Allergic rhinitis (AR) is a common allergic disease characterized by paroxysmal sneezing, nasal itching, nasal congestion, and runny nose caused by IgE-mediated immune responses to inhaled allergens (Ciprandi et al., 2015). The immune response involves inflammation of the mucosa, which is driven by the activation of type 2 helper T (Th2) cells (Bousquet J. et al., 2008). AR affects 10 to 40% of the world’s population, with a higher prevalence as high as 50% in some countries (Bousquet P. J. et al., 2008; Brożek et al., 2017). The prevalence of AR among Chinese children has been reported to be 15.79%, and it continues to increase (Hu et al., 2017). AR contributes to inefficiency at school, sleep problems, and reduces children’s chances of participating in outdoor activities (Devillier et al., 2016). Regretfully, the exact etiology of AR and its underlying biological mechanism are still unclear (Emeryk et al., 2019). A growing number of studies in recent years have suggested that imbalances in microecology are related to the occurrence of allergic disease (Zimmermann et al., 2019; Barcik et al., 2020; Shah and Bunyavanich, 2021). Microecology dysbiosis, especially in genetically susceptible hosts, may be a cofactor in the development of allergic diseases due to its role in undermining immune balance, including the proportion of effector T cells and regulatory T (Treg) cells (Salem et al., 2018).

In the 1980s, Strachan proposed the “hygiene hypothesis”, which suggests that children living in rural areas, having close contact with animals and drinking unpasteurized cow’s milk had a lower incidence of developing allergic diseases in the future (Huang et al., 2017). In 2015, the “microbiome hypothesis” was proposed, which suggested that the disruption of gut microbiome-mediated immune tolerance due to antibiotic use, infection, and other factors could eventually promote the development of the immune system towards allergy. The symbiosis between host and microbiome plays an essential role in maintaining immune homeostasis and human health, thus, changes in the gut microbiota are believed to be an important factor in the development of allergic disease (Mccoy and Köller, 2015).

Gut microbiota is in dynamic equilibrium and can regulate itself according to the change of environment. Children’s gut microbiota is less resistant and stable than adults and is sensitive to external factors such as the use of antibiotic and glucocorticoids (Fang et al., 2021). Glucocorticoids have remarkable local anti-inflammatory and anti-allergic effects and are the most effective drugs to treat allergic diseases in children, it could directly or indirectly affect gut microbial (Zhang et al., 2021; Liu et al., 2022). At the same time, antibiotics are widely used clinically, they could upset the balance of gut microbiota, leading to decline in microbial diversity and the overgrowth of bacteria such as Clostridium difficile (Ianiro et al., 2020).

With the development of the amplification and sequencing of the 16S rRNA gene, we can obtain the distribution map of microbial species presented in different allergic diseases (Su et al., 2021; Yuan et al., 2022). Currently, clinical studies have demonstrated alterations in the composition and function of the gut microbiome in adults and children with AR (Watts et al., 2021; Zhou et al., 2021). However, there is no study on the gut microbiome of children with AR in Chinese Mainland.

Therefore, in order to investigate the alters of children with AR in Chinese Mainland and evaluate the relationship between the gut microbiota and clinical indicators such as Total Nasal Symptom Score (TNSS), Visual Analog Scale (VAS), Quality of Life Score (QOL), Fractional exhaled nitric oxide (FeNO) value etc. We conducted this study, which will contribute to a better understanding of the underlying biological mechanisms of AR, and help to develop more effective prevention and treatment strategies for AR in children.

An increasing amount of research suggests that gut microbiota dysbiosis was closely linked to the incidence and development of allergic diseases (Arrieta et al., 2015; Fujimura et al., 2016; Khadka et al., 2021). However, only one past study investigated the link between gut microbiota and childhood AR, but this study is limited to the Taiwan region (Chiu et al., 2019). Considering that different regional environments may have an impact on microecology. The aims of this study was to investigate the alters of children with AR in Chinese Mainland and evaluate the relationship between the gut microbiota and clinical indicators.

