Functional gastrointestinal disorders (FGIDs) are syndromes characterized by a variety of chronic or recurrent symptoms that are caused by gastrointestinal tract function without an organic cause in the digestive tract.¹ The most prevalent FGIDs in the general population are functional dyspepsia (FD) and irritable bowel syndrome (IBS).² In recent years, there has been a marked increase in the prevalence of FGIDs among children and adolescents.³

Recent evidence suggests that intestinal mucosal immune activation may have a significant pathogenic role in the development of FGIDs.^4-8 A subgroup of FGIDs may also have a disrupted T-helper-2 immunological response, which also occurs in allergy disorders.⁹ Data obtained from birth cohort studies and population and patient-based studies have suggested that allergic diseases such as hay fever/allergic rhinitis, asthma, eczema, and allergic conjunctivitis are associated with the prevalence of both IBS and FD.^9-18 A large study of primary care patients has shown that the prevalence of atopy is higher among patients with multiple FGIDs compared to those with a single FGID.¹⁰ A Swedish study investigated the number of allergic diseases and FGIDs.¹⁸ However, evidence regarding the multimorbidity of allergic diseases and the prevalence of FGIDs remains lacking.

The primary objective of the present study is to examine an association between allergic disease multimorbidity and FGIDs in a young population.

Study Population

In this study, 10 104 students from Ehime University in Japan were recruited between April 2015 and April 2017 and underwent comprehensive health examinations. Participants were distributed a specialized questionnaire related to FD and IBS during their check-ups, the questionnaire being based on the Rome III criteria classification.¹⁹ Additionally, data pertaining to the participants’ digestive medical history, with a specific focus on the diagnosis of organic conditions and symptoms, was collected to supplement the Rome III criteria. The study excluded individuals with organic conditions such as peptic ulcer, esophagitis, Helicobacter pylori infection, inflammatory bowel disease, gastrointestinal cancer, and liver/biliary/pancreatic disorders, a history of abdominal surgery, regular use of non-steroidal anti-inflammatory drugs and steroids, and serious physical symptoms such as weight loss, recurring vomiting, dysphagia, and melena. After 1181 subjects were excluded, the final sample for this study consisted of 8923 participants, all of whom were evaluated for allergic disease and FD or/and IBS. Participants were given the option to withdraw from the study

Definitions of Functional Dyspepsia and Irritable Bowel Syndrome

FD, IBS, and the overlap of FD and IBS were defined in accordance with the Rome III criteria.¹⁹ FD was diagnosed in participants who reported symptoms of postprandial fullness, premature satiety, and/or epigastric pain or burning for the last 3 or more months preceding the diagnosis, with symptom onset occurring at least 6 months prior. IBS was diagnosed in participants who reported recurrent abdominal pain or discomfort for more than 3 days a month for the past 3 months and had at least 2 of the following: amelioration of symptoms with defecation, changes in defecation frequency coinciding with abdominal symptoms, and modifications in stool consistency in association with the onset of abdominal symptoms. Symptom onset at least 6 months before diagnosis was also a criterion that was required to be met.

Assessment of Allergic Diseases

A self-administered questionnaire was used to collect data on allergic diseases diagnosed by medical institutions. The participants answered “YES” or “NO” to whether or not they had been diagnosed with each of the allergic diseases (including allergic rhinitis, atopic dermatitis, hand dermatitis, food allergy, drug allergy, pollen allergy, and asthma) using the questions listed below.

Other Measurements

The self-administered questionnaire was utilized to gather information regarding the study participants’ smoking, drinking, exercise habits, and medical history. Participants who reported current smoking were defined as such. Participants who reported regularly consuming alcoholic beverages were defined as current drinkers. Those who reported engaging in physical activity for at least 1 session per week were classified as possessing a positive exercise habit. Height was accurately measured to the nearest millimeter, with the subject standing in an upright posture, using a stadiometer. Body mass index (BMI) was calculated by dividing weight, in kilograms, by the square of height, in meters.

