Nassif, James P. Di Santo, Caroline Demangel

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Figure 1

The kynurenine pathway of Trp catabolism is activated in HS skin lesions.

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The kynurenine pathway of Trp catabolism is activated in HS skin lesions...
(A) Heatmap showing the relative abundance of metabolites in skin biopsies from HC and patients with HS (H-HS, healthy skin; L-HS, lesional skin). (B) Principal component analysis (PCA) based on metabolite abundance in skin samples. Axes correspond to the 2 first principal components. (C) Volcano plots illustrating pairwise comparisons of relative metabolite levels between groups. (D) Relative levels of Trp metabolites in skin samples from HC and patients with HS, displayed as scatter dot plots with means. **P < 0.01, ***P < 0.001 by Welch’s 2-sample t test for comparisons with HC and matched pairs t test for comparisons of L-HS with matched H-HS, with Benjamini-Hochberg correction for multiple comparisons. (E) Kynurenine pathway of Trp catabolism.

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