There has been an increased incidence in allergic diseases, including allergic asthma, allergic rhinitis, and food allergies in the last 40 years (1). Atopic dermatitis is defined as chronic inflammatory disease of the integumentary system characterized by recurring symptoms, including pruritus, dryness, peeling, blistering, bleeding, and risk for secondary bacterial infection (2). Epidemiological survey has reported 60% of atopic dermatitis occurs in the first year of life (infantile eczema) (3). Previous study (4) indicated that the prevalence of atopic dermatitis in children was as high as 30%. In China, the prevalence of atopic dermatitis in infants was estimated as 64.8% (5). Furthermore, the literature indicated that atopic dermatitis may present as an initial manifestation of an underlying allergic disease process in infants and toddlers. Of note, up to 80% of infants and toddlers diagnosed with atopic dermatitis eventually develop allergic rhinitis or asthma later in childhood (6). Therefore, it is imperative to identify factors that may influence the pathophysiological development of pediatric atopic dermatitis.

Epidemiological studies have identified a number of environmental risk factors that may play a role in the development of atopic dermatitis, such as mode of delivery, breastfeeding status, urban living factors, pet exposure, tobacco exposure, antibiotic therapy and dietary habits (7). Recent research surrounding the “microbiota hypothesis” has acquired increased attention suggesting that allergic processes may stem from an underlying imbalance within the gut microbiota (8). Prior studies indicated that the composition of the gut microbiota was an important factor in the normal development of immune system functioning (9) and that certain gut microbiota and microbial metabolites may promote the production of regulatory peripheral T cells, providing a protective effect against inflammatory processes that drive allergic and autoimmune disease processes (10–12). Moreover, these studies indicate that gut microbiota is an important regulator in the pathogenesis of atopic dermatitis (13–15).

Low diversity of gut microbiota and alternative gut microbial composition were associated with the development of atopic dermatitis in infants and toddlers compared to healthy children (16). Children with atopic dermatitis exhibit a higher abundance of Bacillariophyceae, Clostridium and Enterobacteriaceae, and a lower relative abundance of Bifidobacterium and Lactobacillus (16). Wang et al. (15) found that a decrease in gut microbiota diversity at one week of age was strongly associated with developing atopic dermatitis within the first 18 months of life postpartum. Recently, studies (17–19) also revealed that the maternal gut microbiota during pregnancy was crucial in the development of healthy infantile immune system functioning. Lange et al. (20) reported that higher counts of maternal total aerobes and Enterococci were associated with an increased risk for asthma-like symptoms among infants. Comprehensive analysis of both the maternal and offspring’s gut microbiota may provide insight into establishing key biomarkers for the prediction of subsequent pediatric allergic disease states, including atopic dermatitis, within the first two years of life postpartum. Interpretation of these results may provide a fulcrum on which the development of target-specific pharmaceutical therapies and interventions hinge upon.

However, some inconsistencies were noted regarding the role of gut microbiota in the development of atopic dermatitis in infants and toddlers, which may be explained by time discrepancies in stool sample collection, variable microbiological profiling methods, and poor control of potential confounding variables that may indirectly affect gut microbiota composition (8, 16). Currently, many studies exploring the relationship between gut microbiota and atopic dermatitis are cross-sectional studies with a tendency toward reverse causality, including changes in microbiota composition due to disease manifestations. Few studies have included longitudinal cohort studies linking infant microbiota status to the subsequent development of pediatric atopic dermatitis (21). Additionally, previous literature on the gut microbiota and allergic diseases have solely focused on the postnatal period, but recent findings suggest that maternal gut microbiota status during pregnancy plays a pivotal role in fetal immune development (22, 23) and may drive the evolution of allergic diseases in respective offspring (20, 24).

There remain few relevant population studies to investigate the important relationship between maternal gut microbiota during pregnancy and the risk for infantile atopic dermatitis. Therefore, this study was a 2-year prospective cohort study to investigate the relationships between maternal-offspring’s gut microbiota during pregnancy and the subsequent risk for development of atopic dermatitis in offspring up to two years postpartum.

This was the first study to explore the effects of involving maternal-offspring microbiota status on the subsequent risk for development of atopic dermatitis in infants and toddlers up to two years. Our findings suggested that the enrichment and reduction of certain gut microbiota were strongly associated with the development of atopic dermatitis in infants and toddlers. These findings provide a basis for the development of interventions in the risk reduction and treatment of atopic dermatitis in infants and toddlers.

