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Abstract

Children are susceptible to allergic rhinitis (caused by external allergens) accompanied by functional gastrointestinal disease, which seriously affects physical and mental health. Antihistamines and nasal spray hormones are commonly used in clinical treatment, but these drugs often have unsatisfactory efficacy and result in high recurrence rates. Therefore, understanding the pathogenesis of allergic rhinitis with functional gastrointestinal disease and seeking safer treatment and prevention methods is essential. Herein, molecular ecology and immunoassays were used to analyze correlations between pediatric allergic rhinitis with functional gastrointestinal disease and both the intestinal microbiota and gastrointestinal peptide levels. Fifty healthy children (healthy group) and 80 children with allergic rhinitis with functional gastrointestinal disease (case group: evenly divided into a control group (conventional drug therapy) and an intervention group (conventional drug therapy + glutamine+probiotics)), were enrolled. Bifidobacterium and Lactobacillus counts and the gastrin and motilin levels were lower in the case group than in the healthy group, whereas Enterobacter, yeast, and Enterococcus counts and the somatostatin, serotonin, and vasoactive intestinal peptide levels were higher. Post treatment, intestinal microbiota indices, gastrointestinal peptide levels, and intestinal barrier function were better in the intervention group than in the control group (p < 0.05). The intervention group had a significantly higher total therapeutic response rate (95.00%) than the control group (77.50%). The intestinal microbiota was closely associated with gastrointestinal peptide levels. Treatment with glutamine and probiotics regulated these levels, re-established balance in the intestinal microbiota, and restored intestinal barrier function.

Keywords

Allergic rhinitis functional gastrointestinal disease intestinal microbiota gastrointestinal peptides glutamine probiotics

Introduction

Allergic rhinitis, also known as hay fever, is an IgE-mediated, non-infectious inflammatory disorder of the mucous membrane that is caused by exposure to allergens; it occurs in subjects from all age groups.¹ Owing to their immature immune system and low resistance to disease, children are more susceptible to stimuli from external allergens, which cause allergic rhinitis. The main clinical symptoms of allergic rhinitis are rhinocnesmus, sneezing, and nasal congestion. Treatment primarily involves immunoregulation and drug treatment, and avoiding contact with allergens is recommended.^2,3 Clinical studies have shown that several types of allergic rhinitis are often accompanied with different degrees of gastrointestinal disease, which not only leads to a protracted disease course and affects the health and long-term quality of life in children, but also makes treatment difficult.⁴ Functional gastrointestinal disease is a type of gut-brain interaction disorder. Although this disease does not cause pathological changes in organs, it can lead to reflux, functional diarrhea, rumination syndrome, abdominal pain, and other digestive disorders. The conventional treatment included the administration of spasmolytic agents and prokinetic agents in the gastrointestinal tract and regulation of gastrointestinal sensation, but it could not achieve the desired clinical outcomes.⁵ Currently, the mechanism underlying the pathogenesis of allergic rhinitis with functional gastrointestinal disease remains undetermined. However, several studies have suggested that it is related to dysregulation of the mucosal immune system and dysfunction of the central nervous system. In addition, abnormal secretion of gastrointestinal peptides and imbalance of the intestinal microbiota have been suggested to play an important role in reducing gastrointestinal motility.^6,7 Thus, active regulation of gastrointestinal peptides and re-establishment of a balanced intestinal microbiota are critical for the treatment of pediatric allergic rhinitis with functional gastrointestinal disease. Therefore, the current study analyzed the correlation between pediatric allergic rhinitis with functional gastrointestinal disease and both the intestinal microbiota and levels of gastrointestinal peptides. We also examined the effects of treatment on these two disease variables. Moreover, we proposed a targeted therapy to enhance clinical efficacy, improve quality of life in children, and provide a scientific basis for the treatment of such diseases.

