Gut microbiota-derived indole-3-propionic acid protects the airway barrier through activating AhR/IL-22 signaling in cigarette smoke-induced chronic obstructive pulmonary disease

The gut microbiota (GM) has emerged as a mechanistic regulator for respiratory inflammation diseases via the gut-lung axis, yet its role in chronic obstructive pulmonary disease (COPD) remains unclear. In this study, we constructed a mouse model of cigarette smoke exposure (CSE). We performed 16 S rRNA sequencing and untargeted metabolomics to determine whether the GM is altered in COPD mice and to investigate differential metabolites. Fecal microbiota transplantation (FMT) was conducted to validate the role of GM on COPD mice. Furthermore, the protective roles of indole-3-propionic acid (IPA) were assessed in COPD mice and CSE-treated pNHBE cells. The role of the aryl hydrocarbon receptor (AhR) was confirmed using COPD mice with AAV-shAhR and AAV-AhR. We demonstrated that COPD mice exhibit gut dysbiosis characterized by decreased abundance of Allobaculum, Bifidobacterium, and Akkermansia. Untargeted metabolomics revealed that the tryptophan metabolism pathway was downregulated, and the IPA level was significantly reduced. CSE triggered airway barrier protein ZO-1 and occludin dysfunction in vivo and in vitro. The expression of ZO-1 and occludin was partially rescued in the COPD mice following FMT. Furthermore, the expression of AhR was significantly decreased in COPD mice and CSE-treated pNHBE cells. The supplemental IPA activated AhR and increased IL-22 level, enhanced the expression of ZO-1 and occludin, improved lung function indices, and reduced the level of IL-6 and IL-1β. Such protective effects of IPA were significantly reduced in COPD mice treated with AAV-shAhR. By comparison, the expression of ZO-1 and occludin and lung function indices were significantly improved in COPD mice treated with AAV-AhR. Clinically, reduced IPA level was associated with AhR expression ( r = 0.6401, P < 0.05) and worsening FEV1% pred ( r = 0.5536, P < 0.05) in patients with COPD. This study proposes a novel role of the GM in protecting against airway barrier injury via the IPA-AhR signaling pathway, which may be a potential agent for clinical promise in COPD. Gut microbiota-derived IPA protects the airway barrier through activating AhR/IL-22 signaling in CS-induced COPD.