Comorbid functional dyspepsia reflects IL-33–mediated airway neuronal dysfunction in asthma - 13/07/24

Doi : 10.1016/j.jaci.2024.06.008

Keima Ito, MD ^a, Yoshihiro Kanemitsu, MD, PhD ^a,^⁎ , Takashi Ueda, PhD ^b,^⁎ , Takeshi Kamiya, MD, PhD ^c, Eiji Kubota, MD, PhD ^d, Yuta Mori, MD, PhD ^a, Kensuke Fukumitsu, MD, PhD ^a, Tomoko Tajiri, MD, PhD ^a, Satoshi Fukuda, MD, PhD ^a, Takehiro Uemura, MD, PhD ^a, Hirotsugu Ohkubo, MD, PhD ^a, Yutaka Ito, MD, PhD ^a, Yasuhiro Shibata, MD, PhD ^b, Natsuko Kumamoto, MD, PhD ^b, Shinya Ugawa, MD, PhD ^b, Akio Niimi, MD, PhD ^a
^a Department of Respiratory Medicine, Allergy, and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
^b Department of Anatomy and Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
^c Department of Medical Innovation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
^d Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

^∗Corresponding author: Yoshihiro Kanemitsu, MD, PhD, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan, 467-8601.1 KawasumiMizuho-choMizuho-kuNagoya467-8601Japan^∗Takashi Ueda, PhD, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan, 467-8601.1 KawasumiMizuho-choMizuho-kuNagoya467-8601Japan

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Graphical abstract

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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.

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Key words : Asthma, capsaicin, functional dyspepsia, interleukin-33, neuronal dysfunction

Abbreviations used : BALF, C2/5, C-CS, FD, Feno, FSSG, GERD, GI, GSRS, ICS, J-LCQ, OVA, PGP9.5, T2, TRPV1, VAS