Atopic dermatitis (AD) is a globally prevalent skin inflammation with a particular impact on children. Current therapies for AD are challenged by the limited armamentarium and the high heterogeneity of the disease. Thus, radically different approaches are needed to address a significant unmet need in AD patients. A novel promising therapeutic target for AD is the microbiota.
1. Introduction
Atopic dermatitis (AD), also known as eczema, is a skin inflammation that exhibits chronic, persistent, pruritic lesions, and is often associated elevated levels of IgE
[1][2]. AD affects 10–20% of the population during their lifetime in developed countries, with a particularly high prevalence among children
[2][3]. Its prevalence is also rapidly increasing in developing nations
[4][5]. The established pathogenesis of AD involves the initiation of barrier disruption, followed by the activation of type 2 (T
H2) immune responses
[2][6]. Variants in the filaggrin (
FLG), the gene encoding an important skin barrier protein, represent a significant risk factor for AD
[7][8][9]. AD is often associated with the development of asthma and food allergies, which is known as “atopic march”
[10]. Physical therapies that moisturize the skin, preventing water loss, controlling xerosis, and relieving barrier disruptions, are recommended for AD patients
[11]. While corticosteroids remain the standard anti-inflammatory treatment against AD, the efficacy of blocking T
H2 responses is recognized by various clinical trials
[12][13][14][15][16][17][18][19]. Unfortunately, the limited armamentarium
[20] and the high heterogeneity of the disease
[21] make the management of AD challenging. Therefore, novel therapeutic strategies needed for AD treatment.
The past two decades have highlighted the role of commensal microbiota in health homeostasis and disease
[22]. As the largest and outmost organ of the body, the human skin has been estimated to host about 1 billion bacteria per 1 cm
2 area
[23]. Conversely, the gastrointestinal tract harbors the largest microbiota population in the body, exceeding 10
14 bacterial cells
[24][25]. AD is probably the most well-characterized disease in which skin dysbiosis plays a causal role
[6]. In addition, AD is also associated with gut dysbiosis
[26]. The investigations from the pre-clinical animal studies and the emerging human 3D skin models furthered the understanding on the complex interplay between the microbiota and the AD context
[27][28].
2. The Skin Microbiota Alternation in AD Patients: A Particular Focus on Staphylococcus aureus
It is now well established that changes in the normal skin microbiota composition, a condition known as dysbiosis, contribute to the disruption of cutaneous immune homeostasis and promotes the development of skin diseases, including AD
[29][30]. Studies that have demonstrated the association of AD with skin dysbiosis are summarized in
Table 1. AD is often accompanied with dysbiosis, featured by increased colonization of staphylococcal species and decreased richness and diversity of other bacterial communities
[31].
S. aureus, a dominant species among the family of Staphylococcae, can be 100 times more abundant in AD skin compared to normal healthy skin
[32]. On the skin surface,
S. aureus secretes virulence factors, including phenol-soluble modulins (PSMs) and proteases, thus disrupting normal skin barrier functions, which alter the epidermal environment favouring the development of AD
[33][34][35][36][37].
The increased abundance of
S. aureus colonization in AD is associated with a depletion in the coagulase-negative staphylococcal species (CoNS), such as
S. epidermidis,
S. hominis, and other skin commensal bacterial communities, including
Streptococcus salivarius,
Propionibacterium,
Streptococcus,
Acinetobacter,
Corynebacterium,
Prevotella and Proteobacteria
[31][38][39][40]. In contrast, these skin commensal microbiota produce antimicrobial substances that inhibit the growth of pathogenic
S. aureus and its biofilm formation
[30][41][42]. In the non-lesional skin samples of AD patients, CoNS are the dominant bacterial communities
[38]. However, their abundances were lower on the skin of healthy individuals compared with non-lesional AD skin
[38][43]. This suggests the existence of complex interactions between the different skin microbial communities, which modulate the host’s susceptibility to AD.
Table 1. Summary of the studies demonstrating the dysbiosis of skin microbiota in AD.
Year |
Subjects, Numbers |
Methods |
Results (Alternations of Skin Microbiota) |
Reference |
2012 |
11 Infants with AD and 12 healthy controls |
16S rRNA gene sequencing |
AD infants: ↓S. salivarius and ↑S. aureus |
[40] |
2012 |
12 Children with AD and 11 healthy controls |
16S rRNA gene sequencing |
AD lesion: ↑S. aureus and ↑S. epidermidis |
[31] |
2013 |
13 AD patients and 49 healthy controls |
16S rRNA gene sequencing |
AD patients: ↑S. aureus, ↓-diversity |
[44] |
2015 |
21 AD infants and 17 healthy controls |
Real-time PCR analysis of skin scratches |
AD infants: ↑S. aureus |
[45] |
2016 |
128 AD patients (59 young children at 2–12 years, 13 teenagers at 13–17 years, and 56 adults at 18–62 years of age), 68 age-matched healthy controls (13 young children, 10 teenagers, 45 adults) |
16S rRNA gene sequencing |
Children with AD: ↑Streptococcus, ↑Granulicatelle, ↑Gemella, ↑Rothia, ↑Haemophilus Adults with AD: ↑Propionibacterium, ↑Corynebacterium, ↑Staphylococcus, ↑Lactobacillus, ↑Finegoldia, ↑Anaerococcus |
[46] |
2016 |
Three male first cousins aged 50–53 years |
16S rRNA gene sequencing |
AD patients: ↑S. aureus |
[47] |
2017 |
10 AD infants, 10 age-matched healthy controls |
16S rRNA gene sequencing |
AD infants: ↑Staphylococcus |
[29] |
2017 |
49 AD patients and 30 non-AD subjects |
16S rRNA gene sequencing |
AD patients: ↓S. epidermidis, ↓S. hominis |
[30] |
2017 |
27 AD patients and 6 healthy controls |
High-throughput pyrosequencing |
AD patients: ↑Staphylococcus, ↑Pseudomonas, and ↑Streptococcus, ↓Alcaligenaceae (f), ↓Sediminibacterium, and ↓Lactococcus |
[48] |
2018 |
10 AD patients and 10 healthy controls |
16S rRNA gene sequencing |
AD patients: ↑S. aureus, ↓-diversity |
[38] |
2019 |
91 AD patients, 134 psoriasis patients, and 126 healthy controls |
16S rRNA gene sequencing |
AD patients: ↑S. aureus, ↓S. epidermidis and ↓Corynebacterium |
[49] |
2019 |
172 AD patients and 120 healthy controls |
16S rRNA gene sequencing |
AD patients: ↑Staphylococcus |
[50] |
2020 |
11 AD patients |
16S rRNA gene sequencing |
AD skin lesions: ↑S. aureus, ↓C. pseudogenitalium |
[51] |
2020 |
67 AD patients and 28 healthy controls |
16S rRNA gene sequencing |
AD skin lesion: ↑Staphylococcus (S. aureus and S. epidermidis), ↓Corynebacterium, ↓Micrococcus, ↓Cutibacterium and ↓Streptococcus |
[52] |
2020 |
7 AD patients and 10 healthy controls |
16S rRNA gene sequencing, and Staphylococcus specific SLST sequencing |
AD patients: ↑Staphylococcus, ↓Propionibacterium |
[53] |
2021 |
28 AD patients and 14 healthy controls |
16S rRNA gene sequencing |
AD patients: ↑S. aureus, ↓S. capitis and ↓Micrococcus sp. |
[54] |