J Neurogastroenterol Motil 2024; 30(2): 125-128  https://doi.org/10.5056/jnm24040
Exploring the Atypical Allergy Spectrum in Disorders of Gut-Brain Interactions: From Food to Aeroallergens
Kewin T H Siah1,2 and Yong Sung Kim3,4*
1Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 2Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore; 3Digestive Diseases Research Institute, Wonkwang University, Iksan, Jeollabuk-do, Korea; and 4Good Breath Clinic, Gunpo, Gyeonggi-do, Korea
Correspondence to: *Yong Sung Kim, MD
Digestive Disease Research Institute, Wonkwang University, Iksan-daero 460, Iksan, Jeonlabuk-do 54538, Korea
Tel: +82-63-859-2670, E-mail: wms89@hanmail.net

Article: Multimorbidity of allergic diseases is associated with functional gastrointestinal disorders in a young Japanese population
Yamamoto Y, Furukawa S, Miyake T, et al
(J Neurogastroenterol Motil 2024;30:229-235)
Received: March 7, 2024; Accepted: March 25, 2024; Published online: April 30, 2024
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Disorders of gut-brain interactions (DGBI), including functional dyspepsia (FD) and irritable bowel syndrome (IBS), constitute a spectrum of gastrointestinal (GI) disorders with widespread implications throughout the digestive system. These conditions are underpinned by intricate pathophysiological mechanisms, encompassing dysregulated gut motility, heightened visceral sensitivity, compromised intestinal barrier function, disrupted gut microbiota balance, and immune dysregulation.1 While the precise pathophysiology of IBS remains incompletely understood, prevailing consensus acknowledges the involvement of both innate and adaptive immune responses, ultimately leading to chronic, low-grade inflammation within the intestinal milieu.1,2 Furthermore, the interplay of allergic immune cells, including mast cells, eosinophils, and IgE-mediated pathways, adds further complexity to our comprehension of DGBIs.2 Even psychological stress, a common risk factor for DGBI, is known to affect the enteric nervous system with an alteration of the immune response.3 The intriguing correlation between allergy and DGBIs is substantiated by a body of research elucidating their frequent co-occurrence with allergic conditions such as asthma, allergic rhinitis, and allergic dermatitis.4

In this Journal of Neurogastroenterology and Motility issue, Yamamoto et al5 reported that multiple allergic diseases are correlated positively with the prevalence of FD and IBS in a young Japanese population. They reported that drug allergies and allergic rhinitis were positively linked to FD and IBS, respectively. However, food allergies, which have long gained attention as a possible cause of GI symptoms, were not related to FD or IBS in this study. The search for food antigens contributing to IBS remains ongoing and inconclusive.6 Attempts to pinpoint specific food allergies have yielded mixed results.6 Studies in both adults and children suggest an association between self-reported food allergy or intolerance and IBS, yet definitive evidence linking these reactions to IBS remains elusive.4,7 Traditional approaches to elucidate the role of food allergy in DGBIs were hindered by the limited significance of serum or skin testing with common food allergens. To address these limitations, scientists have explored unconventional and innovative methods to investigate this relationship, as illustrated in Table.8-14 Studies injected allergens directly into the gastric or colonic mucosa, revealing mucosal reactions correlated with food allergy history, independent of standard tests. Patients with primary Sjögren’s syndrome who had a positive rectal mucosal response to cow milk protein fulfilled the criteria for diarrhea-predominant or alternating IBS. Innovative approaches like confocal laser endomicroscopy revealed immediate mucosal reactions in IBS patients following duodenal application of food antigens despite delayed clinical symptoms, underscoring the complex nature of luminal allergy in DGBIs. In addition, recent advancements in understanding the mechanisms of atypical food allergy have ignited interest, shedding light on the potential role of intraluminal antigens in eliciting GI symptoms.15

Table. Studies With Direct Gastrointestinal Mucosal Challenge in Patients With Food-related Gastrointestinal Symptoms or Irritable Bowel Syndrome

SubjectAllergen challengeMain findingsEffect of test-based exclusion diet
IPEC test (Reimann et al8,9)
Patients with a food allergy historyInjecting food allergens into gastric mucosa by gastroscopy

Endoscopy: swelling, erosions, and bleeding in 100% of patients

↑lymphocyte, tissue histamine, and mast cell in food allergy patients → ↓tissue histamine and mast cell after provocation

