Microbiological Research 281 (2024) 127595

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Microbiological Research
journal homepage: www.elsevier.com/locate/micres

Atopic dermatitis: Pathophysiology, microbiota, and metabolome – A

comprehensive review
Shahnawaz Mohammad a, 1, Md. Rezaul Karim b, c, 1, Safia Iqbal b, d, Jung Hyeok Lee a,
Ramya Mathiyalagan a, e, Yeon Ju Kim a, e, Dong Uk Yang a, e, *, Deok Chun Yang a, e, *
a
Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Republic of Korea
b
Department of Biopharmaceutical Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Republic of Korea
c
Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh
d
Department of Microbiology, Varendra Institute of Biosciences, Affiliated by Rajshahi University, Natore, Rajshahi 6400, Bangladesh
e
Department of Oriental Medicinal Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Republic of Korea

A R T I C L E I N F O A B S T R A C T

Keywords: Atopic dermatitis (AD) is a prevalent inflammatory skin condition that commonly occurs in children. Genetics,
Atopic dermatitis environment, and defects in the skin barrier are only a few of the factors that influence how the disease develops.
Pathophysiology As human microbiota research has advanced, more scientific evidence has shown the critical involvement of the
Gut-skin microbial dysbiosis
gut and skin bacteria in the pathogenesis of atopic dermatitis. Microbiome dysbiosis, defined by changed di­
Homeostasis
Metabolomics
versity and composition, as well as the development of pathobionts, has been identified as a potential cause for
recurring episodes of atopic dermatitis. Gut dysbiosis causes "leaky gut syndrome" by disrupting the epithelial
lining of the gut, which allows bacteria and other endotoxins to enter the bloodstream and cause inflammation.
The same is true for the disruption of cutaneous homeostasis caused by skin dysbiosis, which enables bacteria
and other pathogens to reach deeper skin layers or even systemic circulation, resulting in inflammation.
Furthermore, it is now recognized that the gut and skin microbiota releases both beneficial and toxic metabolites.
Here, this review covers a range of topics related to AD, including its pathophysiology, the microbiota-AD
connection, commonly used treatments, and the significance of metabolomics in AD prevention, treatment,
and management, recognizing its potential in providing valuable insights into the disease.

1. Introduction problems, which results in a lower overall quality of life (Ferrucci et al.,
2021).
The skin inflammatory condition known as atopic dermatitis (AD) or Pruritus, lichenification, a continuously relapsing course, personal
atopic eczema presents with chronic, persistent, and itchy lesions and/or familial history of atopic dermatitis, and minor aspects that
(Eichenfield et al., 2014). Dermatitis is a combination of the Greek consider less specific symptoms make up the diagnostic criteria for AD
words derma (skin) and itis (inflammation), resulting in skin inflam­ (Andersen et al., 2016). Several tools can be used to evaluate and score
mation (Thomsen, 2014). AD affects about 20% of children globally and clinical signs and assess the severity of atopic dermatitis (AD). These
is becoming more prevalent (Williams et al., 2008). Some children with tools estimate the extent of affected areas and various symptoms.
AD will grow out of the clinical symptoms as they get older, but around Typically, the Eczema Area and Severity Index (EASI) and the Scoring of
half might eventually acquire allergic asthma, and about two-thirds Atopic Dermatitis Index (SCORAD) are preferred for this purpose
could develop allergic rhinitis, in a process termed as "Atopic March” (Leshem et al., 2015).
(Ricci et al., 2006). Skin itching is a common symptom of AD. This
creates a vicious cycle that causes irritation, scratching, itching, and 2. Physiopathology of AD
ongoing skin damage. In addition to the obvious physical symptoms,
people with AD frequently experience depression, anxiety, and sleep The development of atopic dermatitis (AD) is accompanied by a

* Corresponding authors at: Graduate School of Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Republic of Korea.
E-mail addresses: dongukyang83@gmail.com (D.U. Yang), dcyang@khu.ac.kr (D.C. Yang).
1
These authors contributed equally to this work

https://doi.org/10.1016/j.micres.2023.127595
Received 17 July 2023; Received in revised form 11 October 2023; Accepted 24 December 2023
Available online 3 January 2024
0944-5013/© 2023 Published by Elsevier GmbH. This article is made available under the Elsevier license (http://www.elsevier.com/open-access/userlicense/1.0/).
S. Mohammad et al. Microbiological Research 281 (2024) 127595

range of risk factors, including genetic predisposition environmental polymers produce FLG monomers, that relate to the formation of SC and
influences and family history. According to research, there is a 1.5-fold keratin filament accumulation (Thyssen and Kezic, 2014). Urocanic acid
greater chance that a child may have AD if a parent has an atopic con­ and pyrrolidine carboxylic acid, two FLG breakdown products, help
dition. The risk of developing AD increases by 3 times if one parent has hydrate SCs and maintain the skin’s acidic pH (Egawa and Kabashima,
AD and by 5 times if both parents have the condition (Torres et al., 2018). It is widely established that FLG null mutations reduce the
2019). effectiveness of the epidermal barrier and increase the risk of AD (Irvine
The pathophysiology of AD is intricate and remains incompletely et al., 2011). The presence of one or two filaggrin null alleles can
comprehended at present. Genetics, environment, immunological dys­ contribute to the onset of AD at an early age, and this condition may
regulation, altered skin and gut microbiota, and other variables all play persist into adulthood (Barker et al., 2007). In African American with
a role in the condition (Fig. 1). It is assumed that the various clinical both AD and ichthyosis vulgaris, FLG null mutations are more prevalent,
symptoms of AD result from the integration of these factors, in different with one study reporting them in 22.2% of cases (Polcari et al., 2014).
intensities and combinations (Weidinger et al., 2018). Skin infections and a higher risk of severe AD with earlier onset and
longer persistence are also linked to FLG mutations, particularly ho­
mozygous variants. Heterozygous FLG mutations, which cause a 50%
2.1. Genetics decrease in expressed protein, are present in 10% of European pop­
ulations (Irvine et al., 2011). Nevertheless, FLG mutations are only one
The FLG gene on chromosome 1q2 encodes the essential structural aspect of the pathophysiology of AD. For instance, individuals from
protein, FLG (filaggrin protein), in the stratum corneum (Kaufman et al., Japanese and Korean communities are less likely to carry FLG mutations
2018). Dephosphorylation and proteolytic cleavage of Pro-FLG

Fig. 1. Mechanism of Atopic Dermatitis (AD) pathophysiology: Skin barrier dysfunction, allergen exposure, environmental factors, and imbalances in the skin-gut
microbiota; contribute to AD development. Additionally, the mutation in the filaggrin gene (FLG) causes an increase in trans-epidermal water loss (TEWL), elevated
pH levels, and disrupted production of host defense peptides, all of which contribute to the dysfunction of the skin barrier. Consequently, this impaired barrier allows
for easier entry of allergens into the skin and promotes Staphylococcus aureus colonization. S. aureus present on the skin facilitates the formation of biofilms and the
production of virulence factors. They facilitate the degranulation of mast cells, resulting in the release of inflammatory cytokines and histamine, also contribute to
elevated levels of IgE. Following the disruption of the skin barrier, keratinocytes produce immunoregulatory cytokines like IL-1β, IL-25, IL-33, and TSLP. These
cytokines stimulate Langerhans and dendritic cells, triggering the activation of Th2, Th17, and Th22 immune responses. Langerhans cells activate mast cells, thereby
promoting Th1 immune response. Th2 cells release cytokines such as IL-4, IL-5, IL-13, IL-31, and IL-33, This further disrupts barrier function by reducing the
expression of filaggrin (FLG). The itch-scratch cycle is intensified by mast cell degranulation and sensory nerve amplification, leading to aggravated barrier
dysfunction. Recent studies have highlighted the involvement of Th17-related cytokines in the development of AD. The presence of a leaky gut resulting from gut
dysbiosis allows microbiota metabolites and proinflammatory cytokines such as tryptophan and LPS to circulate and reach the skin. Upon reaching the skin, these
substances trigger a robust Th2 immune response, resulting in substantial tissue damage.

