Bifidobacterium pseudolongum enriched by arctigenin orchestrates cough variant asthma via the acetate-aryl hydrocarbon receptor-interleukin-33 axis

Gut microbiota dysbiosis is significantly associated with the onset and progression of cough variant asthma (CVA). Targeting and improving gut microbiota dysbiosis may serve as a promising strategy for CVA. Suhuang antitussive capsule (SH) is the sole clinically approved traditional Chinese patent medicine specifically indicated for managing CVA. Herein, we initially identified arctigenin (AG) as one of the effective components detected and preliminarily screened from SH for its potential in treating CVA. AG significantly ameliorates ovalbumin (OVA)-induced CVA symptoms, alleviates gut dysbiosis, and improves intestinal barrier function. Specifically, AG alleviates CVA symptoms in a gut microbiota-dependent manner, as demonstrated by antibiotic treatment and fecal microbiota transplantation (FMT). 16S rRNA sequencing revealed that AG treatment could notably enrich the commensal bacterium Bifidobacterium pseudolongum (B. pseudolongum), which is typically reduced in CVA. The mono-colonization with B. pseudolongum also showed a reduction in CVA severity. GC-MS metabolomic analysis identified acetate as the key and main serum metabolite induced by B. pseudolongum. We demonstrated that acetate enters pulmonary circulation and activates the aryl hydrocarbon receptor (AHR). Validation using AHR antagonists, siRNA knockdown, Chromatin Immunoprecipitation (ChIP) assays, luciferase reporter experiments, and molecular docking confirmed that acetate-mediated AHR activation suppresses Interleukin-33 (IL-33) secretion from lung epithelial cells, thereby preventing CVA progression. These findings suggest AG, one of the effective components in SH, exhibits prebiotic-like effects to alleviate CVA and highlight the potential of targeting specific gut microbiota species for CVA treatment.