Valerie Rocabado Camacho

Matricula :25017

DERMATOLOGIA

TRABAJO PRACTICO
RESUMEN:

La microbiota de la piel y el intestino desempeñan un papel crucial en la patogénesis de la

dermatitis atópica (DA), con una alteración de la diversidad de la microbiota que modula el
desarrollo y el curso de la EA. La disminución de la diversidad del microbioma se correlaciona
con la gravedad de la enfermedad, particularmente en la piel lesional de la EA. La pica es una
marca distintiva de la EA con un tratamiento insatisfactorio hasta ahora. La evidencia reciente
sugiere un posible papel de la microbiota en la alteración de la pica en la EA a través de las
interacciones intestino-piel-cerebro. Los metabolitos microbianos, las citocinas proinflamatorias
y el deterioro de la respuesta inmune conducen a una modulación de la picazón independiente
de la histamina, la interrupción de la barrera epidérmica y la sensibilización central de los
mecanismos de la picazón. El impacto positivo de los probióticos en el alivio de la picazón en la
EA apoya esta hipótesis, que puede conducir a nuevas estrategias para controlar la picazón de la
piel en los pacientes con EA.

La microbiota es el grupo de microorganismos que habitan todos los sitios anatómicos del
cuerpo. Estudios recientes han demostrado que la microbiota puede actuar como reguladores del
sistema inmunitario en la salud humana, lo que puede conducir a avances preventivos y/o
terapéuticos. El desequilibrio de la microbiota, llamado disbiosis, puede causar el desarrollo de
algunas enfermedades inflamatorias y sistémicas autoinmunes. El descubrimiento de una
microbiota muy diversa conduce al cambio de la "hipótesis de la higiene" a la "hipótesis de la
biodiversidad".

La dermatitis atópica (DA) es una de las enfermedades inflamatorias crónicas de la piel más
comunes con una fisiopatología compleja y varias características clínicas. Los estudios han
demostrado que los pacientes con EA exhiben una diversidad reducida en la piel y la microbiota
intestinal, y la gravedad de la enfermedad se correlaciona negativamente con la diversidad de la
microbiota en la piel. Recientemente, las alteraciones en la interacción entre la microbiota y los
componentes de la vía de la picazón han surgido como un mecanismo avanzado por el cual la
microbiota está involucrada en la fisiopatología de la EA

Cells. 2022 Dec; 11(23): 3930.

Published online 2022 Dec 5. doi: 10.3390/cells11233930

PMCID: PMC9736894

PMID: 36497188

An Altered Skin and Gut Microbiota Are Involved in the Modulation of Itch in Atopic Dermatitis
Catharina Sagita Moniaga,1,2 Mitsutoshi Tominaga,1,3 and Kenji Takamori1,3,4,*

Alexander E. Kalyuzhny, Academic Editor

Author information Article notes Copyright and License information PMC Disclaimer

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Abstract

Skin and gut microbiota play an important role in the pathogenesis of atopic dermatitis (AD). An alteration of

the microbiota diversity modulates the development and course of AD, e.g., decreased microbiome diversity

correlates with disease severity, particularly in lesional skin of AD. Itch is a hallmark of AD with unsatisfying

treatment until now. Recent evidence suggests a possible role of microbiota in altering itch in AD through gut–

skin–brain interactions. The microbial metabolites, proinflammatory cytokines, and impaired immune

response lead to a modulation of histamine-independent itch, disruption of epidermal barrier, and central

sensitization of itch mechanisms. The positive impact of probiotics in alleviating itch in AD supports this

hypothesis, which may lead to novel strategies for managing itchy skin in AD patients. This review summarizes

the emerging findings on the correlation between an altered microbiota and gut–skin–brain axis in AD,

especially in modulating itchy skin.

Keywords: skin, gut, microbiota, itch, atopic dermatitis

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1. Introduction

Microbiota is the group of microorganisms that inhabit all anatomical sites of the body. Previous studies have

been focused on microbiota as an agent of disease; however, recent studies have shown that the microbiota

can act as regulators of the immune system in human health [1]. The advanced findings on the potential roles

of microbiota in human disease may lead to preventative and/or therapeutic breakthroughs [2].

The imbalance of the microbiota is called dysbiosis, which can cause the development of some inflammatory

and systemic autoimmune diseases [2]. The discovery of a widely diverse microbiota leads to the change of the

“hygiene hypothesis” into the “biodiversity hypothesis.” The association between the decrease in

environmental biodiversity and increase in the prevalence of inflammatory and, especially, allergic diseases

has been reported [1].

As the largest organ in human body, the skin is colonized by >100 microbial phylotypes and 1000 different

bacterial species, with most of them being harmless or even beneficial to their host [2,3]. Studies have

highlighted the diversity and skin site specificity of microbial communities on human subjects [4,5,6], which

are highly variable depending on endogenous host factors, topographical location, and exogenous

environmental factors [3].

Atopic dermatitis (AD) is a one of the most common chronic inflammatory skin diseases with a complex

pathophysiology and various clinical features [7,8]. The pathophysiology of AD consists of complex

interactions between epidermal barrier disruption, skin microbiota dysbiosis, and altered type 2 immune

responses [8,9]. Chronic itch is known as one of the main symptoms in AD patients especially via non-

histaminergic itch signaling pathways, which usually persists despite the administration of medication

[10,11,12].

