Investigating the skin microbiome in recessive dystrophic epidermolysis bullosaCompleted
|Project lead||Dr Ignacia Fuentes, Dr. Christina Guttmann-Gruber, Dr. Andrew South|
|Organisation||Centro de Genética y Genómica, Santiago, CHILE|
|Partner organizations & collaborators||EB House Austria, Salzburg Austria: Dr. Christina Guttmann-Gruber |
and Thomas Jefferson University, Philadelphia, Pennsylvania USAEB: Dr. Andrew P South
|Start date / Duration||01. Jan 2016 / 36 months|
|Funder(s) / Co-Funder(s)||Others, DEBRA Austria, DEBRA Chile|
|Other funder(s)||Thomas Jefferson University, USA |
A*STAR Strategic Positioning Fund (SPF)
|Research area||Skin cancer & fibrosis, Symptom prevention & relief|
Publications related to the projectsReduced Microbial Diversity Is a Feature of Recessive Dystrophic Epidermolysis Bullosa-Involved Skin and Wounds.
Short lay summary
Recessive dystrophic epidermolysis bullosa (RDEB) is complicated by a variety of pathologies, but poor wound healing and persistent wounds are especially concerning as these are highly prone to malignant transformation. Delayed wound healing has been associated with reduced microbial diversity and the presence of certain bacterial species in the wound. Additionally, recent evidence in murine models demonstrated that microbial infection is crucial to the development of wound-induced skin tumors (Hoste et al., Nat Commun 2015). Together, the evidence underscores the significance of characterizing the microbial triggers that potentially contribute to wound chronicity and tumorigenesis in these patients.
The skin has its own unique ecosystem consisting of a diverse milieu of microorganisms (microbiome), most of which are harmless or even beneficial to their host. Distinct alterations to the microbiome have been associated with various pathological skin conditions, including delayed wound healing. Improving wound healing is a primary goal in the clinical management of RDEB patients who are at high risk of developing life-threatening squamous cell carcinomas in areas of chronic wounds. Importantly, it has also been shown that wound-induced skin cancer is linked to microbial infection in murine models. For these reasons, we sought to profile alterations in the microbiome in RDEB skin under conditions of homeostasis and wounding. To this end, DNA was isolated from skin- and wound-swabs sampled from two separate patient cohorts in Chile and Austria and subjected to shotgun metagenomic sequencing to characterize microbial composition and diversity in these contexts, as well as in comparison to healthy control individuals. Comparing sequencing data obtained from the forehead, a site typically not involved in EB, we observed similar diversity between non-EB and RDEB samples. However, in other body sites, microbial diversity was reduced in non-wounded RDEB skin compared to intact healthy control skin, and even further reduced in RDEB wounds. The species composition of the skin microbiota varied between Chilean and Austrian cohorts, as can be expected given their different geographical locations, with the Austrian cohort exhibiting a predominance of Staphylococcus species. Regardless of these differences, our analyses revealed an increased relative abundance of Staphylococcus species in RDEB wounds compared to unwounded skin, as well as in nonwounded RDEB skin compared to controls, in both cohorts. The data potentially point to an enhanced susceptibility of RDEB patients to Staphylococcus species colonization compared to control individuals.
- DEBRA strategic goal: Improve wound healing
- Project goal: To determine the diversity and composition of the skin microbiome in RDEB intact skin, RDEB wounds and healthy controls.
- Preceding / follow-on projects and related projects: Based on these results we will characterize the contribution of persistent microbial infection to the stepwise process of malignant transformation in RDEB keratinocytes. Furthermore, a follow-up project led by Dr. Fuentes is currently investigating the role of the skin microbiome and host immunity in wound healing in epidermolysis bullosa (FONDECYT Regular 1181093).
What did this project achieve?
This research demonstrated that, similar to chronic wounds in other settings, reduced microbial diversity is a feature of RDEB wounds, and is accompanied by an increase in abundance of pathogenic S. aureus as a predominant wound colonizer, with potential consequences for cell-endogenous and exogenous tumorigenic processes. In this respect, a separate study led by Dr. South has demonstrated that RDEB tumor cells show an upregulation of pathways involved in S. aureus infection (Cho et al., Sci Transl Med 2018). The data highlight the importance of antimicrobial strategies in the management of RDEB wounds and underscores ongoing efforts by the EB House Austria to evaluate the vitamin D analogue calcipotriol (which can enhance innate antimicrobial defense) as a wound healing agent in RDEB.