International Journal of

Review Article Dermatology and Venereology

The Role of Intestinal Microbiota in Atopic

Dermatitis
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Wen Zuo1 and Cai-Hong Sun2,*

1
School of Clinical Medicine, Jiangsu University, Zhenjiang, Jiangsu 212000, China; 2 The Second Affiliated Hospital of Nanjing
University of Chinese Medicine, Jiangsu Second Chinese Medicine Hospital, Nanjing, Jiangsu 210017, China.
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Abstract
The early intestinal microbiota plays an important role in immune regulation, and the unbalanced composition may
increase the occurrence of allergic diseases, including atopic dermatitis. This review summarizes the latest studies
in the occurrence and development of intestinal microflora and its relationship with atopic dermatitis. These results
are conducive to understand the differences in the composition of intestinal microbiota between patients with atopic
dermatitis and healthy people, and provide a potential intervention for prevention or treatment of atopic dermatitis.
Keywords: intestinal microbiota, atopic dermatitis, probiotics, microbial preparation

Introduction and young children.5 Although, the therapeutic effects of

Atopic dermatitis (AD) is one of the most common
chronic skin diseases, which is considered as the first step
in the atopic march,1 closely related to the occurrence of
allergic diseases such as asthma and rhinitis. Over the
past few decades, the prevalence of AD has increased rap-
idly worldwide, especially in developing countries, and
affects about 15% to 30% of children and 2% to 10% of
adults.2 The intense itching and scratching accompanied
by AD may cause severe insomnia in patients, impairing
the quality of life, and creating substantial burdens to
patients and even the whole society.3 The pathogenesis of
AD is multi-factorial, which is the result of the interaction
of skin barrier function, genetic susceptibility, immune
system development, environmental trigger, pharmaceu-
tical, and other agents.4
It was found that the ratio of intestinal bifidobacteria
and clostridium in atopic children was lower than that in
healthy children in composition of gut microbiota (GM),
indicating that appropriate gut-colonising microbes may
reduce the risk of developing atopic diseases in infants
* Corresponding authors: Dr. Cai-Hong Sun, The Second Affiliated Hospital
of Nanjing University of Chinese Medicine, Jiangsu Second Chinese Medicine
Hospital, Nanjing, Jiangsu, Jiangsu 210017, China. E-mail: njsuncaihong@163.
com.
Conflicts of interest: The authors reported no conflicts of interest.
Copyright © 2022 Hospital for Skin Diseases (Institute of Dermatology), Chinese
Academy of Medical Sciences, and Chinese Medical Association, published by
Wolters Kluwer, Inc.
This is an open-access article distributed under the terms of the Creative Commons
Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is
permissible to download and share the work provided it is properly cited. The work
cannot be changed in any way or used commercially without permission from the
journal.
International Journal of Dermatology and Venereology (2022) 5:3
Received: 2 July 2020, Revised: 2 December 2020, Accepted: 18 February 2021
doi: 10.1097/JD9.0000000000000152
155
probiotics on AD seemed to be heartening in some stud-
ies, the safety and effectiveness of microbial agents are
still inconclusive. However, the research in this field is
still in process and will hopefully better supply a depth
of findings about how probiotics may contribute to the
prevention or treatment of AD.
In this review, we searched the "PubMed”, "Web of
Science", "Sci-Hub", "CNKI" in a period from 2009 to
2020 using “atopic dermatitis” and (“Gut Microbiota”
OR “Intestinal Microbiota”), “hygiene hypothesis”,
and “microbial preparation” as searching words to
summarized the latest studies in the occurrence and
development of intestinal microflora and its relation-
ship with AD.
