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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Cell. Infect. Microbiol.</journal-id>
<journal-title>Frontiers in Cellular and Infection Microbiology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Cell. Infect. Microbiol.</abbrev-journal-title>
<issn pub-type="epub">2235-2988</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fcimb.2023.1137275</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Cellular and Infection Microbiology</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>
<italic>Lactobacillus</italic> for the treatment and prevention of atopic dermatitis: Clinical and experimental evidence</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Xie</surname>
<given-names>Anni</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn003">
<sup>&#x2020;</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chen</surname>
<given-names>Ailing</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn003">
<sup>&#x2020;</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1207462"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chen</surname>
<given-names>Yuqing</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<xref ref-type="author-notes" rid="fn003">
<sup>&#x2020;</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Luo</surname>
<given-names>Zichen</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1883919"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jiang</surname>
<given-names>Shanyu</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Chen</surname>
<given-names>Daozhen</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/739008"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Yu</surname>
<given-names>Renqiang</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>*</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/1312456"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Department of Neonatology, Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University</institution>, <addr-line>Wuxi</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Research Institute for Reproductive Health and Genetic Diseases, Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University</institution>, <addr-line>Wuxi</addr-line>, <country>China</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Department of Child Health Care, Wuxi Maternity and Child Health Care Hospital, Wuxi School of Medicine, Jiangnan University</institution>, <addr-line>Wuxi</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>Edited by: Shengjie Li, Nanchang University, China</p>
</fn>
<fn fn-type="edited-by">
<p>Reviewed by: Chen Li, Free University of Berlin, Germany; Fen Zhang, The Chinese University of Hongkong, China</p>
</fn>
<fn fn-type="corresp" id="fn001">
<p>*Correspondence: Daozhen Chen, <email xlink:href="mailto:chendaozhen@163.com">chendaozhen@163.com</email>; Renqiang Yu, <email xlink:href="mailto:yurenqiang@njmu.edu.cn">yurenqiang@njmu.edu.cn</email>
</p>
</fn>
<fn fn-type="equal" id="fn003">
<p>&#x2020;These authors have contributed equally to this work</p>
</fn>
<fn fn-type="other" id="fn002">
<p>This article was submitted to Intestinal Microbiome, a section of the journal Frontiers in Cellular and Infection Microbiology</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>16</day>
<month>02</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="collection">
<year>2023</year>
</pub-date>
<volume>13</volume>
<elocation-id>1137275</elocation-id>
<history>
<date date-type="received">
<day>04</day>
<month>01</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>30</day>
<month>01</month>
<year>2023</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2023 Xie, Chen, Chen, Luo, Jiang, Chen and Yu</copyright-statement>
<copyright-year>2023</copyright-year>
<copyright-holder>Xie, Chen, Chen, Luo, Jiang, Chen and Yu</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>Atopic dermatitis (AD) is a chronic inflammatory skin disease, accompanied by itching and swelling. The main pathological mechanism of AD is related to the imbalance between Type 2 helper cells (Th2 cells) and Type 1 helper cells (Th1 cells). Currently, no safe and effective means to treat and prevent AD are available; moreover, some treatments have side effects. Probiotics, such as some strains of <italic>Lactobacillus</italic>, can address these concerns <italic>via</italic> various pathways: i) facilitating high patient compliance; ii) regulating Th1/Th2 balance, increasing IL-10 secretion, and reducing inflammatory cytokines; iii) accelerating the maturation of the immune system, maintaining intestinal homeostasis, and improving gut microbiota; and iv) improving the symptoms of AD. This review describes the treatment and prevention of AD using 13 species of <italic>Lactobacillus</italic>. AD is commonly observed in children. Therefore, the review includes a higher proportion of studies on AD in children and fewer in adolescents and adults. However, there are also some strains that do not improve the symptoms of AD and even worsen allergies in children. In addition, a subset of the genus <italic>Lactobacillus</italic> that can prevent and relieve AD has been identified <italic>in vitro</italic>. Therefore, future studies should include more <italic>in vivo</italic> studies and randomized controlled clinical trials. Given the advantages and disadvantages mentioned above, further research in this area is urgently required.</p>
</abstract>
<kwd-group>
<kwd>atopic dermatitis</kwd>
<kwd>
<italic>Lactobacillus</italic>
</kwd>
<kwd>type 2 helper cells</kwd>
<kwd>gut microbiota</kwd>
<kwd>immunomodulation</kwd>
</kwd-group>
<contract-sponsor id="cn001">Government of Jiangsu Province<named-content content-type="fundref-id">10.13039/501100002949</named-content>
</contract-sponsor>
<contract-sponsor id="cn002">Wuxi Municipal Bureau on Science and Technology<named-content content-type="fundref-id">10.13039/501100008109</named-content>
</contract-sponsor>
<contract-sponsor id="cn003">Wuxi Health and Family Planning Commission<named-content content-type="fundref-id">10.13039/501100016308</named-content>
</contract-sponsor>
<contract-sponsor id="cn004">Wuxi Health and Family Planning Commission<named-content content-type="fundref-id">10.13039/501100016308</named-content>
</contract-sponsor>
<counts>
<fig-count count="2"/>
<table-count count="3"/>
<equation-count count="0"/>
<ref-count count="184"/>
<page-count count="20"/>
<word-count count="10875"/>
</counts>
</article-meta>
</front>
<body>
<sec id="s1" sec-type="intro">
<label>1</label>
<title>Introduction</title>
<p>Atopic dermatitis (AD) is a chronic inflammatory skin disease, and patients frequently experience complications from concurrent allergic conditions. The annual incidence of AD has increased in the recent years, particularly in children. Based on the Finnish national database, the prevalence of AD varies by age group, with the highest prevalence in the age group 0-14 years (47.46%), followed by that in 15-60 year olds (43.74%) (<xref ref-type="bibr" rid="B135">Salava et&#xa0;al., 2022</xref>). The actual prevalence of AD between 6 months and 12 years has been reported at 11% in Israel (<xref ref-type="bibr" rid="B162">Weil et&#xa0;al., 2022</xref>). One report showed that the incidence of AD in infants aged 3 months in China was 40.81% (<xref ref-type="bibr" rid="B42">Guo et&#xa0;al., 2019</xref>). Patient quality of life can be severely affected, as AD causes scratching, itching, and a rash. The financial burden on households increases with disease severity (<xref ref-type="bibr" rid="B162">Weil et&#xa0;al., 2022</xref>). The incidence of AD is strongly correlated with heredity and environment (<xref ref-type="fig" rid="f1">
<bold>Figure&#xa0;1</bold>
</xref>). In other words, people with AD often have a family history of AD, and the incidence of AD may increase when the father or mother has a particular allergy. Although the exact mechanisms of AD have not yet been elucidated, impaired immunological function and dysregulation of the skin barrier are considered to be the primary pathogenic mechanisms (<xref ref-type="bibr" rid="B175">Yang et&#xa0;al., 2020</xref>). Concurrently, environmental factors such as poor eating habits, sudden lifestyle changes, and certain allergenic stimuli are also associated with AD. A climatic conditions closely associated with an elevated risk of AD is low vapor pressure (<xref ref-type="bibr" rid="B178">Yokomichi et&#xa0;al., 2022</xref>). In Chongqing, China, infants exposed to polluted air are at an increased risk of developing AD (<xref ref-type="bibr" rid="B90">Luo et&#xa0;al., 2022</xref>). Psychological factors also play an important role in AD development; subsequently, AD leads to fluctuating depressive symptoms (<xref ref-type="bibr" rid="B17">Chatrath et&#xa0;al., 2022</xref>). As a result, individuals with AD can be caught in a vicious cycle.</p>
<fig id="f1" position="float">
<label>Figure&#xa0;1</label>
<caption>
<p>Causes and Consequences of the AD. Several factors contribute to the development of AD, such as air pollution, low vapor pressure, heredity, psychological factors, ethnicity, dysregulation of the skin barrier, dysbiosis of gut microbes, and lack of immune function. AD contributes to the itchiness and financial burden.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-13-1137275-g001.tif"/>
</fig>
<p>Although the pathogenesis of AD is not clear, decades of research indicate that the mechanisms of AD can potentially be attributed to genetic factors, environmental exposures, impaired skin barrier, abnormal immune function, and microbial imbalances. This suggests that AD is a systemic organ-related allergic disease. One study demonstrated an increased probability of early AD in maternal offspring due to dysregulated interferon signaling cascade (<xref ref-type="bibr" rid="B139">Schedel et&#xa0;al., 2023</xref>). Patients with high-risk genes tend to develop AD earlier (<xref ref-type="bibr" rid="B48">Hikino et&#xa0;al., 2022</xref>). A notable manifestation of AD is pruritus, which causes patients to scratch vigorously (<xref ref-type="bibr" rid="B179">Yosipovitch et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B146">Steinhoff et&#xa0;al., 2022</xref>). After skin rupture, the epidermal barrier is damaged, and antigens penetrate the skin, producing chemokines and inflammatory mediators (IL-25, IL-33, and thymic stromal lymphopoietin). Th cells polarize to Th2 and produce IL-4, IL-13, and IL-5 (<xref ref-type="bibr" rid="B22">Cosmi et&#xa0;al., 2019</xref>; <xref ref-type="bibr" rid="B128">Renert-Yuval and Guttman-Yassky, 2020</xref>). Th1, Th17, Th22, and other pathways are activated; a variety of cytokines and growth factors involved in inflammatory immune responses through the Janus kinase (JAK) pathway are produced and enhance Th2 cell differentiation (<xref ref-type="bibr" rid="B8">Bao et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B129">Rerknimitr et&#xa0;al., 2017</xref>). Scratching coupled with endogenous and other exogenous triggers, such as histamine, proteases, substance P, various interleukins, and environmental allergens leads to keratinocyte activation, and intensified skin inflammation. Inflammatory mediators and multi-pathway inflammation cause intensive scratching and further damage to the skin barrier. Moreover, bacteria take advantage of the situation and the vicious circle continues. Under physiological conditions, the skin microenvironment maintains immune homeostasis and reduces skin colonization by pathogenic bacteria. Diversity of the gut microbiome is significantly lower in infants with AD (<xref ref-type="bibr" rid="B1">Abrahamsson et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B117">Penders et&#xa0;al., 2013</xref>). The presence of <italic>Staphylococcus aureus</italic> was detected on the skin of 90% of patients with AD, and this pathogen can lead to disease progression (<xref ref-type="bibr" rid="B120">Powers et&#xa0;al., 2015</xref>; <xref ref-type="bibr" rid="B9">Blicharz et&#xa0;al., 2019</xref>). <italic>Staphylococcus aureus</italic> secretes staphylococcal enterotoxins A, B, and C and toxic shock syndrome toxin 1 (TSST-1), which activate lymphocytes and macrophages (<xref ref-type="bibr" rid="B108">Nakatsuji and Gallo, 2019</xref>). In addition, staphylococcal enterotoxin B promotes the expression of IL-31. IL-31 inhibits the expression of polyfilament proteins and antimicrobial peptides, which favor <italic>Staphylococcus aureus</italic>. Importantly, IL-31 is a key factor in itching (<xref ref-type="bibr" rid="B101">Meng et&#xa0;al., 2018</xref>). Previous studies showed that mediators produced by <italic>Staphylococcus aureus</italic> promotes adhesion, colonization, and spread to the skin. These mechanisms are complex and interact. In future, scientists may also identify new mechanisms that are yet to be discovered.</p>
<p>The gut plays an important role in the immune response. At the same time, Natural killer (NK) T cells, innate lymphoid cells, and intestinal flora regulate each other to maintain intestinal homeostasis and normal immune function (<xref ref-type="bibr" rid="B14">Cairo and Webb, 2022</xref>). In addition, healthy gut flora has a protective effect against food allergies (<xref ref-type="bibr" rid="B100">M&#xe9;ndez et&#xa0;al., 2021</xref>). Disturbances of the intestinal microbiome in early infancy worsen immune dysfunction in children with AD (<xref ref-type="bibr" rid="B85">Lee et&#xa0;al., 2022</xref>). In addition, a study showed that transplanting fecal microbiota to restore gut ecology provides a new method for treating AD (<xref ref-type="bibr" rid="B67">Kim et&#xa0;al., 2021</xref>). Lower microbial diversity has been associated with a higher incidence of AD (<xref ref-type="bibr" rid="B35">Galazzo et&#xa0;al., 2020</xref>). Moreover, greater severity of clinical manifestations in patients with AD has been associated with a lower number of <italic>Bifidobacteria</italic> in the intestine (<xref ref-type="bibr" rid="B161">Watanabe et&#xa0;al., 2003</xref>). Conversely, higher amounts of pathogenic <italic>Clostridium difficile</italic> have been detected in the stool of patients with AD (<xref ref-type="bibr" rid="B118">Penders et&#xa0;al., 2007</xref>). In one region of Brazil, children with AD have a higher prevalence of <italic>Clostridium difficile</italic> and a lower abundance of <italic>Lactobacillus</italic> (<xref ref-type="bibr" rid="B99">Melli et&#xa0;al., 2020</xref>). <italic>Clostridium difficile</italic> causes a decrease in beneficial bacteria, loss of immune function, and increased intestinal permeability. Studies have shown that colonization of the gut flora precedes AD changes (<xref ref-type="bibr" rid="B35">Galazzo et&#xa0;al., 2020</xref>); therefore, a timely intervention in the gut microbiota could be a promising preventive approach. Diet has an important impact on the colonization of gut microbes in early infancy (<xref ref-type="bibr" rid="B35">Galazzo et&#xa0;al., 2020</xref>). In early infancy, microbes are primarily affected by type of delivery; however, food becomes an important factor starting at 13 weeks (<xref ref-type="bibr" rid="B35">Galazzo et&#xa0;al., 2020</xref>). Food allergies and AD are closely related, and approximately one-third of children have both AD and food allergies (<xref ref-type="bibr" rid="B53">Hui-Beckman et&#xa0;al., 2023</xref>). Food-induced AD most likely occurs in children with severe AD (<xref ref-type="bibr" rid="B130">Robison and Singh, 2019</xref>). Food allergies increase the permeability of the intestine, making it easier for allergens to trigger the submucosal immune system through the intestinal barrier (<xref ref-type="bibr" rid="B86">Lee et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B36">Gao et&#xa0;al., 2021</xref>). Cytokines and inflammatory mediators produced after the activation of the immune system further increase intestinal permeability. The interaction between the gut microbiota and skin has been called the gut-skin axis by some authors (<xref ref-type="bibr" rid="B92">Mahmud et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B155">Varela-Trinidad et&#xa0;al., 2022</xref>). Healthy gut flora is beneficial for healthy skin.</p>