Statistical Methods

The number of allergy diseases was divided into the following 4 categories: 0 (reference), 1, 2, and 3 or more. Estimations of crude odds ratios (ORs) and their 95% confidence intervals (CIs) for FD, IBS, and the overlap of FD and IBS related to allergy diseases were performed using a logistic regression analysis. The analysis was adjusted to account for potential confounding variables, including age, sex, BMI, current drinking, current smoking, and exercise habit, using multiple logistic regression. Statistical analysis was carried out using SAS software version 9.4 (SAS Institute Inc, Cary, NC, USA), and all statistical tests were performed using a two-tailed hypothesis with a significance level of P < 0.05.

Participant Characteristics

The characteristics of the 8923 study participants are presented in Table 1. The mean age and BMI were 20.1 years and 21.35 kg/m², respectively. The proportion of men was 61.4% (n = 5478) in this cohort. The frequency of smoking, drinking, and exercise habits were 5.9%, 10.9%, and 39.3%, respectively. The most frequent allergic disease was pollen allergy (27.0%), followed by allergic rhinitis (18.9%). The frequency of food allergy and drug allergy was 2.5% and 0.4%, respectively. The percentage of subjects with 1 or more allergic diseases was 40.3%. The number of subjects with 3 or more allergic diseases was 2.8%. In the 8923 study participants, the prevalence of FD, IBS, and the overlap of FD and IBS were 1.9%, 6.5%, and 1.1%, respectively.

Table 1 . Clinical Characteristics of 8923 Study Participants

Variables	Total (N = 8923)
Age (yr)	20.1 ± 2.8
Sex (male/female)	5478/3445
BMI (kg/m2)	21.35 ± 3.05
Smoking	527 (5.9)
Drinking	973 (10.9)
Exercise habit	3508 (39.3)
Allergy diseases
Allergic rhinitis	1686 (18.9)
Atopic dermatitis	548 (6.1)
Hand dermatitis	74 (0.8)
Food allergy	226 (2.5)
Drug allergy	35 (0.4)
Pollen allergy	2405 (27.0)
Asthma	168 (1.9)
Number of allergy diseases
0	5328 (59.7)
1	2428 (27.2)
2	921 (10.3)
3 or more	246 (2.8)
FD	168 (1.9)
IBS	576 (6.5)
Overlap of FD and IBS	101 (1.1)

BMI, body mass index; FD, functional dyspepsia; IBS, irritable bowel syndrome.

Data are presented as mean ± SD, n/n, or n (%).

Association Between Each Allergic Disease and Functional Gastrointestinal Disorders

Table 2 presents the crude and adjusted ORs and 95% CIs for the association between each allergy disease and FD or IBS. After adjustment, drug allergy and pollen allergy were independently positively associated with FD (adjusted OR for drug allergy: 5.06 [95% CI, 1.20-14.57]; and pollen allergy: 1.57 [95% CI, 1.14-2.15]). Allergic rhinitis and pollen allergy were independently positively associated with IBS (adjusted OR for allergic rhinitis: 1.40 [95% CI, 1.15-1.71]; and pollen allergy: 1.52 [95% CI, 1.27-1.82]). There was no significant difference in the association between food allergies and IBS in this cohort study. Only pollen allergy was independently positively associated with the FD and IBS overlap group (adjusted OR was 1.54 [95% CI, 1.02-2.31]).

Table 2 . Crude and Adjusted Odds Ratios and 95% Confidence Intervals for Allergy Diseases Related to Functional Dyspepsia or/and Irritable Bowel Syndrome

