Mechanistic Insights Into the Modulation of Gut Microbiota and ERK Signaling by Morusin in Juvenile Rats with Post-Infectious Cough.

BACKGROUND: Post-infectious cough (PIC) is a leading cause of chronic cough in children, often persisting after respiratory infections and significantly impairing quality of life. Current therapies, such as montelukast sodium (MAS), offer only partial symptom relief and do not target the underlying inflammatory and microbiota-driven mechanisms. Emerging evidence suggests that the lung-gut axis, ERK pathway activation, and cytokine-microbiota interactions are central to PIC pathogenesis. Morusin, a prenylated flavonoid from Morus alba, possesses anti-inflammatory and barrier-protective activities and may uniquely modulate both ERK signaling and gut microbiota, offering mechanistic advantages over conventional treatments. METHODS: A juvenile rat model of PIC was induced by smoke exposure, lipopolysaccharide nasal instillation, and capsaicin atomization. Rats were assigned to control, model, morusin, or MAS groups. Physiological outcomes, histology, and immunostaining were assessed, including body weight, airway resistance, goblet cells, cytokines (IL-4, IL-6, IL-10), and phosphorylated ERK1/2 (p-ERK1/2) in lung and colon tissues. Gut microbiota was profiled via 16S rRNA sequencing, with correlation analyses linking microbial changes to cytokine and signaling profiles. RESULTS: Morusin improved systemic parameters (body weight, salivary flow, skin hydration), reduced airway hyperreactivity, and normalized anxiety-like behaviors, effects not observed with MAS. Both morusin and MAS reduced lung goblet cell hyperplasia and inflammatory cytokines, but only morusin suppressed p-ERK1/2 in both lung and colon tissues and reshaped the gut microbiota. Morusin enriched beneficial genera (Lactobacillus, Akkermansia) and reduced pro-inflammatory taxa (Ruminococcus, Lachnospiraceae_NK4A136_group). Correlation analyses confirmed strong links between microbial shifts, cytokine balance, and ERK modulation. CONCLUSION: Morusin alleviates PIC through systemic, mucosal, and behavioral improvements, combined with unique modulation of gut microbiota and ERK signaling across the lung-gut axis. These findings highlight morusin's novel mechanistic advantage over MAS and support its potential as a translational therapy for pediatric PIC.