In this research, we observed that the alpha diversity in the gut microbiota was decreased, beta diversity and gut microbiota structure were significantly changed in AR children compared to HCs. The conclusions of our study showed a more significant statistical difference compared to the previous ones (Chiu et al., 2019). This study mainly found that the occurrence of AR in children is associated with changes in gut microbiota diversity. As compared to HCs, the Shannon index in AR children was significantly reduced, particularly at the family and genus levels. Similar trends were observed with the Simpson index and OTU count. Reduced gut microbiota diversity weakens their ability to resist external interferences, and it is believed to be an important indicator of whether the gut microbiota is stable or not (Bäckhed et al., 2012). Other studies also shown that people with allergic diseases have lower gut microbiota diversity than healthy ones. Hua et al. analyzed 16S rRNA gene data obtained from US public database and found that the increased incidence of allergic diseases in adults was positively correlated with the reduction in gut microbiota diversity (Melli et al., 2016). Meanwhile, Bisgaard et al. reported that the decrease in gut microbiota diversity at 1 month and 12 months after birth increased the risk of AR in children in the first 6 years of life (Bisgaard et al., 2011). All of the above studies suggest that a decrease of gut microbiota diversity may influence the development of allergic diseases.

This study also found that the gut microbiota composition of children with AR significantly differs from HCs at various levels. At the phylum level, there is a certain difference in the proportion of Bacteroidetes and Firmicutes between the two groups, with a higher relative abundance of Bacteroidetes in AR children. Similar findings of Bacteroidetes abundance in fecal samples of allergy sufferers have been reported in other studies. Data analysis from the American Gut Project revealed that the phylum Bacteroidetes was more abundant in adults with nut and pollen allergies than in healthy adults (Melli et al., 2016). A study from Japan also showed that infants with high abundance of Bacteroidetes were more prone to developing allergic diseases after the age of 2 (Songjinda et al., 2007). Bacteroidetes and Firmicutes are the most common phyla in fecal microbiota, and they play important roles in gut health and immune regulation through the production of short-chain fatty acids (SCFAs) (Brody, 2020). In general, the presence of Bacteroidetes was often linked to a higher production of acetate and propionate, whereas the presence of Firmicutes was often linked to a higher production of butyrate (den Besten et al., 2013). Of all the SCFAs, butyrate is a key component in keeping the colon healthy by serving as a source of energy for colonic epithelial cells and regulating tight junction expression to preserve the integrity of the gut barrier (Rauf et al., 2022). Lack of butyrate can cause transfer of inflammatory molecules and antigens to the submucosa and the circulatory system, leading to localized and systemic inflammatory reactions. The prevalence of Bacteroidetes over Firmicutes may decrease the production of butyrate, thereby impacting the integrity of the gut barrier (Rauf et al., 2022) and the gut permeability of allergic disease patients is significantly higher than that of healthy controls (Benard et al., 1996; Majamaa and Isolauri, 1996). This implies that alterations in the abundance of Bacteroidetes and Firmicutes have an impact on the incidence and progression of allergic diseases, prompting the need for more research to clarify the connection between the level of butyrate-producing bacteria and intestinal permeability in patients with atopic diseases.

At the family level, there was a significant increase in the relative abundance of Enterobacteriaceae in the AR group. Enterobacteriaceae are Gram-negative facultative anaerobes, including intestinal bacteria such as Escherichia coli, Shigella, and Salmonella. Some strains of Enterobacteriaceae can adhere to the intestinal mucosa and stimulate immune reactions (Kim et al., 2018). Studies have found that in patients with allergies, the quantity of Enterobacteriaceae increases significantly. This phenomenon could be associated with the disturbance of the gut microbiota, leading to potential impacts on host immune and allergic responses (Zimmermann et al., 2019). Because E. coli and Shigella have the same 16S rRNA gene sequence, it is difficult to identify the specific adherent Enterobacteriaceae species only by 16S sequencing. Therefore, we will perform metagenomic sequencing in the future to determine the exact types of adherent Enterobacteriaceae.

