Prof Brigitte Dréno, Dermatologist-oncologist, France (Nantes)
Among our organs, the skin stands out for its visibility and size. It is on its surface and in its appendices that a second organ develops, i.e. the skin microbiome, made up of a myriad of micro-organisms, bacteria, viruses and eukaryotes. The skin of foetuses is sterile, so the microbiome appears at birth, taking advantage of the environment to characterise itself and therefore differing depending on whether childbirth took place by vaginal delivery or by caesarean section. Bacterial density is higher on the surface of the epidermis: the composition of the microbiome sampled by scratch testing differs from that collected via biopsy.
Four categories (phyla) of bacteria colonise the skin
- Actinobacteria, Firmicutes, Bacteroidetes and Proteobacteria.
- Cutibacterium and Staphylococcus are of particular interest to dermatologists.
The composition of the microbiome changes over time:
On the face, Firmicutes predominate in children, while Proteobacteria are more numerous in adults. Biodiversity also changes over time, leading to chronic inflammation in the elderly. Diversity is a crucial element of the normal skin microbiome, which must be successfully maintained. The microbiome profile is obtained using traditional cultures, 16S RNA gene sequencing and, more recently, shotgun metagenomic sequencing.
The microbiome is involved in all the key phases of wound healing
A rupture in the skin barrier destroys the microbiome that exists on the skin and creates an area rich in skin nutrients that favours the growth of opportunistic commensal or pathogenic microbes that compete with one another. This leads to an increase in skin pH and water loss, promoting the development of pathogens.
Dysbiosis in a wound varies according to its origin and the terrain in which it occurs (leg ulcer, burn, diabetic foot ulcer, etc.). For example, diabetic ulcers are mainly colonised by Streptococcus, burns by Gram-negative bacteria, and pressure ulcers by anaerobic bacteria: these different microbiomes require different treatments.
What happens when there is a wound?
A neo-microbiome appears two weeks after a wound forms, resembling that of the dermis and the deep layers of the epidermis. A healed lesion therefore does not have the same microbiome as the normal surrounding skin. The stratum corneum is covered in antimicrobial peptides (AMPs) called “antibiotic-like peptides” and thus forms an antimicrobial barrier.
If a pathogenic microbe penetrates the stratum corneum, the epidermis develops a new defence strategy: during the healing
process, there are constant interactions between commensal bacteria, their antimicrobial peptides and keratinocytes: therapeutically, the aim is to restore this balance.
To summarise, there are three targets in the skin microbiome for wound healing:
- Commensal bacteria prevent pathogenic invasions by producing antimicrobial peptides;
- Accelerate healing by limiting the duration of inflammation via the innate immune system;
- Induce the production of T-cells specific to the commensal microbes, which promote tissue repair.
Each commensal bacterium has a skin barrier protection function: it protects the skin from invasion by other pathogenic microbes
- Cutibacterium acnes interacts with Staphylococcus epidermidis, with both bacteria having self-regulating capacities.
- C. acnes maintains the skin pH at 5.
- Streptococcus thermophilus and Staphylococcus epidermidis are involved in ceramide production.
Lastly, many commensal bacteria act to inhibit the development of S. aureus. Activation of the innate immune system by the skin microbiome can have a negative impact:
- Excessive production of proteases, reactive oxygen species and other bio-active substances that delay healing;
- Certain external factors can alter the activity of the skin microbiome: age, nutrition, comorbidities, genetic factors, etc.
- Induction of chronic inflammation when acute inflammation has not been controlled;
- Formation of biofilms by certain bacteria.
This means efforts need to be made to strike a balance. In 60% of wounds, chronic activation of the innate immune system is accompanied by the development of a biofilm by the bacteria in the wound bed, which maintains chronic inflammation and delays wound healing.
Stress, whether physiological or psychological, modifies the profile of the skin microbiome, alters the innate immune system and stimulates the formation of a biofilm, resulting in the development of chronic neurogenic inflammation. Discovery of an injury causes the brain to send signals to the nerve endings around the sebaceous glands to produce substance P. Substance P receptors in these glands cause sebum to be produced; this in turn leads to changes in the microbiome, particularly as regards Staphylococcus aureus and epidermidis.
Therapeutic approaches take account of the fact that a healed wound does not regain the microbiome of normal skin. The aim of treatment is to restore a skin microbiome as close as possible to the normal microbiome.
- Thanks to bacteriophages, which are intra-bacterial viruses capable of targeting resistant bacteria, Anglo-Saxons have developed topical and oral bacteriotherapy using bacterial transplants, probiotics (live bacteria), prebiotics (bacterial extracts), a combination of pro- and prebiotics, and postbiotics (antimicrobial peptides). Bacterial resistance, particularly that of C. acnes, can thus be reduced by phages, which should reduce the need for antibiotics.
- Probiotics from lactic acid bacteria: induce the migration and differentiation of keratinocytes and fibroblasts, stimulate the formation of collagen, reduce the inflammatory phase and accelerate wound healing in rats.
