Parkinson’s disease (PD) is the fastest-growing neurodegenerative disease in the world1. Gastrointestinal (GI) dysfunction can occur decades before motor impairments and in up to 80% of individuals living with PD2–4. We investigated peripheral relationships that may underlie mechanisms along the gut–blood axis that contribute to PD progression. Single-cell multiomic spatial molecular imaging (SMI) of colonic tissue localized and identified inflammatory injury within epithelial cells that appear to be associated with iron mishandling in both inflammatory bowel disease (IBD) and PD biosamples. We found that both the single-cell SMI of RNA and protein revealed parallel cross-modal dysregulation in the gut epithelium, in both IBD and PD biosamples. These data are accompanied by plasma (PD) and stool (IBD) protein depletion of CCL22. Our findings suggest iron mishandling along the gut barrier likely contributes to systemic inflammation, which may be one catalyst that primes circulating immune cells to body-first PD progression.