In the AR group, the relative abundance of Subdoligranulum, Agathobacter, and Roseburia at the genus level was significantly lower when compared to healthy controls. Subdoligranulum, a member of the Ruminococcaceae family, can activate the neonatal Treg cells’ MyD88/ROR-γt pathway, thus effectively preventing food allergies (Duncan et al., 2004). The newly discovered Agathobacter belongs to the Lachnospiraceae family (Ahn et al., 2016) and Roseburia has become a potential health marker for gut microbiota due to its anti-inflammatory properties (Tamanai-Shacoori et al., 2017). Subdoligranulum, Agathobacter, and Roseburia can all produce butyrate, promoting gut health by providing energy to host cells and maintaining the integrity of the gut barrier (Ahn et al., 2016; Deaver et al., 2018). The decrease in relative abundance of Subdoligranulum, Agathobacter, and Roseburia in children with AR may indicate a decrease in butyrate levels and gut barrier disruption.

The cellular mechanism behind AR primarily involves the differentiation of CD4⁺ T cells into Th2 cells. This results in an imbalance of the Th1/Th2 ratio, thus promoting B cell activation and class switching to IgE (Kulkarni et al., 2011). Additionally, it causes the differentiation of B cells into IgE-producing plasma cells, as well as mast cell and eosinophil activation to release inflammatory mediators (Wang et al., 1992; Iinuma et al., 2018). Previous studies have demonstrated that an imbalanced gut microbiota can activate innate and adaptive immune cells, which may contribute to the onset of atopic diseases in children (Fujimura et al., 2016). In addition, SCFAs, which are metabolic products of gut microbiota, serve as mediators of communication between the immune system and gut microbiota (Milligan et al., 2017). SCFAs facilitate the differentiation of T cells into both regulatory and effector T cells, maintaining the balance between anti-inflammatory/pro-inflammatory responses, and promoting the establishment of immune tolerance (Park et al., 2015). Our study discovered alterations of gut microbiota in AR children, particularly, a reduction in the prevalence of butyrate-producing bacteria. This finding possibly supports the conclusion that SCFAs can prevent allergic respiratory diseases through their effects on T cells (Cait et al., 2018).

This study has some limitations. First, the sample size is relatively small, as most of the children had already used corticosteroids or antihistamines before their visit to the hospital. Second, the classification level in this study is relatively high, mainly at the phylum, family, and genus levels. Therefore, further research is needed to explore the changes in gut microbiota at the species level in children with AR to provide more precise microbiota-based treatments in the future. Lastly, as the role of gut microbiota metabolites in diseases becomes increasingly important, future studies will also perform metabolomics to further understand the changes in gut microbiota metabolites in children with AR.

In summary, we observed a close relationship between childhood AR and gut microbiota, confirming the changes in gut microbiota composition and diversity in children with AR. We believe that gut microbiota has the potential for diagnosis and treatment of childhood AR, and also provides some ideas for mechanism of AR.

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 at: https://figshare.com/s/8b5ae4eaa3489e55578c.

The experimental procedures were approved by the Ethics Committee of Xijing Hospital at the Fourth Military Medical University in Xi’an, China (approval number: KY20222169-F-1). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

PZ, XZ, HT, FJ, ZJ, HW, YZ, JL, JZ, and XS contributed to the study conception and design. PZ, XZ, and HT had the idea for the article. HW, YZ, and JL performed the data collection. The data analysis was performed by PZ and XZ. The first draft of the manuscript was written by PZ. XS and JZ critically revised the work. FJ and ZJ commented on several drafts. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (82170026); Technological Innovation Guidance Special Project of Shaanxi Province (2022QFY01-09); Natural Science Basic Research Plan in Shaanxi Province (2022JQ-764) and Discipline Promotion Project of Xijing Hospital (XJZT18MJ23 and XJZT21L11); and Clinical Research Project of Air Force Military Medical University (2022LC2210).

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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