PAR2 signaling shapes microbial and metabolic remodeling along the gut-lung axis

Introduction: Protease activated receptor (PAR2) is a prominent sensor of environmental and microbial proteases and may serve as an important interface between the host epithelium and mucosal microbes. However, whether PAR2 helps shape microbial community structure and function at barrier surfaces remains unclear. To address this, we examined how PAR2 deficiency or activation affects microbial composition and metabolic potential across the gut lumen, airway lumen, and lung tissue in the context of exposure to protease-rich house dust mite allergen (HDM) exposure. Methods: Wild type and PAR2 deficient littermates of both sexes received a single intranasal challenge with phosphate buffered saline, HDM extract, or a selective PAR2 agonist. Microbial communities from feces, bronchoalveolar lavage fluid (BALF), and lung tissue were profiled using 16S rRNA gene sequencing and PICRUSt2 based functional inference to assess compartment specific taxonomic and metabolic responses. Results: Alpha and beta diversity remained stable across all experimental groups, but distinct conditions resulted in compartment specific remodeling of the microbial population. At baseline, PAR2 deficiency altered multiple genera in the gut and lung and shifted predicted pathways linked to amino acid, lipid, and sulfur metabolism. HDM induced broad taxonomic and functional changes in the gut and lung tissue, including shifts in coenzyme A biosynthesis, reductive TCA activity, lysine fermentation, and nucleotide biosynthesis, while producing only limited taxonomic changes in BALF. PAR2 signaling accounted for a substantial portion of HDM driven remodeling, and direct PAR2 activation reproduced many compartment specific effects, including mucin derived sugar degradation in the gut and suppression of nucleotide biosynthesis in the lung. Sex moderately modified microbial and metabolic responses, with males and females exhibiting divergent, condition dependent functional biases across gut and lung. Conclusion: These findings identify PAR2 as a mucosal niche modifying receptor whose activation or loss reshapes microbial composition and metabolic potential along the gut-lung axis.