Studies have shown that AD patients exhibit reduced diversity in the skin and gut microbiota, with disease

severity being negatively correlated with microbiota diversity in the skin. Moreover, the relationship between

the increased level of Staphylococcus aureus in the skin, particularly during AD flares, disease severity, and

skin microbiota diversity reduction has been reported [13]. Recently, the alterations in the interaction

between the microbiota and components of the itch pathway have been arising as an advanced mechanism by

which the microbiota are involved in the pathophysiology of AD [13,14,15,16]. However, there have been only

a few studies on this issue. Therefore, in this review, we aimed to summarize the updated data on skin and gut

microbiota dysbiosis, gut–skin–brain axis, and itch in AD.

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2. Skin Microbiota

The skin is inhabited by approximately 106 bacteria per square centimeter. The skin microbiota are acquired

at birth and undergoes alterations throughout human life. This community stabilizes as we approach

adulthood, but it continues to evolve in response to various host and environmental factors that each person

might possess, i.e., a personalized skin microbiota [2,17].

Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria are prominent in skin microbiota. The most

abundant phylum on the skin is the Actinobacteria, whereas Gram-positive Staphylococcus

epidermidis and Cutibacterium acnes are mostly found in the human epithelia and sebaceous follicles,

respectively [1,18]. Studies have also demonstrated differences in the skin microbiomes at different life stages
[19]. At 2 days of age, babies have area-specific differences in their skin microbiota that might affect the future

development of disease [19,20].

The skin microbiota consists of two groups of microbes, e.g., permanent residents and temporary residents

(transient microorganisms), which emerge from the environment and persist for hours to days [21]. Skin

microbiota and microbial colonization are dependent on the physiology and anatomy of the skin site [17,18].

Further, human skin consists of the following four microenvironments: dry, moist, sebaceous, and others

(sweat glands, hair follicles, dermal layers) [4]. Each microenvironment has a distinct microbiota.

Corynebacteria, Proteobacteria, and Flavobacteriales are prominent on dry areas, whereas Proteobacteria,

Corynebacteria, Staphylococcus are prominent on moist areas. Sebaceous microenvironments, such as the face

and upper body, are inhabited mainly by Cutibacterium and Staphylococcus [18].

Each person may have a different skin microbiota. The influencing factors of these differences can be classified

into intrinsic and extrinsic factors. Intrinsic factors include age, genotype, body temperature and pH, and host

immune system. Extrinsic factors include clothing choices, climate, humidity, antibiotic use, detergent and

emollient use, surface contact factors such as antiperspirant, and frequency of hygiene [1].

2.1. Role of Skin Microbiota in Atopic Dermatitis

Healthy controls and AD patients showed different configurations of the skin microbiota at different sites.

Even though the composition of bacteria was strongly dependent on the anatomic area, the relative abundance

of Staphylococci, particularly S. aureus, was increased across all skin sites in patients with AD, with the largest

increases on chronic lesions as compared with acute lesions or non-lesional skin. Up to now, S. aureus has been

the most studied microbiota in AD patients, followed by S. epidermidis and S. haemolyticus [22,23].

A low bacterial diversity is the common characteristic of lesional skin in AD [23]. The relative abundance of S.

aureus is increased, while a decrease in Cutibacterium, Proteobacteria, Streptococcus, Corynebacterium,

and Prevotella is found [24]. The abundance of S. aureus in patients with AD was 70% on lesional skin and 39%

on non-lesional or healthy skin of the same patient, confirming the correlation between S. aureus and disease

severity [25]. The S. aureus strain structure isolated from AD lesional skin from that of non-lesional skin is

different. Several S.aureus proteins are known to adhere to host molecules in the stratum corneum. It has been

reported that the severe AD is prone to carry the clonal complex 1 (CC1, better adherence) strains, while

asymptomatic individuals carry the CC30 (less adherence) strains [26].

Biofilm formation by AD-associated S. aureus has been reported to have a major role in the chronic persistence

of S. aureus on AD skin lesions and difficulties of eradicating it using antibiotics. The biofilm is the prominent

mode of growth of the skin microbiota, which facilitates adhesion and persistence in the cutaneous

microenvironment, thus contributing to the skin barrier function and local immune responses [27]. The S.

aureus biofilm promptly grows on the epidermis, inducing oxygen depletion and disruption in the defensive

barrier function of the skin [28].

S. aureus activates protease receptors which leads to an alteration of the skin barrier of AD patients by

releasing endotoxins and enterotoxins that stimulate mast cells, causing inflammation and impairment of

keratinocytes. This activation also increases the production of type 2 cytokines, such as thymic stromal

lymphopoietin (TSLP), IL-4, and IL-13 [29]. S. aureus secretes proteases and phenol-soluble modulin α

(PSMα), which lead to endogenous epidermal proteolysis and skin barrier damage that promoted

inflammation in mice. Moreover, clinical isolates of different coagulase-negative staphylococci (CoNS) species

residing on normal skin, such as S. epidermidis, S. hominis, and S. lugdunensis, produced autoinducing peptides

that inhibit the S. aureus accessory gene regulation system, in turn decreasing PSMα expression. This

protective process is impaired when S. aureus is the dominant species in the skin [30].