Characteristics of intestinal microbiota
Composition and development of intestinal
microbiota
According to the metabolic characteristics of bacteria,
intestinal microorganisms can be divided into anaerobes,
facultative anaerobes, and aerobes. According to the
effect on the host, it can be divided into commensal bac-
teria, conditional pathogenic bacteria, and pathogenic
bacteria. Among them, commensal bacteria are the dom-
inant intestinal flora, accounting for more than 99% of
intestinal microorganisms, mainly composed of anaer-
obes and facultative anaerobes, such as Bifidobacterium
and Lactobacillus.6 The intrauterine environment and
fetus are generally considered sterile. However, it was
found that Lactobacillus and Bifidobacterium can be
detected in placental biopsies. Some scholars hold the
view that this phenomenon may be caused by the trans-
location of maternal intestinal bacteria through the
bloodstream.7 Therefore, it can be considered that the
establishment of GM first takes place in the intrauterine
fetal period.
 Zuo and Sun, Int J Dermatol Venereol (2022) 5:3
The colonization types of intestinal microorganisms
depend on the mode of birth and feeding, hygiene lev-
els, and medication use. A relatively stable configura-
tion of permanent colonization is reached in children
by approximately 4 years of age.8 The succession of
intestinal microbial colonization occurs primarily early
in life, especially in the first year of life, and any dis-
tortion of GM function could potentially give rise to a
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wide range of diseases.9 Some studies have shown that,
compared to adults, the proportion of anaerobes (espe-
cially Bacteroides and Clostridium) is lower in the early
intestinal flora of infants. The relatively sterile intesti-
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nal tract of the newborn is first colonized by faculta-
tive anaerobes (Enterobacteriaceae, Enterococcus, etc)
because of the abundance of oxygen. About a week later,
oxygen is consumed to establish a reduced environment
suitable for the colonization of anaerobes. With passage
of time, a large number of anaerobes will settle in the
infant gut, and the number of facultative bacteria species
gradually decreases until they are outnumbered by 10
to 1000 times in adults as they propagate. Therefore, at
the age of one, the infant GM converges towards to an
“adult” mode.8
In the past few years, several studies have illustrated
that there are some differences in the composition of GM
in children exposed to variable conditions. Many maternal
factors contribute to the establishment and colonization
of infant GM, such as prenatal conditions, time and mode
of delivery, diet, age, body mass index, smoking index,
socio-economic status, breastfeeding, and the use of anti-
biotics.7 In the early colonization of the infant intestinal
tract, the maternal gut is the most important source of
Escherichia coli, Bifidobacterium, and Bacteroides. This
point of view can be explained by the delayed coloniza-
tion (as long as 12 months) with these stains seen in the
gut of infants delivered by cesarean section. What's more,
maternal vagina and breast milk are important sources
of Streptococci and Lactobacillus. Compared to formula-fed
infants, breast-fed infants have a relatively simple GM,
which is dominated by Bifidobacterium. In addition,
other bacteria (such as Clostridium, Enterobacter, and
Klebsiella) come from food items, other infants, or non-
living environment.9
In addition to the mode of delivery, there is a strong
correlation between the number of older siblings and
the establishment of GM. It has been showed that, com-
pared to the only children, the colonization rates of
Lactobacillus and Bacteroides increase in children with
one or more siblings. This phenomenon is more striking
with the increase of the number of siblings.10
Intestinal microbiota and immune system
The intestinal microbiota mainly serves the following
functions: producing certain nutritional components,
maintaining homeostasis of the intestinal environment,
stimulating the development and maturation of the
immune system and resisting pathogens. Furthermore, it
affects allergic conditions on a number of levels, including
generating short-chain fatty acids (SCFAs), amino acids
and vitamins, participating in the differentiation of intes-
tinal epithelial cells, inducing oral tolerance, also involved
in the formation and maintenance of intestinal mucosal
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International Journal of Dermatology and Venereology
barrier, and resisting the intestinal colonization of patho-
genic microorganisms.8
Early intestinal flora plays an important role in adjusting
the immune system, and “imbalanced” composition may
increase hypersensitivity. The lymphoid tissue, located in
the gastrointestinal tract, distributes about 70% to 80% of
the immune cells, known as gut-associated lymphoid tissue.