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than patients from Western ethnicities (Yu et al., 2013). Moreover, consistent immune abnormalities are observed. While Th1 and regula­
around 40% of those with FLG-null alleles do not display AD traits, and tory responses are diminished, there is an increase in
most AD patients with FLG mutations eventually outgrow the condition Th17/Th22-associated mediators in comparison to adult disease
(O’Regan et al., 2008). (Brunner et al., 2018). A separate study investigated cutaneous immune
dysregulation in Han Chinese individuals with AD. Similar to AD cases in
2.2. Environment Japanese and Korean populations, significant increases in epidermal
hyperplasia, parakeratosis, Th2 responses, as well as markers associated
Although the absence of consensus for FLG does not rule out the with Th17/IL-22 and Th17/Th23 were evident. Moreover, SCORAD
possibility of another host-related factor being the primary cause of AD scores demonstrated strong correlations with the expressions of IL-5
development, it does support the notion that environmental stimuli are IL-17A and IL-31. In comparison to the immunophenotype seen in Eu­
the primary cause across the board. Exposure to pollution and excessive ropean American AD cases, the Chinese AD phenotype was character­
soap usage can compromise the microbial skin barrier, which can result ized by heightened Th17 expression and reduced expression of
in the development of AD (Celebi Sozener et al., 2022). According to the Th1/IFN-γ-related markers (Chan et al., 2018).
Biodiversity Hypothesis, exposure to natural environments enriches the
human microbiome, encourages immune balance, and serves as a safe­ 3. Human microbiota
guard against allergies and inflammatory disorders (Haahtela, 2019).
Among populations in South Germany, Austria, and Switzerland, being Each person has trillions of commensals, symbiotic, and pathogenic
exposed to farming environments, rich in microbiota provided protec­ microorganisms in his body, most of which are bacteria. These organ­
tion against asthma and atopy (Ege et al., 2011). In Finnish Karelia, isms make up the human microbiota (Robertson et al., 2019). Micro­
research supported the biodiversity hypothesis by quantifying homes’ biome is the term used to describe the aggregate genomes of these
natural surroundings. Healthy teenagers living in biodiverse environ­ microorganisms in a certain environment (Valdes et al., 2018). Although
ments had more plant species around their houses and diverse skin these germs may be found on the interior and exterior surfaces of several
bacteria as compare to the allergic subjects. This diversity was associ­ body areas including the skin, oral mucosa, vagina, digestive tract and
ated with increased IL-10 expression in blood cells, suggesting enhanced airway, they are mostly present in the colon (which contains about 1014
immune tolerance (Hanski et al., 2012). In natural environments, we are bacterial cells), followed by the skin (Chen et al., 2020). The gut
exposed to a diverse mix of chemicals, microbiota, and particles through microbiota is even regarded an "essential organ," with nearly 150 times
inhalation and ingestion. Urban environments have a unique cocktail of the number of genes as the whole human genome (Wang et al., 2017).
these substances, but little is known about their composition and their Skin and gut microbiome, also called the "second genome," and ge­
impact on the immune system (Moore, 2015). Modern lifestyles netic and immunological factors influence human health (Grice and
involving widespread chemical use, pollution, and changes in household Segre, 2012). Our skin and gut microbiomes serve two major purposes:
technology, like the use of laundry detergents, have raised risks by firstly, they defend us against infections, and secondly, they are essential
increasing the permeability of the skin and mucosal surfaces (Wang for preserving the delicate equilibrium between protective effectiveness
et al., 2019). and harmful inflammation (Rapin et al., 2017). In 2011, the idea that
biodiversity loss could lead to immune dysfunction and disease was
2.3. Immune Dysregulation introduced (von Hertzen et al., 2011), and it received further support
from allergy-related observational data in 2012 (Hanski et al., 2012).
The immunological imbalance hypothesis states that an imbalance of Population growth and extensive natural resource exploitation, coupled
T cells drives AD, mainly types 1 and 2 of T helper cells. In the acute with cultural evolution, have transformed global living conditions. The
phase of AD, the latest type prevails, whereas in the inflammatory urban lifestyle is now reshaping the human microbiome and immune
chronic phase, the second type becomes dominant (Thomsen, 2014). response in unprecedented ways (Haahtela, 2019). Microbial diversity
The production of interleukins (ILs), such as IL-4, IL-5, IL-13, IL-31, and influences health and disease. Healthy skin has a diverse microbiota, but
tumor necrosis factor-alpha (TNF-α) (Brandt and Sivaprasad, 2011), is conditions like atopic eczema can lead to Staphylococcus aureus invasion,
mainly attributed to antigen-activated TH2 cells, whereas IL-31 is disrupting this balance. Clinicians may prescribe antibiotics to eliminate
associated with the onset of pruritus, and IL-5 induces eosinophil the pathogen and corticosteroids to reduce inflammation. Genetic
recruitment (Furue et al., 2018). IL-4 induces IgE antibodies by B cells. variability and strain diversity impact pathogenicity and antibiotic
The binding of IgE antibodies to the specific receptor FcεRI on mast cells response (Salava and Lauerma, 2014). According to research, the di­
initiates a signaling cascade that leads to an increase in mast cell versity of bacteria in the human microbiome declines in AD patients, but
degranulation, intracellular Ca2+ concentration, and release of allergy the overall number of bacteria in the microbiome does not decline when
mediators such as histamine, prostaglandins, leukotrienes, and b-hex­ compared to healthy individuals (Shi et al., 2016). In the Copenhagen
osaminidase(De Benedetto et al., 2009). Mast cell activation leads to the birth cohort study, a decrease in the variety of gut microbiota in infancy
release of cytokines associated with Th17 (IL-6, IL-17A, IL-23) (Cesare was linked to a higher risk of developing allergic diseases during school
et al., 2008), and proinflammatory cytokines (IL-1β, IL-6 and IL-8) (Kee age (Bisgaard et al., 2011).
et al., 2017), as well as chemokines (macrophage inflammatory protein
[MIP]− 1α, MIP-1β, regulated on activation normal T cell expressed and 3.1. Skin microbiota
secreted, monocyte chemoattractant protein-1). These mediators, along
with TH1-derived mediators (IL-1β, IL-6, IL-8, IL-10, and interferon The skin has a surface area of around 2 m2, but considering ap­
[IFN]- γ), trigger the chronic inflammatory phase of AD. pendages, the skin’s contact surface area with the skin microbiome
The disease heterogeneity in AD may be partially attributed to dis­ significantly increases (at least 30 m2) (Gallo, 2017), making it the
parities in genetics and immune dysregulation between pediatric and biggest organ in the human body. Anatomical variations and physical
adult patients (Ramírez-Marín and ASilverberg, 2022). An examination elements such as humidity, temperature, and lipid content influence
of atopic dermatitis (AD) patients across various age groups (0–5, 6–11, several microhabitats that exist on the skin (Baquero et al., 2021). The
12–17, and ≥18 years) revealed age-related differences in systemic skin microbiota is made up of two types of microbes: temporary and
immune profiles. Infants and children with AD exhibited elevated counts permanent residents, which arise from their surroundings and last for
of skin-homing central and effector memory T-cells in comparison to hours or days (Cogen et al., 2008). The human skin has four different
control subjects, and these counts declined as AD patients aged (Czar­ microenvironments with unique microbiota: wet (Staphylococcus, Cor­
nowicki et al., 2020). In nonlesional, early-onset pediatric AD skin, ynebacteria, and Proteobacteria), dry (Flavobacteriales, Proteobacteria, and

