Systems Biology Framework Unravels Molecular Substrates Underlying Comorbidity Between Parkinson’s and Crohn’s Disease

In an era of global aging, the escalating burden of chronic disease comorbidity presents a major clinical challenge, making it imperative to decipher the molecular underpinnings of such links to advance diagnostics and therapies. The mechanistic basis for the comorbidity between Parkinson’s and Crohn’s disease, in particular, remains obscure. Systems biology framework in the current study deciphers this enigmatic nexus by integrating genetic architecture with tissue-specific functional genomics and pathway network. A significant shared genetic landscape is established, converging on host-pathogen interactions and barrier integrity. Translating this to a functional context reveals profound transcriptional synergy, wherein the blood milieu in Crohn’s disease is highly aligned with the substantia nigra pathological state of Parkinson’s disease. The physical conduit for this aberrant crosstalk is identified as a sequential breach of the gut epithelial, gut-vascular, and blood-brain barriers. These findings culminate in a cohesive “gut-blood-brain axis” model, positing a directional cascade where peripheral inflammation in Crohn’s disease directly facilitates central nervous system degeneration. This work reframes the etiology of Parkinson’s disease, positioning peripheral inflammatory triggers as direct contributors to neurodegeneration and offering a new paradigm for therapeutic intervention.