It includes Peyer patch and mesenteric lymph node. The
intestinal antigens can be captured by dendritic cells (DC)
in Peyer patch through M cells on the surface of intestinal
cells. Gut-associated lymphoid tissue interplay with intesti-
nal bacteria which are collected by intestinal epithelial cells
and DC through the pattern recognition receptors such as
toll-like receptor and nucleotide-binding oligomerization
domain.11 Intestinal microorganisms are able to drive Treg
cells differentiation by activating distinct tolerogenic DCs
in the gut, while Treg cells consequently maintain immune
tolerance by down regulating the response level of the body
to extrinsic antigen or autoantigen.
The intestinal microbiota contributes to the decompo-
sition of indigestible complex polysaccharides and plays
an important role in the production of certain nutritional
components (such as SCFAs, vitamin K and folic acid),
having a great impact on the host immune system. Butyrate
plays a major role in the production of SCFAs. Butyrate-
producing bacteria is a functional group of variable
Grampositive anaerobes, which could produce butyrate as
the terminal metabolite from carbohydrate fermentation.
This group of bacteria strengthen gut barrier function by
up-regulating the expression of tight junction proteins
and suppressing pro-inflammatory signaling pathways. In
addition, butyrate regulates the activation and prolifera-
tion of Tregs in the colon and enhances the ability of Tregs
to inhibit the proliferation of CD4+ T cells.12 In short, GM
is involved actively in the regulation of host immune func-
tion, and is closely related to the development and matu-
ration of the immune system (Fig.1).
Intestinal microbiota and AD
After birth, the maturation of intestinal mucosal immune
system requires the continuous stimulation of microbial
flora, and the early exposure of intestinal microorganisms
transforms Th1/Th2 balance into Th1-directed immune
response. Hence absent or insufficient microbial stimula-
tion contributes to the decrease in intestinal surface area,
alteration in mucosal enzyme types, mucosal barrier and
mucosal IgA system, and loss of oral tolerance. Unbalanced
intestinal flora is conducive to the persistence of neonatal
Th2-guided immune response, leading to the occurrence
of atopic diseases, which may persist into adulthood.13
Hygiene hypothesis
According to the “hygiene hypothesis,” an excessively
clean modern public hygienic environmental pattern
reduces the stimulating effect of microbes on the immune
system, making children more likely to develop aller-
gic diseases.14 The hypothesis was extended later by the
“microbiota hypothesis of allergic diseases” to emphasize
the role of GM in shaping the development of the host
immune system in early life.15 There is a long-term inter-
action between external stimuli and GM, which is very
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Figure 1 The functions of GM and the characteristics of GM in AD patients. AD: atopic dermatitis; GM: gut microbiota.
