Lactiplantibacillus Plantarum GUANKE Alleviates Allergic Asthma by Restricting Monocyte‐to‐DC Differentiation Via Microbiota‐Associated IAA

ABSTRACT Emerging evidence highlights the role of the gut microbiota in allergic asthma, with microbial metabolites mediating distal immune responses. This study investigated the protective efficacy of Lactiplantibacillus plantarum GUANKE and the mechanisms associated with dendritic cell (DC)‐driven allergic airway inflammation (AAI). GUANKE conferred both prophylactic and therapeutic protection by attenuating airway hyperresponsiveness and Th2‐driven inflammation while partially restoring regulatory T cell (Treg) population. Antibiotic depletion and fecal microbiota transfer indicated that GUANKE‐mediated protection was associated with remodeling of the indigenous microbiota and microbiota‐dependent restoration of circulating indole‐3‐acetic acid (IAA). Targeted serum metabolomics further revealed lower circulating IAA levels in patients with asthma than in healthy controls. Exogenous IAA reduced CX3CR1 + Ly6C − monocytic precursors and pulmonary CD11b + DC accumulation. These reductions were preserved after CD11c‐specific aryl hydrocarbon receptor (AhR) deletion and accompanied by reduced JAK3‐STAT3 signaling, lower STAT3 occupancy at the Jag1 promoter, and attenuation of the Jag1‐Notch4‐Hey1 axis. Pharmacological STAT3 activation or Jagged1‐mediated Notch reactivation partially reversed the effects of IAA. Collectively, these findings link microbiota‐associated IAA restoration to GUANKE‐mediated protection and implicate STAT3‐Jag1‐Notch4 signaling in monocyte‐to‐DC differentiation during AAI.