Materials and methods

Clinical information

The case group consisted of 80 patients with allergic rhinitis with functional gastrointestinal disease. We included patients who: met both the diagnostic standard for allergic rhinitis according to the guidelines for diagnosis and treatment of pediatric allergic rhinitis (2010, Chongqing)⁸ and the diagnostic standard for functional gastrointestinal disease from the new Rome IV criteria for functional gastrointestinal disorders in infants and toddlers⁹; were ≤3 years old; and had not received prior surgical treatment or glucocorticoid therapy; and had had no respiratory infection for at least 2 weeks before treatment. The family members of the patients provided written informed consent. We excluded: patients in a state of persistent asthma or severe asthma attack; patients with immunodeficiency diseases and coagulation dysfunction; patients with severe diseases in vital organs such as the heart, liver, kidneys, and brain; patients with congenital diseases; patients allergic to the drug therapy used in this study; and breastfed infants.

The healthy group consisted of 50 healthy children who had undergone a physical examination in the children’s health care department of our hospital. There was no medical history of rhinitis, allergic diseases, asthma, or allergies in these individuals and their families. There were 27 males and 23 females in the healthy group; their ages ranged from 2–35 months, with an average age of 14.64 ± 3.13 months. There were 45 males and 35 females in the case group; their ages ranged from 4–33 months, with an average age of 13.09 ± 4.11 months. Clinical data from the two groups were well balanced (p > 0.05). This study was approved by the ethics committee of Hunan Children’s Hospital (Hunan, China).

Sample collection

One gram of fresh stool sample was collected from the children. The internal area of the middle section of the stool was transferred into collection tubes and stored at −80°C (SANYO MDF-382E(N) freezer, Sanyo Corporation) until use. A total of 2 mL of venous blood was collected and placed in a vacuum blood collection tube containing 3.2% sodium citrate anticoagulant. After collection, the tube was immediately inverted and mixed, and centrifuged at room temperature at 605 × g for 5 min (BY-600C medical centrifuge, Beijing Baiyang Medical Device Co., Ltd.). The upper plasma was collected and stored at −80°C.

Detection methods

Examination of stool microbiota by 16S rRNA sequencing

Stool samples were thawed at room temperature and DNA was extracted. The 16S rRNA V4 domain primer was used for polymerase chain reaction amplification. The primers used were as follows: 515F: GTGYCAAGCMGCCGCGGTAA; 806R: GGACTACNVGGGTWTCTAA; fragment size: 290 bp. The amplified products were purified and sequenced and then processed with high-throughput sequencing. After optimizing the effective sequence, operational taxonomic unit clustering was performed. The QIIME analysis platform was used to calculate the Rarefaction estimate and Shannon diversity index value for each sample to evaluate the α-diversity of the intestinal microbiota.

Determination of gastrointestinal peptide levels

The levels of gastrin (GAS), motilin (MOT), somatostatin (SS), serotonin (5-HT), and vasoactive intestinal peptide (VIP) were determined through immunoassay analysis (Shenzhen Mindray Biomedical Electronics Co., Ltd.).

Grouping and administration

The 80 patients in the case group were divided into a control group (40 cases) and an intervention group (40 cases). The control group received conventional drug therapy, consisting of gastrointestinal motility drugs (domperidone in tablet form, 10 mg taken orally three times/day),¹⁰ a glucocorticoid (budesonide nasal spray, one 64 µg spray each side, each morning and evening),¹¹ and levocabastine (levocabastine nasal spray, one 5 mg/mL spray each side, each morning and evening).¹² In addition to this treatment, the intervention group was further treated with a combined therapy of probiotics (Minliting, main ingredients: Lactobacillus reuteri GL-104, Lactobacillus paracasei GL-156, and Lactobacillus rhamnosus MP-108; Yimeng Biotechnology Co., Ltd.; 1.5 g taken orally three times/day) and L-glutamine granules (National drug approval No.: H20040245; Chengdu Lisite; daily dose of 0.25 g/kg, split into two doses, taken orally).¹³ The medication course lasted 12 weeks, and both groups were administered one course of treatment.

Evaluation criteria

Clinical efficacy

The evaluation criteria for clinical efficacy were established based on the guidelines for diagnosis and treatment of pediatric allergic rhinitis and the clinical symptoms and signs of functional gastrointestinal disease. Sneezing, nasal discharge, nasal congestion, reflux, functional diarrhea, and abdominal pain were scored from 1 to 3 based on the degree of severity, and the total score was calculated. After one course of treatment, a more than 50% reduction in the total symptoms and signs score was considered significantly effective, a 20–50% reduction was considered as effective, and a less than 20% reduction in the total score was considered ineffective.