Our results indicated that there was a lower abundance of Prevotella in mothers assigned to the atopic dermatitis group versus the control group. But no statistical difference was noted in the subsequent analysis, likely due to the small sample size. However, these results reflected to some extent that the enrichment of Prevotella during pregnancy may serve as a protective factor against the development of pediatric allergic diseases. Vuillermin et al. (24) discovered that an increased abundance of Prevotella in pregnant women was associated with a decreased risk for the development of food allergies in respective offspring. Prevotella is a gram-negative anaerobic bacterium that ferments dietary fiber to produce metabolites, including short-chain fatty acids (SCFAs) and succinic acid (28, 29). SCFAs demonstrate significant anti-inflammatory effects and may influence fetal immune development through the production of interleukin-10 (IL-10) producing regulatory T cells (11). Additionally, succinic acid can stimulate the development, migration, and function of innate immune cells (30). In addition, Prevotella produces endotoxins that negatively affect fetal immune development and increase the risk for allergic outcomes via toll-like receptor-4-dependent pathways (31).

Previous work (32) indicated that an increased abundance of Bacteroides, an anaerobic bacterium belonging to the Bacteroidaceae, promoted the secretion of IL-6 and IL-23 in dendritic cells. IL-6 and IL-23 can promote the differentiation of Th17 cells and the secretion of IL-17. Th17 cells trigger inflammatory pathways that increase the risk for development of chronic autoimmune and allergic disease states (33). Therefore, the association between increased Bacteroides and the risk for atopic dermatitis is further understood by Bacteroides-associated cytokine production with notable systemic downstream effects. Our study further supports this finding in that a higher abundance of Bacteroides was noted in mothers of infants with atopic dermatitis, without adjusting for covariates. Our results also revealed maternal carrier with the higher abundance of Pseudomonas and Candidatus Stoquefichus during pregnancy was risk factor for atopic dermatitis in infants and toddlers after the adjustment of potential covariates. Pseudomonas belonging to the Proteobacteria phylum is an opportunistic pathogen, it has been shown to induce a type 2 immune response leading to the production of mucin, which is used as an energy source by pathogens (34, 35). Candidatus Stoquefichus belongs to the class of Bacilli. Notably, there was limited data regarding the biological implications of these genera in atopic dermatitis. Further investigation of these genera as it relates to human application involving the gut microbiota should be considered in future studies.

Initially, our findings indicated a higher alpha diversity of the gut microbiota in mothers of the atopic dermatitis group compared to mothers in the control group. However, the relationship between maternal Shannon index and infantile atopic dermatitis was not significant after controlling for relevant covariates, consistent with findings of previous work (36). Hiromi Tanabe et al. (36) reported an increase in the total diversity of maternal gut microbiota during pregnancy in the atopic dermatitis group compared to mothers in control group, however, this difference was not statistically significant. Although the relationship between maternal gut microbiota during pregnancy, and the risk for development of atopic dermatitis in respective offspring remains controversial, our results indicated that enrichment and reduction of certain maternal gut microbiota during pregnancy were associated with the subsequent development of atopic dermatitis in infants and toddlers. This data provided a new perspective for preventative and interventional measures to minimize the development of allergic diseases in infants and toddlers.

Our study included postpartum analysis involving the examination of offspring gut microbiota status up to two years of age, and the potential pathophysiological impact involving the microbiota-immune axis and risk for pediatric atopic dermatitis. Hong et al. (2) noted a higher abundance of Klebsiella in infants with documented atopic dermatitis (2). Rhoads et al. (37) reported a higher abundance of Klebsiella in infants with colic, further substantiating the potential systemic inflammatory effects of Klebsiella. A prior study (38) demonstrated an increased abundance of Parabacteroides in infants presenting with atopic dermatitis. Our study further supports this finding in that a higher abundance of Parabacteroides and Klebsiella was noted in infants with atopic dermatitis, without adjusting for covariates. Our results showed that infants and toddlers in the atopic dermatitis group presented with a higher abundance of Eubacterium xylanophilum group at birth, Ruminococcus gauvreauii group at 1 year and UCG-002 at 2 years after adjusting for covariates. Eubacterium xylanophilum group and Ruminococcus gauvreauii group belong to the family of Lachnospiraceae. Previous study (39) noted a significant increase in the abundance of Lachnospiraceae in infants and toddlers presenting with atopic dermatitis. Additionally, Xu et al. (40) discovered that Ruminococcus gauvreauii group was positively associated with systemic immune response mechanisms mediated via pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6. Therefore, Ruminococcus gauvreauii group can initiate an inflammatory signaling cascade that may facilitate the pathophysiological development of allergic disease processes, including pediatric atopic dermatitis. However, there was no direct association between the above genera and risk for the development of atopic dermatitis in infants and toddlers in previous study (16). Particularly, the role of the genus UCG-002 in the development of atopic dermatitis in infants and toddlers was unclear. Further studies involving the above three genera would be needed to explore its role in mechanisms of allergic disease.

