Breath volatiles reflect diabetic gastroparesis and its recovery by activating Nav1.8-expressing neurons in mice

Abstract Patients with diabetic gastroparesis (DG) experience chronic, challenging symptoms and currently lack effective treatment options. This study examined whether activating Na v 1.8-expressing neurons could improve gastric motility and whether volatile organic compounds (VOCs) in exhaled breath could serve as non-invasive indicators of disease status and treatment response. In streptozotocin-induced male diabetic mice, chemogenetic activation of Na v 1.8-expressing neurons improved gastric motility in DG mice. At the same time, breath VOC profiles differed between DG and non-diabetic controls, with diabetic (3 weeks post-induction) and DG (8–12 weeks) mice showing higher 1-butanol levels than the controls. Two VOCs (2,4-dimethyl-1-heptene and 4-methylheptane) formed a potential treatment-response biomarker panel associated with improved gastric emptying, and the classification model achieved an area under the curve of 0.83 in distinguishing stimulated from non-stimulated states. Our data identified Na v 1.8-expressing neurons as potential modulators of gastric motility and exhaled VOC patterns as exploratory non-invasive markers of disease dynamics, offering a proof-of-concept framework for neuro-modulatory and breath-test-based strategies to monitor and manage gastroparesis.