Targeting the cutaneous microbiota in atopic dermatitis: 'A new hope' or 'attack of the CoNS'?

Although evidence showing that Staphylococcus aureus (S. aureus) is directly causative of atopic dermatitis (AD) is still lacking, there is evidence that S. aureus abundance is associated with disease flares and therapeutic responses. Patients receiving ATx201 OINTMENT 2% twice-daily had a significant reduction in the abundance of S. aureus and increasing Shannon diversity of skin microbiome compared to vehicle after seven days. A small molecule with a narrow-spectrum effect, especially on S. aureus, might be an attractive alternative for the treatment of AD.

Atopic dermatitis (AD) is a disease characterised by itchy and inflamed skin frequently associated with skin infections and has been clearly shown to have an altered skin bacterial flora when compared to non‐AD subjects. A recent meta‐analysis reported the prevalence of Staphylococcus aureus (S. aureus) carriage by patients with AD was 70% on lesional skin compared with 39% on non‐lesional skin of the same patients or skin of healthy controls. , The rate of S. aureus colonisation was related to disease severity.

Although evidence showing that S. aureus is directly causative of AD is still lacking, there is evidence that S. aureus abundance is associated with disease flares and therapeutic responses, and S. aureus colonisation can drive AD‐like disease in mice.

Coagulase‐negative staphylococci (CoNS) are a heterogeneous group of nearly 40 species that compose the majority of the Staphylococcus genus. Some CoNS species are able to fight against pathogens. Several previously unknown and potent anti‐S. aureus molecules have been discovered to be produced by skin CoNS species, such as S. epidermidis, S. hominis and S. lugdunensis. , The antimicrobial activity was identified as antimicrobial peptides (AMPs) produced by CoNS species including S. epidermidis and S. hominis. These AMPs were strain‐specific, highly potent and synergised with the human AMP LL‐37 that could selectively kill S. aureus. Some recent studies also suggest that topical application of commensal organisms such as S. hominis or Roseomonas mucosa could reduce AD severity, which supports an important role for commensals in decreasing S. aureus colonisation in patients with AD. Another study also showed that the human commensal S. caprae may compete with S. aureus by inhibiting quorum sensing. Through signal interference, S. caprae reduces methicillin‐resistant S. aureus burden in both skin colonisation and infection.

In this issue of Clin Transl Med, Weiss et al. investigated the potency and the spectrum of ATx201 (niclosamide) in pre‐clinical models and further analysed its propensity for resistance evolution. The impact of ATx201 OINTMENT 2% on the skin microbiome and load of S. aureus was then assessed in a clinical trial in patients with mild‐to‐severe AD. They found that ATx201 has a narrow distribution of minimal inhibitory concentration (0.125–0.5 μg/ml) consistent with its mode of action – targeting the proton motive force effectively stopping cell growth. In a Phase II trial of 36 patients with mild‐to‐severe AD, they showed that patients receiving ATx201 OINTMENT 2% twice daily had a significant reduction in the abundance of S. aureus and increasing Shannon diversity of skin microbiome compared to vehicle after 7 days. However, the impact of ATx201 on the healthy skin microbiota and specificity of ATx201's effect to S. aureus remains to be fully elucidated. Accordingly, higher‐resolution metagenomics and longer treatment duration such as 28, 42 or 84 days are still needed along with approaches to quantitate whether increases in Shannon diversity result primarily from a reduction in S. aureus or a regrowth of the commensal microbiota. Furthermore, direct evidence of clinically significant improvement is still lacking.

Microbiome therapies are emerging therapies with the objective to reduce the abundance of S. aureus and increase microbial diversity by introducing one or more beneficial commensal strains. It was reported that transplantation of S. hominis and S. epidermidis strains reduced the bacterial load of S. aureus on the skin of AD patients, through exerting antimicrobial activity towards S. aureus. The presence of Esp‐secreting S. epidermidis was also shown to eliminate the nasal colonisation of S. aureus by diminishing the biofilm formation of S. aureus. While therapies based on addition of living bacteria represent a promising therapeutic approach, it remains unclear whether the use of transplants of specific commensal bacteria can eliminate resistant strains on the human AD skin. Long‐term stability of using commensal microorganism is another concern.

S. epidermidis has commonly been regarded as a beneficial skin microbe to against S. aureus. However, a recent study found that the overabundance of S. epidermidis on some atopic patients can act similarly to S. aureus. Some strains of S. epidermidis may cause skin barrier damage and inflammation through secretion of the cysteine protease EcpA, and that this correlated with human disease severity. These findings suggest that S. epidermidis may shift from a beneficial commensal to a deleterious pathogen similar to S. aureus in the permissive growth conditions of AD skin. Some unique CoNS strains, such as S. hominis A9 and C5, are able to inhibit the S. epidermidis accessory gene regulator (agr) quorum sensing system and thus prevent S. epidermidis‐induced skin damage. S. hominis A9 has been shown to have the capacity to kill S. aureus, whereas S. hominis C5 synthetic autoinducing peptide was shown to inhibit the S. aureus agr system. Therefore, such commensal CoNS strains might be potential therapeutic tools to reduce S. aureus colonisation and both S. aureus and S. epidermidis toxin production in AD. The above findings indicate the complexity of the interactions between commensal CoNS and deleterious S. aureus and suggest that using S. epidermidis as the treatment for dysbiosis in AD may further damage the skin and cause inflammation. Thus, a small molecule with a narrow‐spectrum effect, especially on S. aureus, might be an attractive alternative for the treatment of AD.

CONFLICT OF INTEREST

None.