Another well-known factor of AD pathogenesis is the alteration in epidermal lipid metabolism that leads to

changes in the composition of fatty acids (FAs), ceramides, and cholesterol [31] and can influence the structure

of the microbiota in AD [15]. Baurecht et al. investigated interactions between microbiota structure and

diversity and epidermal lipid composition: high levels of unsaturated long-chain FAs were associated with an

increase in the abundance of Cutibacterium and Corynebacterium, while high levels of saturated short-chain

FAs were associated with a reduction in the abundance of these genera. Further, an increase in the abundance

of S. aureus was associated with higher levels of the ceramide CER-[AS] [22]. Li et al. found that the levels of

some ceramides (CER[AH]C38–C52, CER[AP]C40), some very-long-chain ceramides (CER[EOH]C66–C70 and

CER[EOS]C70), some triglycerides, and unsaturated FAs (16:1 and 18:1) were significantly lower in patients

with AD having positive S. aureus colonization state than in those without [32]. These studies provide an

interesting interaction between epidermal lipid composition and structure and diversity of the microbiota in

AD.

2.2. Relationship between Skin Microbiota and Itchy Atopic Dermatitis

Recent advances in itch research has elucidated that multiple factors that disturb the normal functional

correlation between the skin barrier and microbiota, e.g., protease activity and skin pH, may contribute to the

increased activation of the non-histaminergic itch pathway in AD patients. In addition, nerve fibers as itch
transmitters may interact with the microbiota and peptides involved in microbial function via an array of

receptors [13].

A study by Blicharz et al. evaluated the scoring atopic dermatitis (SCORAD) index components depicting itch

intensity (excoriations, subjective evaluation of itch, and sleep loss) in adult AD patients. Lesional and non-

lesional skin showed a higher frequency of S. aureus colonization than controls (81.8% and 57.6% vs. 5.6%,

respectively). S. aureus abundance on lesional/non-lesional skin is positively correlated with sleep loss and

excoriations. The mean values of excoriations were higher in patients colonized by S. aureus than in those

without S. aureus. This study concluded that S. aureus skin colonization may be one of the factors aggravating

itch in AD [16].

Commensal and pathogenic species inhabiting the skin both express proteases, which are used as virulence

factors. For example, S. aureus proteases enable pathogen penetration by degrading collagen and elastin,

which are essential components of connective tissue in the dermis, and lead to skin barrier disruption [33].

Proteases cleave the N-terminus of the protease-activated receptors (PAR-2 and PAR-4) that manifest on

different cell types, including sensory neurons, and mediate itch [34,35]. One of the characteristics of AD is

proteases overactivity. Comparative analysis of the complete transcriptome from the skin biopsies from

healthy controls and AD patients showed that the genes encoding PAR-2 and -4 (F2RL1 and F2RL3) were

higher in itchy AD skin than in skin from healthy controls Likewise, the largest increase in PAR-2 expression

occurred in itchy AD skin, followed by less increase in non-lesional skin [36].

S. aureus, such as δ-toxin, can directly generate type 2 immune response by activating the immune cells and

producing inflammatory mediators, such as IL-4, IL-13, and TSLP [14,27]. Oetjen et al. reported that the dorsal

root ganglion in mice and humans expressed IL-4Rα and IL-13Rα, and that IL-4 and IL-13 can directly activate

sensory neurons, thereby inducing an itch [37]. Further, IL-4 and IL-13 can reduce the expression of anti-

microbial peptide (AMP), which causes a more permissive-skin AD to S. aureus colonization [27].

The structure and function of the microbiota are also significantly influenced by the skin pH and, thus, also by

itch. Commensal bacteria thrive on healthy skin with an acidic pH (pH 4–6), while pathogenic bacteria such

as S. aureus thrive at neutral pHs. AD is associated with an increase in skin pH to ≥6.5, promoting the

colonization of S. aureus, directing to dysbiosis and an increased abundance of microbiota-derived serine

proteases [38]. Moreover, the enhancement of pH also activates endogenous skin proteases (pH optimum at

8), leading in further activation of the keratinocyte PAR-2 receptors and non-histaminergic pathway [39].
Delta-hemolysin and PSMα produced by S. aureus induced degranulation of human mast cells in a dose-

dependent manner and mediates skin pathology in AD [40,41]. The antigens of S. aureus have been reported to

induce IL-31, which is the first cytokine that is known to mediate itch by directly operating on sensory neurons

[42], in vivo and in vitro in individuals with AD, implying that S. aureus can aggravate not only disease flares

but also the itch in AD [42]. Whether this is secondary to the hyperstimulation of the Th2-type response or

other mechanisms is not certain [16].

The abovementioned data revealed that S. aureus colonization of the skin lesions and non-lesional skin is

associated with higher values of itch determinants in AD. S. aureus seems to cause hyperstimulation of the

immune system and overexpression of itch mediators, suggesting that the overabundance of S. aureus may

contribute to the intensity of pruritus through a non-histaminergic mechanism [16].

