The Lung Microbiome Modulates Pain‐Like Behavior Via the Lung–Brain Axis in a Nitroglycerin‐Induced Chronic Migraine Mouse Model

Abstract Chronic migraine is one of the most common pain disorders, characterized by significant disability and a lack of safe, long‐term, and effective treatment options. Recent studies highlight the interaction between the lung microbiota and the central nervous system. In this study, a nitroglycerin (NTG)‐induced chronic migraine model is constructed in male C57BL/6 mice to explore these interactions. Notable alterations are observed in the lung microbiota of migraine‐afflicted mice. Notably, there is a marked decrease in Proteobacteria in the chronic migraine group, associated with short‐chain fatty acids and 5‐hydroxytryptamine (5‐HT). After the intratracheal injection of neomycin, the diversity of the lung microbiota is altered, resulting in the relief of migraines. This effect is also observed in mice that receive neomycin‐treated bronchoalveolar lavage fluid (BALF) transplantation, further demonstrating the role of lung microbiota in this process. The altered lung microbiota activate the pulmonary vagus nerve via the Brain‐derived neurotrophic factor‐tropomyosin receptor kinase B (BDNF‐TrkB) pathway in the lung, which projects to the central nucleus of the solitary tract (NTS) and the dorsal raphe nucleus (DRN). This activation, in turn, stimulates the 5‐HT neurons in the DRN, resulting in increased serotonin levels that contribute to pain relief in the chronic migraine model.