Single-cell multiomics identifies both shared and unique features of immune dysfunction in Parkinson’s disease and inflammatory bowel disease colon, plasma and stool

Abstract 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 PD2,3,4. We investigated peripheral relationships that may underlie mechanisms along the gut-blood axis that contribute to PD pathogenesis. Single-cell multiomic spatial molecular imaging (SMI) of colonic tissue localized 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 the catalyst that primes circulating immune cells to body-first PD pathogenesis. Competing Interest Statement The authors have declared no competing interest. Footnotes Contributor information: MacKenzie L. Bolen, Email: m.bolen{at}ufl.edu Marc Buendia, Email: mmoro{at}recerca.clinic.cat Ji Shi, Ph.D., Email: shi.ji{at}mayo.edu Hannah Staley, Ph.D., Email: hannah.staley{at}duke.edu Jennifer M., Kachergus, Email: hussey.jennifer{at}mayo.edu Philip A. Efron, MD., Email: philip.efron{at}surgery.ufl.edu Gwoncheol Park, Email: gp21p{at}fsu.edu Ravinder Nagpal, Ph.D., Email: rnagpal{at}fsu.edu Stephan D. Alvarez, Email: stephan.alvarez{at}surgery.ufl.edu Qing-Shan Xue, Ph.D., Email: qsxue{at}ufl.edu Nikolaus R. McFarland MD., Ph.D., Email: nikolaus.mcfarland{at}neurology.ufl.edu Ellen M. Zimmermann, MD, Email: ellen.zimmermann{at}medicine.ufl.edu Christopher E. Forsmark, MD, Email: chris.forsmark{at}medicine.ufl.edu Kelly B. Menees, Ph.D., Email: Kmenees{at}iu.edu Azucena Salas, Ph.D., Email: asalas1{at}recerca.clinic.cat E. Aubrey Thomas, Ph.D., Email: thompson.aubrey{at}mayo.edu Malú Gámez Tansey, PhD, Email: mgtansey{at}iu.edu Funding statement: This work was supported in part by NIH 7RF1AG057247 (MGT), 4R01NS128800 (MGT), 5R35GM140806-05 (PAE), the Parkinson’s Foundation Research Center of Excellence award (MGT), and the joint efforts of The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and the Aligning Science Across Parkinson’s (ASAP) initiative. MJFF administers the grant ASAP-020527 on behalf of ASAP and itself. These data were also supported by the Bryan W. Robinson Foundation (MLB) as well as the Parkinson’s Foundation PF-VSA 1293721 (MLB, mentorship by EAT). For open access, the author has applied a CC-BY public copyright license to the Author Accepted Manuscript (AAM) version arising from this submission. MB was funded by grant PRE2022-102617 from the Ministerio de Ciencia e Innovacion, Spain. Conflict of interest and financial disclosures: No authors declare competing interests. This version of the manuscript has been revised to update the following: word count, author affiliations, acronyms, and journal formatting requirements.