Introduction

Atopic dermatitis (AD) is a chronic, recurring, itchy skin disease with an incidence of 0.2% to 25% [1, 2]. Recent epidemiological survey data in China [

Methods

This sco** review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis(PRISMA) extension for Sco** Reviews [16]. The methodological framework for sco** reviews developed by Arksey et al. was used, which comprises five stages: identifying the research question, identifying relevant studies, selecting studies, charting the data and collating, summarizing and reporting the results. Ethical approval was not necessary for this sco** review because a literature review did not require ethical approval based on the related research guidelines.

Eligibility criteria

The research question was constructed and developed according to the PICO framework (Population, Intervention, Comparison, Outcome). To be eligible for inclusion in this study, the reports had to meet following criteria: the study focused on the AD Children with age < 16 years old; studies focused on the preventions or treatments associated with gut microbiota; randomized controlled trials (RCTs), quasi experimental or experimental studies, cohort designs; the paper was reported in English or Chinese. We excluded narrative reviews, experts’ opinions and papers published in other languages.

Search strategy

Two authors independently searched following databases: Pubmed, CINAHL (EBSCO), MEDLINE, Cochrane library, Cochrane central register of controlled trials, China National Knowledge Infrastructure (CNKI) and Wanfang Database, China Biomedical Literature Database (CBM) for studies focused on gut microbiota and AD in children. The search time limit was from the inception of databases to January 15, 2022. Besides, we searched Google Scholar for potentially related reports. The reference lists of included papers were also screened out to identify any additional relevant papers. The following Boolean search strategy was used to search above databases (Ti: atopic dermatitis ∗ OR dermatitis ∗) AND (Ti: microbiota ∗ OR gut microbiota ∗ OR probiotics ∗ or gastrointestinal ∗) AND (Ti: children ∗ OR child ∗ or pediatric ∗) OR (Ti: prevention ∗ OR treatment ∗). The keywords used were synonyms generated by the databases used and MeSH terms.

Data processing and extraction

Two authors independently screened the initial papers identified through the search. The title and abstract of these papers were evaluated based on the inclusion and exclusion criteria to judge their suitability for further stages of review. The retained papers following this process were rescreened by full text to assess the eligibility. A template was developed to allow extraction of the characteristics of each of the studies. This template also allowed recording of the decision made by each reviewer as to whether the paper should be included or excluded or if the decision was uncertain. The result achieved by the two reviewers was evaluated and compared. Any disagreements were resolved by further discussion and reaching consensus.

The extracted data included the name of first author, author affiliation information, year of publication, report title, study purpose, study design, sample size, the characteristics of participant, outcome indicators, results and main conclusions.

Data analysis

We conducted thematic synthesis proposed by Thomas et al. to answer this sco** review's research question. There are three stages in the thematic synthesis: the free line-by-line coding of the findings of primary literature; the organization of these “free codes” into related areas to construct “descriptive” themes; the development of “analytical” themes. In develo** the theme of this co** review, each reviewer first performed line-by-line coding and descriptive theme generation. Furthermore, two reviewers discussed and integrated the patterns that appear in those themes to generate categories as themes as interpretations beyond the original literature's content.

Results

Study inclusions

The first database search yielded 465 reports for possible inclusion. Title and abstract review identified 128 articles for full-text review. After full-text review, we removed 84 additional articles for failure to meet inclusion criteria. Finally, 44 studies were included in this sco** review (Fig. 1).

Fig. 1
figure 1

The flow diagram for literature review

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Characteristics of included literature

Of the included 44 reports, the authors were from 19 countries, the United States was the country with the most authors, followed by the United Kingdom and China. In terms of regions, Europe had the largest number of researchers, followed by Asia and south America. There were 30 observation studies and 14 intervention studies.

Gut microbiota and AD development

The species and quantity of human microorganisms are abundant, and as symbiotic organisms, they form the human micro-ecosystem together with the host of human body. Under normal circumstances, the microbiota adheres, colonizes, and reproduces in specific parts of the human body, forming a biofilm barrier, thereby inhibiting the invasion of pathogenic bacteria and maintaining the dynamic balance between the human body and microorganisms [17, 18]. The classic “hygiene hypothesis” holds that urbanized lifestyles, excessive hygiene, and the widespread use of antibiotics can lead to imbalances in human microecology and induce or aggravate allergic diseases such as AD [19]. The skin and the gut are the two main micro-ecosystems of the human body. Some studies have found that compared with the normal population, the diversity of skin and intestinal microbiota in children with AD is reduced before the onset of the disease, which can lead to a shift in the immune response to the T helper 2 (Th2) and increase the possibility of AD onset [20, 21].

During the investigation of Swedish and Estonian children [22, 23], Estonian children had very few allergies, and their intestinal microbiota was dominated by Lactobacillus. However, the main intestinal microbiota of Swedish children was Clostridium, so there were many allergic symptoms. For non-allergic individuals, allergic infants had low levels of lactobacilli in their guts, along with a large number of aerobic bacteria. The results of in vitro and in vivo experiments [24, 25] showed that Lactobacillus could regulate the immune system and resist allergy. Elevated fecal caproic acid levels suggest altered gut microbial communities in infants with allergic symptoms [26, 27]. Experimental data [28] had showed that the intestinal bifidobacteria, gram-positive aerobic bacteria and enterococci were relatively few, but children with a high number of Clostridium and Staphylococcus aureus are prone to allergic symptoms.