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Corynebacteria), sebaceous (Cutibacterium and Staphylococcus), and common skin commensal can also have harmful effects on the skin by
others (dermal layers, hair follicles, sweat glands) (Grice and Segre, increasing the S. aureus cytolytic activity and inducing the production of
2011). According to research on fungal communities, the genus Malas­ pro-inflammatory cytokines (Lo et al., 2011). Byrd et al. used shotgun
sezia predominates on healthy human skin, particularly on arms and the metagenome sequencing to analyze the skin microbiome in AD patients.
chest (Malassezia globose), face (Malassezia restricta), and trunk regions They found that the severity of AD is associated with specific strains of
(Malassezia sympodialis). A variety of fungal communities such as microorganisms, especially in severe cases, suggesting that certain
Malassezia, Cryptococcus, Aspergillus, Epicoccum, Rhodotorula, and others strains may contribute to the pathogenicity of S. aureus in AD through
have colonized the foot sites (Findley et al., 2013). The skin microbiota unique virulence factor combinations (Byrd et al., 2017). Comparative
can also change based on an individual surroundings, age, health, and genomics analysis indicated that S. aureus strains found in individuals
nutritional state.. with AD were notably enriched in virulence factors, whereas
S. epidermidis strains in the same context exhibited variations in genes
3.1.1. Skin microbial mechanism: Table 1 related to interactions between species and metabolic processes. In both
cases, the exchange of genetic material between different staphylococcal
3.1.1.1. Skin microbiota dysbiosis in AD. The skin in AD is characterized species played a pivotal role in shaping the gene composition (Saheb
by a decreased diversity and imbalanced expression of microbes. This is Kashaf et al., 2023). Malassezia species permeate the epithelial barrier in
specifically exhibited as a decline in the genera Streptococcus, Cuti­ patients with AD, producing immune cell activation and skin inflam­
bacterium, Corynebacterium, Prevotella, and Acinetobacter, a considerable mation. Moreover, Malassezia allergens might cause a specific IgE
rise of Staphylococcus, notably S. aureus. The presence of S. aureus was response, which aggravates the condition (Nowicka and Nawrot, 2019).
observed in 70% of individuals with AD disease on their lesional skin Studies showing a link between skin dysbiosis and AD are summarized in
and 39% on their non-lesional or healthy skin, indicating a correlation Table 2.
between S. aureus and the severity of the disease (Totté et al., 2016).
S. aureus is the most common bacterial species related to AD. Being an 3.1.2. Skin-barrier dysfunction in AD
opportunistic pathogen, it is highly suited to stick on skin, break the The distinction between health and disease is delicate, with the skin
epithelial barrier, and activate the host immune system, which leads to barrier playing a crucial role in preventing the infiltration of both
skin inflammation (Fyhrquist et al., 2019). Cutibacterium acnes, a commensal and pathogenic microorganisms. The primary reasons for
the dysbiosis seen in AD have been hypothesized to be changes in the
bacterial habitat from normal skin to AD lesions. An abnormal physical
Table 1 skin barrier elevates the pH on the skin surface, promoting the devel­
The mechanisms and relative factors contributing to the severity of AD. opment of S. aureus (Knor et al., 2011). The presence of
Factors Possible mechanism in AD severity References fibronectin-binding proteins (FnBPs) enhances the invasion of S. aureus,
particularly when interacting with the host cell receptor integrin alpha5
↑pH, ↓AMPs Favors S. aureus growth (Miajlovic et al.,
2010) beta1 through cellular or soluble fibronectin (Sinha et al., 1999).
Coproporphyrin III Induces the aggregation of S. aureus and (Wollenberg Staphylococcal toxins may encourage the development of cutaneous vi­
the development of biofilm et al., 2014) ruses, indicating that S. aureus colonization may spread viral infections
SAgs (TSST-1) Bind to MHC-II and stimulate T cells to (Kim et al., in the skin (Bin et al., 2012). Taken together, these findings show that
produce cytotoxic cytokines, increases 2006)
infections are a major problem in AD, and it is critical to characterize the
IgE production, mast cell degranulation
stimulates epidermal inflammation infections that result from skin barrier dysregulation in AD patients in
Protein A Induces inflammatory response in (Spaulding order to prevent and treat them.
keratinocytes via the TNFR1 receptor et al., 2013)
α-toxin Damages keratinocytes, exacerbates the (Brauweiler
3.1.3. S. aureus pathogenicity in AD
barrier disruption and promote AD like et al., 2014)
inflammation The best-understood link between skin microbiota and AD is the
δ-toxin Mast cells degranulation and induces (Nakamura association with S. aureus, which is frequently present on the skin of
skin inflammation et al., 2013) individuals with AD (Gong et al., 2006). Skin-barrier dysfunction
EcpA S. epidermis cysteine protease, disrupt (Cau et al., brought on by AD makes S. aureus colonization easier (Alexander et al.,
skin barrier, increases TEWL and disease 2021)
2020). Filaggrin deficiency is linked to increased S. aureus in the cuta­
severity
Clumping factor B Attachment to corneocytes in the (Fleury et al.) neous microbiome (Clausen et al., 2018). S. aureus induces the pro­
stratum corneum using loricrin or other duction of endogenous proteases in keratinocytes, which worsens the
ligands. barrier dysfunctions (Williams et al., 2017). S. aureus also secretes
Fibronectin-binding Enhance S. aureus binding to fibronectin (Cho et al.,
δ-toxin and α-toxin as key pathogenic agents (Berube and Bubeck
proteins 2001)
PSMs Induce proinflammatory responses (Nakagawa
Wardenburg, 2013). IgE enhances the ability of δ-toxin to cause
linked to AD in keratinocytes et al., 2017) degranulation without lysing murine mast cells. In mice, cutaneous
Staphopain, Cleaves the antimicrobial peptide LL-37, (Sonesson et al., inflammation characterized by increased IL-4 and IgE levels could not be
Aureolysin protect S. aureus from AMPs 2017) brought on by S. aureus lacking δ-toxin (Nakamura et al., 2013).
↑Serine protease Increase PAR-2 and modify the (Komatsu et al.,
S. aureus produces short amphipathic peptides called phenol-soluble
(kallikreins) processing of filaggrin and cathelicidin, 2007)
promotes S. aureus colonization and modulins (PSM), includes PSMα and PSMβ; which have similar func­
weakens the skin barrier tions to δ-toxin (Peschel and Otto, 2013).
MGL_1304 Fungal protein, causes type 1 allergy in (Hiragun et al., Moreover, PSMα promotes keratinocytes to produce proin­
AD patients 2013)
flammatory cytokines including IL-1α and IL-36α, which recruit neu­
MgSAP1 Fungal protease, inhibit the (Li et al., 2018a)
development of a biofilm by
trophils and activate Th17 cells as well as stimulates γδ T cells (Liu et al.,
hydrolyzing the S. aureus Protein A 2017). In mice, skin irritation can be induced by a pore-forming cyto­
lysin known as α-toxin (Hong et al., 2014). Under normal conditions, the
S. aureus: Staphylococcus aureus, AMPs: Anti-microbial peptides, SAgs: Staphy­
expression of filaggrin and sphingomyelinase decreases the vulnerability
lococcal superantigens, TSST-1: Toxic shock syndrome toxin-1, TNFR1: Tumor
necrosis factor receptor-1, PAR 2: Protease activated receptor 2, MHC-II: Major of keratinocytes to α-toxin (Brauweiler et al., 2013). Moreover, S. aureus
histocompatibility class II, α-toxin: Alpha toxin, δ-toxin: Delta toxin, S. epidermis: can penetrate the dermis from the epidermis, where it comes into con­
Staphylococcus epidermis, TEWL: Transepidermal water loss, PSMs: Phenol- tact with immune cells and initiates the TH2 reactions by increasing the
soluble modulins release of IL-4, IL-13, IL-22, thymic stromal lymphopoietin (TSLP), and

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Table 2
A summary of previous studies on the dysbiosis of skin microbiota in AD.
Year Article title Type of Study Methods Outcomes Reference