<p>Various treatments have been used in AD, including topical glucocorticoids and immunosuppressive agents, phototherapy, and narrow-spectrum ultraviolet radiation B. AD is a chronic inflammatory disease that affects patients with impaired skin barrier function. The long-term administration of topical corticosteroids carries a high risk. Topical corticosteroids are the mainstream treatment for moderate to severe AD; however, they have side effects, such as hormonal dermatitis, when used in large, long-term doses in combination with potent hormonal creams. In addition, prolonged use of topical corticosteroids may cause serious side effects, such as adrenal insufficiency (<xref ref-type="bibr" rid="B10">B&#xf6;ckle et&#xa0;al., 2014</xref>). Additionally, patients hesitate to use glucocorticoids (<xref ref-type="bibr" rid="B91">Maghen et&#xa0;al., 2019</xref>). Immunosuppressant treatment for AD may cause conjunctivitis (<xref ref-type="bibr" rid="B167">Wollenberg et&#xa0;al., 2018</xref>) or lymphopenia (<xref ref-type="bibr" rid="B7">Bakker et&#xa0;al., 2018</xref>) in some patients. Narrow-spectrum ultraviolet radiation B has a relieving effect on AD (Ben <xref ref-type="bibr" rid="B104">Mordehai et&#xa0;al., 2022</xref>); however, long-term use may cause abnormal skin reactions. Moreover, some biological drugs are expensive and have side effects (<xref ref-type="bibr" rid="B125">Puar et&#xa0;al., 2021</xref>). Patients receiving dupilumab treatment were reported to suffer from eye discomfort (<xref ref-type="bibr" rid="B103">Miniotti et&#xa0;al., 2022</xref>). Owing to the above reasons, safe and effective treatments for AD remain limited. Recently, treatment with probiotics has been proposed to regulate the gut microbiome in AD. The gut microbiome plays an essential role in the maintenance of host homeostasis and immunomodulation. Imbalances in microbial flora can contribute to many diseases. Intestinal microbial dysbiosis is the leading cause of AD-like symptoms (<xref ref-type="bibr" rid="B66">Kim et&#xa0;al., 2020a</xref>). Oral administration of <italic>L. sakei</italic> proBio65 (<xref ref-type="bibr" rid="B127">Rather et&#xa0;al., 2021</xref>) and <italic>L. salivarius</italic> LS01 can improve the quality of life of children (<xref ref-type="bibr" rid="B112">Niccoli et&#xa0;al., 2014</xref>) and adults (<xref ref-type="bibr" rid="B27">Drago et&#xa0;al., 2011</xref>) with AD. In an experimental model, maternal mice and their offspring orally supplemented with <italic>L. reuteri</italic> Fn041 maintained the balance of the immune response to prevent AD (<xref ref-type="bibr" rid="B126">Qi et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B182">Zhao et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B184">Zhou et&#xa0;al., 2022</xref>).</p>
<p>
<italic>Lactobacillus</italic> is a naturally occurring rod-shaped bacterium that is a part of the normal flora in some organs of humans, animals, and plants. The storage conditions for <italic>Lactobacillus</italic> are simple. <italic>L. sakei</italic> proBio65 live and inactivated bacteria can improve AD symptoms and enhance the function of skin barrier (<xref ref-type="bibr" rid="B60">Jeong et&#xa0;al., 2020a</xref>; <xref ref-type="bibr" rid="B127">Rather et&#xa0;al., 2021</xref>). Administration <italic>L. paracasei</italic> KBL382 alleviated AD by modulating immune responses (<xref ref-type="bibr" rid="B66">Kim et&#xa0;al., 2020a</xref>). <italic>L. paracasei</italic> KBL382 reduced serum levels of immunoglobulin E (IgE) and immune cell infiltration (<xref ref-type="bibr" rid="B66">Kim et&#xa0;al., 2020a</xref>). Moreover, supplementation with <italic>L. rhamnosus</italic> HN001 substantially reduced the cumulative prevalence of AD (<xref ref-type="bibr" rid="B165">Wickens et&#xa0;al., 2008</xref>). These findings suggest that <italic>Lactobacillus</italic> may provide an alternative strategy for the treatment and prevention of AD. In this review, we focus on the role of <italic>Lactobacillus</italic> as a novel therapeutic agent for AD.</p>
</sec>
<sec id="s2">
<label>2</label>
<title>Classification of <italic>Lactobacillus</italic> and its mechanism of prevention and treatment of AD</title>
<p>Probiotics are living microorganisms such as <italic>Lactobacillus</italic> spp., <italic>Bifidobacterium</italic> spp., <italic>Enterococcus</italic> spp., <italic>Streptococcus</italic> spp., <italic>Propionibacterium</italic> spp., <italic>Bacillus cereus</italic> spp., and <italic>Saccharomyces boulardii</italic> that benefit the host. <italic>Lactobacillus</italic> spp. is the most widely used probiotic microorganism. The genus <italic>Lactobacillus</italic> includes more than 200 species (<xref ref-type="bibr" rid="B148">Sun et&#xa0;al., 2015</xref>), and can be subdivided into at least 24 phylogenetic groups (<xref ref-type="bibr" rid="B183">Zheng et&#xa0;al., 2015</xref>). Several <italic>Lactobacillus</italic> species have been studied for AD prevention and treatment (<xref ref-type="fig" rid="f2">
<bold>Figure&#xa0;2</bold>
</xref>), including <italic>L. rhamnosus</italic>, <italic>L. plantarum</italic>, <italic>L. acidophilus</italic>, <italic>L. sakei</italic>, <italic>L. reuteri</italic>, <italic>L. salivarius</italic>, <italic>L. paracasei</italic>, <italic>L. casei</italic>, <italic>L. delbrueckii</italic>, <italic>L. fermentum</italic>, <italic>L. johnsonii</italic>, <italic>L. pentosus</italic>, and <italic>L. brevis</italic>. These <italic>Lactobacillus</italic> species have been reported to produce a variety of substances, such as organic acids, hydrogen peroxide, low-molecular-weight antimicrobials, bacteriocins, and adhesion inhibitors. <italic>Lactobacillus</italic> products stimulate innate immunity and promote balanced microbial communities through the competitive rejection and antimicrobial activity against pathogenic bacteria (<xref ref-type="bibr" rid="B39">Goldstein et&#xa0;al., 2015</xref>). Administration of <italic>Lactobacillus</italic> decreased the serum levels of IgE (<xref ref-type="bibr" rid="B147">Sunada et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B156">Wakabayashi et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B151">Tanaka et&#xa0;al., 2009</xref>; <xref ref-type="bibr" rid="B122">Prakoeswa et&#xa0;al., 2017</xref>), and achieved a balance of Th1/Th2 (<xref ref-type="bibr" rid="B165">Wickens et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B82">Kwon et&#xa0;al., 2018</xref>; <xref ref-type="bibr" rid="B72">Kim et&#xa0;al., 2019a</xref>; <xref ref-type="bibr" rid="B182">Zhao et&#xa0;al., 2022</xref>). Moreover, the intestinal barrier (<xref ref-type="bibr" rid="B165">Wickens et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B66">Kim et&#xa0;al., 2020a</xref>; <xref ref-type="bibr" rid="B182">Zhao et&#xa0;al., 2022</xref>), immune function (<xref ref-type="bibr" rid="B165">Wickens et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B72">Kim et&#xa0;al., 2019a</xref>; <xref ref-type="bibr" rid="B66">Kim et&#xa0;al., 2020a</xref>) and skin barrier (<xref ref-type="bibr" rid="B96">Mariman et&#xa0;al., 2016</xref>) have been improved after the administration of <italic>Lactobacillus.</italic> The mechanisms of the 13 kinds of <italic>Lactobacillus</italic> are listed in <xref ref-type="table" rid="T1">
<bold>Table&#xa0;1</bold>
</xref>. <italic>Lactobacillus</italic> shows certain effects on both animals and humans with AD (<xref ref-type="table" rid="T2">
<bold>Tables&#xa0;2</bold>
</xref>, <xref ref-type="table" rid="T3">
<bold>3</bold>
</xref>). <italic>Lactobacillus</italic> has high economic value in biotechnology, food production, and therapeutic applications.</p>
<fig id="f2" position="float">
<label>Figure&#xa0;2</label>
<caption>
<p>
<italic>Lactobacillus</italic> for the treatment and prevention of AD. AD is common in children. <italic>Lactobacillus</italic> accelerates the maturation of the immune system, maintains intestinal homeostasis, improves the gut microbiome, and ultimately improves the symptoms of AD.</p>
</caption>
<graphic mimetype="image" mime-subtype="tiff" xlink:href="fcimb-13-1137275-g002.tif"/>
</fig>
<table-wrap id="T1" position="float">
<label>Table&#xa0;1</label>
<caption>
<p>Mechanism of action of <italic>Lactobacillus</italic> in the treatment of AD.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="left">Probiotic</th>
<th valign="top" align="center">strain</th>
<th valign="top" align="center">Mechanism of action</th>
<th valign="top" align="center">Reference</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" rowspan="4" align="center">
<bold>
<italic>L. rhamnosus</italic>
</bold>
</td>
<td valign="top" align="center">RHT3201</td>
<td valign="top" align="center">decrease of eosinophil cationic protein, eosinophil count, IL-31, and serum IgE concentration</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B88">Lee et&#xa0;al., 2016</xref>; <xref ref-type="bibr" rid="B60">Jeong et&#xa0;al., 2020a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">HN001</td>
<td valign="top" align="center">enhanced gut barrier function, influence on the immune system and a more balanced Th1/Th2 immune profile</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B165">Wickens et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">LGG</td>
<td valign="top" align="center">decreased IL-10<break/>protection against pathogenic macromolecules in the gut and accelerated immunological maturation, regulation of the immune response, stimulation of peripheral blood cells to secrete IL-10 and transforming growth factor &#x3b2;</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B62">Kalliom&#xe4;ki et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B138">Sawada et&#xa0;al., 2007</xref>; <xref ref-type="bibr" rid="B12">Boyle et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B97">Marsella, 2009</xref>; <xref ref-type="bibr" rid="B110">Nermes et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B98">Marsella et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B15">Carucci et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">CGMCC 1.3724 (LPR)</td>
<td valign="top" align="center">reduction of plasma total IgE, upregulation of IFN-&#x3b3; production at the skin level</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B151">Tanaka et&#xa0;al., 2009</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="3" align="center">
<bold>
<italic>L. acidophilus</italic>
</bold>
</td>
<td valign="top" align="center">L-92</td>
<td valign="top" align="center">activation of regulatory T cells and Th1 cells, decrease of eosinophil count and increase of change ratio for serum TGF-&#x3b2;, prevention of IgE-mediated hypersensitivity, modulation of Th1/Th2 balance</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B143">Shah et&#xa0;al., 2010</xref>; <xref ref-type="bibr" rid="B154">Torii et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B56">Inoue et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B174">Yamamoto et&#xa0;al., 2016</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">L-55</td>
<td valign="top" align="center">decrease of serum total IgE level</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B147">Sunada et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">LAVRI-A1</td>
<td valign="top" align="center">increase of allergen sensitization in infants</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B153">Taylor et&#xa0;al., 2007</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="5" align="center">
<bold>
<italic>L. plantarum</italic>
</bold>
</td>
<td valign="top" align="center">MG4221</td>
<td valign="top" align="center">inhibition of inflammatory and allergic reactions and regulation of the NF-&#x3ba;B/MAPK pathways in keratinocytes</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B51">Hong et&#xa0;al., 2021a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">LM1004</td>
<td valign="top" align="center">decrease of mRNA levels of Th2 and Th17 cell transcription factors, increase of transcription factors of Th1 and Treg cells, galactin-9, filaggrin, enhanced immunomodulation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B72">Kim et&#xa0;al., 2019a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">CJLP133</td>
<td valign="top" align="center">upregulation of total IgE levels, increased TGF-&#x3b2; expression, increased proportion of regulatory T cells at baseline</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B71">Kim et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">IS-10506</td>
<td valign="top" align="center">decreased levels of serum IgE, IL-4, and IL-17, increased the levels of Foxp3+ to IL-10 ratio, downregulate Th2 adaptive immune response</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B122">Prakoeswa et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">NCIMB8826</td>