Our study demonstrated an important association involving reduced abundance of Gemella and Veillonella with an increased risk for atopic dermatitis in infants and toddlers. However, it is important to note that our findings were not entirely consistent with previous studies. Los-R et al. (41) discovered a positive correlation between the development of allergic disease in infants and presence of Gemella. Moreover, Huang et al. (42) noted a higher abundance of Gemella in infants presenting with asthma, while Simonyte et al. (43) indicated that reduced abundance of Veillonella in infancy was associated with an increased risk of asthma. Despite the notable discrepancies in previous literature findings, the anti-allergic effects of Gemella and Veillonella should be explored and considered in future applications. Veillonella, an anaerobic gram-negative coccus, can ferment lactic acid to propionate and acetate (44). Gemella is obligatory fermentative, producing either a mixture of acetic and lactic acids or an equimolar molar mixture of acetic acid and CO₂ depending on the abundance of oxygen (45). Therefore, both Gemella and Veillonella can produce SCFAs. SCFAs, such as butyrate, propionate, and acetate, are primary energy sources with anti-inflammatory and immunomodulatory effects (46). Previous studies also found lower levels of fecal SCFAs (i.e., acetate, butyrate and valerate) were associated with the development of atopic dermatitis in infants (47, 48). These findings cannot be generalized at this time as they require further investigation in studies involving larger sample sizes.

Our findings couldn’t determine significant differences in the gut microbiota diversity between atopic dermatitis and control children involving infants and toddlers at different ages, inconsistent with other relevant studies (16, 21). We suspected that these inconsistencies may be a result of variable dietary habits of both maternal and infant origin. Differences in breastfeeding rates and maternal diet may affect the gut microbiota composition of infants and toddlers across different populations. Other plausible causes of discrepancy include individual environmental influences and underreported perinatal/postnatal factors. Therefore, a comprehensive analysis of all potential variables must be considered when exploring the complex relationship between gut microbiota and the development of pediatric atopic dermatitis.

While our findings did not indicate an association between exogenous influences and subsequent development of atopic dermatitis in infants and toddlers, prior studies have indicated otherwise (49, 50). A possible limitation influencing the overall results of our study includes our small sample size, which proved to be insufficient in detecting any statistical significance in exogenous influence and the development of pediatric atopic dermatitis. Therefore, it is imperative that we consider a larger sample size to control for these variables in an effort to elucidate the relationship among exogenous influences that may pose an indirect effect on infantile gut-microbiota status in the development of atopic dermatitis and other allergic processes.

Our study presents with strengths and weaknesses. Our study was a longitudinal cohort study allowing us to explore the relationship between gut microbiota in the first two years of life and risk for pediatric atopic dermatitis. Additionally, this served as a pilot study to investigate the relationship between changes in maternal gut microbiota during pregnancy and the development of atopic dermatitis in infants and toddlers, closing the gap in current research on maternal gut microbiota and subsequent atopic dermatitis of infants and toddlers in China. However, there were some distinct limitations of our study that require rectification for future applications. Principally, the sample size was insufficient for generalization of the data obtained. Moreover, we did not collect a complete medical history of both maternal and paternal subjects which is necessary for determining additional genetic components that may contribute to the development of pediatric atopic dermatitis. 16S rRNA sequencing was also a limitation of this study as it cannot provide sequences in a resolution like shotgun sequencing and provides no information about the functional capacity of the gut microbiota. Additionally, a further genetic function prediction or the measurements of SCFAs are suggested to be conducted to explore the clinical relevance to the changes in fecal microbiota in future studies.

Results of this study supported that enrichment and reduction of certain gut microbiota in mother-offspring pairs were associated with an increased risk of atopic dermatitis in infants and toddlers. The enrichment of Gemella and Veillonella in the microbiota of offspring appear to exhibit protective properties against the development of atopic dermatitis. Moreover, the results indicated that the enrichment of Prevotella during pregnancy may serve as a protective factor in the development of allergic diseases in offspring. The enrichment of Pseudomonas, Candidatus Stoquefichus during pregnancy and Ruminococcus gauvreauii group, Eubacterium xylanophilum group and UCG-002 in offspring were risk factors for the development of atopic dermatitis in the offspring. Collectively, these findings provide a basis for continued research involving the gut-microbiota-immune axis and for the development of target-specific interventions in the prevention of pediatric atopic dermatitis.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ncbi.nlm.nih.gov/, PRJNA482931.

The studies involving human participants were reviewed and approved by the Research Ethics Boards of Medical School of Wuhan University (JKHL2017-03-03). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

XF wrote all sections of the manuscript and performed the analysis. XF and YL contributed to the conception and design of the study. TZ, JD, and NW contributed to data collection. CH, JB, and YL contributed to the manuscript revisions. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (grant number 81903334).

We were grateful for the technical support from Shanghai Majorbio Bio-pharm Technology Co., Ltd.

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.

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