2012 Temporal shifts in the skin microbiome 12 AD patients, 11 16S-rRNA gene AD lesion: ↑S. aureus and ↑S. epidermidis (Kong et al., 2012)
associated with disease flares and treatment in healthy controls sequencing ↓Streptococcus, ↓Propionibacterium, and
children with AD ↓Corynebacterium
2013 The altered landscape of the human skin 13 AD patients, 49 16S-rRNA gene AD patients: ↓microbial diversity, (Oh et al., 2013)
microbiome in patients with primary healthy controls sequencing ↑S. aureus
immunodeficiencies
2014 Distribution of Malassezia species on the skin of 18 AD patients, 18 PCR-RFLP AD patients: ↑M. sympodialis, (Jagielski et al.,
patients with atopic dermatitis, psoriasis, and healthy controls 2014)
healthy volunteers assessed by conventional and
molecular identification methods
2015 Effects of S. aureus and S. epidermidis secretomes 21 AD patients, 17 Real Time -PCR AD children: ↑S. aureus with ↑IgE level (Laborel-Préneron
isolated from the skin microbiota of atopic healthy controls et al., 2015)
children on CD4 + T cell activation
2016 Exploring Staphylococcus epidermidis in atopic 100 AD Patients Binomial logistic AD patients: ↑S. epidermidis (Hon et al., 2016)
eczema: friend or foe? regression
2017 Skin microbiome before development of atopic 10 AD infants, 10 healthy 16S-rRNA gene 12-month-old infants: Before AD ↓ (Kennedy et al.,
dermatitis: Early colonization with commensal controls sequencing S. aureus, 2017)
staphylococci at 2 months is associated with a After AD: ↓ commensal staphylococci
lower risk of atopic dermatitis at 1 year
2017 Staphylococcus aureus and Staphylococcus 11 AD children, 7 Shotgun ↑SCORAD: ↑S. aureus, AD flares: (Byrd et al., 2017)
epidermidis strain diversity underlying pediatric healthy controls metagenomic ↑S. aureus strains (AD03. A2, AD06. E13,
atopic dermatitis sequencing AD04. E17, AD11. E17, AD01. F1) and
↑S. epidermis clades (A29, A30)
2018 Epidermal lipid composition, barrier integrity, 10 AD patients. 10 16S-rRNA gene AD patients: ↑S. aureus, ↓microbial (Baurecht et al.,
and eczematous inflammation are associated healthy controls sequencing diversity 2018)
with skin microbiome configuration
2019 Nasal and skin microbiomes are associated with 198 AD patients: 108 16S-rRNA gene Skin lesion: ↑S. aureus, Nose: ↑Moraxella, (Totté et al., 2019)
disease severity in pediatric atopic dermatitis lesional skin and 90 nasal sequencing, qPCR both: ↑Staphylococci
samples
2020 Cheek Microbial Communities Vary in Young 25 AD children, 28 16S-rRNA gene AD children: ↓microbial diversity, (Song et al., 2020)
Children with Atopic Dermatitis in China healthy controls sequencing ↑S. aureus, ↑Aerococcus and ↑Finegoldia
2021 Skin dysbiosis in the microbiome in atopic 10 AD patients, 5 healthy Shotgun AD patients: ↓α-diversity, ↑S. aureus, (Bjerre et al., 2021)
dermatitis is site-specific and involves bacteria, controls metagenomic ↑Propionibacterium phages PHL041 and
fungus and virus PHL092, ↑Staphylococcus epidermidis
phages CNPH82 and PH15
2022 Skin microbiome and its association with host 48 AD patients 16S-rRNA gene AD patients: ↑S. aureus (Rauer et al., 2023)
cofactors in determining atopic dermatitis sequencing
severity
2023 Staphylococcal diversity in atopic dermatitis NIH cohort: 44 AD Shotgun NIH cohort; AD flares: ↑S. aureus ST5, and (Saheb Kashaf et al.,
from an individual to a global scale patients, 10 healthy metagenomic and S. epidermidis STs (ST5, ST7, ST16, ST35, 2023)
controls;Global scale: whole genome and ST59)
298 AD patients, 175 sequencing Global scale; ↑S. aureus ST5, ST8 in USA,
healthy controls European continent, Singapore

other cytokines linked to AD (Nakatsuji et al., 2016). Toll-like receptor 2 non-antibiotic CoNS strains to thrive, leading to increased S. aureus. In
(TLR2) is the predominant binding site for the pathogen-associated Th17 inflammation, higher host AMP expression directly inhibits
molecular patterns (PAMPs) from S. aureus (Fournier, 2012). TLR2 S. aureus survival (Nakatsuji et al., 2023). Certain bacterial antimicro­
signaling plays a dual role in the etiology of AD. Activation of TLR2 bial peptides (AMPs), including short peptide bacteriocins and heterol­
induces the synthesis of TSLP and the degranulation of mast cells (Vu ogous autoinducing peptides isolated from the commensal microbiome,
et al., 2010), rapid upregulation of claudin 1, a tight junction protein, hold promise for treating AD by selectively inhibiting S. aureus or its
and antimicrobial peptides (AMPs) can help protect against AD by the virulence, and/or through immunomodulatory mechanisms (Joshi et al.,
differentiated epidermal layers in healthy skin (Kuo et al., 2013). 2023).
Cutibacterium acnes produces a thiopeptide RiPP called cutimycin,
3.1.4. Antimicrobial peptides (AMPs)’ role in AD which selectively inhibits Staphylococcus members without affecting
Host-derived AMPs commonly known as host defense peptides those belonging to the genera Corynebacterium and Cutibacterium
(HDPs), can be either induced or constitutively expressed by a variety of (Claesen et al., 2020). PSMγ and PSMδ are peptides produced by
cell types, including keratinocytes, sebocytes, immune cells, and dermal Staphylococcus epidermidis that prevent pathogenic bacteria from
preadipocytes. Numerous studies have demonstrated that antimicrobial growing on the skin (Cogen et al., 2010). In a limited cohort study, the
peptides (AMPs) such as human β-defensin (hBD)− 1, cathelicidin LL- transplantation of specific strains of S. epidermidis and S. hominis, which
37, S100A7 protein, and hBD-3 can enhance the levels of proteins produce antimicrobial peptides (synergized with the human AMP
associated with tight junctions, thereby promoting epidermal barrier LL-37), led to notable reductions in the abundance of S. aureus among
function (Akiyama et al., 2014), However, these are found in reduced patients with AD (Nakatsuji et al., 2017). On the other hand, mast cells
quantities in AD skin, accompanied by heightened expression of S100A7 secrete IL-31 when stimulated by hBDs and LL-37, It plays a crucial role
and RNase7 (Harder et al., 2010). Furthermore, the increased preva­ in the regulation of itch sensation in patients with skin disorders
lence of S. aureus on atopic skin and during disease exacerbations has (Niyonsaba et al., 2010). The generation of IL-4, IL-13, and IL-31 by
been associated with impaired HDPs expression (Kong et al., 2012). In a T-cells, which are all associated with the development of AD, can be
study lower production of AMPs from IL-4Rα activation, selectively stimulated by hBDs (Kanda and Watanabe, 2012). LL-37 may upregulate
impairs the survival of antibiotic-producing coagulase-negative Staph­ Th2-related cytokines, including IL-31, IFN-γ, IL-22, and oncostatin M in
ylococcus (CoNS) strains. In Th2 inflammation, decreased AMPs allow activated T-cells, potentially promoting inflammation in

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T-cell-mediated skin disorders. (Kanda et al., 2012). The above infor­ with AD, lack overall biological α-diversity, in addition to having high
mation suggests certain antimicrobial peptides (AMPs) play a role in the levels of Enterobacteriaceae and low levels of Bifidobacterium and
development of AD, and an overabundance of AMPs could harm the Bacteroides (Arboleya et al., 2016). Compared to healthy controls, AD
inflammatory condition of individuals with AD. patients have larger percentages of the bacteria Staphylococcus. aureus,
Escherichia coli and Clostridium difficile in their gut microbiome, whereas
Bifidobacteria, Bacteroidetes, and Bacteroides have lower percentages.
3.2. Gut microbiota Escherichia coli and Clostridia in the colon may cause eosinophilic
inflammation, which may contribute to the processes causing AD
The human gut, with over 100 trillion (1014) microbes, is one of the (Nylund et al., 2015). A preliminary large-scale cohort investigation
most diverse and complex ecosystem (2012). Two bacterial groups, the revealed that children with AD had higher levels of Escherichia coli and
gram-positive Firmicutes and the gram-negative Bacteroidetes, Clostridium difficile colonization than infants without AD (Penders et al.,
comprise the majority of bacteria living in the adult gut, with the Acti­ 2007). Compared with healthy controls, AD patients had low pro­
nobacteria, Verrucomicrobia, and Fusobacteria phyla being represented portions of Akkermansia, Lactobacillus, Faecalibacterium prausnitzii, and
at subdominant levels and varying greatly from person to person (Aru­ Bifidobacterium (Fang et al., 2021). Short-chain fatty acids (SCFAs) are
mugam et al., 2011). Many variables, such as genetics, delivery method, microbial byproducts that are widely known for their anti-inflammatory
age, nutrition, environment and medical interventions, have an impact properties. A decreased risk of AD is strongly linked to high fecal levels
on the composition and activity of gut microbiota (Clemente et al., of SCFAs (Song et al., 2016), which have been found to have elevated
2012). Healthy human intestinal microbiota has high diversity, but levels of butyrate-producing bacteria, such as Coprococcus eutactus,
dysbiosis may be linked to decreased diversity (Bäckhed et al., 2012). compared to those with severe AD (Nylund et al., 2015). Several studies
Many studies have established a link between gut dysbiosis and a range have shown that AD and intestinal dysbiosis are linked, particularly in
of diseases, like inflammatory bowel disease, obesity, Crohn’s disease, infancy (Table 3).
Alzheimer’s disease, cancer, Parkinson’s disease, neuropsychiatric dis­ "The exposome" is the term used to describe the cumulative impact of
orders and multiple sclerosis (Liu et al., 2022). The gut microbiota external factors to which an individual is exposed over the course of
produces several metabolites and signaling molecules such as their lifetime (Miller and Jones, 2014). The exposome has the potential
short-chain fatty acids, post-translationally modified peptides, oligo­ to modulate the host’s immune system, which can result in modified
saccharides, amino acid metabolites, non-ribosomal peptides and gly­ immune responses that contribute to the onset of atopic and allergic
colipids, which modulate the individual’s overall immune response conditions (Stefanovic et al., 2020). The composition and diversity of
(Donia and Fischbach, 2015). Thus, the intestinal microbiota is a the gut microbiota are influenced by multiple factors, which encompass
possible target for controlling the host’s immunological responses. host genetics, dietary choices, exposure to antibiotics, and a range of
environmental elements (Khosravi et al., 2014). Exposure to environ­
3.2.1. Gut microbiota dysbiosis in AD mental and consumer product chemicals, such as bisphenols and
The gut microbiota starts to develop at birth and begins to diversify phthalates, can significantly affect the gut microbiota. This impact can
about six months postnatally. By developmental mechanisms, the gut result in oxidative stress, altered immune responses, and disruptions in
microbiota stabilizes up-to the third year of life (Hooper et al., 2012). carbohydrate and lipid metabolism (Chiu et al., 2020). The Danish Na­
The gut microbiome acts as the first line of defense against pathogens by tional Birth Cohort found a link between prenatal antibiotic exposure
adhering to them, generating antimicrobial compounds, and triggering and AD within the first 18 months of life, but only when antibiotics were
immunological responses in the host (Carding et al., 2015). It is hy­ used during both early and late pregnancy (Timm et al., 2017).
pothesized that gut dysbiosis/ imbalance has a significant impact on the
etiological process of AD. According to a few cohort studies, children