<td valign="top" align="center">amelioration of skin pathology, improvement of skin barrier integrity, skin thickening, and diminished excoriations</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B96">Mariman et&#xa0;al., 2016</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="3" align="center">
<bold>
<italic>L. sakei</italic>
</bold>
</td>
<td valign="top" align="center">ProBio65</td>
<td valign="top" align="center">increased expression of Foxp3+ transcription factor, Modulation of the expression levels of inflammatory cytokines IL-10 and IL-12, inhibition of mast cell activation, improvement of allergen-induced skin inflammation, downregulation of IgE and IL-4 production</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B116">Park et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B74">Kim et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B127">Rather et&#xa0;al., 2021</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">KCTC 10755BP</td>
<td valign="top" align="center">decreased chemokine levels</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B169">Woo et&#xa0;al., 2010</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">WIKIM30</td>
<td valign="top" align="center">modulation of allergic Th2 responses, enhanced Treg generation and increased relative abundance of intestinal bacteria that are positively related to Treg generation</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B82">Kwon et&#xa0;al., 2018</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="3" align="center">
<bold>
<italic>L. reuteri</italic>
</bold>
</td>
<td valign="top" align="center">Fn041</td>
<td valign="top" align="center">regulation of systemic Th1 and Th2 cytokine ratios and promotion of CD4+CD25+Foxp3+ regulatory T cell proliferation in mesenteric lymph nodes, regulation of intestinal microbiota</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B182">Zhao et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">JCM 1112</td>
<td valign="top" align="center">dependent on the presence of Toll-like receptor 2 and the induction of TNF-&#x3b1;-induced protein 3 and cylindromatosis in HaCaT cells</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B64">Kawahara et&#xa0;al., 2018</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">ATCC55730</td>
<td valign="top" align="center">modulation of the <italic>in vivo</italic> the cytokine pattern at an extra-intestinal site</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B102">Miniello et&#xa0;al., 2010</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="center">
<bold>
<italic>L. salivarius</italic>
</bold>
</td>
<td valign="top" align="center">LS01</td>
<td valign="top" align="center">Initiation of intestinal immunity, rebalancing of the changed intestinal microbiota, modulation of Thl/Th2 cytokine profiles</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B27">Drago et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B28">Drago et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B112">Niccoli et&#xa0;al., 2014</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">PM-A0006</td>
<td valign="top" align="center">immune-modulating effects</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B170">Wu et&#xa0;al., 2012</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="3" align="center">
<bold>
<italic>L. paracasei</italic>
</bold>
</td>
<td valign="top" align="center">CBAL74</td>
<td valign="top" align="center">steroid sparing effect</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B24">D'Auria et&#xa0;al., 2021</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">KBL382</td>
<td valign="top" align="center">increased immunosuppressive response and modified metabolic functions of gut microbiota</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B66">Kim et&#xa0;al., 2020a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">WK3001</td>
<td valign="top" align="center">diminished mast cell infiltration and plasma IgE levels, suppression of immediate hypersensitivity reactions and IL-4 mRNA expression in the auricles</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B156">Wakabayashi et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="3" align="center">
<bold>
<italic>L. casei</italic>
</bold>
</td>
<td valign="top" align="center">KCTC 12398BP</td>
<td valign="top" align="center">isolation of P14 protein decreased the levels of IL-4 in RAW264.7 and Balb/c splenocytes <italic>in vitro</italic> and ex vivo</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B68">Kim et&#xa0;al., 2015b</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">DN-114001</td>
<td valign="top" align="center">effect on gut microbiota</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B77">Klewicka et&#xa0;al., 2011</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">JCM 1134<sup>T</sup>
</td>
<td valign="top" align="center">modulation of the serum levels of IgE and cytokines and eosinophil count</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B113">Ogawa et&#xa0;al., 2006</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="3" align="center">
<bold>
<italic>L.&#xa0;delbrueckii</italic>
</bold>
</td>
<td valign="top" align="center">subsp. Bulgaricus LB-2</td>
<td valign="top" align="center">influence on both Th1 and Th2 through induction of Treg cells and secretion of IL-10</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B144">Sheikhi et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">OLL1073R-1</td>
<td valign="top" align="center">attenuation of IL-6 secretion from lymph node cells and reduced IL-6 levels in inflamed tissues, such as auricles</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B63">Kano et&#xa0;al., 2013</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">R-037</td>
<td valign="top" align="center">induce IL-12 and Th1</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B160">Watanabe et&#xa0;al., 2009</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. fermentum</italic>
</bold>
</td>
<td valign="top" align="center">VRI 003 PCC&#x2122;</td>
<td valign="top" align="center">increased TNF-&#x3b1; responses to both heat-killed <italic>Staphylococcus aureus</italic> and heat-killed <italic>Lactobacillus</italic>
</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B123">Prescott et&#xa0;al., 2005</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. johnsonii</italic>
</bold>
</td>
<td valign="top" align="center">NCC533</td>
<td valign="top" align="center">reduction of the gene expression of proinflammatory cytokines (IL-8, IL-12 and IL-23) and CD86</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B57">Inoue et&#xa0;al., 2007</xref>)</td>
</tr>
<tr>
<td valign="top" rowspan="2" align="center">
<bold>
<italic>L. brevis</italic>
</bold>
</td>
<td valign="top" align="center">NS1401</td>
<td valign="top" align="center">restoration of the Th1/Th2 balance through enhancing Th1-mediated immunity</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B21">Choi et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">SBC8803</td>
<td valign="top" align="center">increased IgE production, increased production of immunosuppressive cytokines such as IL-10 and TGF-b1</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B141">Segawa et&#xa0;al., 2008a</xref>)</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T2" position="float">
<label>Table&#xa0;2</label>
<caption>
<p>Effects of <italic>Lactobacillus</italic> on the clinical manifestations of AD.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="left">Probiotic</th>
<th valign="top" align="center">strain</th>
<th valign="top" align="center">Participants</th>
<th valign="top" align="center">Interventions</th>
<th valign="top" align="center">Outcome</th>
<th valign="top" align="center">Reference</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. rhamnosus</italic>
</bold>
</td>
<td valign="top" align="center">RHT3201</td>
<td valign="top" align="center">100 children (aged 1&#x2013;12 years) with moderate AD</td>
<td valign="top" align="center">1.0 &#xd7; 10<sup>10</sup> CFU (no details were provided)</td>
<td valign="top" align="center">decreased SCORAD total score and levels of eosinophil cationic protein</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B60">Jeong et&#xa0;al., 2020a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">HN001</td>
<td valign="top" align="center">mothers from 14&#x2013;16 weeks gestation</td>
<td valign="top" align="center">6&#xd7;10<sup>9</sup> CFU/d, from 14-16 weeks gestation until 6 months post-partum if breastfeeding</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B163">Wickens et&#xa0;al., 2018</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">High risk infants</td>
<td valign="top" align="center">6&#xd7;10<sup>9</sup> CFU/d, 9&#xd7;10<sup>9</sup> CFU/d, indirectly from 35 weeks gestation until 6 months after birth if breastfeeding, and directly from birth until 2 years</td>
<td valign="top" align="center">decreased cumulative prevalence of eczema, SCORAD score, and skin prick tests sensitization</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B166">Wickens et&#xa0;al., 2013</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">425 children</td>
<td valign="top" align="center">6 &#xd7;10<sup>9</sup> CFU, 9 &#xd7;10<sup>9</sup> CFU/d, from 35 weeks gestation until birth, continued to 6 months after birth in mothers if breastfeeding, and from birth until 2 years in all infants</td>
<td valign="top" align="center">reduced cumulative prevalence of eczema at 4 years</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B164">Wickens et&#xa0;al., 2012</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">Pregnant women, 474 infants at risk of allergic disease</td>
<td valign="top" align="center">6&#xd7;10<sup>9</sup> CFU/d, pregnant women from 35 weeks gestation until 6 months if breastfeeding, infants receive the same treatment from birth to 2 years</td>
<td valign="top" align="center">reduced risk of eczema</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B165">Wickens et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">LGG</td>
<td valign="top" align="center">250 pregnant women carrying infants at high risk of allergic disease</td>
<td valign="top" align="center">1.8&#xd7;10<sup>10</sup> CFU/d, from 36 weeks gestation until delivery</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B11">Boyle et&#xa0;al., 2011</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">100 AD patients (aged 6&#x2013; 36 months)</td>
<td valign="top" align="center">1&#xd7;10<sup>10</sup> CFU/d, for 12 weeks</td>
<td valign="top" align="center">reduced SCORAD scores</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B15">Carucci et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">159 mothers, 132 children at high risk</td>
<td valign="top" align="center">1&#xd7;10<sup>10</sup> CFU/d, for 4 weeks</td>
<td valign="top" align="center">improved AD</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B62">Kalliom&#xe4;ki et&#xa0;al., 2003</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">39 infants with AD</td>
<td valign="top" align="center">3.4&#xd7;10<sup>9</sup> CFU/d</td>
<td valign="top" align="center">increased proportions of CD19<sup>+</sup> CD27<sup>+</sup> B cells and fewer infection</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B110">Nermes et&#xa0;al., 2011</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">131 children (6&#x2013;24 months old)</td>
<td valign="top" align="center">10<sup>10</sup> CFU, 6 months</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B134">Rose et&#xa0;al., 2010</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">35 infants (aged less than 1 year) with atopic eczema</td>
<td valign="top" align="center">4 weeks</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B136">Salmi et&#xa0;al., 2010</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">11 adults and 73 infants</td>
<td valign="top" align="center">1.8&#xd7;10<sup>10</sup> CFU/d, for 7 days. 1.8&#xd7;10<sup>10</sup> CFU/d, from 36 weeks gestation until delivery</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B12">Boyle et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">105 pregnant women</td>
<td valign="top" align="center">5&#xd7;10<sup>9</sup> CFU, twice daily</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B79">Kopp et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">infants (aged 3&#x2013;12 months) with mild-to-moderate AD</td>
<td valign="top" align="center">5&#xd7;10<sup>9</sup> CFU, for 12 weeks</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B41">Gr&#xfc;ber et&#xa0;al., 2007</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">54 infants (aged 1&#x2013;55 months) with moderate to severe AD</td>
<td valign="top" align="center">10&#xd7;10<sup>9</sup> CFU/d, for 8 weeks</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B33">F&#xf6;lster-Holst et&#xa0;al., 2006</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L.&#xa0;acidophilus</italic>
</bold>
</td>
<td valign="top" align="center">L-92</td>
<td valign="top" align="center">57patients with AD(&#x2265; 16 years)</td>
<td valign="top" align="center">20.7 mg/d, for 24 weeks</td>
<td valign="top" align="center">decreased investigator global assessment, eczema area and severity index, and AD score</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B174">Yamamoto et&#xa0;al., 2016</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">49 AD patients (aged &#x2265; 16 years)</td>
<td valign="top" align="center">20.7 mg/d, for 8 weeks</td>
<td valign="top" align="center">decreased SCORAD scores and eosinophil count</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B56">Inoue et&#xa0;al., 2014</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">20 children (age 4&#x2013;15 years)</td>
<td valign="top" align="center">3&#xd7;10<sup>10</sup> CFU/d, for 8 consecutive weeks</td>
<td valign="top" align="center">ameliorated symptoms of AD in Japanese children and effect on serum concentrations of thymus</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B154">Torii et&#xa0;al., 2011</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">LAVRI-A1</td>
<td valign="top" align="center">153 children</td>
<td valign="top" align="center">3&#xd7;10<sup>9</sup>/d, from birth to 6 months.</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B124">Prescott et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">231 pregnant atopic women and babies</td>
<td valign="top" align="center">3&#xd7;10<sup>9</sup>/d, for the first 6 months of life</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B153">Taylor et&#xa0;al., 2007</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">178 children</td>