Variable	Prevalence (%)	Crude OR (95% CI)	Adjusted OR (95% CI)
FD
Allergic rhinitis
No	127/7237 (1.8)	1.00	1.00
Yes	41/1686 (2.4)	1.40 (0.97-1.97)	1.41 (0.98-2.00)
Atopic dermatitis
No	157/8375 (1.9)	1.00	1,00
Yes	11/548 (2.0)	1.07 (0.54-1.90)	1.05 (0.54-1.87)
Hand dermatitis
No	166/8849 (1.9)	1.00
Yes	2/74 (2.7)	1.45 (0.24-4.68)	1.46 (0.24-4.77)
Food allergy
No	161/8697 (1.9)	1.00	1.00
Yes	7/226 (3.1)	1.70 (0.71-3.39)	1.58 (0.66-3.18)
Drug allergy
No	165/8888 (1.9)	1.00	1.00
Yes	3/35 (8.6)	4.96 (1.18-14.02)	5.06 (1.20-14.57)
Pollen allergy
No	105/6518 (1.6)	1.00	1.00
Yes	63/2405 (2.6)	1.64 (1.19-2.25)	1.57 (1.14-2.15)
Asthma
No	162/8755 (1.9)
Yes	6/168 (3.6)	1.97 (0.76-4.13)	1.97 (0.76-4.18)
IBS
Allergic rhinitis
No	436/7237 (6.0)	1.00	1.00
Yes	140/1686 (8.3)	1.41 (1.16-1.72)	1.40 (1.15-1.71)
Atopic dermatitis
No	534/8375 (6.4)	1.00	1.00
Yes	42/548 (7.7)	1.22 (0.87-1.67)	1.20 (0.86-1.65)
Hand dermatitis
No	570/8849 (6.4)	1.00	1.00
Yes	6/74 (8.1)	1.28 (0.50-2.73)	1.36 (0.52-2.90)
Food allergy
No	554/8697 (6.4)	1.00	1.00
Yes	22/226 (9.7)	1.59 (0.99-2.43)	1.56 (0.97-2.40)
Drug allergy
No	573/8888 (6.5)	1.00	1.00
Yes	3/35 (8.6)	1.36 (0.33-3.81)	1.34 (0.32-3.79)
Pollen allergy
No	369/6518 (5.7)	1.00	1.00
Yes	207/2405 (8.6)	1.57 (1.31-1.87)	1.52 (1.27-1.82)
Asthma
No	567/8755 (6.5)	1.00	1.00
Yes	9/168 (5.4)	0.82 (0.39-1.52)	0.78 (0.37-1.45)
Overlap of FD and IBS
Allergic rhinitis
No	76/7237 (1.1)	1.00	1.00
Yes	25/1686 (1.5)	1.42 (0.88-2.20)	1.42 (0.88-2.21)
Atopic dermatitis
No	94/8375 (1.1)	1.00	1.00
Yes	7/548 (1.3)	1.14 (0.48-2.30)	1.12 (0.47-2.27)
Hand dermatitis
No	99/8849 (1.1)	1.00	1.00
Yes	2/74 (2.7)	2.45 (0.40-7.97)	2.75 (0.45-9.12)
Food allergy
No	96/8697 (1.1)	1.00	1.00
Yes	5/226 (2.2)	2.03 (0.71-4.55)	1.88 (0.66-4.23)
Drug allergy
No	101/8888 (1.14)	1.00	1.00
Yes	0/35 (0.0)	NA	NA
Pollen allergy
No	63/6518 (1.0)	1.00	1.00
Yes	38/2405 (1.6)	1.65 (1.09-2.45)	1.54 (1.02-2.31)
Asthma
No	97/8755 (1.1)	1.00	1.00
Yes	4/168 (2.4)	2.18 (0.66-5.28)	2.15 (0.65-5.25)

FD, functional dyspepsia; IBS, irritable bowel syndrome; NA, not applicable.

Adjusted for age, sex, body mass index, current drinking, current smoking, and exercise habit.

Data are presented as n (%).

Association Between the Number of Allergic Diseases and Functional Gastrointestinal Disorders

Table 3 shows the crude and adjusted ORs and 95% CIs for the number of allergy diseases related to FD or IBS. The prevalence of FD with 0, 1, 2, and 3 or more allergic diseases was 1.6%, 2.0%, 3.0%, and 3.3%, respectively (Figure). After adjusting for confounding factors, the group with 2 allergic diseases was independently and positively associated with FD, and allergic disease multimorbidity tended to correlate with the prevalence of FD (adjusted OR for 2 allergic diseases: 1.95 [95% CI, 1.24-2.98], P for trend = 0.003). The prevalence of IBS with 0, 1, 2, and 3 or more allergic diseases was 5.4%, 7.6%, 7.9%, and 11.8%, respectively (Figure). The number of allergic diseases was independently positively associated with IBS (adjusted ORs for 1 allergic disease: 1.40 [95% CI, 1.15-1.69]; 2 allergic diseases: 1.47 [95% CI, 1.12-1.91]; 3 or more allergic diseases: 2.22 [95% CI, 1.45-3.28], P for trend = 0.003). The prevalence of the overlap of FD and IBS with 0, 1, 2, and 3 or more allergic diseases was 1.0%, 1.1%, 1.4%, and 2.7%, respectively (Figure). The multimorbidity of allergic diseases tended to correlate with the FD and IBS overlap group (P for trend = 0.018).