Table 3
A summary of previous studies on the dysbiosis of gut microbiota in AD.
Year Article title Type of Study Methods Outcomes Reference

2012 Low diversity of the gut microbiota in 20 AD infants, 20 16S-rDNA 454- AD infants: ↓microbial diversity, (Abrahamsson et al.,
infants with atopic eczema healthy controls pyrosequencing ↓Bacteroides, ↓Proteobacteria 2012)
2013 Establishment of the intestinal microbiota 1402 infants Real Time-PCR AD infants: ↑Clostridia, ↑ Clostridium cluster I (Penders et al.,
and its role for atopic dermatitis in early 2013)
childhood
2015 Faecalibacterium prausnitzii subspecies-level 90 AD patients, 42 16S-rRNA gene AD patients: ↑Faecalibacterium prausnitzii (Song et al., 2016)
dysbiosis in the human gut microbiome healthy controls sequencing ↓Butyrate and propionate producing bacteria
underlying atopic dermatitis
2016 Clostridia in the gut and onset of atopic 12 AD infants, 12 16S-rRNA gene AD infants: ↑ Clostridia (Lee et al., 2016)
dermatitis via eosinophilic inflammation healthy controls sequencing
2018 Fecal Microbiome and Food Allergy in 82 AD children 16S-rRNA gene AD children: ↑Firmicutes, ↑Actinobacteria, (Fieten et al., 2018)
Pediatric Atopic Dermatitis: A Cross- sequencing ↑Bacteroidetes, ↑Proteobacteria
Sectional Pilot Study
2019 Gut microbiota profile in children affected 19 AD children, 18 Real Time-PCR and AD children: ↑Faecalibacterium, ↑Oscillospira, (Reddel et al., 2019)
by atopic dermatitis and evaluation of healthy controls 16S-rRNA gene ↑Bacteroides and ↓Bifdobacterium, ↓Blautia,
intestinal persistence of a probiotic mixture sequencing ↓Coprococcus, ↓Eubacterium
2020 Imbalance of Gut Streptococcus, 22 transient AD, 26 Pyrosequencing Transient AD: ↓Streptococcus, ↑Akkermansia, (Park et al., 2020)
Clostridium, and Akkermansia Determines persistent AD infants, Persistent AD: ↓Clostridium, ↓Akkermansia,
the Natural Course of Atopic Dermatitis in 84 healthy controls ↑Streptococcus,
Infant
2021 Differences in gut microbiota between 19 AD children, 20 16S-rRNA gene AD patients: ↑Bacteroidetes, ↑Bacteroidales, (Su et al., 2021)
allergic rhinitis, atopic dermatitis, and skin other allergic diseases sequencing ↑Bacteroidia, ↑Romboutsia, ↑Sutterella
urticaria: A pilot study
2023 Longitudinal Analysis of Association 26 AD children, 29 16S-rRNA gene AD children: ↓microbial diversity, (Chaiseksamphan
Between Gut Microbiota and Atopic healthy controls sequencing ↑Aerococcaceae family, et al., 2023)
Dermatitis in Thai Children: A Birth Cohort ↑Erysipelotrichaceae family
Study