2.3. Neuropeptides, Skin Microbiota, and Itch

Several neuropeptides secreted by the skin, including substance P (SP), are known to be involved in the

pathophysiology of itch in AD. The increased virulence of some bacteria, including Bacillus and Staphylococci,

can be induced by localized increases of SP in the skin. In addition, the calcitonin gene-related peptide has

been reported to modulate the virulence of S. epidermis, another key component of the skin microbiota. Thus,

neuropeptides in the skin appear to act as host signals for the microbiota and play an important role in skin

homeostasis and disease pathophysiology [43].

Thirteen mammalian Toll-Like Receptors (TLRs) have been identified and characterized. TLR3, TLR7, TLR8,

and TLR9 are localized in the endosome to detect nucleic acids derived from viruses, bacteria, or damaged

cells. TLR3 recognizes viral double-stranded RNA (dsRNA), TLR7 and TLR8 recognize single-stranded RNA

(ssRNA) found during viral replication [44]. Studies have suggested that sensory neurons can detect the

microbiota via TLR. Liu et al. reported that functional TLR7 is expressed in C-fiber primary sensory neurons

that highly co-localized with transient receptor potential subtype V1 (TRPV1) and gastrin-releasing peptide,

and it is an important mediator of itch transmission [45]. TLR3 is also displayed by small-sized primary

sensory neurons in dorsal root ganglions, and its binding with ligands stimulates neuronal activity and itch

[46].

2.4. Skin–Brain Axis and Itchy Skin

It is known that stress exacerbates itch via the skin–brain axis. Recently, the microbiota has emerged as a

major player to regulate this axis, especially during stress aroused by actual or perceived homeostatic
challenge. The routes of communication between the microbiota and brain are gradually being resolved and

involve neurochemicals (i.e., acetylcholine, histamine, catecholamines, corticotropin) that originate from the

microbiota [15].

Since stress can aggravate itch, it is believed that the brain is occupied in the final common stage of itch

processing [47]. Stress acts via the central nervous system (CNS) and changes the microbiota through the

release of neurochemicals [48]. The component of the stress response, such as glucocorticoids, may repress

AMP release/localization in the epidermis, impair skin barrier, and promote host susceptibility to infection.

Skin microbiota, especially the CoNS, are sensitive to catecholamines. Catecholamines also strengthen bacterial

attachment to host tissues and increase bacteria virulence. Catecholamines induce the biofilm formation

of Pseudomonas aeruginosa and Escherichia coli, which enhances USA300 methicillin-resistant S.

aureus virulence. Norepinephrine, epinephrine, dopamine, and their structurally related inotropes

(dobutamine and isoprenaline) raise staphylococcal growth by 5-log orders or more. [15]. Thus, the effect of

stress on the skin microbiota may be twofold: dampening the host defense to infection and adjusting the

microenvironment ideal for pathogens [49].

The amygdala is thought to be vulnerable to microbial influences [50]. Study of germ-free (GF) mice suggested

that the amygdala transcriptome becomes hyperactive in the absence of microbiota [51]. This hyperactive

state is in line with the altered pain sensitivity [52] and stress response in GF mice [53]. However, how

microbial signals navigate through the skin–brain axis to reach the amygdala specifically is still unknown.

2.5. Association of Skin Microbiota and Itchy Skin of Non-AD Disease

Cirrhosis is a late stage of scarring (fibrosis) of the liver. Patients with cirrhosis have intestinal dysbiosis and

are prone to itching. Bajaj et al. reported that the composition of microbiota at all skin sites differed between

controls and patients with cirrhosis and between patients with compensated and decompensated cirrhosis.

Skin microbiomes of patients with cirrhosis (especially those with decompensation) contained a higher

relative abundance of Gammaproteobacteria, Streptococaceae, and Staphylococcaceae. These bacterial taxa

were associated with serum levels of autotaxin and bile acids (BAs), which were higher in patients with VAS

scores ≥ 5 [54].

Senile pruritus is a common skin disease in the elderly. A study among senile pruritus patients showed that,

compared with the healthy control group, the patients had significantly lower skin hydration and higher pH

value [55]. The α-diversity of skin microbials was significantly increased in senile pruritus patients, with an

increase of Acinetobacter and Lactobacillus, and decrease of Cutibacterium. The pH value and skin hydration
were positively associated with observed species diversity and Lactobacillus, whereas the transdermal water

loss was negatively related to Lactobacillus. Thus, the damaged skin barrier function and skin dysbiosis

complemented each other and were probably related with the occurrence of senile pruritus; however, the

definite mechanism needs further study [55].

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3. Gut Microbiota

The human gut possesses one of the most complex and generous ecosystems colonized by more than 100

trillion microorganisms [56,57]. The predominance of the bacteria residing in the adult gut belong to two

bacterial phyla, the gram-negative Bacteroidetes and the gram-positive Firmicutes; and the others represented

at subdominant levels are the Actinobacteria, Fusobacteria, and Verrucomicrobia phyla, which vary

dramatically among individuals [58,59,60]. The concept of ‘enterotype clusters’ was introduced to effectively

classify the different microbial colonizations and structures [58,59]. The results of metagenomics sequencing

of fecal samples confirmed the three robust clusters dominated by Bacteroides (enterotype

1), Prevotella (enterotype 2), and Ruminococcus (enterotype 3) [3].

