Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec;154(6):1422-1433.
doi: 10.1016/j.jaci.2024.06.008. Epub 2024 Jun 21.

Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma

Keima Ito  1 , Yoshihiro Kanemitsu  2 , Takashi Ueda  3 , Takeshi Kamiya  4 , Eiji Kubota  5 , Yuta Mori  1 , Kensuke Fukumitsu  1 , Tomoko Tajiri  1 , Satoshi Fukuda  1 , Takehiro Uemura  1 , Hirotsugu Ohkubo  1 , Yutaka Ito  1 , Yasuhiro Shibata  6 , Natsuko Kumamoto  6 , Shinya Ugawa  6 , Akio Niimi  1
Affiliations

Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma

Keima Ito et al. J Allergy Clin Immunol. 2024 Dec.

Abstract

Background: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear.

Objective: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction.

Methods: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined on the basis of capsaicin concentration that induced at least 2 coughs (C2) or 5 coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation.

Results: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 ≤ 2.44 μmol) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-IL-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared to their counterparts.

Conclusion: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.

Keywords: Asthma; capsaicin; functional dyspepsia; interleukin-33; neuronal dysfunction.

PubMed Disclaimer

Conflict of interest statement

Disclosure statement Supported in part by a research grant from MSD Life Science Foundation, Public Interest Incorporated Foundation (RA-020 to Y.K.), a research grant from the Japanese Respiratory Society Research Grants Program (to K.I.), and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT; 24K11373 to Y.K.). Disclosure of potential conflict of interest: K. Ito reports speaker honoraria from AstraZeneca. Y. Kanemitsu reports research grants from Novartis, MSD, and Sanofi; and honoraria for lectures, presentations, and educational events from GSK, AstraZeneca, Kyorin, Sanofi, Novartis, and Zeria. K. Fukumitsu reports research grants from Novartis, GSK, and Daiichi Sankyo. S. Fukuda reports speaker honoraria from AstraZeneca. T. Uemura reports honoraria for lectures and presentations from AstraZeneca, MSD, Novartis, and Chugai. H. Ohkubo reports research grants and honoraria for lectures from Boehringer Ingelheim. A. Niimi reports honoraria for lectures and presentations from AstraZeneca, Kyorin, Novartis, GSK, Sanofi; and personal fees for participating on advisory boards from AstraZeneca, MSD, Kyorin, and Bayer. The rest of the authors declare that they have no relevant conflicts of interest.