important for maintaining the dynamic balance of intes-
tinal mucosal immune system.16 As a consequence, the
early imbalance of GM homeostasis has been considered
to be a critical factor in the development of atopic dis-
eases, and the deficiency of immune regulation is supposed
to be the basis of the increase in the incidence of chronic
immune inflammatory diseases.10 As a further revision of
this hypothesis, it is believed that the change of intestinal
colonization patterns in infancy is a significant cause for
the increase in the prevalence of allergic diseases.15
Decreased diversity of intestinal florae
The characteristics of intestinal microbiota in patients
with AD present quantitative, qualitative, and functional
modifications. Quantitative changes are represented by
the decreased number of Bifidobacterium species, while
the qualitative modifications showed the predominance
of B. adolescentis (the more common strain in adult
feces). In addition, the functional changes of intestinal
flora in children with AD included decreased adhesion of
Bifidobacterium species to intestinal mucosa, decreased
production of IL-10, and increased secretion of Th2
proinflammatory cytokines.16
Commensal intestinal bacteria promote the produc-
tion of regulatory cytokines (such as IL-10) mediated
by tolllike receptor 2 to obtain protective and regula-
tory immunity against anaphylaxis. Decreased microbial
157
exposure or dysfunction of this pathway may hinder
IL-10-mediated immunosuppression.17 With the rapid
development of microbial detection technology, more and
more studies have shown that the decline of GM diversity
increases the incidence of AD. Some scholars believe that
the decrease in the diversity of GM in childhood is related
to the increased risk for allergic diseases, because repeated
exposure to differential bacterial antigens will enhance
immune regulation by inhibiting the response to intestinal
contents and allergens. The results show that low intesti-
nal microbial diversity in the first month after birth is asso-
ciated with the increase in the incidence of AD at the age
of two years old.18 A research involving 35 children with
AD and 27 healthy controls showed that there were some
differences in the composition and relative abundance
of intestinal flora between children with AD and normal
children.19 Similarly, in 2019, Melli et al.20 confirmed
that AD children have different fecal microbiota patterns
with higher detection rate of Clostridium difficile, greater
abundance of Bifidobacteria, and lower abundance of
Lactobacillus, regardless of their socioeconomic status.
Longitudinal analysis of fecal microbial composition in
infants at 3 days, 1 month, 3 months, and 1 year old indi-
cated that in infants with eczema in the first two years of
life, higher abundance of Enterobacteriaceae [coefficient
(B): 1.081, 95% confidence interval (CI): 0.229–1.933,
P = 0.014] and Clostridium perfringens [coefficient (B):
0.521, 95% CI: 0.556–0.988, P = 0.03] were observed.
 Zuo and Sun, Int J Dermatol Venereol (2022) 5:3
While in those with eczema at 5 years old, it revealed that
the abundance of Bifidobacterium was lower [coefficient
(B): −27.635, 95% CI: −50.040 to −5.231, P = 0.018].21
Bifidobacterium is widely considered to be beneficial to
human health. In the study of allergic diseases, mice and
in vitro models have been established to highly empha-
sized the potential role of Bifidobacterium in reducing
inflammation by inducing the production of anti-inflam-
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matory cytokines, inhibiting Th2 immune response and
IgE production. Therefore, the lack of Bifidobacterium in
children with AD may lead to the suppression of anti-in-
flammatory effects.15
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In patients with AD, some SCFA-producing bacteria
such as Bifidobacterium, Brucella,and Propionibacterium
also decreased significantly.22 As mentioned, SCFAs is of
special significance to maintain the health of the host,
so the decrease in SCFAs production may contribute to
intestinal barrier dysfunction, increased intestinal perme-
ability, and inflammation in patients with AD.15
To summarize, the differences in the composition of
GM between AD patients and healthy people suggest that
general scholars should consider the absent or depleted
strains in GM as potential probiotic candidates in the
future research of AD prevention and treatment.
Treatment of AD with microbial preparation
Probiotics are coined by the Food and Agriculture
Organization of the United Nations and the World
Health Organization as “the living microorganisms that
when administered in adequate amounts, can confer a
health benefit on the host.” Nowadays, Lactobacillus and
Bifidobacterium are the most commonly available stains
of probiotics clinically.
Probiotics were initially thought to have beneficial
effects by improving the composition and homeostasis of
GM. However, plenty of evidence shows that probiotics
could also be instrumental in regulating immune func-
tion. Probiotics down-regulate the production of Th2
cytokines by stimulating IL-10 and transforming growth
factor-β. Multiple animal experiments have shown that
a variety of probiotic stains could prevent the develop-
ment of allergic diseases by inhibiting Th2, Th17, and
thymic interstitial lymphoid reaction via a mechanism
that may involve CD4+CD25+Foxp3+Tregs in mesenteric
lymph nodes. These results suggest that probiotics may
be a powerful potential treatment for atopic diseases.23
Gruber et al.24 believed that probiotics partially mimic
the nature of breast milk, and early intervention by
adding probiotics has been carried on to infants suscep-
tible to AD administer to reduce the incidence of AD.