Probiotics and AD

Probiotics are live microorganisms that help to promote the balance of microbiota, have immune regulation, antioxidant and antibacterial effects, and have been widely used in the prevention and treatment of allergic diseases in children [29]. Th2-type inflammation is the basic feature of AD [30]. On the one hand, oral probiotics can inhibit the Th2 response and make the immune response develop in the direction of Th1 [31]. On the other hand, it can induce immune tolerance and maintain the balance of Th1/Th2, so as to achieve the effect of treating AD [32, 33]. Previous studies have mostly focused on oral probiotics, and topical and oral probiotics are the new hotspots in the research on the relationship between microbiota and AD in recent years. It has been found that oral probiotics can reduce the abnormal colonization of Staphylococcus aureus and other bacteria, restore the diversity of microbiota, help the recovery of intestinal barrier function, and alleviate the clinical symptoms of AD [34].

Epidemiological surveys [35, 36] showed that the proportions of Clostridium, Clostridium difficile, Escherichia coli and Staphylococcus aureus in the gut microbiota of AD patients increased, while the proportions of Bifidobacterium and Bacteroides decreased, suggesting the pathogenesis of AD is closely related to the disturbance of intestinal microbiota. In 2020, Jiang et al. [56, 57]. The influence of various factors changes the changes in the microbiota in the human body, and the composition of intestinal microbes will also be changed if drugs are used for treatment [58].

In terms of dermatopathology, Luo et al. [59] have treated 80 AD children with randomized, double-blind, placebo trial, and the results have showed that after probiotic treatment, their intestinal bacteria were significantly reduced. The group was tested, and the beneficial bacteria were significantly improved, and the allergy symptoms also improved. Probiotics can effectively promote the formation of endogenous barrier mechanisms in children with atopic dermatitis, reduce intestinal inflammation, and avoid allergic symptoms. IL-10 levels increased in the children after continued treatment. Previous study [60] report randomized, double-blind, placebo trial to treat 90 children with moderate and severe atopic dermatitis as experimental subjects, and have used probiotics for adjuvant treatment, and scored itching after 16 weeks. The results have showed that, the degree of itching in children who received probiotic adjuvant therapy is significantly reduced, which have indicated that probiotic adjuvant therapy had a certain effect on the sensitivity of children's skin. At present, there are not many RCTs with rigorous design that can show that probiotics can reduce the severity of AD, and its exact therapeutic effects and safety remain to be further investigated [61].

AD is a Th2-biased inflammatory disorder caused by a combination of complex factors [62]. If the intestinal mucosal immune system is not stimulated by intestinal microorganisms in the early stage of development, the natural development of the immune system will be inhibited, and Treg cells will not be mature enough to regulate certain balances such as Th1/Th2 [11, 63]. By comparing the intestinal microbiota of infants with atopic dermatitis and healthy infants, study [64] has found that the content of Clostridium in the intestine of the former is relatively high, while the content of Bifidobacterium and Lactobacillus in the intestine of healthy infants is higher. It’s been reported that indole-3-carbaldehyde, which is a tryptophan product metabolized by gut microbiota, can alleviate skin inflammation in a mouse model of atopic dermatitis by inhibiting Th2-type cytokine secretion and IgE production. Previous study [65] has pointed out that Bifidobacterium Lactobacillus triple viable bacteria tablets (the ingredients are Bifidobacterium longum, Lactobacillus bulgaricus and Streptococcus thermophilus, 4 tablets/time, 3 times a day for a total of 12 weeks) can increase the number of AD children. These attempts to improve the disease and delay the recurrence of intestinal bifidobacteria and lactobacilli microbiota have brought new hope for the management of chronic disease in children with AD. It is worth noting that the balance of human microbiota is easily affected by various factors such as age, immune status, and external environment, and the therapeutic effect of probiotics is closely related to the strain, timing and dose of administration [66,67,68]. Large-scale randomized, double-blind, placebo-controlled clinical trials are still needed to determine the effective strains, appropriate doses, and duration of treatment of probiotics for AD prevention and treatment.

Several review articles about probiotics and gut microbiota with AD were already published and should be considered. Fang et al. [28] have focused on the the potential mechanisms of probiotics on alleviating AD via upregulation of epidermal barrier and regulation of immune signaling, and the possible effective substances on AD, which provide the supports for targeting gut microbiota to AD prevention and treatment. Disamantiaji et al. [69] have included a total of 5 studies, and have concluded that probiotics supplementation in the management of eczema in children does not show a clinically relevant difference vs. standard treatment in reducing eczema severity. We focused on the relationship of gut microbiota and AD in the children population, with more studies included, we have found that probiotics may be an effective and safe treatment option for AD. Still, the current research results have great heterogeneity on the role of probiotics for AD treatment. Therefore, the results of this review must be considered with some limitations. The most significant limitation was that the language of searching databases were limited to English and Chinese, there can be many studies on the gut microbiota and AD in children reported in other language. Besides, the clinical trials with rigorous design are very few, future studies with larger sample size and rigorous design are needed to elucidate the role of gut microbiota in AD development and treatment.

Conclusions

In conclusion, the current research evidences have showed that the gut microbiota is closely related to the occurrence and development of AD. Probiotics can help immune cells to exert anti-allergic effects on AD, including enhanced antigen degradation and pro-inflammatory immune responses. Intestinal probiotics can regulate immune cells and immune factors, inhibit the reproduction of pathogens in the intestinal tract, and enhance the intestinal epithelial barrier function. It is worth noting that the specific mechanism of action related to the occurrence and development of intestinal microbiota and AD is not yet clear. Besides, the therapeutic effect and safety of probiotics in children with AD still need to be further confirmed.