<td valign="top" align="center">3 &#xd7; 10<sup>9</sup> CFU/d, for 6 months</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B59">Jensen et&#xa0;al., 2012</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. plantarum</italic>
</bold>
</td>
<td valign="top" align="center">CJLP133</td>
<td valign="top" align="center">76 children (median age of 7.1 years) with moderate-to-severe AD</td>
<td valign="top" align="center">1&#xd7;10<sup>10</sup> CFU/d, for 12 weeks</td>
<td valign="top" align="center">increased proportion of Treg cells with concurrent decrease in TGF-&#x3b2; mRNA expression</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B71">Kim et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">children (aged 12 months to 13 years)</td>
<td valign="top" align="center">0.5&#xd7;10<sup>10</sup> CFU, twice a day for 12 weeks</td>
<td valign="top" align="center">lower SCORAD score at week 14 in the probiotic group than that in the placebo group; higher SCORAD score in the probiotic group from weeks 2 to 14 than that in the placebo group; <italic>L. plantarum</italic> CJLP133 significantly decreased total eosinophil count, logarithmic IFN-&#x3b3; and IL-4</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B46">Han et&#xa0;al., 2012</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">IS-10506</td>
<td valign="top" align="center">22 children with mild and moderate AD</td>
<td valign="top" align="center">10<sup>10</sup> CFU, twice daily for 12 weeks</td>
<td valign="top" align="center">decreased SCORAD and levels of IL-4, IFN-&#x3b3;, and IL-17; upregulation of Foxp3+ to IL-10 ratio</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B122">Prakoeswa et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. sakei</italic>
</bold>
</td>
<td valign="top" align="center">ProBio65</td>
<td valign="top" align="center">Children (aged 3&#x2013;9 years) and adolescents (aged 10 to 18) with AD</td>
<td valign="top" align="center">1 &#xd7; 10<sup>10</sup> cells/d per sachet (400 mg)</td>
<td valign="top" align="center">decreased SCORAD total score when compared with baseline and potential improvement of skin barrier functions</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B127">Rather et&#xa0;al., 2021</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">KCTC 10755BP</td>
<td valign="top" align="center">88 children (aged 2&#x2013;10 years) with AEDS</td>
<td valign="top" align="center">5&#xd7;10<sup>9</sup> CFU, twice daily for 12 weeks</td>
<td valign="top" align="center">decreased total SCORAD scores</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B169">Woo et&#xa0;al., 2010</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. reuteri</italic>
</bold>
</td>
<td valign="top" align="center">ATCC55730</td>
<td valign="top" align="center">patients (aged 4&#x2013;10 years)</td>
<td valign="top" align="center">10<sup>8</sup> CFU/d, for 8 weeks were prescribed as 1 tablet once per day (2 hours before meals)</td>
<td valign="top" align="center">no significant differences</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B102">Miniello et&#xa0;al., 2010</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">mothers and their babies</td>
<td valign="top" align="center">1&#xd7;10<sup>8</sup> CFU/d, from gestational week 36 until delivery</td>
<td valign="top" align="center">diminished IgE-associated eczema and skin prick test reactivity</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B2">Abrahamsson et&#xa0;al., 2007</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. salivarius</italic>
</bold>
</td>
<td valign="top" align="center">LS01</td>
<td valign="top" align="center">patients (aged 25&#x2013;63 years)</td>
<td valign="top" align="center">5&#xd7;10<sup>9</sup> CFU/d, for a month</td>
<td valign="top" align="center">decreased SCORAD index and the count of Staphylococcus Aureus.</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B26">Drago et&#xa0;al., 2014</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">43 patients (aged 0&#x2013;11 years) with AD</td>
<td valign="top" align="center">1&#xd7;10<sup>9</sup> CFU/sachet, 2 sachets/d, for 8 weeks, and 1 sachet/day for the following 8 weeks</td>
<td valign="top" align="center">improved SCORAD score and itching</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B112">Niccoli et&#xa0;al., 2014</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">38 patients (aged 18&#x2013;46 years) with moderate/severe AD</td>
<td valign="top" align="center">1&#xd7;10<sup>9</sup> CFU/g, twice daily, for 16 weeks</td>
<td valign="top" align="center">decreased SCORAD score</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B28">Drago et&#xa0;al., 2012</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">38 patients (aged from 18 to 46 years) with moderate/severe AD</td>
<td valign="top" align="center">1&#xd7;10<sup>9</sup> CFU/g, twice daily, for 16 weeks</td>
<td valign="top" align="center">improved SCORAD score and dermatology life quality index</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B27">Drago et&#xa0;al., 2011</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">PM-A0006</td>
<td valign="top" align="center">60 children (aged 2&#x2013;14 years) with moderate to severe AD</td>
<td valign="top" align="center">2&#xd7;10<sup>9</sup> CFU, twice daily, for 8 weeks</td>
<td valign="top" align="center">decreased SCORAD scores range 8 weeks and 10 weeks. <italic>L. salivarius</italic> PM-A0006 significantly reduced medication use frequency and eosinophil cationic protein levels at 8 weeks. <italic>Lactobacillus salivarius</italic> PM-A0006 reduced AD intensity</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B170">Wu et&#xa0;al., 2012</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. paracasei</italic>
</bold>
</td>
<td valign="top" align="center">CBAL74</td>
<td valign="top" align="center">58 infants and young children with moderate to severe AD (aged 6&#x2013;36 months)</td>
<td valign="top" align="center">8 g/d for 12 weeks</td>
<td valign="top" align="center">decreased SCORAD index</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B24">D'Auria et&#xa0;al., 2021</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">GM-080</td>
<td valign="top" align="center">infants with AD (aged 4&#x2013;30 months)</td>
<td valign="top" align="center">1&#xd7; 1,010 equivalent CFU, for 16 weeks</td>
<td valign="top" align="center">decreased CCL17 levels and TEWL in lesions and unaffected skin</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B176">Yan et&#xa0;al., 2019</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">K71</td>
<td valign="top" align="center">34 adults with AD</td>
<td valign="top" align="center">100 mg/d (~2 &#xd7; 10<sup>11</sup> bacteria), over 12 weeks</td>
<td valign="top" align="center">decreased skin severity scores compared with baseline</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B105">Moroi et&#xa0;al., 2011</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. casei</italic>
</bold>
</td>
<td valign="top" align="center">DN-114001</td>
<td valign="top" align="center">40 children (aged 6&#x2013;18 months) with AD</td>
<td valign="top" align="center">10<sup>9</sup> cells/d, for 3 months</td>
<td valign="top" align="center">decreased SCORE index</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B77">Klewicka et&#xa0;al., 2011</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. delbrueckii</italic>
</bold>
</td>
<td valign="top" align="center">subsp. Bulgaricus LB-2</td>
<td valign="top" align="center">20 children (age 1&#x2013;12 years) with AD</td>
<td valign="top" align="center">co-cultured with different concentrations of UV killed bacteria in RPMI-1640 plus 10% FCS for 48/72 h</td>
<td valign="top" align="center">upregulated the secretion of IL-10, IL-12, and IFN-&#x3b3;, and decreased secretion of IL-4.</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B144">Sheikhi et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. fermentum</italic>
</bold>
</td>
<td valign="top" align="center">VRI 003 PCC&#x2122;</td>
<td valign="top" align="center">53 children with moderate or severe AD</td>
<td valign="top" align="center">1&#xd7;10<sup>9</sup> twice daily for 8 weeks</td>
<td valign="top" align="center">increased Th1-type cytokine IFN-&#x3b3; responses to PHA and SEB</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B123">Prescott et&#xa0;al., 2005</xref>)</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="T3" position="float">
<label>Table&#xa0;3</label>
<caption>
<p>Effects of <italic>Lactobacillus</italic> on the experimental AD.</p>
</caption>
<table frame="hsides">
<thead>
<tr>
<th valign="top" align="left">Probiotic</th>
<th valign="top" align="center">strain</th>
<th valign="top" align="center">Experimental animal</th>
<th valign="top" align="center">Interventions</th>
<th valign="top" align="center">Outcome</th>
<th valign="top" align="center">Reference</th>
</tr>
</thead>
<tbody>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. rhamnosus</italic>
</bold>
</td>
<td valign="top" align="center">RHT3201</td>
<td valign="top" align="center">six-week-old female NC/Nga mice</td>
<td valign="top" align="center">1&#xd7;10<sup>8</sup>, 1&#xd7;10<sup>9</sup>, or 1&#xd7;10<sup>10</sup> cells/d, for 8 weeks.</td>
<td valign="top" align="center">improved dermatitis scores and frequency of scratching</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B88">Lee et&#xa0;al., 2016</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">LGG</td>
<td valign="top" align="center">two litters of Beagles (same sire and dam) with AD</td>
<td valign="top" align="center">200 &#xd7; 10<sup>9</sup> CFU/d, ten Culturelle<sup>&#xae;</sup> capsule;<break/>offspring from the second pregnancy, LGG, 100 &#xd7; 10<sup>9</sup> CFU/d</td>
<td valign="top" align="center">decreased allergen-specific IgE and partially prevented AD</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B98">Marsella et&#xa0;al., 2012</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">2 adult beagles with severe AD and 16 pups</td>
<td valign="top" align="center">One capsule containing a minimum of LGG 20&#xd7;10<sup>9</sup> CFUs;<break/>first litter female dogs did not receive LGG.<break/>During the second pregnancy, a dosage of 10 capsules/d LGG from week 3 of gestation and continued throughout lactation.<break/>During the third pregnancy, 5 capsules/d from 3 weeks to 6 months of age</td>
<td valign="top" align="center">decreased serum titer of allergen-specific IgE and moderated reaction to intradermal testing</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B97">Marsella, 2009</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">specific pathogen-free NC/Nga mice</td>
<td valign="top" align="center">30&#x2013;50 mg/d</td>
<td valign="top" align="center">increased plasma IL-10 levels and enhanced IL-10 mRNA expression in both Peyer&#x2019;s patches and mesenteric lymph nodes</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B138">Sawada et&#xa0;al., 2007</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">CGMCC 1.3724 (LPR)</td>
<td valign="top" align="center">specific-pathogen free pregnant NC <italic>/</italic> NgaTnd mice, pups until 12 weeks of age</td>
<td valign="top" align="center">5 &#xd7;10<sup>8</sup> CFU<italic>/</italic> ml</td>
<td valign="top" align="center">decreased clinical symptoms of dermatitis, reduced scratching frequency</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B151">Tanaka et&#xa0;al., 2009</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L.&#xa0;acidophilus</italic>
</bold>
</td>
<td valign="top" align="center">L-92</td>
<td valign="top" align="center">ICR mice<break/>BALB/c mice<break/>BALB/c and NC/Nga mice</td>
<td valign="top" align="center">3 and 30 mg/kg</td>
<td valign="top" align="center">inhibited vascular permeability in both passive cutaneous anaphylaxis</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B143">Shah et&#xa0;al., 2010</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">L-55</td>
<td valign="top" align="center">female NC/Nga mice (5 weeks old) with AD-like skin lesions</td>
<td valign="top" align="center">1 and 10 mg/d, for 75 days</td>
<td valign="top" align="center">inhibited dermatitis score, ear swelling, scratching behavior</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B147">Sunada et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. plantarum</italic>
</bold>
</td>
<td valign="top" align="center">MG4221</td>
<td valign="top" align="center">NC/Nga mice (male, 4 weeks old)</td>
<td valign="top" align="center">a single dose (7 &#x3bc;g&#xb7;cm<sup>&#x2212;2</sup>) of 200 &#x3bc;L of PM2.5 (500 &#x3bc;g&#xb7;mL<sup>&#x2212;1</sup>) with 2% dinitrochlorobenzene<break/>another single dose (7 &#x3bc;g&#xb7;cm<sup>&#x2212;2</sup>) of 200 &#x3bc;L of PM2.5 (500 &#x3bc;g&#xb7;mL<sup>&#x2212;1</sup>) with 0.2% dinitrochlorobenzene</td>
<td valign="top" align="center">decreased transepidermal water loss and erythema; decreased scratching behavior</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B51">Hong et&#xa0;al., 2021a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">LM1004</td>
<td valign="top" align="center">AD-induced rat (histamine-induced vasodilation) and mouse (pruritus and contact dermatitis)</td>
<td valign="top" align="center">2 &#xd7; 10<sup>12</sup> cells, for 28 days</td>
<td valign="top" align="center">reduced vasodilation, pruritus, edema, and serum histamine</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B72">Kim et&#xa0;al., 2019a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">NCIMB8826</td>
<td valign="top" align="center">APOC1+/+ mice</td>
<td valign="top" align="center">3&#xd7;10<sup>8</sup> CFU, three times a week, for 8 weeks</td>
<td valign="top" align="center">ameliorated skin pathology, improved skin barrier integrity, eliminated of skin thickening, and fewer excoriations</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B96">Mariman et&#xa0;al., 2016</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. sakei</italic>
</bold>
</td>
<td valign="top" align="center">ProBio65</td>
<td valign="top" align="center">dogs with CAD</td>
<td valign="top" align="center">2 &#xd7; 10<sup>9</sup> CFU/g, for 2 months</td>
<td valign="top" align="center">reduced disease severity index, CASESI score values</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B75">Kim et&#xa0;al., 2015a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">25 male 6-week-old NC/Nga mice</td>