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3.2.2. Gut microbial mechanism species like Bifidobacterium and Lactobacillus can produce γ-amino­
The gut-brain-skin axis idea has received support from several butyric acid (GABA), which can indirectly reduce skin itching (Jin et al.,
studies since Donald M. Pillsbury and John H. Stokes initially proposed 2014). Indirectly, the gut microbiota may modify bloodstream cytokine
that alterations in gut microbes might cause skin inflammation-causing levels, which may impact on stress, anxiety, and brain function
disorders like acne (Bowe and Logan, 2011). The gut-skin axis has been (Yokoyama et al., 2015). Stress-induced cortisol secretion can alter the
implemented to treat various chronic skin conditions, including AD, and composition of the gut microbiome, leading to changes in gut epithelial
basic skin conditions like acne. Toxic compounds from the gut micro­ permeability and barrier function (Cryan and Dinan, 2012). The gut
biota therefore affect and accelerate AD symptoms through specific microbiome and its metabolites can directly affect the skin, regulating
routes, including the immunologic, metabolite, and neuroendocrine skin bacteria. Dysfunction in the intestinal wall allows microbial me­
pathways, and the underlying pathways need to be researched. tabolites to enter the circulation, accumulate in the skin, and disrupt
skin homeostasis. (Salem et al., 2018).
3.2.2.1. Immunologic pathway. An imbalance in T helper (Th)1/Th2 is
associated with AD, leading to the release of Th2 cytokines such as 4. Current therapeutic approaches in AD
interleukin (IL)− 4, IL-5, and IL-13, increased IgE production, and
S. aureus binding to the skin of AD patients (Huang et al., 2017). Den­ The treatments for AD have four primary goals: Improvement of
dritic cells (DCs) in the mucosa, macrophages, and epithelial cells are all patients’ quality of life, pathology severity reduction, avoiding new in­
different ways that probiotics interact with them. Probiotic strains fections, and long-term disease management. Current therapy strategies
significantly contribute to the immunologic mechanism of AD by either advise applying emollients to the skin to hydrate it, reduce skin
promoting immunological tolerance signaling through stimulation of inflammation, and regenerate the skin structure (Igawa, 2019). One of
anti-inflammatory cytokines like IL-10 and TGF-β, or immune activation the main therapy modalities for AD is the use of moisturizers to soften
signaling by increasing IL-12, IL-18, and TNF-α (Smits et al., 2005). the skin. Pharmaceutical strategies include topical corticosteroids for
Macrophages and dendritic cells promote Treg cell development, inflammation reduction, antibiotics to cure diseases caused by microbes
maintaining immune tolerance through a balanced effector/Treg cell and calcineurin inhibitors to stop the spread of eczema and minimize
ratio and an IL-10/TGF-enriched cytokine environment. The ex vivo inflammation. Further potential treatments include immunomodulation
CD4 + T cell cytokine production pattern shows a decline in the by systemic immunosuppressant medication delivery and phototherapy
Th2-related cytokine IL-4 and an accompanying rise in the Th1-related (Thomsen, 2014).
cytokine IFN‑γ. Moreover, lactobacilli promotes the in vitro produc­ Emollients play a crucial role in preserving skin moisture, but they
tion of IL-12 by macrophages (Park et al., 2017). In a human investi­ are not effective in treating certain disorders, such as S. aureus in­
gation, healthy people who supplemented with Lactobacillus paracasei fections, and there is no conclusive evidence to suggest that their use can
experienced less skin sensitivity and trans-epidermal water loss (Gue­ reduce the severity of AD (Simpson et al., 2014). In patients with
niche et al., 2014). S. aureus infections, antibiotics are advised, although there is not
currently enough data to support the use of topical antibiotics in this
3.2.2.2. Metabolic pathway. The process of fermenting indigestible condition (Sathishkumar and Moss, 2016). Antihistamines are
carbohydrates by gut microbes results in the production of short-chain frequently used to reduce general itching. However, instead of effec­
fatty acids (SCFAs), which are directly linked to the reduction of clin­ tively treating eczema, these medications are used to reduce its symp­
ical symptoms of AD. When SCFAs interact with the gut epithelial bar­ toms (Thomsen, 2014). An alternate method to treat AD uses the
rier, they can have anti-inflammatory and immune-modulating effects systemic immunosuppressant medicines mycophenolate, methotrexate,
(Smith et al., 2013). In cohort research, the correlation between the mofetil, and azathioprine (Weidinger and Novak, 2016). By eliminating
prevalence of butyrate-producing bacteria in children and the severity of bacteria, most notably S. aureus, a bleach wash reduces AD clinical
AD was negative, indicating that butyrate may have a role in alleviating symptoms and restores surface microbiota. Due to its antibacterial
the symptoms of AD (Nylund et al., 2015). The metabolite D-tryptophan, properties, less topical corticosteroids or antibiotics may be required
produced by Lactobacillus, Bifidobacterium, and Lactococcus, decreased (Maarouf and Shi, 2018). For a long time, sodium hypochlorite (NaClO)
the production of Th2-associated CCL17 in KM-H2 cells (Kepert et al., has been employed as a disinfectant in everyday life. NaClO may effi­
2017). In human DCs, it markedly reduced IL-12, IL-5 and IFN-γ pro­ ciently destroy most bacteria, viruses, fungi, and spores, when mixed
duction and raised IL-10 production. Lactobacillus, Bifidobacterium, and with water. After bleach bath therapy, research found a considerable
Roseburia species can convert omega-3 and omega-6 polyunsaturated reduction in the S. aureus population and Eczema Area and Severity
fatty acids to conjugated linoleic acid (CLA), a naturally occurring un­ Index (EASI) score (Wong et al., 2013). An overview of the present AD
saturated fatty acid that can inhibit histamine release (Kishino et al., therapy strategies is provided in Table 4.
2013). Oral CLA supplementation significantly reduced the severity of
AD-like skin lesions by inhibiting the COX-2/5-LOX and TLR4/NF-kB 5. The metabolomics approach in the prevention and treatment
signaling pathways (Checa et al., 2015). The results indicate that CLA of AD
has a significant potential to reduce AD through its anti-inflammatory
effects. Precision medicine is important because of the highly diverse char­
acteristics of atopic dermatitis. According to unique omics profiles,
3.2.2.3. Neuroendocrine pathway. Recent studies indicate that the gut precision medicine combines cutting-edge diagnostic and therapeutic
microbiota secretes neuroendocrine chemicals that modulate the gut- techniques to predict, prevent, and cure diseases. In the area of precision
skin axis. Based on the available evidence, alterations in microbiome medicine, metabolomics will play a significant role (Jacob et al., 2019).
composition and ratios may influence the production of beneficial To understand how changes in metabolites are related to physi­
neurotransmitters and neuromodulators, which could be associated with ological/pathological changes in biological samples (mainly cells, tis­
the severity of AD symptoms (Cryan and Dinan, 2012). Moreover, they sues, and bodily fluids), metabolomics may perform a thorough analysis
can regulate immune system dysregulation and skin barrier disruption, of the metabolites present in such samples. Skin metabolomics has
two major pathophysiology involved in the AD onset. The gut micro­ recently attracted more attention from the scientific community because
biome has both direct and indirect effects on the gut-skin axis. For of its ability to characterize disorders including cystic fibrosis, Parkin­
example, the production of tryptophan by the gut microbiota can son’s disease and lung cancer in addition to skin disorders (Elpa et al.,
directly contribute to skin itching. On the other hand, certain bacterial 2021). Additionally, many gut bacteria release important metabolites
produced from the host’s food that support differentiation, migration,

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Table 4 5.1. Long chain fatty acids

Overview of currently used AD treatments.
Treatment Mechanism/ benefits Adverse effects References Long-chain fatty acids (LCFAs) serve as essential nutrients and play
crucial roles in regulating immunological responses besides acting as
Moisturizers ↑Hydration, ↓TEWL, Not much effective (Seite et al.,
↓S. aureus against S. aureus 2014; sources of energy. The body absorbs LCFAs from dietary components,
colonization, Czarnowicki where they are then converted into lipid metabolites. Among LCFAs,
↑microbial diversity, et al., 2016) there are two essential fatty acids Omega-3 (ω3) and Omega-6 (ω6) fatty
↑AMPs acids because mammals can’t produce these. Anti-allergic and anti-
TCS Skin receding or skin (Brunner
inflammatory effects of ω3 FAs have long been known (Miyata and
↓Proinflammatory
cytokines, stretch marks, striae, et al., 2016)
normalized rosacea Arita, 2015). The Docosahexaenoic acid (DHA) and Eicosapentaenoic
cytokines/ acid (EPA) -containing fish oil supplements during pregnancy were
chemokines (IL-13, linked to improve the clinical severity of AD in the first year (Denburg
IL-22 and CCL17)
et al., 2005). Infants who were fed breast milk with a high content of
and epidermal
proteins (keratin 16 saturated fat and a low content of omega-3 fatty acids had an increased
and loricrin) likelihood of developing AD (Hoppu et al., 2005). This fact suggests the
TCI ↓Proinflammatory Burning, redness, and (El-Batawy significance of DHA and EPA in the development of infants. As a result,
cytokines pruritus et al., 2009) the US Food and Drug Administration has approved the use of the
Phototherapy ↑Foxp3+ regulatory Skin aging, (Kim and
NbUVB (311- T cells, ↑microbial hyperpigmentation, Kim, 2019)
LC-FAs, ARA, and DHA in newborn formulae. As anti-inflammatory
313 nm) diversity on skin, skin cancer agents EPA, DHA and other naturally occurring PPAR agonists
UVA-1 (340- ↓synthesis of (including cis-9, trans-11 conjugated linoleic acid (CLA), rosmarinic
400 nm) superantigen by acid, biochanin A and luteolin) may be used for treating AD (Mueller
S. aureus, ↓SCORAD
et al., 2008). In the colon, probiotic bacteria endogenously produce CLA
Dupilumab Anti-IL-4 and IL-13 Headache, (Simpson
gastrointestinal et al., 2016) ( from linoleic acid. Probiotics may thus have a therapeutic impact on AD
disturbances, DAOSD Achten et al., due to the synthesis of CLA (Zhou et al., 2008).
2023) Commensal bacteria, particularly Lactobacillus plantarum, produce
Cyclosporine A Inhibits IL-2 and the Nephrotoxicity, (Kim et al., lipid metabolites (conjugated linoleic acids, oxo fatty acids, and hydroxy
function of T hypertension, 2015)
fatty acids) that are derived from omega-6 fatty acids (Kishino et al.,
lymphocytes, headaches, nausea,
↓inflammation diarrhea, electrolyte 2013). Research has shown that Bifidobacterium breve and Bifidobacte­
imbalance, rium pseudocatenulatum, which produce CLA, can alleviate colitis by
Azathioprine ↓Total serum IgE liver dysfunction, (Hon et al., changing the gut microbiota and affecting TLR4/NF-kB signaling (Chen
level leukopenia and 2009)
et al., 2021). It is hypothesized that consuming probiotics influences
gastrointestinal
disturbances systemic immune responses and promotes the synthesis of CLA in the
Omalizumab Higher affinity to local reaction at the (Holm et al., colon. L. plantarum JBCC105683 and JBCC105645, are highly
FcεRI, ↓serum IgE injection site, 2017) CLA-producing bacteria, that dramatically reduce the clinical signs of
level headache, AD by lowering IL-4 and raising IFN-γ levels (Park et al., 2017). Topical
Ozonated oil/ ↓S. aureus and No side effects (Song et al.,
CLA application preserves skin pH and enhances skin moisture.
water methicillin-resistant 2018)
S. aureus (MRSA), Furthermore, it has been demonstrated that it can reduce the expression
↓NGF expression, of pro-inflammatory enzymes such as inducible nitric oxide synthase
↓Th2 cytokines (iNOS) and cyclooxygenase-2 (COX-2), as well as cytokines IL-1β, IL-6,
expression, ↑IL-10
and TNF-α in inflamed mouse skin (Tang et al., 2021).
Probiotic ↓SCORAD ↓IL-4, No major adverse (Prakoeswa
therapy ↓IFNγ, ↓IL-17, ↑IL- effects et al., 2017;
Several processes, including transcription, signal transduction,
10↑, ↑Treg cells, Michelotti peroxisome proliferator-activated receptor [PPAR] family) and gene
↓TNF ↓TSLP et al., 2021) expression via receptors (e.g., GPR40, GPR120) are involved in the anti-
Bacteriotherapy ↓ S. aureus and No serious adverse (Nakatsuji allergic effects of lipids (Julia et al., 2015). Well-known LCFA receptors
PSMα, inhibits event et al., 2021)
include GPR40 and GPR120. Binding to GPR40 and GPR120 receptors
quorum sensing, No
significant impact on on macrophages, DHA can reduce inflammation by preventing activa­
eczema severity tion of the NLRP3 inflammasome (Yan et al., 2013).
ATx201 Reduces S. aureus No side effects (Weiss et al.,
(Niclosamide) colonization, ↑skin 2022)
5.2. Short chain fatty acids
Shannon diversity

