Impact of microbiota and mites in vitiligo skin.
Vitiligo is a chronic dermatosis that induces an acquired depigmentation of the skin and hair by loss of melanin-producing cells called melanocytes. It affects approximately 0.5 to 2% of the world population. The pathogenesis of vitiligo is complex. The role of the adaptive immune cells in the loss of melanocytes is now well known. More recently, the key role of innate immunity and the disruption of epidermal junctions, which causes melanocyte detachment from the epidermal junction, have been highlighted as a possible mechanism in melanocyte loss. However, the factors responsible for this trigger are currently unknown. Environmental factors are likely to be involved in the initiation or exacerbation of vitiligo. Based on these data and with the aim of finding new therapeutic targets, we were interested in studying the microbiota of vitiligo patients (both stool and skin) compared to healthy microbiota and to examine the impact of environmental factors such as ubiquitous house dust mite (HDM) that may be involved in this disease.
In the first part of our study, we obtained swabs and biopsies of lesional and non-lesional skin as well as stool and blood samples from vitiligo patients. We detected a reduced richness and diversity of the microbiota in the stools of vitiligo patients compared to healthy subjects. Skin swabs showed a higher diversity than biopsies. Swabs from lesion sites were predominantly depleted of Staphylococcuscompared to those from non-lesion sites. Sampling of deeper layers from the same patients showed differences in ᾳ and β diversity between samples with decreased species richness and distribution in the lesional site. The microbiota of lesional skin biopsies had a distinct composition, which was depleted of commensal bacteria such as Bifidobacterium and Bacteroides but was enriched in Proteobacteria, Streptococcus, Mycoplasma, and mitochondrial DNA (mtDNA). The latter increased in patients with increased innate immunity and stress markers in their blood. These data underline a potential link between skin dysbiosis, mitochondrial damage and immunity in patients with vitiligo.
In the second part of this work, given the importance of environmental factors in vitiligo and knowing that the house dust mite (HDM) is a normal component of skin microbiota, we were interested in the contribution of HDM in the pathophysiology of vitiligo. HDM are environmental allergens with potent protease activity, known for their trigger in the lungs and onset of allergic disease and asthma. Here, we detected the presence of Der p1 (major HDM allergen) in vitiligo skin. We showed HDM to induces a mixed Th1/Th2 immune response in cultured keratinocytes and to cause a specific cleavage of adhesion protein E-cadherin, resulting in melanocyte detachment from the basal membrane. This mechanism was driven by cysteine proteases and MMP-9. Inhibition of MMP-9 or cysteine proteases dose-dependently restored E-cadherin expression and inhibited melanocyte detachment in the skin. Our results were confirmed using a 3D skin model and ex vivo using human skin explants. Vitiligo skin was more sensitive to HDM than healthy controls showing increased melanocyte detachment, as well as an increased detection of soluble E-cadherin in cultured supernatants in the presence of HDM. Together, these results highlight the impact of HDM in skin integrity and melanocyte loss which may drive skin depigmentation in vitiligo patients.
Together, our work demonstrates dysbiosis in vitiligo compared to healthy skin and identifies HDM, a microbial component, as a potential important environmental trigger in initiation and/or progression of vitiligo and opens new innovative and new therapeutic perspectives for this debilitating disease.
Vitiligo, microbiota, keratinocyte, House dust mites, E-cadherin, melanocyte.
President of the jury :
Dr. Robert BALLOTTI
Dr. Véronique DELMAS
Prof. Denis JULLIEN
Dr. Katia BONIFACE
Prof. Thierry PASSERON
Thesis Director :
Dr. Meri TULIC