<td valign="top" align="center">5&#xd7;10<sup>9</sup> CFU/ml, 200 &#x3bc;L/d, for 2 weeks</td>
<td valign="top" align="center">improved condition of skin and reduced scratching frequency</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B74">Kim et&#xa0;al., 2013</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">mice triggered by allergen</td>
<td valign="top" align="center">1 &#xd7;10<sup>8</sup> CFU/mL, 200 &#x3bc;L/d, for 2 weeks</td>
<td valign="top" align="center">faster recovery of AD</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B116">Park et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">WIKIM30</td>
<td valign="top" align="center">wild-type male BALB/c mice</td>
<td valign="top" align="center">2 &#xd7; 10<sup>9</sup> CFU bacteria, 200 &#x3bc;L/d</td>
<td valign="top" align="center">reduced AD-like skin lesions</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B82">Kwon et&#xa0;al., 2018</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. reuteri</italic>
</bold>
</td>
<td valign="top" align="center">Fn041</td>
<td valign="top" align="center">seven-week-old male and female BALB/C mice</td>
<td valign="top" align="center">1&#xd7;10<sup>9</sup> CFU/d, once a day, 100 &#x3bc;L each time, each time</td>
<td valign="top" align="center">suppressed AD symptoms such as skin swelling, mast cell and eosinophil infiltration</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B182">Zhao et&#xa0;al., 2022</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">Japan Collection of Microorganisms 1112</td>
<td valign="top" align="center">specific pathogen-free male NC/Nga mice (aged 10 weeks)</td>
<td valign="top" align="center">0.1% (w/v) <italic>Lactobacillus</italic> water extract (LW)-treated, and 1.0% (w/v) LW-treated;<break/>0.1% LW in 80% ethanol, or 1.0% LW in 80% ethanol, twice weekly for one week</td>
<td valign="top" align="center">suppressed the development of house dust mite-induced atopic skin lesions and thymus and activation-regulated chemokine expression</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B64">Kawahara et&#xa0;al., 2018</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. paracasei</italic>
</bold>
</td>
<td valign="top" align="center">KBL382</td>
<td valign="top" align="center">mice with Dermatophagoides farinae extract -induced AD</td>
<td valign="top" align="center">1 &#xd7; 10<sup>9</sup> CFU/d, for 4 weeks</td>
<td valign="top" align="center">reduced AD-associated skin lesions and epidermal thickening</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B66">Kim et&#xa0;al., 2020a</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">K71</td>
<td valign="top" align="center">41 dogs with mild to moderate cAD</td>
<td valign="top" align="center">5 mg/kg, once daily, for 12 weeks</td>
<td valign="top" align="center">decreased CADESI, and pruritus scores; the reduced medication scores</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B114">Ohshima-Terada et&#xa0;al., 2015</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">WK3001</td>
<td valign="top" align="center">five-week-old male NC/Nga mice</td>
<td valign="top" align="center">basic diet at concentrations of 0.03% (low dose) or 0.3% (high dose)</td>
<td valign="top" align="center">reduced development of AD-like skin lesions</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B156">Wakabayashi et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. casei</italic>
</bold>
</td>
<td valign="top" align="center">KCTC 12398BP</td>
<td valign="top" align="center">male NC/Nga mice</td>
<td valign="top" align="center">1, 10, and 100 &#x3bc;g/mL of P14<break/>0.1, 0.2, 1, 5, and 10 &#x3bc;g/mL of P14</td>
<td valign="top" align="center">downregulated AD index and scratching score in AD-like NC/Nga mice</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B68">Kim et&#xa0;al., 2015b</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">JCM 1134<sup>T</sup>
</td>
<td valign="top" align="center">six-week-old male NC/Nga mice</td>
<td valign="top" align="center">NC/Nga mice were divided into four groups of six each and administered CD, DD (500 mg of dextran per day)<break/>LD (1&#xd7;10<sup>7</sup> CFU of lyophilized <italic>L.</italic> casei subsp. casei per day)<break/>LDD (1&#xd7;10<sup>7</sup> CFU of lyophilized <italic>L.</italic> casei subsp. casei and 500 mg of dextran per day)<break/>(control diet; CD)<break/>(dextran diet; DD)<break/>(<italic>L.</italic> casei subsp. casei diet; LD)<break/>(<italic>L. casei</italic> subsp. casei and dextran diet; LDD)</td>
<td valign="top" align="center">decreased clinical skin severity scores and total IgE levels</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B113">Ogawa et&#xa0;al., 2006</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. delbrueckii</italic>
</bold>
</td>
<td valign="top" align="center">OLL1073R-1</td>
<td valign="top" align="center">specific-pathogen-free female NC/Nga mice and BALB/c mice, (4- or 5-wk-old).</td>
<td valign="top" align="center">bacterial, 1 mg/d</td>
<td valign="top" align="center">inhibited development of dermatitis and elevation of an acute inflammation marker, serum amyloid A</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B63">Kano et&#xa0;al., 2013</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">R-037</td>
<td valign="top" align="center">female BALB/c mice (5-weeks-old) and male NC/Nga mice (7-weeks-old)</td>
<td valign="top" align="center">5 g/d/mouse, from day 0 to day 55</td>
<td valign="top" align="center">reduced inflammatory auricular thickness and alleviated the AD clinical score</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B160">Watanabe et&#xa0;al., 2009</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. johnsonii</italic>
</bold>
</td>
<td valign="top" align="center">NCC533</td>
<td valign="top" align="center">NC/NgaTnd mice</td>
<td valign="top" align="center">4 weeks</td>
<td valign="top" align="center">suppressed exacerbation of the clinical severity of dermatitis and suppressed epidermal hyperplasia and infiltration of inflammatory cells in skin</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B150">Tanaka et&#xa0;al., 2008</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center"/>
<td valign="top" align="center">pups of 4 pregnant NC/Nga mice.</td>
<td valign="top" align="center">10<sup>10</sup> cells, from 20 to 22 days of age <italic>via</italic> oral administration</td>
<td valign="top" align="center">enhanced gene expression of the proinflammatory cytokines [interleukin-8 (IL-8), IL-12 and IL-23] and decreased gene expression of CD86</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B57">Inoue et&#xa0;al., 2007</xref>)</td>
</tr>
<tr>
<td valign="top" align="center">
<bold>
<italic>L. brevis</italic>
</bold>
</td>
<td valign="top" align="center">NS1401</td>
<td valign="top" align="center">female NC/Nga mice (24 Six-weeks old)</td>
<td valign="top" align="center">5 &#xd7; 10<sup>8</sup> CFU/d per mouse, for 8 weeks</td>
<td valign="top" align="center">reduced skin thickness and infiltration of mast cells and eosinophils in skin lesions and the size and number of immune cells in draining lymph nodes</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B21">Choi et&#xa0;al., 2017</xref>)</td>
</tr>
<tr>
<td valign="top" align="center"/>
<td valign="top" align="center">SBC8803</td>
<td valign="top" align="center">male 5-week-old NC/Nga mice</td>
<td valign="top" align="center">0%, 0.05% or 0.5%, once a week for 9 weeks.</td>
<td valign="top" align="center">inhibited ear swelling, and suppressed the development of dermatitis.</td>
<td valign="top" align="center">(<xref ref-type="bibr" rid="B141">Segawa et&#xa0;al., 2008a</xref>)</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="s3">
<label>3</label>
<title>Monostrain <italic>Lactobacillus</italic> in the treatment and prevention of AD</title>
<sec id="s3_1">
<label>3.1</label>
<title>
<italic>Lactobacillus rhamnosus</italic> -effective prevention and treatment of AD in both animal and clinical experiments</title>
<p>
<italic>L. rhamnosus</italic> is the most studied species of Lactobacillus (<xref ref-type="bibr" rid="B119">Petrova et&#xa0;al., 2021</xref>). The peptidoglycan of <italic>L. rhamnosus</italic> CRL1505 can regulate the immune function of human intestinal epithelial and dendritic cells (<xref ref-type="bibr" rid="B137">Salva et&#xa0;al., 2021</xref>). Early exposure to LGG in dogs with AD had long-term immune effects and significantly reduced allergen-specific IgE despite the lack of a clear clinical effect (<xref ref-type="bibr" rid="B97">Marsella, 2009</xref>; <xref ref-type="bibr" rid="B98">Marsella et&#xa0;al., 2012</xref>). In clinical trials, infants aged 0&#x2013;2 years had a reduced incidence of atopic eczema when their mothers have been administered LGG during pregnancy (<xref ref-type="bibr" rid="B62">Kalliom&#xe4;ki et&#xa0;al., 2003</xref>). The preventive effect of LGG extended to 4 years (<xref ref-type="bibr" rid="B62">Kalliom&#xe4;ki et&#xa0;al., 2003</xref>). LGG may enhance the gut barrier function and promote immune response development in infants with AD (<xref ref-type="bibr" rid="B110">Nermes et&#xa0;al., 2011</xref>). In 2016, researchers observed that <italic>L. rhamnosus</italic> IDCC 3201 tyndallizate (RHT3201) had the potential to treat AD. The mast cell count and serum IgE concentration in axillary lymph node cells were decreased in RHT3201-fed NC/Nga mice compared with those in the control group (<xref ref-type="bibr" rid="B88">Lee et&#xa0;al., 2016</xref>). Another animal experiment concluded that heat-treated LGG could improve the symptoms of NC/Nga mice with AD (<xref ref-type="bibr" rid="B138">Sawada et&#xa0;al., 2007</xref>). In 2020, Jeong and colleagues (<xref ref-type="bibr" rid="B60">Jeong et&#xa0;al., 2020a</xref>) found that RHT3201 had a therapeutic effect on AD in children. <italic>L. rhamnosus</italic> GG (LGG) is a strain of <italic>L. rhamnosus</italic> that regulates gut flora and reduces conditional pathogenic bacteria (<xref ref-type="bibr" rid="B19">Chen et&#xa0;al., 2020b</xref>). When children with AD were supplemented with LGG, the clinical severity and quality of life improved (<xref ref-type="bibr" rid="B15">Carucci et&#xa0;al., 2022</xref>). Simultaneously, the use of topical steroids was reduced (<xref ref-type="bibr" rid="B15">Carucci et&#xa0;al., 2022</xref>).</p>
<p>
<italic>L. rhamnosus</italic> decreases the concentrations of eosinophilic cationic protein, eosinophil count, IL-31 (<xref ref-type="bibr" rid="B60">Jeong et&#xa0;al., 2020a</xref>), and serum IgE (<xref ref-type="bibr" rid="B151">Tanaka et&#xa0;al., 2009</xref>; <xref ref-type="bibr" rid="B88">Lee et&#xa0;al., 2016</xref>); supports a better Th1/Th2 balance (<xref ref-type="bibr" rid="B165">Wickens et&#xa0;al., 2008</xref>); prevents pathogenesis caused by large molecules in the intestine; accelerates immune maturation (<xref ref-type="bibr" rid="B110">Nermes et&#xa0;al., 2011</xref>); stimulates peripheral blood cells to secrete IL-10 (<xref ref-type="bibr" rid="B62">Kalliom&#xe4;ki et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B138">Sawada et&#xa0;al., 2007</xref>); converts growth factor &#x3b2; (<xref ref-type="bibr" rid="B62">Kalliom&#xe4;ki et&#xa0;al., 2003</xref>), and upregulates the production of IFN-&#x3b3; at the skin level (<xref ref-type="bibr" rid="B151">Tanaka et&#xa0;al., 2009</xref>). However, not all <italic>L. rhamnosus</italic> strains are equally effective. <xref ref-type="bibr" rid="B164">Wickens et&#xa0;al. (2012)</xref> studied the efficacy of <italic>L. rhamnosus</italic> HN001 and HN019 in atopic diseases and demonstrated that <italic>L. rhamnosus</italic> HN001 was more effective in improving AD than <italic>L. rhamnosus</italic> HN019 (<xref ref-type="bibr" rid="B164">Wickens et&#xa0;al., 2012</xref>). Moreover, the protective effect on eczema can persist two years when <italic>L. rhamnosus</italic> HN001 is administered to children with AD (<xref ref-type="bibr" rid="B165">Wickens et&#xa0;al., 2008</xref>). In addition, <italic>L. rhamnosus</italic> HN001 can prevent atopic sensitization in the long term (<xref ref-type="bibr" rid="B166">Wickens et&#xa0;al., 2013</xref>). Moreover, several studies have shown that the protective effect of LGG against AD requires further investigation. Two randomized controlled trials have shown that prenatal LGG treatment was not associated with a reduced risk of eczema (<xref ref-type="bibr" rid="B12">Boyle et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B11">Boyle et&#xa0;al., 2011</xref>). No clear causal relationship between the positive effects of LGG and infantile eczema has been reported (<xref ref-type="bibr" rid="B33">F&#xf6;lster-Holst et&#xa0;al., 2006</xref>; <xref ref-type="bibr" rid="B41">Gr&#xfc;ber et&#xa0;al., 2007</xref>; <xref ref-type="bibr" rid="B79">Kopp et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B134">Rose et&#xa0;al., 2010</xref>).</p>
<p>Some probiotics affect multiple immune pathways through different mechanisms and protect against the pathogenesis of eczema (<xref ref-type="bibr" rid="B165">Wickens et&#xa0;al., 2008</xref>). However, supplementation mothers with <italic>L. rhamnosus</italic> HN019, was not effective in preventing eczema in infants, indicating that <italic>L. rhamnosus</italic> HN019 is less likely to be passed on to infants through breast milk (indirect supplementation route) (<xref ref-type="bibr" rid="B163">Wickens et&#xa0;al., 2018</xref>). One of the reasons that prenatal LGG was not shown to prevent eczema in infants may be that the impact of prenatal probiotic therapy on fetal B cell development was not excluded (<xref ref-type="bibr" rid="B12">Boyle et&#xa0;al., 2008</xref>). Prenatal LGG intake may not directly contribute to the effects of postpartum breast milk regulation. It is possible that postpartum intake by nursing mothers can alter immunity and/or microbiota to benefit breast milk composition (<xref ref-type="bibr" rid="B11">Boyle et&#xa0;al., 2011</xref>). Probiotics are commonly added to dairy products (<xref ref-type="bibr" rid="B41">Gr&#xfc;ber et&#xa0;al., 2007</xref>), which can also affect the efficacy of <italic>L. rhamnosus</italic> in AD. It is important to note that the number of participants who completed the study and the subgroups analyzed were insufficient. In addition, the complexity of human life makes it challenging to achieve homogeneity. In addition, eczema in early infancy can naturally improve, and more than 40% of patients with AD recover around the age of 3 years (<xref ref-type="bibr" rid="B55">Illi et&#xa0;al., 2004</xref>). Moreover, it is more difficult for clinical trials to recruit sufficient human participants than for animal studies to include a sufficient number of animals.</p>