The composition and functions of the gut microbiota are affected by several factors including genetics, mode of

delivery, age, diet, geographic location, and medical treatments [61,62]. The gut is an anaerobic environment

in which native species have co-evolved with the host. While the aerobic pathogenic species cannot invade and

colonize this environment, diseases may develop when anaerobic and facultative pathogenic species invade

the gut. High diversity defines healthy human gut microbiotas, while reduction in diversity may be associated

with dysbiosis [59]. Studies have shown a possible direct relationship between gut dysbiosis and a variety of

diseases (the gut–brain axis), such as inflammatory bowel diseases including colitis and Crohn’s disease,

obesity, cancer [61,62], Parkinson’s disease, Alzheimer’s disease, multiple sclerosis [63], and

neurophyschiatric disorders [64].

Starting at the first month of life, the gut microbial community plays an essential role in the maturation of the

human immune system. The acquisition of the gut microbiota begins at birth, after which it diversifies at

approximately 6 months after birth. Through the development process, the stability of the gut microbiota is

achieved during the third year of life [65]. Gut microbiotas produce many metabolites and signal molecules,

such as post-translationally modified peptide, amino acid metabolites, acids (short-chain), oligosaccharides,

glycolipids, and non-ribosomal peptides, which affect the systemic immune response of an individual [14,66].

Therefore, the gut microbiota are a potential target for regulating immune responses in the host [67].
3.1. Atopic Dermatitis and Gut Microbiota

The gut dysbiosis association in patients with AD has been introduced for some time [68]. A reduction of

diversity of the gut microbiota has also been reported to cause AD development [69]. A cross-sectional study

among children showed that a diversity of gut microbiota was closely associated with a decreased risk of AD

[70]. It is believed that the gut microbiota in early life is associated with age of onset, severity, flares,

remission, and phenotype of AD. In addition to the gut microbiota diversity in itself, the interactions between

specific gut microbiota, established immune systems, and harmonization of the gut microbiota and the host

may define the development of AD [71].

The gut microbiota in infants with AD are significantly less diverse than those in healthy controls, and several

signature microbes from the genera Lactobacillus, Bacteroides, and Clostridium have been identified [72].

Higher levels of Clostridium difficile, E. coli, and Bacteroides were found in the gut of atopic infants compared to

healthy controls [14,69,73,74]. Clostridium and E. coli in the gut can participate in the occurrence of

inflammatory conditions [73]. Contrarily, lower levels of Akkermansia, Lactobacillus, Faecalibacterium

prausnitzii, and Bifidobacterium were found in AD patients, compared to healthy controls [67,74,75,76].

Butyrate-producing bacteria are more abundant in healthy infants or infants with mild AD, as compared to

infants with severe AD [77].

The gut microbiota can control the immune system of the body and skin. The condition of the gut microbiota

greatly affects the differentiation of naïve T cells to other types of Th cells, such as Th1, Th2, Th17, or

Foxp3+ Tregs. Tregs prevent dysfunctional T cells from differentiating into Th cells and inhibit the

inflammatory activities of immune cells

[65,78]. Bifidobacterium, Lactobacillus, Clostridium, Bacteroides, Streptococcus, and their metabolites, such as

propionic and butyric acids, are known for their capability in inducing the polarization and expansion of Treg

cells [79].

The gut flora produces a vast amount of metabolites, which may enter the circulation, traveling throughout the

body and affecting distant sites of the organism. This process can reach high levels when the epithelial barrier

integrity of the gut is disrupted, leading to increased intestinal permeability, referred to as the “leaky gut

syndrome” [80]. The short-chain fatty acids (SCFAs), such as butyrate, propionate, acetate, and lactate, are

products of fiber fermentation by the gut microbiota, which are known to promote epithelial barrier integrity

of the gut and exert anti-inflammatory effects [81]. Intriguingly, intestinal dysbiosis has been demonstrated in

AD patients, and a clear reduction of SCFAs has been detected. Hence, a leaky gut in AD patients favors toxins,
poorly digested foods, and gut microorganisms to penetrate the body circulation and leads to skin

inflammation. When these reach the skin, a strong Th2 reaction may be induced, causing further tissue damage

[82].

The “gut–skin” axis has been proposed and is recognized as a new target to prevent and treat AD. Gut and skin

have several similar characteristics and are parts of the overall immune and endocrine systems. The

development of gut diseases is commonly accompanied by cutaneous lesioned manifestations, implying that

the association between them may affect each other’s states [67]. Especially, the colonization and alteration of

the gut microbial were reported prior to any clinical manifestations in early life, indicating gut microbial

symbiosis as one of the causes of AD [83]. Advanced studies support the presence of a gut–skin axis that is

mediated by neuroendocrine molecules produced by the gut microbiome [84,85]. The data suggest that

compositional and proportional differences in the gut microbiome are connected to the generation of diverse

favorable neurotransmitters and neuromodulators, which are associated with the degree of AD symptoms

[71]. Therefore, targeting gut microbial alterations may be an alternative to regulate immune responses and

ameliorate cutaneous health in AD patients [67].