Figure 1. The association between number of allergy diseases and the prevalence of functional gastrointestinal disorders. FD, functional dyspepsia; IBS, irritable bowel syndrome.

Table 3 . Crude and Adjusted Odds Ratios and 95% Confidence Intervals for Number of Allergy Diseases Related to Functional Dyspepsia or/and Irritable Bowel Syndrome

Variable	Prevalence (%)	Crude OR (95% CI)	Adjusted OR (95% CI)
Number of allergy diseases
FD
0	84/5328 (1.6)	1.00	1.00
1	48/2428 (2.0)	1.26 (0.87-1.79)	1.23 (0.85-1.75)
2	28/921 (3.0)	1.96 (1.25-2.98)	1.95 (1.24-2.98)
3 or more	8/246 (3.3)	2.10 (0.93-4.12)	1.94 (0.85-3.83)
P for trend			0.003
IBS
0	290/5328 (5.4)	1.00	1.00
1	184/2428 (7.6)	1.42 (1.18-1.72)	1.40 (1.15-1.69)
2	73/921 (7.9)	1.50 (1.14-1.94)	1.47 (1.12-1.91)
3 or more	29/246 (11.8)	2.32 (1.52-3.43)	2.22 (1.45-3.28)
P for trend			0.001
Overlap of FD and IBS
0	52/5328 (1.0)	1.00	1.00
1	27/2428 (1.1)	1.14 (0.71-1.80)	1.10 (0.68-1.74)
2	16/921 (1.7)	1.79 (0.99-3.08)	1.75 (0.97-3.02)
3 or more	6/246 (2.4)	2.54 (0.97-5.51)	2.21 (0.88-5.08)
P for trend			0.018

FD, functional dyspepsia; IBS, irritable bowel syndrome.

Adjusted for age, sex, body mass index, current drinking, current smoking, and exercise habit.

In the present study, pollen allergy was independently and positively associated with FD, IBS, and the overlap of FD and IBS. Allergic rhinitis was independently positively associated with IBS. The positive association between number of allergic diseases and prevalence of both FD and IBS was found. This is the first study to show the association between the multimorbidity of allergic diseases and FGIDs in a young population.

In a large primary care study,¹⁰ the prevalence of atopic conditions (pollen allergy/allergic rhinitis, asthma, eczema, and allergic conjunctivitis) was higher in the FGIDs groups compared with a control group without FGIDs. The odds of having pollen allergy/allergic rhinitis were 3.7-fold higher in the multiple-FGIDs group than in a control group without FGID. In a case-control study of 7235 adult primary care patients in the United Kingdom (UK), IBS symptoms were more prevalent in subjects with asthma and allergic rhinitis.²⁰ In a prospective trial using structured questionnaires in the US, the prevalence of IBS based on the Rome II criteria in subjects with atopic symptoms was 3.2-times higher than in those without these symptoms.²¹ In a Japanese cross-sectional study, IBS based on the Rome III criteria is positively associated with prevalence of allergic diseases.²² In a Taiwanese retrospective study of children, a history of allergic diseases including allergic rhinitis was positively associated with the development of IBS.²³ In a Taiwanese database study,²⁴ female patients with allergic rhinitis more frequently visited clinics for IBS. Thus, the findings in the present study were consistent with these previous findings.

The present study showed an independent, positive association between drug allergy and FD. Similar findings were reported from the UK. In a UK study of 1000 new patients, the prevalence of drug allergy in patients with FGIDs was higher than in those with organic gastrointestinal disorders.²⁵ Given that this is a cross-sectional study, drug allergy might be more likely to occur in the presence of FGIDs. Patients with IBS often visit medical facilities even for minor ailments.^26-28 The high frequency of visits to medical facilities may have increased exposure to many kinds of drugs, resulting in a higher frequency of drug allergy. Female sex was a risk factor for FGIDs.²⁹ A meta-analysis showed that female sex was associated with the prevalence of self-reported medication allergy.³⁰ Further studies regarding drug allergy and FGIDs was warrant in the future.