<p>
<italic>L. rhamnosus</italic> has been shown to be effective in the prevention and treatment of AD in both animal and clinical experiments. However, future research needs to continue to explore different strains of <italic>L. rhamnosus</italic> and use strains with excellent laboratory efficacy in clinical trials. Effective strains of <italic>L. rhamnosus</italic> can be passed on to the offspring from the mother, and subsequently, infants may potentially not develop AD.</p>
</sec>
<sec id="s3_2">
<label>3.2</label>
<title>Some strains of <italic>Lactobacillus acidophilus</italic> alleviate symptoms of AD and show good safety</title>
<p>
<italic>L. acidophilus</italic> is a commercially significant probiotic isolated from the human gastrointestinal tract (<xref ref-type="bibr" rid="B13">Bull et&#xa0;al., 2013</xref>). Moreover, it is an important class of bioprotective agents (<xref ref-type="bibr" rid="B5">Anjum et&#xa0;al., 2014</xref>). Supplementation with <italic>L. acidophilus</italic> L-92 significantly reduced vascular permeability in diseased mice and attenuated the clinical symptoms of AD (<xref ref-type="bibr" rid="B143">Shah et&#xa0;al., 2010</xref>). The administration of <italic>L. acidophilus</italic> L-92 not only significantly attenuated AD symptoms in children (<xref ref-type="bibr" rid="B154">Torii et&#xa0;al., 2011</xref>), but also improved the symptoms in adults (<xref ref-type="bibr" rid="B56">Inoue et&#xa0;al., 2014</xref>). <italic>L. acidophilus</italic> triggers an anti-inflammatory response (<xref ref-type="bibr" rid="B38">Goh et&#xa0;al., 2021</xref>). <italic>L. acidophilus</italic> L-92 inhibited the inflammatory response dominated by Th2 cells by activating regulatory T (Treg) and Th1 cells (<xref ref-type="bibr" rid="B174">Yamamoto et&#xa0;al., 2016</xref>). <italic>L. acidophilus</italic> L-55 decreased the occurrence of anaphylactic dermatitis-like skin lesions in NC/Nga mice by decreasing serum total IgE levels (<xref ref-type="bibr" rid="B147">Sunada et&#xa0;al., 2008</xref>). However, the findings on several strains of <italic>L. acidophilus</italic> have been inconsistent. For example, there is no evidence that <italic>L. acidophilus</italic> NCFM can improve AD (<xref ref-type="bibr" rid="B83">Larsen et&#xa0;al., 2011</xref>). Supplementation with <italic>L. acidophilus</italic> LAVRI-A1 in children with allergies did not reduce the risk of dermatitis (<xref ref-type="bibr" rid="B153">Taylor et&#xa0;al., 2007</xref>; <xref ref-type="bibr" rid="B124">Prescott et&#xa0;al., 2008</xref>; <xref ref-type="bibr" rid="B59">Jensen et&#xa0;al., 2012</xref>), and the sensitization rate in the <italic>L. acidophilus</italic> LAVRI-A1 group was significantly higher than that in the control group (<xref ref-type="bibr" rid="B153">Taylor et&#xa0;al., 2007</xref>).</p>
<p>In early studies, <italic>L. acidophilus</italic> demonstrated good safety and efficacy in children with AD, and future studies in mothers are ongoing or are expected to begin soon. In addition, the time required to evaluate clinical outcomes is insufficient. The detailed interplay between the early microbial environment and the developing immune system remains largely unknown and requires further exploration. Overall, the findings suggest that not every strain of <italic>L. acidophilus</italic> has the potential to prevent or treat AD. The effect of <italic>L. acidophilus</italic> on the prevention of AD requires further study.</p>
</sec>
<sec id="s3_3">
<label>3.3</label>
<title>
<italic>Lactobacillus plantarum</italic> regulates the host immune system to improve AD symptoms</title>
<p>
<italic>L. plantarum</italic> is a rod-shaped lactic acid-producing bacterium that is used in probiotics and silage production. <italic>L. plantarum</italic> has the potential to be a highly effective immunomodulatory probiotic in the human gut microbiome. In recent years, an increasing number of studies have shown the health benefits of <italic>L. plantarum</italic>. (<xref ref-type="bibr" rid="B140">Seddik et&#xa0;al., 2017</xref>). The extract of fermented blueberry black rice containing <italic>L. plantarum</italic> MG4221 had an effect similar to that of dexamethasone, but with fewer side effects; oral administration of FBBBR in NC/Nga mice reduced skin dryness, erythema, and scratch behavior (<xref ref-type="bibr" rid="B51">Hong et&#xa0;al., 2021a</xref>). <italic>L. plantarum</italic> NCIMB8826 can soothe the skin of mice with AD, strengthen the skin barrier, and alleviate scratching (<xref ref-type="bibr" rid="B96">Mariman et&#xa0;al., 2016</xref>). Supplementation with <italic>L. plantarum</italic> CJLP133 and IS-10506 has been shown to be beneficial for treating AD in children (<xref ref-type="bibr" rid="B46">Han et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B71">Kim et&#xa0;al., 2017</xref>; <xref ref-type="bibr" rid="B122">Prakoeswa et&#xa0;al., 2017</xref>). In addition, <italic>L. plantarum</italic> IS-10506 has an immunomodulatory effect and can effectively relieve AD symptoms in adults (<xref ref-type="bibr" rid="B121">Prakoeswa et&#xa0;al., 2022</xref>).</p>
<p>
<italic>L. plantarum</italic> BF_15 can successfully colonize murine intestines by rebalancing intestinal microbiota (<xref ref-type="bibr" rid="B181">Zhang et&#xa0;al., 2020</xref>). The extract of fermented blueberry black rice containing <italic>L. plantarum</italic> MG4221 inhibited the production of serum IgE and Th2 cell-related cytokines, suggesting that fermented blueberry black rice may be an essential functional food in AD (<xref ref-type="bibr" rid="B51">Hong et&#xa0;al., 2021a</xref>). Additionally, oral administration of <italic>L. plantarum</italic> NCIMB8826 reduced the number of mast cells in the colon. Finally, <italic>Staphylococcus aureus</italic> infection is the main reason for the exacerbation of AD-like symptoms, but <italic>L. plantarum</italic> can alleviate AD-like symptoms by inhibiting <italic>Staphylococcus aureus</italic> (<xref ref-type="bibr" rid="B73">Kim et&#xa0;al., 2020b</xref>). Additionally, lipoteichoic acids isolated from <italic>L. plantarum</italic> and <italic>Staphylococcus aureus</italic> have shown anti-AD effects. Lipoteichoic acid combination therapy can alleviate AD by reducing the formation of membrane attack complexes and inhibiting Th1 reactions (<xref ref-type="bibr" rid="B70">Kim et&#xa0;al., 2019c</xref>). Notably, <italic>L. plantarum</italic> LM1004 not only regulates the host immune system and gut microbiota, but is also promising for the treatment of AD and obesity in humans (<xref ref-type="bibr" rid="B72">Kim et&#xa0;al., 2019a</xref>). Collectively, the preliminary evidence suggests <italic>L. plantarum</italic> is a potential therapeutic strategy. Moreover, it has an acceptable safety profile in adults. <italic>L. plantarum</italic> improves the symptoms of AD, although it is ineffective in preventing AD. Future research should focus on the preventive effects of <italic>L. plantarum</italic> on AD. <italic>L. plantarum</italic> is a promising <italic>Lactobacillus</italic> strain that can be further explored to improve treatment options and efficacy.</p>
</sec>
<sec id="s3_4">
<label>3.4</label>
<title>
<italic>Lactobacillus sakei</italic> has potential as a supplement for the treatment of AD due to its anti-inflammatory and skin barrier protective properties</title>
<p>
<italic>L. sakei</italic> was isolated from fermented meat, fish, and kimchi. <italic>L. sakei</italic> KDP is a potent antioxidant and antibacterial agent (<xref ref-type="bibr" rid="B37">Ghoneum and Abdulmalek, 2021</xref>). <italic>L. sakei</italic> 07, combined with <italic>Bifidobacterium bifidum</italic> B10, regulates immunity and the gut microbiota (<xref ref-type="bibr" rid="B159">Wang et&#xa0;al., 2019</xref>). Oral administration of live and inactivate (<xref ref-type="bibr" rid="B74">Kim et&#xa0;al., 2013</xref>; <xref ref-type="bibr" rid="B127">Rather et&#xa0;al., 2021</xref>) <italic>L. sakei</italic> probio65 can increase skin sebum content and improve the function of the skin barrier (<xref ref-type="bibr" rid="B127">Rather et&#xa0;al., 2021</xref>). <italic>L. sakei</italic> probio65 inhibits AD-like skin lesions and may serve as an influential novel anti-inflammatory medication that resolves AD symptoms in mice (<xref ref-type="bibr" rid="B74">Kim et&#xa0;al., 2013</xref>). In experimental dogs (<xref ref-type="bibr" rid="B75">Kim et&#xa0;al., 2015a</xref>) and mice (<xref ref-type="bibr" rid="B116">Park et&#xa0;al., 2008</xref>) with AD, orally administered <italic>L. sakei</italic> probio65 significantly reduced the disease severity index without clear side effects. Supplemental treatment with <italic>L. sakei</italic> KCTC 10755BP has the potential to alleviate the clinical severity of AD syndrome in children (<xref ref-type="bibr" rid="B169">Woo et&#xa0;al., 2010</xref>).</p>
<p>
<italic>L. sakei</italic> WIKIM30 was isolated from kimchi and can significantly reduce AD-like skin lesions, regulate allergic Th2 responses, increase the relative abundance of intestinal bacteria positively correlated with Treg production, and has potential in AD treatment (<xref ref-type="bibr" rid="B82">Kwon et&#xa0;al., 2018</xref>). Current research shows that <italic>L. sakei</italic> can be anti-inflammatory and can protect the skin barrier. <italic>L. sakei</italic> has the potential to be used as a therapeutic supplement in AD. <italic>L. sakei</italic> originates from fermented foods, and direct intake of fermented foods may have the same effect. As mentioned above, both live and inactivated <italic>L. sakei</italic> have been shown to be effective. Fermented foods such as kimchi are popular and readily available, and patients can effortlessly benefit and achieve improvement of AD. Future research can further apply <italic>L. sakei</italic> in clinical practice and investigate its preventive effect on AD. In addition, the therapeutic effects of other strains of <italic>L. sakei</italic> can also be explored.</p>
</sec>
<sec id="s3_5">
<label>3.5</label>
<title>
<italic>Lactobacillus reuteri</italic> supplementation is effective in preventing AD</title>
<p>
<italic>L. reuteri</italic> has been reported to occur naturally in the intestines of all vertebrates and mammals. <italic>L. reuteri</italic> induces neonatal IgA production (<xref ref-type="bibr" rid="B106">Mu et&#xa0;al., 2021</xref>). <italic>L. reuteri</italic> survives in the gastrointestinal tract of mammals and benefits host health (<xref ref-type="bibr" rid="B29">Engevik et&#xa0;al., 2021</xref>). <italic>L. reuteri</italic> NK33 can be used to improve gut dysbiosis (<xref ref-type="bibr" rid="B47">Han et&#xa0;al., 2020</xref>). <italic>L. reuteri</italic> strain, the Japan Collection of Microbiology 1112, significantly inhibited the expression of allergic lesions and thymus and activation-regulated chemokines at the site of lesions in NC/Nga mice (<xref ref-type="bibr" rid="B64">Kawahara et&#xa0;al., 2018</xref>). Prenatal and postnatal supplementation with <italic>L. reuteri</italic> Fn041 effectively prevented the fetus from developing AD, remodeled the intestinal ecology, and improved the immune function of Peyer&#x2019;s patches (<xref ref-type="bibr" rid="B126">Qi et&#xa0;al., 2022</xref>; <xref ref-type="bibr" rid="B184">Zhou et&#xa0;al., 2022</xref>). <italic>L. reuteri</italic> Fn041 regulated the intestinal flora and significantly inhibited AD symptoms by regulating the systemic ratio of Th1 and Th2 cytokines in mice (<xref ref-type="bibr" rid="B182">Zhao et&#xa0;al., 2022</xref>). <italic>L. reuteri</italic> DYNDL22M62 attenuated AD symptoms by modulating gut bacteria in mice (<xref ref-type="bibr" rid="B31">Fang et&#xa0;al., 2022</xref>). Mothers and their babies supplied with <italic>L. reuteri</italic> ATCC 55730 had a lower prevalence of IgE-associated eczema at 2 years of age (<xref ref-type="bibr" rid="B2">Abrahamsson et&#xa0;al., 2007</xref>). However, in another clinical trial, <italic>L. reuteri</italic> ATCC 55730 did not improve clinical symptoms (<xref ref-type="bibr" rid="B102">Miniello et&#xa0;al., 2010</xref>). This may be because the small sample size. Alternatively, the duration of the experiment may have been too short. <italic>L. reuteri</italic> has been extracted from the gastrointestinal tract of all mammals, and future studies could explore the reasons for an absence of this <italic>L.</italic> and whether higher abundance of <italic>L. reuteri</italic> is beneficial. <italic>L. reuteri</italic> appears to have preventive and therapeutic effects in animals. Further clinical research on <italic>L. reuteri</italic> is required to explore the treatment and prevention of AD.</p>
</sec>
<sec id="s3_6">
<label>3.6</label>
<title>
<italic>Lactobacillus salivarius</italic> actively improves the quality of life in children and adult patients with AD</title>
<p>
<italic>L. salivarius</italic> is a Lactobacillus species that occurs in the human gastrointestinal tract and oral mucosa. It produces bacteriocins, and is used as a probiotic. It modifies the gastrointestinal system to alleviate intestinal diseases and promote host health (<xref ref-type="bibr" rid="B111">Neville and O'Toole, 2010</xref>). <italic>L. salivarius</italic> is valuable for both animals and humans. <italic>L. salivarius</italic> can reduce pathogen colonization of the gastrointestinal tract of animals (<xref ref-type="bibr" rid="B52">Hong et&#xa0;al., 2021b</xref>). Administration of <italic>L. salivarius</italic> can prevent and treat a variety of chronic diseases in humans (<xref ref-type="bibr" rid="B18">Chaves et&#xa0;al., 2017</xref>), including AD, asthma, cancer, and bad breath (<xref ref-type="bibr" rid="B26">Drago et&#xa0;al., 2014</xref>). The combined administration of <italic>L. salivarius</italic> PM-A0006 and fructooligosaccharides exhibited a notable anti-AD effect compared with either therapy alone in the treatment of children with moderate-to-severe AD (<xref ref-type="bibr" rid="B170">Wu et&#xa0;al., 2012</xref>). <italic>L. salivarius</italic> LS01 can help manage AD in children and improve their quality of life; moreover, partial effect remains after termination of medication (<xref ref-type="bibr" rid="B112">Niccoli et&#xa0;al., 2014</xref>). <italic>L. salivarius</italic> LS01 actively improves the quality of life in adult patients with AD by regulating the balance of Th1/Th2 (<xref ref-type="bibr" rid="B27">Drago et&#xa0;al., 2011</xref>; <xref ref-type="bibr" rid="B28">Drago et&#xa0;al., 2012</xref>; <xref ref-type="bibr" rid="B65">Kim et&#xa0;al., 2014</xref>). Additionally, <italic>L. salivarius</italic> has shown efficacy in improving AD in existing studies. As the name suggests, <italic>L. salivarius</italic> is present in the oral cavity. The study of the oral environment is of great significance for increasing <italic>L. salivarius</italic>. The preventive effect of <italic>L. salivarius</italic> on AD requires further study. However, the long-term safety and persistence of <italic>L. salivarius</italic> remains to be studied. More potent subspecies of <italic>L. salivarius</italic> are yet to be discovered.</p>