Effectiveness + significant effectiveness = total effectiveness

Indicators of intestinal microbiota and quantification of gastrointestinal peptides

The detection methods used were as described in the previous section (“Detection methods”), and were performed before and after treatment.

Intestinal barrier function

The level of diamine oxidase (DAO) was measured using chemical colorimetry (Shanghai Yiji Industrial Co., Ltd.) before and after treatment. In addition, the level of D-lactic acid was measured using colorimetry (Shanghai Mingbo Biotechnology Co., Ltd.), and the levels of endotoxin (ETX) were measured using a limulus lysate test (Shanghai Medical Laboratory), before and after treatment. All tests were performed by strictly following the manufacturers’ instructions.

Statistical analysis

SPSS 23.0 software was used for statistical analysis. Measurement data were assessed using normal distribution. Measurement data are presented as $\bar{x} \pm s$ . A two independent samples t-test was used to compare means between two groups. A paired t-test was used to compare means before and after interventions within groups. A one-way ANOVA was used for the comparison of means between several groups. The least significant difference test was used for pairwise comparison of the homogeneity of variances. Count data are presented as percentages and were analyzed using the Chi-squared test. Correlation was analyzed using Pearson’s r. Differences with p values <0.05 were considered statistically significant.

Results

Comparison of the intestinal microbiota between the healthy and case groups

The counts of Bifidobacterium and Lactobacillus were lower in the case group than in the healthy group, whereas the counts of Enterobacter, yeast, and Enterococcus were higher in the case group (p < 0.05). This suggested that the intestinal microbiota in patients with pediatric allergic rhinitis with functional gastrointestinal disease was imbalanced (Figure 1).

Figure 1.

Parameters of intestinal microbiota in the healthy and case groups (lgCFU/g). Bifidobacterium and Lactobacillus counts were significantly lower in the case group than in the healthy group. Enterobacter, yeast, and Enterococcus counts were significantly higher in the case group than in the healthy group. ^ap < 0.05 in comparison with the healthy group..

Comparison of gastrointestinal peptide levels between the healthy and case groups

The levels of GAS and MOT were lower and the levels of SS, 5-HT, and VIP were higher in the case group than in the control group (p < 0.05). This suggested abnormal secretion of gastrointestinal peptides in patients with allergic rhinitis with functional gastrointestinal disease (Figure 2).

Figure 2.

Levels of gastrointestinal peptides in the healthy and case groups. (a) The levels of GAS were significantly lower in the case group than in the healthy group. (b) The levels of SS were significantly lower in the case group than in the healthy group. (c) The levels of 5-HT were significantly lower in the case group than in the healthy group. (d) The levels of VIP were significantly lower in the case group than in the healthy group. (e) The levels of MOT in the case group were significantly higher than in the healthy group. ^ap < 0.05 in comparison with the healthy group.

Correlations between the intestinal microbiota and gastrointestinal peptide levels

Pearson correlation analysis identified that Bifidobacterium and Lactobacillus counts were positively correlated with the levels of GAS and MOT (r > 0, p < 0.05) and negatively correlated with the levels of SS, 5-HT, and VIP (r < 0, p < 0.05). This suggested a close correlation between the intestinal microbiota and gastrointestinal peptide levels in patients with allergic rhinitis and functional gastrointestinal disease (Table 1).

Table 1.

Correlations between intestinal flora and gastrointestinal peptide levels (r (p)).

Peptide	Bifidobacterium	Lactobacillus	Enterobacter	Yeast	Enterococcus
GAS	0.714 (0.000)	0.668 (0.000)	−0.444 (0.011)	−0.431 (0.014)	−0.549 (0.001)
SS	−0.538 (0.001)	−0.408 (0.021)	0.377 (0.033)	0.697 (0.000)	0.594 (0.000)
5-HT	−0.623 (0.000)	−0.435 (0.013)	0.460 (0.008)	0.388 (0.028)	0.721 (0.000)
VIP	−0.549 (0.001)	−0.609 (0.000)	0.712 (0.000)	0.697 (0.000)	0.583 (0.000)
MOT	0.532 (0.001)	0.487 (0.000)	−0.549 (0.000)	−0.612 (0.000)	−0.634 (0.000)

Comparison of demographic data between the control and intervention groups

Differences in sex, age, course of allergic rhinitis, and clinical manifestations between the intervention and control groups were not statistically significant (p > 0.05), suggesting that the data from the two groups could be compared (Table 2).