Thus far, there are many theories to clarify the beneficial
effects of microbial preparations on atopic diseases,25
as summarized below: (1) changing the expression and
redistribution of tight junction proteins, reducing intes-
tinal permeability, thus limiting the absorption of harm-
ful molecules from the intestinal cavity and promoting
the restoration of skin barrier function; (2) promoting
secretory IgA to improve intestinal defensive capability,
and intensify competition with pathogenic bacteria for
nutrients and adhesion sites, and consuming intestinal
nutrients to inhibit the proliferation of pathogenic bac-
teria at the same time, thus reducing the survival rate
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International Journal of Dermatology and Venereology
of pathogenic bacteria; (3) regulating the function of
immune system in different ways and maintaining the
normal Th1/Th2 balance.
Meanwhile, a large number of animal and human
experiments have shown that probiotics and other micro-
bial preparations can prevent and treat AD in children,22
which can reduce the incidence of AD and effectively
improve the severity of the disease. Although the results
are not in complete accord, which may be due to the
selection of probiotic strains, combinations, doses or the
selection of different study populations, resulting in dif-
ferent immune responses, they also provide a potential
treatment for the prevention or treatment of AD.
In addition, a number of studies have shown that food
ingredients such as probiotics and vitamins are also found
in fermented foods (FF), which are defined as foods or bev-
erages produced by controlled microbial growth and the
conversion of food ingredients through enzymatic action,
such as yogurt, kefir, kimchi, sauerkraut, natto, sour dough
bread.26 In general, most FF contain potential probiotic
microorganisms, such as Lactobacillus microorganisms in
FF can reach the intestinal tract, which potentially contrib-
ute to supplementation of certain microbes, manipulation
of intestinal microbial communities, immunomodulation,
and fortification of the intestinal barrier. Yogurt is the most
representative FF. A hospital-based birth cohort study
shows that there is a negative correlation between yogurt
consumption in infants and AD at the age of five (United
Kingdom Working Party criteria: adjust odds ratio, 0.70;
95% CI, 0.51–0.97; P = 0.03).27 Moreover, maternal con-
sumption of FF during pregnancy may reduce the incidence
rate of AD in infants, which is also confirmed by existing
literature.28 Certainly, other categories of FF have also been
shown to have a considerable impact on the composition
of GM.26 These findings provide some new insights into the
treatment of AD to a greater or lesser extent.
Conclusion
The intestinal microbial system is huge and complex,
and is closely related to the development and maturation
of the immune system. AD is one of the most common
chronic inflammatory skin disease. The imbalance of
early intestinal microbial homeostasis is considered to be
the key factor in the development of atopic diseases, and
the deficiency of immune regulation is the basis of the
increase in the incidence of chronic immune inflamma-
tory diseases. At present, the method of fecal microflora
analysis has been applied to most studies on the interac-
tion between intestinal microbiota and AD. However, this
method cannot be fully used to evaluate the relationship
between intestinal microbiota and immune mechanism.
In addition, the pathogenesis of AD is not completely
clear, and it is impossible to clearly confirm the impact
of GM disorders on AD. More large-scale experiments
need to be carried out to clarify the relationship between
intestinal microbiota and AD, in order to provide a refer-
ence for the rational use of microbial agents and probi-
otic foods, as mentioned above, to improve the intestinal
microbial environment, and to provide a theoretical basis
for dermatologists and pediatrics clinical frontline work-
ers to prevent and treat AD. The main limitation of this
review is the lack of variety in literature resource. In this
 Zuo and Sun, Int J Dermatol Venereol (2022) 5:3www.ijdv-dermatol.com
paper, we mainly chose the most common databases to
search for relevant journal papers, such as “PubMed” and
“CNKI”. Therefore, our conclusion may be more com-
prehensive with the support of further research.
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