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Background: Bronchial asthma is a prevalent chronic inflammatory disorder of the airways, with children representing a particularly vulnerable population. Early intervention is critical for the management of pediatric asthma. The pathogenesis of asthma is primarily characterized by a Th2‐immune response that drives excessive secretion of inflammatory cytokines, leading to allergic airway inflammation. Emerging evidence indicates that gut microbiota‐derived metabolites modulate immune cells and influence asthma development and progression. Among these metabolites, indole derivatives with immunomodulatory properties have attracted increasing interest; however, the role of specific indole compounds in asthma remains poorly defined. This study aimed to inves-tigate the effect of indole‐3‐propionic acid (IPA), a key microbiota‐derived indole metabolite, on allergic airway inflammation in a juvenile murine model of asthma, and to elucidate the underlying immunological mechanisms, with a focus on regulatory T cells (Tregs) and the Programmed cell death protein 1 (PD-1)/Programmed cell death ligand 1 (PD-L1) pathway.
Methods: An asthma model was established in young mice via sensitization and challenge with ovalbumin (OVA). We evaluated the impact of IPA on pulmonary inflammation, airway hyperresponsiveness, inflammatory cell infiltration, cytokine profiles, and OVA‐specific immunoglobulins. In addition, we analyzed Treg populations and the expression of PD‐1 and PD‐L1 in lung tissues.
Results: Our results demonstrated that OVA‐induced asthmatic mice exhibited significantly enhanced airway reactivity and pronounced inflammatory cell infiltration in lung histology. Bronchoalveolar lavage fluid (BALF) analysis revealed elevated total leukocyte counts, predominantly eosinophils and neutrophils. Levels of Th2 cytokines (IL‐4, IL‐5, and IL‐13) were markedly increased in BALF, while concentrations of the anti‐inflammatory cytokine IL‐10 were decreased. Serum levels of OVA‐specific IgE and IgG1 were elevated, further confirming a Th2‐skipped immune response. Furthermore, a significant reduction in Treg frequency was observed in the lung tissues of asthmatic mice, accompanied by upregulation of PD‐1 and PD‐L1. Treatment with IPA effectively mitigated airway inflammation and reversed these immunological alterations by restoring Treg levels and modulating PD‐1/PD‐L1 expression.
Conclusions: In conclusion, our findings indicate that IPA alleviates allergic airway inflammation in asthmatic juvenile mice by promoting Treg recruitment and function, potentially through the PD‐1/PD‐L1 axis. This study highlights the therapeutic potential of targeting microbial metabolite‐mediated immunoregulation and provides new insights into early prevention and treatment strategies for asthma.
DOI: 10.7754/Clin.Lab.2025.251102
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