Conversely, no association between allergy disorders and IBS in several studies. In an Indian study of 70 adult patients, no association between asthma and IBS was found.³¹ Respiratory syndromes were not associated with IBS in an unselected birth cohort of 1037 subjects from New Zealand.³² In a case-control study from Sweden, the prevalence of atopic diseases was comparable in 223 patients with IBS and 47 healthy controls.³³ The contrasting findings observed in these studies might be partially explained by differences in age, sex, the FGID definition, sample size, and confounding factors.

In the present study, the number of allergic diseases correlated with FD, IBS, and the overlap of FD and IBS. In a Swedish birth cohort study, the prevalence of IBS at 16 years old increased with the increasing number of allergic diseases at 2 months old, while asthma, eczema, and food allergies of participants at 2 months old was associated with IBS at 16 years old.¹⁸ On the hand, no association between FD and allergic diseases was found. Sample size, definitions of allergic diseases and FGIDs, and the number of allergic diseases investigated may have led to differences in the relationship between the number of allergic diseases and FGIDs in the 2 studies.

The underlying mechanism that links the multimorbidity of allergic diseases and FGIDs remains unclear. Up-regulated T-helper-2 immune responses occur in atopy (particularly in asthma and eczema rhinitis/pollen allergy) and FGIDs.⁹ Disordered cellular immunity was shown to play a role in increased mast cell infiltration in the duodenal⁷ and colonic mucosa⁶ in IBS and in the small and large intestine in IBS.⁷ Increasing levels of eosinophils, a biomarker for FD,³⁴ were also shown in the duodenum in FD.³⁵ The finding that the immunological inflammation in FGIDs and atopic diseases overlaps suggests that both disease types may be manifestations of an identical underlying immune malfunction. Additionally, the similarity of gut microbiota between allergy diseases and FGIDs had been reported.³⁶ However, further research is required to understand the processes behind the link between allergy disorders and FGID.

Our study has several limitations. First, endoscopy results were not present in the medical record data that were used for this study. However, we excluded subjects who had reported previous organic diseases and serious physical symptoms. Second, data on atopic conditions might have caused some misclassification bias because the assessment of allergic diseases was based on a self-administered questionnaire. However, non-differential misclassification would cause a bias of the odds ratio towards the null. Third, psychological distress such as depression and anxiety, which are commonly reported in patients with FD and IBS, were not adequately assessed. There is no consensus on whether psychological distress influences the association between allergic diseases and FGID.^10,37 Fourth, the association between drug allergy and FD was found. However, in this study, the data regarding the kinds of drug allergy was lacking. Fifth, age affects the prevalence of FGIDs and allergy diseases.^3,38,39 Therefore, it is unclear whether the findings in the present study can be generalized to other ethnic categories and age groups. The main strength of this manuscript is that it is the first study to explore the relationship between allergic disease multimorbidity and FGIDs (FD and IBS) that were diagnosed based on the Rome III criteria in the large sample size from the young population in Japan.

In conclusion, allergic disease multimorbidity is associated with increased FD and IBS in the young population.

The authors would like to thank Mikage Oiwa, Hiromi Miyauchi, Yuko Matsumoto, Takako Yamamoto, Hiroko Suzuki, Masumi Hino, Tomo Kogama, Katsuhiko Kohara, Shuichi Saheki, Katsutoshi Okada, and all of the Health Services Center staff for their support. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

None.

None.

Conception and design: Yasunori Yamamoto and Shinya Furukawa; material preparation and data collection: Aki Kato, Katsunori Kusumoto, and Yuka Saeki; data analysis: Yasunori Yamamoto, and Shinya Furukawa; interpretation of data: Teruki Miyake, Junichi Watanabe, Yukihiro Nakamura, Yoshihiro Taguchi, Tetsuya Yamamoto, Osamu Yoshida, Eiji Takeshita, Yoshio Ikeda, Naofumi Yamamoto, Osamu Yamaguchi, and Yoichi Hiasa; wrote the first draft of the manuscript: Yasunori Yamamoto and Shinya Furukawa; and supervision: Osamu Yamaguchi and Yoichi Hiasa. All authors read and approved the final manuscript.