Commensal Microbiota Regulates Skin Barrier Function And Repair Via Signaling Through The Aryl Hydrocarbon Receptor

Abstract

SUMMARYThe epidermis forms a barrier that defends the body from desiccation and entry of harmful substances, while sensing and integrating environmental signals. The tightly orchestrated cellular changes required for the proper formation and maintenance of this epidermal barrier occur in the context of the skin microbiome. Using germ free mice, we demonstrate the microbiota is necessary for proper differentiation and repair of the epidermal barrier. These effects were mediated by the aryl hydrocarbon receptor (AHR) in keratinocytes, a xenobiotic receptor also implicated in epidermal differentiation. Murine skin lacking keratinocyte AHR was more susceptible to barrier damage and infection, during steady state and epicutaneous sensitization. Colonization with a defined consortium of human skin isolates restored barrier competence in an AHR-dependent manner. We reveal a fundamental mechanism whereby the microbiota regulates skin barrier formation and repair, with far-reaching implications for the numerous skin disorders characterized by epidermal barrier dysfunction.

Yin and Yang: A disrupted skin microbiome and an aberrant host immune response in hidradenitis suppurativa

“…199 Healthy human skin commensals, including Staphylococcus and Corynebacterium, contribute to skin barrier formation, repair and integrity through activation of the AhR receptor in a murine model. 200 Given that AhR is required for barrier formation 199 and AhR activity is reduced in HS skin, 156 it is plausible that dysbiotic HS skin microbes are influencing the skin barrier through their inability to activate AhR. In sum, these studies support that a healthy microbial community is integral to epidermal barrier integrity.…”

The aryl hydrocarbon receptor at the forefront of host‐microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications

“…35 Although Malassezia dysbiosis is associated with skin diseases (eg seborrheic/ atopic dermatitis), 38,39 in dept studies on the effects of the metabolites formed by the different Malassezia species in skin or cocultures of Malassezia isolates with (organotypic) skin are scarce. 40 Evidence from studies on skin commensal bacteria indicate that AHR activation after skin cell exposure to commensal bacteria (eg S. epidermidis, S. warneri and C. aurimucosum 32,36 ) or specific microbial metabolites (eg indole-3-aldehyde 34 ) contributes to epidermal skin barrier function, 36,41 negatively regulates immune cell responses 10 and dampens (experimentally induced) skin inflammation. 34 These effects are generally seen also for non-microbial-derived AHR ligands that are able to activate the AHR which provide a rationale to the therapeutic targeting of AHR for two major inflammatory skin diseases, atopic dermatitis and psoriasis 42,43,44 both characterized by skin barrier defects and chronic inflammation.…”

“…Beyond using AHR agonists, probiotic bacteria (with known potential for AHR metabolite formation) might be useful in manipulating the microbiome-AHR-skin health axis. 36 Alternatively, prebiotic strategies steering the growth of skin microbes, which produce desirable AHR-modulating metabolites may provide new therapeutic modalities for the dermatology field.…”

“…Studies addressing the AHR activating potential and downstream effects by skin microbiota are mostly performed by exposure of AHR reporter cells or primary skin cells to whole bacteria, bacterial lysates or purified metabolites, 32 , 33 , 34 , 35 after which known AHR ligands with differences in receptor affinity and turnover times, like TCDD or FICZ are used to substantiate findings. 36 Skin microbiota include a substantial fungal community, which is dominated by Malassezia species. 37 Malassezia produce a variety of indole metabolites having AHR activating potential (eg indirubin, Malassezin, FICZ).…”

Application of NGS Technology in Understanding the Pathology of Autoimmune Diseases

“…The microbial metabolism of dietary tryptophan produces ligands of aryl hydrocarbon receptor (AhR) [ 115 ] which is of the most studied in the aspect of immunomodulation, reviewed in many articles [ 126 , 156 , 157 , 158 , 159 ]. Its role, including association with microbiome metabolism, has been proved not only in amelioration of inflammation in gastrointestinal tract [ 160 , 161 , 162 ] but also in the aspect of balanced skin physiology [ 163 , 164 , 165 , 166 ].…”