Table 2.

Case group demographics.

Categories	Cases	Male/Female	Age (months)	Course of allergic rhinitis (months)	Clinical manifestation
Categories	Cases	Male/Female	Age (months)	Course of allergic rhinitis (months)	Reflux/functional diarrhea/rumination syndrome/abdominal pain/functional constipation
Control group	40	22/18	12.22 ± 3.67	7.64 ± 2.11	8/5/13/6/8
Intervention group	40	23/17^a	13.56 ± 4.02^a	6.99 ± 2.03^a	7/6/12/8/7^a

^ap > 0.05 in comparison with the control group.

Comparison of clinical efficacy between the control and intervention groups

The total therapeutic response rate in the intervention group (95.00%) was higher than in the control group (77.50%) (p < 0.05). This suggested that the therapeutic efficacy of probiotics combined with L-glutamine in the treatment of allergic rhinitis with functional gastrointestinal disease was relatively high, and that this treatment could promote faster improvement of clinical symptoms and signs (Table 3).

Table 3.

Therapeutic response rates in the control and intervention groups (n (%)).

Category	Cases	Significantly effective	Effective	Ineffective	Total effectiveness
Control group	40	13 (32.50)	18 (45.00)	9 (22.50)	31 (77.50)
Intervention group	40	22 (55.00)	16 (40.00)	2 (5.00)	38 (95.00)^a

^ap < 0.05 in comparison with the control group.

Comparison of the intestinal microbiota between the control and intervention groups

Differences in the counts of intestinal microbiota between the control and intervention groups were not statistically significant pre-treatment (p > 0.05). After treatment, the counts of Bifidobacterium and Lactobacillus were higher and the counts of Enterobacter, yeast, and Enterococcus were lower in the intervention group than in the control group (p < 0.05). This suggested that a combined therapy of probiotics and L-glutamine assisted the regulation of the intestinal microbiota and the re-establishment of the ecological balance of gut microorganisms in patients with allergic rhinitis with functional gastrointestinal disease (Figure 3).

Figure 3.

Comparison of the intestinal microbiota before and after treatment in the control and intervention groups (lgCFU/g). (a) Bifidobacterium counts were significantly higher in the intervention group than in the control group after treatment. (b) Lactobacillus counts were significantly higher in the intervention group than in the control group after treatment. (c) Enterobacteria counts were significantly lower in the intervention group than in the control group after treatment. (d) Counts of yeast were significantly lower in the intervention group than in the control group after treatment. (e) Enterococcus counts were significantly lower in the intervention group than in the control group after treatment. ^ap < 0.05 in comparison with the same group pre-treatment; ^bp > 0.05 in comparison with the control group at the same time point; ^cp < 0.05.

Comparison of gastrointestinal peptide levels in the control and intervention groups before and after treatment

There were no significant differences in the levels of gastrointestinal peptides between the two groups before treatment (p > 0.05). After treatment, the levels of GAS and MOT were higher, and the levels of SS, 5-HT, and VIP, were lower in the intervention group than in the control group (p < 0.05). This suggested that a combined therapy of L-glutamine and probiotics regulated the levels of gastrointestinal peptides in patients with allergic rhinitis with functional gastrointestinal disease and prevented exacerbation of the disease (Figure 4).

Figure 4.

Comparison of gastrointestinal peptide levels between the control and intervention groups before and after treatment. (a) The levels of GAS were significantly higher in the intervention group than in the control group after treatment. (b) The levels of SS were significantly lower in the intervention group than in the control group after treatment. (c) The levels of 5-HT were significantly lower in the intervention group than in the control group after treatment. (d) The levels of VIP were significantly lower in the intervention group than in the control group after treatment. (e) The levels of MOT were significantly higher in the intervention group than in the control group after treatment. ^ap < 0.05 in comparison with the same group pre-treatment; ^bp > 0.05 in comparison with the control group at the same time point; ^cp < 0.05.