TEWL: Trans epidermal water loss, AMPs: Anti-microbial peptides, TCS: Topical Short-chain fatty acids (SCFAs), mostly include butyrate, acetate,
corticosteroid, TCI: Topical calcineurin inhibitors, IL: Interleukin, CCL17: CC propionate, isovalerate, valerate, iso-butyrate and, are the end product
chemokine ligand 17, NGF: Nerve growth factor, DAOSD: Dupilumab-Associated
of the fermentation of dietary fiber and resistant starch by particular gut
Ocular Surface Disease, SCORAD: SCORing Atopic Dermatitis, IFNγ: Interferon-
microbes (Rauf et al., 2022). SCFAs can be transported from the colon to
gamma, Treg cells: Regulatory T cell, TSLP: Thymic stromal lymphopoietin,
FcεRI: Fc receptor of human IgE
distant organs and tissues via the peripheral circulation, and they can
directly influence tissue metabolism and function by binding to G
protein-coupled receptors (GPCRs) found on skin cells, neutrophils,
proliferation and effector function to regulate the host immune system
leukocytes, and other cells (Krejner et al., 2018). Diet can alter the gut
(Brestoff and Artis, 2013). As previously mentioned, the pathophysi­
microbiota, which has a significant effect on general health (Karim et al.,
ology of AD is complex and multifactorial. In this section, we will spe­
2023). SCFAs and dietary fiber enhance the integrity of the epidermal
cifically examine the potential of bacterial metabolites in preventing and
barrier, which eventually prevents the onset of disease and early allergy
treating AD, given that many conventional treatments for AD carry
sensitivity (Trompette et al., 2022). The High fiber diet alters the gut
significant side effects (Table 5) (Fig. 2).
flora by increasing Bacteroidetes and Bifidobacteriaceae while reducing
Firmicutes. Bifidobacteriaceae and Bacteroidetes belonging microbes
preferentially digested the fiber and increases the levels of SCFAs
(Trompette et al., 2014). Faecalibacterium prausnitzii produces butyrate

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Table 5
Mechanism of action of metabolites from useful microorganisms.
Groups Metabolites Associated microbes Mechanism Reference

Short chain Acetate Bifidobacterium spp ↑ Acetylation of the Foxp3 promoter via inhibition of (Miller and Wolin, 1996)
fatty acids HDAC9
Butyrate Clostridium clusters XIVa, Activate GPR109A, Inhibit HDACs, Induces (Nylund et al., 2015; Husted et al.,
Coprococcus eutactus differentiation of naive T-cells into Tregs 2017)
Propionate Bacteroidetes, Clostridia and ↑ Treg differentiation, GPR43 ligand, inhibit HDAC9 (Smith et al., 2013; Reichardt et al.,
some Firmicutes and HDAC6 2014)
Long chain 12,13-dihydroxy-9Z- Enterococcus faecalis ↑ Increased IL-4 production, ↓ regulatory T (Treg) cell (Levan et al., 2019)
fatty acids octadecenoic acid
10-hydroxy-cis-12- Lactobacillus ↓IgE level, ↓ TNF-α, ↑ claudin-1, ↓ dermatitis score in (Kaikiri et al., 2017)
octadecenoic acid the mouse skin
Conjugated linoleic acids Bifidobacterium, Lactobacillus PPARγ ligand, ↓IL-4, ↓ IFN-γ, improve AD symptoms (Bassaganya-Riera et al., 2012;
Park et al., 2017)
Amino acids D-tryptophan Lactobacillus, Bifidobacterium, ↑ Treg cells, ↑ IL-10 production, ↓ IL-5, IL-12 and IFN- (Kepert et al., 2017)
and Lactococcus γ in human DCs

Fig. 2. Mechanisms regulating the development of AD by skin-gut microbiota: The gut microbiota produces short-chain fatty acids (SCFAs), which activate SCFA-
sensing G-protein coupled receptors (GPCRs) while inhibiting histone deacetylases (HDACs). These actions activate signaling cascades that effectively suppress
inflammatory responses and restore the balance between Th1 and Th2 immune cells. Microbial metabolite tryptophan possesses the ability to activate the aryl
hydrocarbon receptor (AHR). this leads to the inhibition of inflammatory responses and aids in improving the epidermal barrier of the skin. Long-chain fatty acids
(LCFAs), a PPAR ligand, reduce the production of pro-inflammatory cytokines like IL-8 and stimulate the production of anti-inflammatory cytokines like IL-10.
Vitamins B2 and B9 play a critical role in maintaining Treg cells, which help regulate immune responses. Vitamin D controls autophagy and the production of
AMPs such as β-defensin and cathelicidin, which reduces the symptoms of AD by inhibiting S. aureus and changing the microbial community. The combined effect of
these pathways benefits AD.

via butyryl-CoA: acetate CoA-transferase from acetate (Duncan et al., inhibit the production of pro-inflammatory cytokines IL-6 and IL-8
2002). Propionate is produced by Bacteroidetes and some Firmicutes induced by TNF or LPS in human endothelial cells (Li et al., 2018b).
through the succinate metabolic pathway (Reichardt et al., 2014) while GPR43 play an anti-inflammatory role in AD. GPR43 is necessary for
acetate is mainly produced by Bifidobacterium spp (Miller and Wolin, Treg cell proliferation and the regulatory actions of Tregs triggered by
1996). SCFAs. GPR43 activation promotes the production of the
SCFAs regulate the immune system through two major mechanisms: anti-inflammatory cytokine IL-10 by T helper cells (Sun et al., 2018).
activating G-protein coupled receptors (GPCRs) and inhibiting histone Activation of GPR109A signaling inhibits the production of
deacetylases (HDACs). pro-inflammatory cytokines such as IL-6, TNF, IL-1β, and CCL2 from
various cells including macrophages, monocytes, epithelial cells, and
5.2.1. Activation of G-protein coupled receptors (GPCRs) adipocytes (Zandi-Nejad et al., 2013).
SCFAs can activate three different GPCRs. Most abundant SCFAs
(Acetate, butyrate and propionate) can activate GPR41 and GPR43, 5.2.2. Inhibition of histone deacetylases (HDACs)
while GPR109A only by butyrate (Husted et al., 2017). Activation of G Histone deacetylases (HDACs) catalyze the removal of acetyl groups
protein-coupled receptors (GPCRs) such as GPR41 and GPR43 can from histone proteins at the ε-N-acetyl lysine amino acid residues