Not tested
COLAP test (Bischoff et al10)
Patients with chronic abdominal symptoms and suspected GI food allergyInjecting food allergens into cecal mucosa by colonoscopy

Colonoscopy: wheal or flare reaction in 77% of patients

Activation of mast cell and eosinophil correlated with COLAP test

No significant relation between SPT and COLAP test, SPT and food intolerance history, and RAST and food intolerance history or COLAP test

Symptoms improved consistently at 6 months in 83% of patients
Rectal mucosal patch technique (Lidén et al11)
Primary Sjögren’s syndrome with food-related symptomsRectal enema and retained 1 hr of cow milk powder suspension

↑MPO, ECP, NO in 38.1% of patients

All patients with cow milk (+) reaction were IBS

Less abdominal symptoms during 6 months

LDPI (Borghini et al12)
Patients with GI and/or extra-GI symptoms related to Ni-containing foodNi sulfate patch on the lower lip mucosa

↑Mucosal perfusion on LDPI at 30 minutes in 100% of patients

Mucosal hyperemia and/or edema at 2 hours in 100% of patients

Local delayed mucosal reaction in 36.4% of patients

Not tested
CLE (Fritscher-Ravens et al13,14)
IBS patients with suspected food intoleranceDuodenal mucosal application of food solutions (wheat, milk, soy, yeast, and egg white)

↑IEL, epithelial leaks/gaps formed, and intervillous spaces widened within 5 minutes after food challenge in CLE (+) patients

CLE (+) patients’ symptoms improved by 50% at 4 weeks and 74% at 6 months

Patients with food-related symptoms

CLE (+) patients had a 4-fold higher atopic disorder than healthy control

SPT and serum IgE are negative in all patients

Duodenal mucosal reaction is immediate, but symptoms were delayed

CLE (+) patients symptom improved by 70% at 3 months and 73% at 6 months

IPEC, Intragastric provocation under endoscopic control; COLAP, colonoscopic allergen provocation; GI, gastrointestinal; SPT, skin prick test; RAST, radioallergosorbent test; MPO, myeloperoxidase; ECP, eosinophil cationic protein; NO, nitric oxide; IBS, irritable bowel syndrome; LDPI, laser doppler perfusion imaging; CLE, confocal laser endomicroscopy; IEL, intra-epithelial lymphocyte.

Notably, in Yamamoto’s study,5 pollen allergies were positively correlated independently of FD, IBS, and FD and IBS overlap. Studies have shown that GI symptoms were more common in patients with allergic diseases like asthma and allergic rhinitis compared to a healthy population.4 Aeroallergens, including pollen, house dust mites, and animal dander, possess the potential to elicit allergic reactions upon inhalation or ingestion.4 These airborne allergens can breach the respiratory-intestinal barrier, instigating allergic inflammatory responses within the GI tract. Research indicates an enhanced sensitization of individuals with IBS to aeroallergens compared to food allergens.4 Further investigations, particularly in Singapore, have identified independent associations between IBS and pet ownership, with atopic patients meeting IBS criteria exhibiting significantly higher levels of cat dander IgE than those without IBS-like symptoms.16 Moreover, a Taiwan study reported that the incidence rate of IBS in children increased with increased exposure to ambient air pollutants such as carbon monoxide, nitrogen dioxide, non-methane hydrocarbons, and methane.17 While some studies have started to link IBS and aeroallergens, there is still no direct evidence that inhalant allergens cause GI symptoms.

Both DGBI and allergic disorders are highly prevalent, suggesting this relationship to allergy is not specific but may be a simple correlation. Interestingly, Yamamoto et al5 reported that the higher the number of allergic diseases, the higher the risk of IBS, FD, or overlap, and this finding suggested that abnormalities in the immune system might have a role in the pathogenesis of DGB. If allergy and IBS have shared pathogenesis, it is necessary to investigate if DGBI also increases along with the waves of allergy epidemics in the future.18 Regarding the treatment aspect, exploring anti-allergy drugs for DGBIs, such as ketotifen, sodium cromoglycate, and ebastin, has shown some promising results.19-21 This avenue offers exciting prospects for therapeutic innovation, although identifying subgroups with allergy-driven etiology is crucial for personalized treatment optimization.

In conclusion, the unresolved issues and uncertainties surrounding the connection between DGBI and allergy require more assertive research. Developing specific biomarkers for allergy status and improving traditional allergy testing methods are critical steps in advancing our understanding of these conditions.

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