Mapping the comorbid landscape of Parkinson’s disease and Crohn’s disease along the gut-blood-brain axis

Parkinson’s disease (PD) and Crohn’s disease (CD) are primarily localized to the brain and gut, respectively. Nevertheless, epidemiological evidence increasingly links these two seemingly unrelated disorders. Although genomic or transcriptomic efforts have been dedicated to understanding this phenomenon, the precise landscape underlying this comorbidity remains elusive. Here, a systematic multi-omics approach is employed to panoramically map this pathogenic nexus for the first time. By curating a comprehensive genetic corpus related to PD and CD from extensive publications, we uncovered a shared genetic architecture converging on biological functions governing host-pathogen interactions and barrier integrity maintenance. Further, multi-tissue transcriptomic datasets were meta-analyzed to validate genomic insights in transcriptional circumstances, which identified pervasive transcriptional synergies of PD and CD pathways within the blood context, indicating in blood CD pathological milieu could create a permissive environment for PD pathogenesis. Finally, delineating the aberrant gut-blood-brain axis through the sequential compromise of gut epithelial barrier, gut-vascular barrier and blood-brain barrier, we revealed a directional cascade where CD intestinal pathology facilitates PD substantia nigra degeneration via blood circulation, establishing a theoretical foundation for preventive and therapeutic interventions for PD and CD comorbidity. Crucially, this study provides a blueprint for dissecting the molecular etiology of comorbidities in other complex diseases affecting disparate anatomical sites.