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(Milazzo et al., 2020). High HDACs activity compromises the function of considerably reduced atopic dermatitis severity scores in a
tight junctions. Butyrate is a powerful HDACs inhibitor among SCFAs meta-analysis (Yang et al., 2022). Vitamin D3 or a symbiotic mixture of
(Sealy and Chalkley, 1978). HDAC9 inhibition has been potentially L. euteri, L. rhamnosus, and B. infantis effectively reduced SCORAD scores
inhibited by acetate leading to increased acetylation of the Foxp3 pro­ in infants with AD (Aldaghi et al., 2022). Study proposes that maternal
moter (Thorburn et al., 2015). Propionate raises the count of Treg cells vitamin D administration enhances colonization of crucial gut bacteria
in cells via the GPR43 receptor (Smith et al., 2013). In the intestinal in infants. Further research required to explore the potential of vitamin
epithelial cells, microbial acetate and butyrate improve epithelial bar­ D as a supplement for expectant mothers and newborns due to its impact
rier function via the production of physiological hypoxia (Hsieh et al., on gut flora and the development of AD. (Talsness et al., 2017). Vitamin
2015). D and their metabolites are essential nutrients in the human diet that
A cohort study showed that the proportion of butyrate-producing have a potential impact on inflammation and oxidative stress, two
bacteria has a negative impact on AD severity in infants, indicating important factors in the medical manifestations of allergic disorders
that butyrate may have helped to reduce the symptoms of AD (Nylund (Hufnagl and Jensen-Jarolim, 2019).
et al., 2015). High levels of propionate and butyrate in feces were found
to reduce early atopic sensitization, and mice receiving butyrate showed 5.4. Amino acids and their derivatives
less severe allergic inflammation (Roduit et al., 2019). Using fermen­
tation in the gut, commensal bacteria may synthesize a variety of SCFAs In total, humans require twenty different amino acids as essential
and hence exert a range of anti-inflammatory/ allergic effects. nutrients. Some amino acids, such as aspartate, alanine, glycine, gluta­
mic acid, cysteine, tryptophan, and glutamate, can be processed by
5.3. Vitamins commensal bacteria and are therefore important for maintaining a
healthy gut microbiome (Mardinoglu et al., 2015). Except for glycine,
The human body needs a total of 13 vitamins, which include the every amino acid has two isomeric forms: L- and D-amino acids.
water-soluble B vitamins (B1, B2, B3, B5, B6, B7, B9, and B12) and C, as Mammalian cells typically combine L-amino acids into proteins, how­
well as the fat-soluble vitamins A, D, E, and K. Bacteria uses vitamins for ever certain bacteria may make and utilize D-amino acids as parts of
their biological processes, much like mammals do. However, unlike their bacterial cell walls (Cava et al., 2011). In fact, a recent study found
mammals, certain bacteria can produce vital vitamins, including mem­ that particular pathogen-free animals had higher cecal amounts of
bers of the B family and vitamin K, and as a result, they represent a various D-amino acids (including D-asparagine, D-alanine, D-proline,
significant extra source of vitamins (Resta, 2009). Vitamin B9, also and D-glutamic acid) than germ-free mice (Sasabe et al., 2016). In
known as folate, is crucial for the maintenance of T-regulatory cells, as colonic tissue from rat colitis models or in vitro macrophages, dietary
they express a high number of folate receptors 4. In fact, intestinal glycine or histidine intake decreased the generation of inflammatory
inflammation develops as a result of vitamin B9 deficiency (Kinoshita cytokines (Andou et al., 2009). Furthermore, glutamate has been shown
et al., 2012). Because different commensal bacteria produce different to potentially increase immune tolerance in the gut-associated lymphoid
amounts of vitamin B9. It may be entirely dependent on this level of tissue (Xue and Field, 2011).
dietary vitamin B9 to sustain Treg cells. D-tryptophan, a bacterial metabolite produced by Lactobacillus,
Based on the vitamin D hypothesis, ensuring adequate vitamin D Lactococcus, and Bifidobacterium, has been shown to increase the
levels and administering supplements during the first year of life may number of Treg cells in the intestines, as well as suppress inflammatory
sensitize children to allergens, reducing their risk of developing food cytokine activity in human dendritic cells and TH2-associated CCL17 in
allergies and asthma (Bozzetto et al., 2012). Calcitriol and vitamin KM-H2 (Kepert et al., 2017). The gut microbiome plays a critical role as
D-VDR signaling directly influence T cells, favoring the development of a source of aryl hydrocarbon receptor (AhR) agonists by converting di­
the more tolerogenic Treg subgroup over the inflammatory effector T etary L-tryptophan into several compounds such as indole,
(Teff; Th1, Th2, and Th17) cells (Dimitrov and White, 2017). Th17 cells indole-3-propionic acid (IPA), indole-3-acetic acid (IAA), 3-methyl
contribute to the development of autoimmune and allergic diseases indole and tryptamine (TA) (Jin et al., 2014). In atopic dermatitis pa­
while also playing a role in the body’s protective immunity. In contrast, tients’ skin, AhR activation was found to be associated with the increase
Treg cells are crucial for regulating autoimmune reactivity (Cheng et al., of filaggrin and loricrin, i.e., key proteins that form the skin barrier. A
2019). The immune system and the microbiome are intricately con­ decline in TEWL is a sign of skin barrier restoration (Fernández-Gallego
nected, with vitamin D playing a crucial role in this relationship. et al., 2021). Indole-3-aldehyde (IAld), which is an AhR agonist pro­
Changes in vitamin D/VDR signaling are linked to microbiome imbal­ duced by the skin microbiota, has been shown to inhibit TSLP expression
ances, which can contribute to intestinal inflammation and and protect mice from MC903-induced AD. It has been observed that AD
extra-intestinal conditions like atopic diseases, highlighting the signifi­ patients have lower levels of IAld in their skin compared to healthy in­
cance of these interactions (Murdaca et al., 2021). Numerous studies dividuals (Yu et al., 2019). AHR signaling is necessary for the synthesis
have shown that vitamin D deficiency or inactivating variations in the of AMPs and can influence the skin microbiota (Smits et al., 2020).
VDR gene are associated with microbiome dysbiosis. This dysbiosis often Lactobacillus reuteri metabolism of tryptophan produces the AHR agonist
leads to increased levels of Proteobacteria and Bacteroidetes phyla and IAld, which stimulates AhR, promotes the release of IL-22, and helps in
inflammatory disorders (Yamamoto and Jørgensen, 2019). For instance, maintaining gut homeostasis (Zelante et al., 2013). This suggests that
in Crohn’s disease patients, vitamin D supplementation promotes the the AHR serves as a mediator in the communication between commensal
growth of beneficial gut bacteria like Alistipes, Barnesiella, Roseburia, microorganisms and host health, and that AHR agonists exhibit potent
Anaerotruncus, and Subdoligranulum. In multiple sclerosis patients, it is anti-atopic dermatitis (AD) effects.
associated with an increase in immune-tolerant Akkermansia, as well as Antimicrobial peptides serve a dual function, acting as immuno­
butyrate-producing Faecalibacterium and Coprococcus, which have modulators and directly eradicating certain microbes. Additionally,
anti-inflammatory properties (Cantarel et al., 2015). AMPs have been identified as crucial contributors to shaping the
A negative correlation exists between blood levels of vitamin D and composition of the local microbiome (Zong et al., 2020). In patients with
the severity of AD, indicating that vitamin D can significantly reduce the AD, LL-37 could potentially reduce itching by increasing the expression
severity of AD (Mutgi and Koo, 2013). Vitamin D regulates autophagy of semaphorin 3 A, a chemorepulsive factor in epidermal nerves that is
and the synthesis of AMPs (such as β-defensin and cathelicidin) which typically downregulated in AD (Umehara et al., 2015). In mice with AD,
inhibits S. aureus and alters the microbial population (Del Pinto et al., subcutaneous injection of hBD-3 alleviated inflammation by harnessing
2017). Oral vitamin D, combination vitamins D and E, mixed vitamins A, its barrier-enhancing properties (Peng et al., 2022). BacSp222, a RiPP
D, and E, and topical vitamin B12 treatment were all linked to originating from the common skin colonizer Staphylococcus

10
S. Mohammad et al. Microbiological Research 281 (2024) 127595

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Jung Hyeok Lee: Editing, Ramya Mathiyalagan: Review & Editing,
Bisgaard, H., Li, N., Bonnelykke, K., Chawes, B.L., Skov, T., Paludan-Müller, G.,
Yeon Ju Kim: Review & Editing, Dong Uk Yang: Review, Editing, and Stokholm, J., Smith, B., Krogfelt, K.A., 2011. Reduced diversity of the intestinal
Supervision, Deok Chun Yang: Review, Supervision, & Editing. microbiota during infancy is associated with increased risk of allergic disease at
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Schittek, B., 2019. Lugdunin amplifies innate immune responses in the skin in
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