3.2. Gut Microbiota and Itch in AD

As explained previously, it is known that the gut microbiota and their dependent metabolites are associated

with the development of chronic diseases, such as AD, which is characterized by chronic itch. Li et al.

investigated the gut microbiota environment in diphenylcyclopropenone (DCP)-evoked chronic itch model in

mice. This study showed the microbiota composition in mice was significantly altered by the DCP-evoked

chronic itch. DCP mice showed significant decrease in α-diversity value and relative abundance of 48 bacteria

at six phylogenetic levels (phylum, class, order, etc.) compared with control mice. Contrarily, the relative

abundance of four bacteria at the genus, phylum, and species level increased in the DCP mice compared with

the control mice. These results suggest that the gut microbiota may play an important role in DCP-evoked

chronic itch in mice [86].

The microbiota of the gut and skin affect each other through neuroendocrine signaling. This effect can occur

via two routes, i.e., direct and indirect [87]. An example of direct signaling is tryptophan produced by intestinal

microbes causing skin itching in AD patients. On the contrary, γ-aminobutyric acid produced

by Lactobacillus and Bifidobacterium in the gut suppresses itch of the skin [84,87]. Through indirect channels,

intestinal microbes adjust the concentration of IL-10 and IFN-γ in the bloodstream, which can lead to

abnormal changes in brain function, resulting in stress. Cortisol, a representative stress hormone in humans,
can alter the gut epithelium permeability and barrier function by changing the composition of the gut

microbiota [14].

Cirrhosis is largely an acquired disorder with multi-system consequences. As mentioned previously, cirrhosis

patients have intestinal dysbiosis and are prone to itching. In addition to the alteration of the skin microbiota,

this study found significant differences in the stool and salivary microbiota in those with greater itching, which

were different from the taxa that separated controls from cirrhosis or compensated from decompensated

cirrhosis. Bajat et al. also identified alterations in the fecal microbiome of patients with cirrhosis, i.e., fecal

microbiota of patients with cirrhosis had a higher relative abundance of Gammaproteobacteria than controls,

which are associated with itching intensity and itch modulators. This implies that a specific signature of the

microbial composition that is present in the gut could be associated with skin itching [54]. A summary of

components involved and the proposed mechanism of an altered microbiota in the skin and gut may modulate

itch in AD as explained in Table 1 and Figure 1.

Figure 1

Proposed mechanism of a microbiota dysbiosis modulates itch in atopic dermatitis. The leaky gut condition

due to gut dysbiosis enables microbiota metabolites and proinflammatory cytokines to circulate and reach the

skin, e.g., tryptophan, LPS, and others. In the skin, decreased microbial diversity and S. aureus colonization lead

to disruption of skin barrier function and the production of pruritoceptors, such as IL-4, IL-13, TSLP, IL-31, and

so on, which trigger an itch sensation in AD.

Table 1

The components of skin and gut alterations in the modulation of itch in atopic dermatitis.
 Skin Gut
Low gut microbiota diversity
Low skin microbiota diversity
 -
 -

Decreased Lactobacillus,
Decreased Cutibacterium, Proteobacteria, Streptococcus,
Bifidobacterium, Akkermansia,
Alteration of Corynebacterium, Prevotella
Corynebacterium, F. prausnitzii
microbiota
 -
 -

Increased S. aureus (primary), S. epidermidis, S.

Increased Escherichia coli,
haemolyticus
Clostridium difficile, Bacteroides
S.aureus-derived toxins, e.g., proteases, PSMα, δ-toxin,
Decreased SCFAs (especially
delta-hemolysin; neuropeptides (e.g., substance P,
Metabolites butyrate), Tregs; increased
calcitonin gene-related peptide), TLRs; neurochemicals
tryptophan
during stress induced itch
Activation of PARs and production of type 2 cytokines by
Proposed δ-toxin → sensory neurons; increased of skin pH; delta-
leaky gut syndrome
mechanism hemolysin-induced IL-31 production; TLRs activate
sensory neuron

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Note: PSMα = phenol-soluble modulin α; SCFs = short-chain fatty acids; TLRs = toll-like receptors.

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4. Different Body Sites Have Different Microbiota with Different Effects on AD

The composition, diversity, and interactions with the host of the microbial communities in different body

habitats are site specific, with alterations in the diversity or metabolic activity of these unique microbiomes

resulting in inflammation and atopic disease [88,89]. In a study comparing the structure and predicted

functions of microbial communities from the skin, oral cavity, and gut, Li et al. [90] revealed that healthy

controls showed different alterations in community-level diversity between microbiomes from the same body

habitats (α-diversity) and patients with AD. In AD patients, the most significant alleviation in α-diversity was

seen in the skin, followed by the oral cavity, while no differences in community structure were found in the gut

microbiota. In addition, alterations in the level of enrichment of specific microbes at the different body habitats

were observed in patients with AD as compared with controls. Staphylococcus was enriched in the skin

samples from patients with AD, while Halomonas was more generous in the skin of healthy controls.

Interestingly, Halomonas was enriched in the oral cavity of AD patients as compared with in the controls,

suggesting that the patterns of enrichment in AD vary according to body habitat. The clinical severity of AD

also differentially correlated with levels of diversity in the different regions: in the skin, microbiome α-

diversity was negatively correlated with skin disease severity, while a positive correlation was seen in the oral

cavity. Analysis of the predicted functional profiles of the microbiome from each habitat sampled revealed an
inverse connection between pathway enrichment in the skin and oral microbiomes: the tryptophan

metabolism was enriched in the oral cavity of patients with AD but was attenuated in the skin. In summary,

this study showed that the different body regions in AD patients possessed differential changes in the

structure of microbial communities, with lower levels of diversity both within and between the skin and oral

microbiomes, simultaneously with inverse associations in predicted microbial function between the two

microbial communities [90].