</sec>
<sec id="s3_7">
<label>3.7</label>
<title>
<italic>Lactobacillus paracasei</italic> has anti-inflammatory properties that can reduce the development of AD-like skin lesions</title>
<p>
<italic>L. paracasei</italic> originates from the healthy human gastrointestinal tract and is widely distributed in food. <italic>L. paracasei</italic> has anti-inflammatory properties that can reduce antigenic pro-inflammatory responses. <italic>L. paracasei</italic> improves immune function by enhancing NK cell function and IFN-&#x3b3; concentrations (<xref ref-type="bibr" rid="B84">Lee et&#xa0;al., 2017</xref>). In addition to a preventive effect on AD-like skin changes in mice <italic>L. paracasei</italic> KW3110 demonstrated inhibitory effects even when supplementation was started after symptoms have appeared (<xref ref-type="bibr" rid="B156">Wakabayashi et&#xa0;al., 2008</xref>). Supplementation with <italic>L. paracasei</italic> KW3110 can significantly reduce the development of AD-like skin lesions in mice, while regulating immunity (<xref ref-type="bibr" rid="B156">Wakabayashi et&#xa0;al., 2008</xref>). Oral supplementation with <italic>L. paracasei</italic> K71 can be used to treat dogs with AD (<xref ref-type="bibr" rid="B114">Ohshima-Terada et&#xa0;al., 2015</xref>). A diet with added K71 can be used as a complementary therapy for adult AD patients (<xref ref-type="bibr" rid="B105">Moroi et&#xa0;al., 2011</xref>). Moreover, <italic>L. paracasei</italic> NL41 reduced inflammation by improving the intestinal environment and maintaining intestinal integrity in rats (<xref ref-type="bibr" rid="B180">Zeng et&#xa0;al., 2021</xref>). Daily oral administration of <italic>L. plantarum</italic> HEAL9 and <italic>L. paracasei</italic> 8700 has been shown to regulate the peripheral immune response in children with celiac disease autoimmunity (<xref ref-type="bibr" rid="B44">H&#xe5;kansson et&#xa0;al., 2019</xref>). <italic>L. paracasei</italic> KBL382 can significantly reduce AD-related lesions and epidermal thickening in mice by modulating the immune response and changing intestinal microbiota composition(<xref ref-type="bibr" rid="B66">Kim et&#xa0;al., 2020a</xref>).</p>
<p>Additionally, heat-killed <italic>L. paracasei</italic> CBA L74 has a minimal effect on steroid use, but its effect on reducing the severity of AD needs to be further studied (<xref ref-type="bibr" rid="B24">D'Auria et&#xa0;al., 2021</xref>). However, there is no evidence that <italic>L. paracasei</italic> GM-080 has a retention effect equivalent to that of glucocorticoids (<xref ref-type="bibr" rid="B176">Yan et&#xa0;al., 2019</xref>). This may be due to the inappropriate selection of <italic>L. paracasei</italic> strains, timing of administration, timing of exposure, and failure to achieve appropriate dosing levels. In conclusion, <italic>L. paracasei</italic> enhances NK cell function and IFN-&#x3b3; concentrations to regulate immune mechanisms and achieve anti-inflammatory effects. Concurrently, <italic>L. paracasei</italic> can improve the intestinal environment and maintain intestinal homeostasis to achieve anti-inflammatory effects. The duration of <italic>L. paracasei</italic> administration does not require special emphasis, and intervention in patients with AD before and after the appearance of symptoms can achieve the desired effect. Hence, these studies might help clarify whether <italic>L. paracasei</italic> can improve intestinal barrier function and maintain immune system balance. Oral administration of <italic>L. paracasei</italic> can prevent and treat AD. However, more clinical experiments are needed to explore prevention of AD with the administration of <italic>L. paracasei</italic>.</p>
</sec>
<sec id="s3_8">
<label>3.8</label>
<title>
<italic>Lactobacillus casei</italic> treats AD by balancing the gut microbiota and immune responses</title>
<p>
<italic>L. casei</italic> is found in many fermented foods and coexists with gut microbiota. It is involved in housekeeping functions, metabolism, cell wall biogenesis, and environmental adaptation (<xref ref-type="bibr" rid="B89">Licandro-Seraut et&#xa0;al., 2014</xref>). <italic>L. casei</italic> CCFM1074 can balance gut microbiota and immune responses (<xref ref-type="bibr" rid="B32">Fan et&#xa0;al., 2021</xref>). <italic>L. casei</italic> regulates the host immune response (<xref ref-type="bibr" rid="B4">Aktas et&#xa0;al., 2016</xref>) and can be used to treat AD. During the Japanese cedar pollen season, NC/Nga mice orally administered <italic>L. casei</italic> Japan Collection of Microorganisms (JCM) 1134T combined with dextran experienced a possible effect on the prevention and treatment of allergic reactions (<xref ref-type="bibr" rid="B113">Ogawa et&#xa0;al., 2006</xref>). Furthermore, researchers screened an active ingredient, protein P14, from the <italic>L. casei</italic> extract, which specifically lowered IgE and IL-4 levels in AD-like NC/Nga mice, suggesting potential therapeutic effects in AD (<xref ref-type="bibr" rid="B68">Kim et&#xa0;al., 2015b</xref>). Similarly, the administration of <italic>L. casei</italic> DN&#x2013;114001 to the diet of children with AD was beneficial to the increase in the count of intestinal flora and its maintenance for five months after the cessation of probiotics (<xref ref-type="bibr" rid="B77">Klewicka et&#xa0;al., 2011</xref>). <italic>L. casei</italic> DN&#x2014;114001 can improve clinical symptoms in children with AD long term (<xref ref-type="bibr" rid="B77">Klewicka et&#xa0;al., 2011</xref>). Overall, these studies provide a good foundation for developing future therapeutic or preventive approaches using <italic>L. casei</italic> in individuals with AD. <italic>L. casei</italic> has an extended effect after stopping supplementation; therefore, the effect of permanent colonization of the intestine after regular supplementation should be studied. Few studies have been conducted on <italic>L. casei</italic> for the treatment of AD. More subspecies of <italic>L. casei</italic> are yet to be identified.</p>
</sec>
<sec id="s3_9">
<label>3.9</label>
<title>
<italic>Lactobacillus delbrueckii</italic> alleviates AD by maintaining and improving intestinal barrier function by stimulating immune cells to reduce inflammatory responses</title>
<p>
<italic>L. delbrueckii</italic> is one of the most economically valuable fermented Lactobacillus species. <italic>L. delbrueckii</italic> maintains and improves the intestinal barrier function by stimulating immune cells (<xref ref-type="bibr" rid="B78">Kobayashi et&#xa0;al., 2019</xref>). <italic>L. delbrueckii</italic> also improved intestinal integrity and immune responses in piglets (<xref ref-type="bibr" rid="B20">Chen et&#xa0;al., 2020a</xref>). <italic>L. delbrueckii</italic> subsp. bulgaricus may be involved in regulation of immune factor secretion in patients with AD (<xref ref-type="bibr" rid="B144">Sheikhi et&#xa0;al., 2017</xref>). IL-6 is a leading cause of dermatitis; whereas oral administration with <italic>L. delbrueckii</italic> subspecies bulgaricus OLL1073R-1 attenuated dermatitis by inhibiting the IL-6 response and restoring the elevation of serum amyloid levels in the NC/Nga mouse model of AD (<xref ref-type="bibr" rid="B63">Kano et&#xa0;al., 2013</xref>). In addition, oral supplementation with heat-treated <italic>L. delbrueckii</italic> R-037 can inhibit the rise of serum total IgE in allergic model mice, decrease inflammation, and alleviate AD; however, its effect on serum total IgE levels needs to be further studied (<xref ref-type="bibr" rid="B160">Watanabe et&#xa0;al., 2009</xref>). Studies in animal (mouse) models and have shown that <italic>L. delbrueckii</italic> plays a role in the management of AD. Experimental samples are easier to obtain in animal experiments than in clinical studies. However, only results of clinical studies that show the efficacy of <italic>L. delbrueckii</italic> will enable its widespread use in the management of patients with AD. In future, it will be necessary to further investigate the use of <italic>L. delbrueckii</italic> in patients with AD, including factors such as the time of supplementation, dosage, and strain activity. Moreover, the understanding of the preventive function of <italic>L. delbrueckii</italic> requires further experiments in both animals and humans.</p>
</sec>
<sec id="s3_10">
<label>3.10</label>
<title>
<italic>Lactobacillus fermentum</italic> regulates the immune response and benefits children with AD</title>
<p>
<italic>L. fermentum</italic> is a gram-positive bacterium. It can improve the functionality and nutritional value of foods (<xref ref-type="bibr" rid="B107">Naghmouchi et&#xa0;al., 2020</xref>). <italic>L. fermentum</italic> can restore homeostasis of the intestinal microflora and regulate the immune response in mice (<xref ref-type="bibr" rid="B131">Rodr&#xed;guez-Nogales et&#xa0;al., 2017</xref>). Mice were immunized with <italic>L. fermentum</italic> NWS29 and exposed to ovalbumin. <italic>L. fermentum</italic> NWS29 inhibited the expression of certain inflammatory factors to achieve an anti-inflammatory effect (<xref ref-type="bibr" rid="B109">Nawaz et&#xa0;al., 2015</xref>). Mice were inoculated with the Salmonella vaccine and <italic>L. fermentum</italic> PC2. When mice were challenged with live <italic>Salmonella typhimurium</italic>, <italic>L. fermentum</italic> enhanced mucosal and immune responses and played a protective role (<xref ref-type="bibr" rid="B30">Esvaran and Conway, 2012</xref>). <italic>L. fermentum</italic> KBL374 and KBL375 can modulate the innate immune response by improving intestinal barrier function and reducing leukocyte infiltration in mice (<xref ref-type="bibr" rid="B58">Jang et&#xa0;al., 2019</xref>). <italic>L. fermentum</italic> CJL-112 protected mice from the deadly influenza virus infection by stimulating macrophages, activating Th1 cells, and increasing immunoglobulin A production (<xref ref-type="bibr" rid="B177">Yeo et&#xa0;al., 2014</xref>). In a clinical trial, <italic>L. fermentum</italic> PCCTM strengthened Th1 IFN-&#x3b3; responses and achieved clinical benefits in children with AD(<xref ref-type="bibr" rid="B123">Prescott et&#xa0;al., 2005</xref>).</p>
<p>
<italic>L. fermentum</italic> MS15 inhibited exogenous IL-10 induced human &#x3b2;-defensin-2 and regulated the response to the inflammatory stimulus (<xref ref-type="bibr" rid="B43">Habil et&#xa0;al., 2014</xref>). In future, <italic>L. fermentum</italic> can be combined with other vaccines to enhance their protective effect (<xref ref-type="bibr" rid="B30">Esvaran and Conway, 2012</xref>). These different strains of <italic>L. fermentum</italic> have been shown to regulate immunity and may also have some effect in the prevention of AD. In future, more research is required to explore the potential of <italic>L. fermentum</italic> in the treatment of AD.</p>
</sec>
<sec id="s3_11">
<label>3.11</label>
<title>
<italic>Lactobacillus johnsonii</italic> improves intestinal inflammation and alleviates the severity of AD<italic>&#x200b;</italic>
</title>
<p>
<italic>L. johnsonii</italic> is a probiotic that can be isolated from dairy products. Notably, <italic>L. johnsonii</italic> BS15 can regulate intestinal inflammation (<xref ref-type="bibr" rid="B16">Charlet et&#xa0;al., 2020</xref>; <xref ref-type="bibr" rid="B171">Xin et&#xa0;al., 2020a</xref>; <xref ref-type="bibr" rid="B172">Xin et&#xa0;al., 2020b</xref>; <xref ref-type="bibr" rid="B157">Wang et&#xa0;al., 2021</xref>). Oral administration of <italic>L. johnsonii</italic> NC553 can relieve the severity of AD and inhibit epidermal hyperplasia and infiltration of inflammatory cells into the skin (<xref ref-type="bibr" rid="B57">Inoue et&#xa0;al., 2007</xref>). Additionally, it relieves skin damage by inhibiting pro-inflammatory cytokines and CD86 (<xref ref-type="bibr" rid="B57">Inoue et&#xa0;al., 2007</xref>). Therefore, early administration of <italic>L. johnsonii</italic> NC553 in mice with allergies may help reduce AD exacerbations (<xref ref-type="bibr" rid="B150">Tanaka et&#xa0;al., 2008</xref>). <italic>L. johnsonii</italic> has been shown to improve intestinal inflammation in animal models. <italic>L. johnsonii</italic> is present in fermented dairy products, and it is worth investigating whether an effective dose can be achieved through daily yogurt intake in children. <italic>L. johnsonii</italic> can also ameliorate skin damage in mice. However, there have been few experiments related to the treatment of AD with <italic>L. johnsonii</italic>, and further research is needed to determine its effectiveness in the prevention and treatment of AD.</p>
</sec>
<sec id="s3_12">
<label>3.12</label>
<title>
<italic>Lactobacillus pentosus</italic> regulates the host immune system and improves systemic inflammatory response</title>
<p>
<italic>L. pentosus</italic> regulates the host immune system and plays an integral role in intestinal health (<xref ref-type="bibr" rid="B93">Ma et&#xa0;al., 2020</xref>). <italic>L. pentosus</italic> KF340 regulates systemic immunity and improves systemic inflammatory response (<xref ref-type="bibr" rid="B76">Kim et&#xa0;al., 2019b</xref>). <italic>L. pentosus</italic> S-PT84 may be involved in the modulation of immune mechanisms to alleviate clinical allergy symptoms (<xref ref-type="bibr" rid="B94">Majumder et&#xa0;al., 2020</xref>). Although administration of <italic>L. pentosus</italic> and placebo can improve symptoms, <italic>L. pentosus</italic> significantly improved the average subjective ratings evaluated using the SCORAD index for allergen-sensitizing AD (<xref ref-type="bibr" rid="B3">Ahn et&#xa0;al., 2020</xref>). <italic>L. pentosus</italic> KF340 reduced cell infiltration and serum IgE levels at the site of lesions in mice by inducing type 1 regulatory T cells (Tr1 cells) that produce IL-10 (<xref ref-type="bibr" rid="B76">Kim et&#xa0;al., 2019b</xref>). <italic>L. pentosus</italic> S-PT84 reduced the concentrations of histamine in the serum, mouse mast cell protease, total IgE, and IgG (<xref ref-type="bibr" rid="B94">Majumder et&#xa0;al., 2020</xref>). The detailed function of <italic>L. pentosus</italic> remains largely unknown and requires further investigation. <italic>L. pentosus</italic> has been shown to exert anti-inflammatory effects and benefit intestinal health. However, there is limited evidence on the efficacy of <italic>L. pentosus</italic> in the treatment and prevention of AD, and further research is needed.</p>
