A novel biological interpretation of neuropsychiatric symptoms in patients with allergic rhinitis: insights from brain functional connectivity gradient and serum multi-omics analysis.

BACKGROUND

The "nose-brain axis" has been proposed as a key mechanism linking allergic rhinitis (AR) to central nervous system (CNS) dysfunction; however, alterations in functional connectivity (FC) gradients remain unexplored in AR. This cross-sectional study aimed to investigate the correlation between brain FC gradients and AR-related peripheral multi-omics profiles, as well as their clinical significance, through multimodal cross scale analysis.

METHODS

We enrolled cross-scale data from 22 AR patients and 20 healthy controls (HCs), including resting-state functional magnetic resonance imaging (rs-fMRI), serum proteomics and metabolomics, and clinical assessments. FC gradient analysis was employed to investigate hierarchical brain functional organization, with gradient values compared at global, regional, and network levels. Multivariate partial least squares (PLS) analysis was used to integrate the multidimensional associations among FC gradients, peripheral molecular signatures, and behavioral phenotypes.

RESULTS

No significant differences were observed at the global or Yeo's seven canonical networks. However, refined regional analysis revealed significant FC gradient alterations predominantly within the Default mode (DMN), Somatomotor (SMN), and Limbic (LN) networks, particularly in RH_Default_Temp_5 (p = 0.0031) and LH_Limbic_OFC_4 (p = 0.0034). These regional gradient abnormalities correlated significantly with AR severity and neuropsychiatric symptoms (p < 0.05), indicating "local fine-tuning" rather than "global collapse" in brain functional remodeling. Multi-omic profiling identified 121 differentially expressed proteins, 197 positive-ion-mode metabolites, 134 negative-ion-mode metabolites. The integrative analysis demonstrated significant associations between these peripheral molecular signatures and AR-related FC gradient alterations. These differentially expressed molecules were primarily enriched in immune response, complement activation, lipids and lipid-like molecules, and cholesterol metabolism pathways.

CONCLUSION

This study provides the first evidence of distinct FC gradient alterations in AR that are coupled to peripheral multi-omic shifts, offering novel insights into CNS mechanisms of AR and identifying potential molecular-neuroimaging biomarkers candidates for precision diagnosis and targeted therapy.