Microbiome-Based Treatments for Itchy AD

Looking at the great role of microbiota on AD, we can hypothesize that microbiota-based therapies are needed

to restore a healthy skin and gut microbiota in AD patients. Some therapies include probiotics treatment,

repopulating AD lesions with beneficial commensals, phage therapies, small molecules and peptides that

counteract S. aureus colonization, humanized monoclonal antibodies that target bacterial toxins, quorum

sensing inhibitors that block virulence factors, bacteriotherapy, and the excimer light treatment [91,92,93,94].

Probiotics by definition are ‘live microorganisms, which, when consumed in adequate amounts, confer a health

effect on the host’ [95]. Prebiotics are non-digestible ingredients that beneficially affect the host by selectively

stimulating growth or limiting gut microbiota [96]. Probiotics and/or prebiotics, as the common regulator for

gut microbiota, have been used to alleviate AD clinical symptoms, but with controversial outcomes (positive or

ineffective). This is related to the complex interaction between the immune response, gut microbiota, and

metabolic activity in the host [67]. Actual health effects have been reported for specific strains of the following

genera: anaerobic microbes

(Lactobacillus, Bifidobacterium, Saccharomyces, Enterococcus, Streptococcus, Pediococcus, Leuconostoc, E. coli),

and the aerobic Bacillus strains [95]. Postbiotics are metabolites from intestinal bacteria, which include

microbial cells, cell constituents, and metabolites [14,97]. Moroi et al. showed that the skin severity scores

were significantly improved after treatment with postbiotic L. paracasei K71 in adult patients with AD

compared to that after placebo administration, whereas the itch scores did not [98]. One of the common

problems among patients with chronic kidney disease is pruritus, which was associated with the accumulation

of calcium phosphate (CaP) under the skin. Skin C. acnes can solubilize CaP by the production of SCFAs, such as

the N-[2-(2-Butyrylamino-ethoxy)-ethyl]-butyramide (BA-NH-NH-BA), a butyric acid derivative. Topical

application of BA-NH-NH-BA onto mouse skin efficaciously improved CaP-induced skin itching [99].

Furthermore, it is suggested that postbiotic compounds from Lactobacilli spp. can employ immunomodulation

activity by increasing the levels of Th1-associated cytokines and reducing Th2-associated cytokine levels

[97]. Table 2 shows the microbiome-based treatment studies related to itching in AD.
Table 2

Microbiome-based treatments for AD itch.

Microbio Alteratio
Mode of
N ta n of Referen
Component Subject Administrat Result
o. Treatme Microbio ce
ion
nt ta
Improvement of
Lactobacillus
1. Probiotic Pediatric AD Oral NA itch and [100]
salivarious LS01
SCORAD index
Improvement of
number of
Dermatophago scratches, AD-
Gut
Lactobacillus ides like skin lesion,
(from
2. Probiotic paracasei KBL38 farinae extract- Oral Foxp3+; [101]
cecum,
2 induced AD reduction of IL-
human)
mice model 31; altered gut
microbiota and
metabolites
Improvement of
Bifidobacterium itch and
3. Probiotic animalis subsp. Adult AD Oral NA dermatology- [102]
lactis LKM512 specific quality-
of-life scores
AD-induced
Reduction of
animal models
vasodilation (rat
Yeast-extracted β- of rat
model), and
1,3/1,6-glucan (histamine-
Gut pruritus, edema,
and/or Lactobacill induced
4. Synbiotic Oral (from and serum [103]
us vasodilation)
fecal, rat) histamine
plantarum LM100 and mouse
(mouse model);
4 (pruritus and
altered gut
contact
microbiota
dermatitis)
Bifidobacterium
breve and Improvement of
5. Synbiotic Healthy adult Oral NA [104]
galactooligosacch skin hydration
aride
Improvement of
Autologo
skin lipid;
us
reduction of
6. microbio S. epidermidis Healthy adult Topical NA [105]
water
me
evaporation and
transplant
skin pH
Decreased skin
Gut sensitivity;
L. paracasei NCC A capsaicin test (from increased rate
7. Probiotic Oral [106]
2461 in healthy adult fecal, of barrier
human) function
recovery
Autologo
Skin Supression
us
S.hominis and S. (from of S. [107,10
8. microbio Adult AD Topical
epidermidis skin, aureus coloniza 8]
me
human) tion
transplant
9. Beneficia Roseomonas Adult and Topical Skin Improvement of [109]
l mucosa pediatric AD (from subjective
commens skin, regional itch,
als human) total itch score,
 Microbio Alteratio
Mode of
N ta n of Referen
Component Subject Administrat Result
o. Treatme Microbio ce
ion
nt ta
and SCORAD
score

Open in a separate window

Note: AD = atopic dermatitis; SCORAD = Scoring Atopic Dermatits.