</sec>
<sec id="s3_13">
<label>3.13</label>
<title>
<italic>Lactobacillus brevis</italic> alleviates symptoms of AD by regulating the immune response<italic>&#x200b;</italic>
</title>
<p>
<italic>L. brevis</italic> is a gram-positive, rod-shaped <italic>Lactobacillus</italic> that is frequently used as a starter culture in silage fermentation, sourdough, and lactic acid-fermented beer and wine. <italic>L. brevis</italic> is widely used in the fermentation industry. Orally administered <italic>L. brevis</italic> SBC8803 can significantly inhibit the production of IgE and severity of AD symptoms, and long-term use can inhibit AD development. However, it did not affect the production of cytokines produced by Th1 and Th2 (<xref ref-type="bibr" rid="B141">Segawa et&#xa0;al., 2008a</xref>). <italic>L. brevis</italic> NS1401, isolated from kimchi, stimulated immune cells to secrete Th1 or Th2 cytokines, balance Th1/Th2, and alleviate AD symptoms (<xref ref-type="bibr" rid="B21">Choi et&#xa0;al., 2017</xref>). <italic>L. brevis</italic> stabilizes the gut microbiota, prevents the growth of pathogenic bacteria, and reduces intestinal inflammation (<xref ref-type="bibr" rid="B45">Han et&#xa0;al., 2021</xref>). <italic>L. brevis</italic> can not only improve disease but also regulate immunity. In nine-week-old female BALB/c mice managed with <italic>L. brevis</italic> KB290 (3 &#xd7; 109 CFU/g), cytotoxicity mediated by mouse splenocytes increased (<xref ref-type="bibr" rid="B34">Fukui et&#xa0;al., 2013</xref>). Similarly, the spleen cells of mice treated with <italic>L. brevis</italic> KCTC12777BP also expressed high levels of TNF-&#x3b1;. <italic>L. brevis</italic> 12777BP improves immunity in mice and prevents organisms from being invaded by pathogens (<xref ref-type="bibr" rid="B61">Jeong et&#xa0;al., 2020b</xref>). The supernatant of <italic>L. brevis</italic> BGZLS10-17 can be divided into two components: a GABA-containing and a GABA-free component (<xref ref-type="bibr" rid="B6">Baji&#x107; et&#xa0;al., 2020</xref>). The supernatant containing GABA relies on ATG5 autophagy to stimulate Foxp3+, IL-10, and transforming growth factor-&#x3b2;, CTLA4 and Sirp-&#x3b1; isoimmunoregulatory molecule expression (<xref ref-type="bibr" rid="B6">Baji&#x107; et&#xa0;al., 2020</xref>). The GABA-free supernatant can also regulate the immune response through other mechanisms (<xref ref-type="bibr" rid="B6">Baji&#x107; et&#xa0;al., 2020</xref>). Heated <italic>L. brevis</italic> KB290 accelerated the secretion of IL-8, induced ERK1/2 phosphorylation, increase p38MAPK phosphorylation, and enhanced the expression of IL-8 mRNA (<xref ref-type="bibr" rid="B173">Yakabe et&#xa0;al., 2013</xref>). Heated <italic>L. fermentans</italic> SBC8803 inhibited IgE production and histamine secretion (<xref ref-type="bibr" rid="B142">Segawa et&#xa0;al., 2008b</xref>). <italic>L. brevis</italic> regulates immunity through various mechanisms and has anti-inflammatory effects. Unfortunately, the prevention and treatment of AD by <italic>L. brevis</italic> remain unclear. <italic>L. brevis</italic> may be an innate probiotic to inhibit AD development, and is a promising <italic>Lactobacillus</italic> strain that requires further research.</p>
</sec>
</sec>
<sec id="s4">
<label>4</label>
<title>Multi-strain <italic>Lactobacillus</italic> for the treatment and prevention of AD</title>
<p>By critically reviewing the current literature, we also address the advantages and major disadvantages of the simultaneous use of two or more strains of probiotics. <italic>Lactobacillus</italic> supplementation can improve AD by regulating the intestinal microbiome. Intestinal flora has the potential to improve AD. In two experiments, administration of a <italic>Lactobacillus</italic> mixture had a preventive effect on AD in hairless mice (<xref ref-type="bibr" rid="B49">Holowacz et&#xa0;al., 2018a</xref>; <xref ref-type="bibr" rid="B50">Holowacz et&#xa0;al., 2018b</xref>). <italic>L. plantarum</italic> CJLP55, CJLP133, and CJLP136 isolated from kimchi inhibited AD-like skin lesions, reduced serum IgE levels, and restored the condition of the skin (<xref ref-type="bibr" rid="B168">Won et&#xa0;al., 2011</xref>). Moreover, multi-strain probiotics have been shown to have immunomodulatory effects and prevent AD in high-risk infants (<xref ref-type="bibr" rid="B81">Kukkonen et&#xa0;al., 2007</xref>). A mixture of heat-inactivated <italic>L. casei</italic> LOCK 0900, <italic>L. casei</italic> LOCK 0908, and <italic>L. paracasei</italic> LOCK 0919 modulated <italic>in vitro</italic> cytokine profiles of allergic children to produce anti-allergic Th1 reactions (<xref ref-type="bibr" rid="B23">Cukrowska et&#xa0;al., 2010</xref>). More specifically, prenatal and postnatal supplementation with a mixture of <italic>Bifidobacterium</italic> BGN4, <italic>L.</italic> aD011, and <italic>Acidophilus</italic> A031 can substantially reduce the probability of developing AD before the age of one year (<xref ref-type="bibr" rid="B69">Kim et&#xa0;al., 2010</xref>). Compared to a single strain, mixed lactic acid bacteria significantly enhanced the ability of Th1 cells to respond. Multi-strain probiotics help maintain good skin function, are beneficial for the treatment of AD (<xref ref-type="bibr" rid="B132">Rosenfeldt et&#xa0;al., 2003</xref>; <xref ref-type="bibr" rid="B158">Wang and Wang, 2015</xref>), and maintain intestinal barrier function in children with AD (<xref ref-type="bibr" rid="B133">Rosenfeldt et&#xa0;al., 2004</xref>). In addition, a mixture of <italic>Lactobacillus</italic> spp. improves the clinical symptoms of adults with AD (<xref ref-type="bibr" rid="B54">Iemoli et&#xa0;al., 2012</xref>).</p>
<p>However, benefits of the use of mixed probiotics should be interpreted with caution. Consumption of formula containing probiotics (<italic>Bifidobacterium longum</italic> BL999 and <italic>L. rhamnosus</italic> LPR) before the age of one year did not effectively prevent eczema in infants at high risk of allergies in Asia (<xref ref-type="bibr" rid="B145">Soh et&#xa0;al., 2009</xref>). Eczema symptoms in infants did not change when <italic>L. paracasei</italic> CNCM I-2116 or <italic>Bifidobacterium lactate</italic> CNCM I3446 were used as an adjunct to basic topical therapy (<xref ref-type="bibr" rid="B40">Gore et&#xa0;al., 2012</xref>). Moreover, there is no evidence that <italic>L.</italic> NFCM and <italic>L.</italic> Bi-07 affect the intestinal flora of children with AD (<xref ref-type="bibr" rid="B83">Larsen et&#xa0;al., 2011</xref>). The combination of probiotics did not have a positive effect on AD treatment, which may be due to several reasons. First, there were differences between strains, different combinations of strains, and individual differences in the study subjects. Second, although the researchers prudently selected the infants, irreversible immune-related events occurred. Therefore, probiotic supplementation had no effect on AD. Moreover, of the reason for the probiotic mixture not achieving the desired effect may be because the mother did not supplement with probiotics before antenatal administration. Asian populations may differ, as this is the first randomized controlled trial to be conducted in Asia (<xref ref-type="bibr" rid="B145">Soh et&#xa0;al., 2009</xref>). In addition, the lack of effect may be due to a smaller bacterial population and a smaller number of experimental subjects (<xref ref-type="bibr" rid="B83">Larsen et&#xa0;al., 2011</xref>). <italic>Lactobacillus</italic> species are complex, the strains are diverse, and their combinations are random and varied. Countless combinations of different strains of the same or different species occur. Perhaps, we can find an effective way to explore the therapeutic effects of these different combinations of strains on AD. Inappropriate strains can have negative effects. Perhaps strains with side effects negate the efficacy of beneficial strains, which needs to be explored further. Moreover, research in Asian populations is limited. The efficacy of mixed strains in AD treatment and prevention should be investigated in Asia, a region with a large population.</p>
</sec>
<sec id="s5" sec-type="conclusions">
<label>5</label>
<title>Conclusion</title>
<p>Based on reviews and meta-analyses, probiotics can prevent or treat AD, and perinatal administration of probiotics can prevent AD (<xref ref-type="bibr" rid="B80">Kuitunen, 2013</xref>; <xref ref-type="bibr" rid="B95">Mansfield et&#xa0;al., 2014</xref>; <xref ref-type="bibr" rid="B115">Panduru et&#xa0;al., 2015</xref>). Children (<xref ref-type="bibr" rid="B152">Tan-Lim et&#xa0;al., 2021</xref>) and adults with moderate to severe AD can also be administered probiotics to treat AD (<xref ref-type="bibr" rid="B65">Kim et&#xa0;al., 2014</xref>). In addition, the preventive effect of probiotics on pediatric AD is better than that of treatment (<xref ref-type="bibr" rid="B87">Lee et&#xa0;al., 2008</xref>). A mixture of <italic>Lactobacillus</italic> and <italic>Bifidobacteria</italic> can effectively reduce the incidence of eczema in infants and young children during the first three years of life (<xref ref-type="bibr" rid="B149">Sun et&#xa0;al., 2021</xref>). The preventive effects of probiotics on eczema appear to last until age of two (<xref ref-type="bibr" rid="B25">Dang et&#xa0;al., 2013</xref>) and extend to the age four years (<xref ref-type="bibr" rid="B80">Kuitunen, 2013</xref>). The variety and specificity of probiotic strains enriches therapeutic options. Nevertheless, there is substantial evidence that LGG supplementation does not reduce the prevalence of eczema (<xref ref-type="bibr" rid="B65">Kim et&#xa0;al., 2014</xref>). Not all <italic>Lactobacillus</italic> strains can be used to treat AD, and further experiments are needed to screen for the most effective <italic>Lactobacillus</italic> strains. Additionally, probiotics require repeated experiments to determine the mechanism of their efficacy against AD, effective dose, optimal administration time, and other characteristics.</p>
<p>In conclusion, since the discovery of <italic>Lactobacillus</italic>, numerous studies have demonstrated that this bacterium has a positive effect on the host (<xref ref-type="table" rid="T2">
<bold>Tables&#xa0;2</bold>
</xref>, <xref ref-type="table" rid="T3">
<bold>3</bold>
</xref>). In addition, previous research demonstrated the robust anti-inflammatory and homeostatic effects of <italic>Lactobacillus</italic>. The various health properties of <italic>Lactobacillus</italic> have been confirmed by different research groups. The mechanisms and beneficial effects of <italic>Lactobacillus</italic> are diverse (e.g., inflammation, immunity, gut health, brain function). Importantly, various types, species, and strains of <italic>Lactobacillus exist</italic>. Different strains from the same species have different functions. Therefore, research findings must be considered with utmost caution. The effect of some <italic>Lactobacillius</italic>, such as <italic>L. rhamnosus</italic> HN001 and <italic>L. casei</italic>, is retained for longer after supplementation; therefore, extending their function and permanent colonization of the intestine after regular supplementation can be studied. A portion of Lactobacillus is isolated from human organs. The absence of normal <italic>Lactobacillus</italic> colonization in some patients and options for restoration of these <italic>Lactobacillus</italic> strains are worth examining. In addition, different subtypes of the same <italic>Lactobacillus</italic> strain may have opposite effects; therefore, the positive and negative effects of the subtypes remain to be studied. A more potent subtype may suppress the effects of the effective subtype. However, most of the <italic>Lactobacillus</italic> strains are commensal or are present in food. Thus, ruling out an external interference in experiments is challenging. Finally, as a promising step towards precision and personalized medicine, <italic>Lactobacillus</italic> may become a food supplement to improve future AD treatments. Additional research is needed to explore other varieties of probiotic strains to enrich treatment options. Moreover, effective methods to preserve the activity and effects of probiotics should be explored. Importantly, additional human studies are needed to support the growing evidence of the beneficial effects observed in animal models of various diseases such as cancer, depression, and obesity.</p>
</sec>
<sec id="s6" sec-type="author-contributions">
<title>Author contributions</title>
<p>AX is responsible for the collection of data and writing of the original manuscript. AC and YC are responsible for the organization of the original manuscript. ZL and SJ are responsible for editing. DC and RY are responsible for the concept development, review of the manuscript and revision. RY is responsible for funding acquisition. All authors contributed to the article and approved the submitted version. </p>
</sec>
</body>
<back>
<sec id="s7" sec-type="funding-information">
<title>Funding</title>
<p>This work was supported by the Jiangsu Provincial Department of Science and Technology (No. BE2022698), the Wuxi Science and Technology Bureau (No.Y20222003), the Wuxi Municipal Medical Innovation Team (No.CXTD2021013), the Wuxi Commission of Health and Family Planning (Nos. SW202201 and M202171) and the Wuxi Young and Middle-aged Medical Talents Project (Nos. BJ2020075 and BJ2020079).</p>
</sec>
<ack>
<title>Acknowledgments</title>
<p>We would like to thank Editage (<uri xlink:href="http://www.editage.cn">www.editage.cn</uri>) for English language editing.</p>
</ack>
<sec id="s8" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="s9" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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