Comparison of intestinal barrier function in the control and intervention groups

Neither treatment induced significant differences in the parameters of intestinal barrier function (p > 0.05). However, the levels of D-lactic acid, ETX, and DAO were lower in the intervention group than in the control group after treatment (p < 0.05). This suggested that a combined therapy of probiotics with L-glutamine improved intestinal barrier function in children with allergic rhinitis with functional gastrointestinal disease (Figure 5).

Figure 5.

Comparison of intestinal barrier function between the control and intervention groups before and after treatment. (a) The level of D-lactic acid in the intervention group was significantly lower than in the control group after treatment. (b) The level of ETX in the intervention group was significantly lower than in the control group after treatment. (c) The level of DAO in the intervention group was significantly lower than that in the control group after treatment. ^ap < 0.05 in comparison with the same group pre-treatment; ^bp > 0.05 in comparison with the control group at the same time point; ^cp < 0.05.

Discussion

In recent years, an increasing number of studies have suggested that abnormal secretion of gastrointestinal peptides and an imbalance of the intestinal microbiota play an important role in the progression of allergic and gastrointestinal diseases. There are trillions of microorganisms in the human intestine and they play important roles in the development of host immunity, intestinal endocrine function, nutritional metabolism, cell proliferation, nerve signal transduction, angiogenesis, and resistance to pathogens. The intestinal microbial ecosystem mainly consists of probiotics and opportunistic pathogens. These two types of microbes constitute a balanced ecological system of intestinal microorganisms that promotes normal intestinal function. Under normal circumstances the ratio and quantity of these microbes are in a balanced state; however, pathogenic factors can lead to an imbalanced ratio between and altered quantities of pathogens and probiotics, resulting in dysregulation of the brain-gut axis and induction of immune disorders in local areas of the intestine that can cause further diseases.¹⁴ Imbalance in the intestinal microbiota mainly affects the activities of the enteric nervous system, mucosal immune function, intestinal permeability, pain regulation, and the hypothalamic-pituitary-adrenal axis. In addition, it may contribute to the pathogenesis of functional gastrointestinal diseases by altering intestinal motility, promoting intestinal permeability and visceral hypersensitivity, and activating immune responses as well as through other pathophysiological mechanisms.^15,16 Both Bifidobacterium and Lactobacillus are probiotics, which can inhibit the abnormal fermentation of harmful bacteria, stimulate the intestinal tract, promote intestinal peristalsis, establish and maintain the normal intestinal microecosystem, invade and colonize the intestinal tract, induce the disorder of intestinal microbiota, and reduce the intestinal mucosal immune barrier. In this study, Bifidobacterium and Lactobacillus counts were lower and Enterobacter, yeast, and Enterococcus counts were higher in the case group than in the healthy group. This suggests that the intestinal microbiota is not balanced in patients with allergic rhinitis with functional gastrointestinal disease, which can not only lead to local inflammation and immune dysfunction but also impair gastrointestinal function. In children, the composition of the intestinal microbiota is still dynamic, and the intestinal immune function is underdeveloped. External environmental factors can lead to an ecological imbalance of the intestinal microbiota, resulting in the expansion of some opportunistic pathogens, migration of normal flora, and decreased counts of probiotics, mainly Bifidobacterium.¹⁷

Gastrointestinal peptides and hormones belong to a group of high-potency biologically active substances. They are mainly secreted by paracrine and endocrine cells in the pancreatic and gastrointestinal mucosa and released by nerve terminals in the gastrointestinal wall and are classified into inhibitory and excitatory gastrointestinal peptides.¹⁸ Gastrointestinal peptides participate in the pathophysiological processes of functional gastrointestinal diseases through two main mechanisms: regulation of gastrointestinal function as neurotransmitters, and regulation of gastrointestinal sensorimotor functions through direct effects on sensory nerve terminals in the smooth muscle cells and gastrointestinal tract.^19,20 GAS promotes segmentation contractions of the small intestine and increases gastric mucosal blood volume and gastrointestinal motility; MOT promotes gastric emptying and gastric contraction and induces the release of pepsin; SS is a gastrointestinal neuropeptide that inhibits the movement of and secretion from the gastrointestinal tract; 5-HT is a brain-gut peptide that participates in gastrointestinal activity and also accelerates the gastrointestinal peristalsis and increasing visceral sensitivity through binding to intestinal receptors; VIP is a non-cholinergic inhibitory gut-brain peptide that inhibits gastrointestinal movement and gastric emptying and reduces gastrointestinal motility and excitability. In this study, the levels of GAS and MOT were lower and the levels of SS, 5-HT, and VIP were higher in the case group than in the healthy group, suggesting abnormal levels of gastrointestinal peptides and impaired intestinal function in patients with allergic rhinitis with functional gastrointestinal disease.