Most probiotics reduced the SCORAD scores and even decreased the risk of developing AD. Niccoli et al.

evaluated the clinical efficacy of a lyophilized form of Lactobacillus salivarious LS01 in pediatric AD patients.

The results of this study reported a significant decrease in SCORAD value and significant improvement in itch

intensity when compared to the placebo control group. These reductions persisted after treatment suspension

[100]. Further, Kim et al. investigated the attenuation of the AD symptoms using L. paracasei KBL382 isolated

from the feces of healthy Koreans. Oral administration of L. paracasei KBL382 for 4 weeks significantly

reduced AD-associated skin lesions, number of scratches, TSLP and IL-31 levels in the skin, and immune cell

infiltration in Dermatophagoides farinae extract-induced AD in mice. In addition, the administration of KBL382

dramatically changed the composition of the gut microbiota in AD mice. Therefore, it is hypothesized that the

administration of KBL382 significantly ameliorates AD-like symptoms by regulating the immune response and

altering the composition of the gut microbiota [101].

Many studies reported that oral probiotic formulations consisted of Lactobacillus strains; however, only

several studies have investigated the positive effects of other bacterial strains or mixtures of different

probiotic bacterial strains in the management of AD. Matsumoto et al. reported that the administration

of Bifidobacterium animalis subsp. lactis LKM512 alleviated itch and considerably improved the dermatology-

specific quality-of-life scores when compared with the controls. The antipruritic and antinociceptive

metabolite kynurenic acid production was increased after administration of LKM512, suggesting an

antipruritic effect of B. animalis [102]. Kim et al. investigated the immunomodulatory effects of oral yeast-

extracted β-1,3/1,6-glucan and/or Lactobacillus plantarum LM1004 against AD-like symptoms in AD-induced

animal models of rat (histamine-induced vasodilation) and mouse (pruritus and contact dermatitis). The

treatment group showed significantly reduced vasodilation in the rat model, and pruritus, edema, and serum

histamine levels in the mouse models. Moreover, in rats with no AD induction, the same treatments

significantly increased the relative abundance of the phylum Bacteroidetes and the genus Bacteroides. In the

treated groups, Bacterial taxa associated with butyrate production, such as Lachnospiraceae and

Ruminococcaceae at the family level and Roseburia at the genus level, were increased. These findings suggest

that the dietary supplementation of β-1,3/1,6-glucan and/or L. plantarum LM1004 has an immense potency
for the treatment of AD via mechanisms that might involve modulation of host immune systems and gut

microbiota [103].

Phenols, for example, phenol and p-cresol produced by gut bacteria, are regarded as bioactive toxins and

serum biomarkers of a disturbed gut environment, which can accumulate in the skin via the circulation and

disrupt keratinocyte differentiation in hairless mice. It has been reported that daily intake of the

probiotic Bifidobacterium breve together with the prebiotic galactooligosaccharide reduced serum total phenol

levels and improved skin hydration in healthy adult women [104]. Restoring a diverse microbiota that

includes commensals will improve the community’s resistance to colonization with pathobionts. S.

epidermidis application on healthy individuals increased the skin lipid content and lowered skin acidic

conditions [105]. Moreover, a clinical study demonstrated that oral supplementation with a probiotic L.

paracasei NCC 2461 decreased skin sensitivity and increased barrier function in a capsaicin-treated group

[106]. A compromised skin barrier is known as a very important factor in treating itch, suggesting the

importance of oral probiotics in the treatment of itch in AD.

Nakatsuji et al. demonstrated that the topical application of commensal skin bacteria (autologous microbiome

transplant, S. hominis, and S. epidermidis) is effective in protecting against pathogen species, with reduced S.

aureus colonization and inhibition of PSMα, improvement of clinical symptoms (including itch), and decreased

local inflammation [107,108]. Another study also conducted a first-in-human topical microbiome

transplantation after collecting the commensal Roseomonas mucosa from healthy subjects. A significant

decrease in SCORAD score and pruritus was noted after the treatment, leading to a lesser need for topical

steroids [109].

Go to:

5. Conclusions

Several studies have demonstrated the link between skin and gut dysbiosis and skin homeostasis imbalances

in the pathophysiology of AD. Recently, the interplay between this concept and itch as a distinctive hallmark of

AD has also been investigated. Studies have shown that the alteration of microbiota in the skin and gut

(attenuation of microbiota diversity) interferes with the mechanism of itch in AD through a non-histaminergic

pathway, perturbation of skin barrier, and central sensitization. Moreover, microbiota-derived treatment,

especially probiotics, has proven its benefit in relieving itch in AD patients. Prevention and therapy of

microbiome dysbiosis could help alleviate itch related to AD. Further insights into the interactions between

human microbiota and itch will provide new targets for future treatment of itchy skin in AD patients.
 Go to:

Funding Statement

This work was partly supported by a Grant-in-Aid for Scientific Research (B) [Grant numbers 20H03568 and

22H02956].

Go to:

Author Contributions

C.S.M. conceived and designed the review, collected and analyzed data, and wrote the manuscript. M.T.

conceived, designed, wrote, and revised the manuscript; K.T. wrote and revised the manuscript. All authors

have read and agreed to the published version of the manuscript.

Go to:

Conflicts of Interest

The authors declare no conflict of interest.

Go to:

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and

institutional affiliations.

Go to:

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