A previous study found that this abnormal secretion of gastrointestinal peptides may be related to the stress response and dysfunction of the brain-gut axis, both contributing to the generation of intestinal microbiota imbalance.²¹ Fu et al.²² found that chronic stress stimulation in rats increased the permeability of the intestinal mucosa and the imbalance of intestinal microbiota and led to stress responses in the neuroendocrine system. This suggested that the brain-gut axis, immune system, and enteric nervous system had synergistic effects on the regulation of the intestinal microbiota. This study further assessed the correlation between the intestinal flora and the levels of gastrointestinal peptides. The results suggested a close correlation and interaction between the two variables, implying that the clinical efficacy and prognosis could be improved via the regulation of the levels of gastrointestinal peptides and by improving the imbalance of the intestinal flora. The current study showed that the therapeutic efficacy in the intervention group was better than that in the control group. The levels of gastrointestinal peptides and multiple parameters of the intestinal flora and intestinal barrier function were improved after treatment. This suggests that the combined therapy of probiotics and L-glutamine in patients with allergic rhinitis with functional gastrointestinal disease had significant therapeutic effects and could regulate the levels of gastrointestinal peptides, re-establish the ecological balance of microbes, and restore intestinal barrier function. Glutamine is the most abundant amino acid in the free amino acid pool and in human peripheral blood, and it is an important energy source for intestinal mucosal cells. It is an essential nitrogen source for the body and inhibits protein degradation, promotes protein synthesis, maintains nitrogen balance, participates in the synthesis of glutathione, improves immune function, and maintains the morphological integrity of the small intestinal mucosa, which further maintains the mucosal structure, metabolism, and function of the intestinal mucosa.²³ Therefore, supplementation of exogenous glutamine could help reduce the translocation of bacterial endotoxins, maintain the integrity of the intestinal mucosa, and accelerate restoration of the intestinal function and barrier. In addition, glutamine could be bonded with a sulfhydryl group to neutralize the toxicity of free radicals. Probiotics, which were similar to glutamine, could neutralize toxic substances in the intestine, inhibit the population growth of intestinal spoilage bacteria, regulate the intestinal microbiota, and improve both intestinal and systemic immune functions.²⁴ Liu et al.²⁵ reported that probiotic treatment in patients with functional constipation could reduce clinical symptoms, regulate the levels of gastrointestinal hormones, and relieve anorectal pressure.

There were some shortcomings in this study, such as the small sample size, comparison to only healthy subjects, and lack of evaluation of drug safety; therefore, further studies are still needed. The relationship between allergy and intestinal flora has not been further studied, which is another shortcoming of this study. As only children with allergic rhinitis were selected, while children with other allergic diseases were not selected, it was impossible to determine whether allergies were directly related to intestinal flora. Therefore, in the next study, the scope will be expanded to further analyze this relationship. In addition, this study found that levels of gastrointestinal peptides were significantly correlated with intestinal flora. However, the correlation between these two variables has not been discussed, and further research is needed to identify whether they work together and participate in the mechanisms of intestinal flora disorder in children.

Conclusion

In conclusion, intestinal flora disturbance and gastrointestinal hormone imbalance were common in pediatric allergic rhinitis with functional gastrointestinal disease, and the intestinal microbiota was closely related to the levels of gastrointestinal peptides. Effective treatment with L-glutamine and probiotics could regulate the levels of gastrointestinal peptides, re-establish the balance of the intestinal microbiota, and restore intestinal barrier function.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Y Kuang

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