Oral Presentation Lorne Infection and Immunity 2022

Microbiota-derived outer membrane vesicles and their proinflammatory role in Parkinson’s disease progression (#44)

Tiana Koukoulis 1 2 , Leah Beauchamp 1 2 , Adityas Purnianto 1 2 , Victoria Lawson 1 3 4 , Neil O'Brien-Simpson 5 6 , Maria Kaparakis Liaskos 7 8 , David Finkelstein 1 , Kevin Barnham 1 2 , Laura Vella 1 2 9
  1. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia
  2. Melbourne Dementia Research Centre, The University of Melbourne, Parkville, VIC, Australia
  3. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, Australia
  4. The Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
  5. Centre for Oral Health Research, Melbourne Dental School, The University of Melbourne, Parkville, VIC, Australia
  6. Bio21 Institute, The University of Melbourne, Parkville, VIC, Australia
  7. Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC, Australia
  8. Research Centre for Extracellular Vesicles, School of Molecular Sciences, La Trobe University, Bundoora, VIC, Australia
  9. Department of Surgery, The University of Melbourne, Parkville, VIC, Australia

Introduction: Microbiotic dysbiosis of the gut is thought to facilitate the pathogenesis of neurodegenerative diseases, such as Parkinson’s disease (PD) through the promotion of inflammation, however, the mechanisms involved remain unclear. We hypothesise that one of these unidentified mechanisms involves the release of Outer membrane vesicles (OMVs) from Gram-negative bacteria. We propose OMVs could drive PD inflammation, due to their enrichment in lipopolysaccharide (LPS) and other potent immune stimulators, their capability to disrupt gastrointestinal barrier integrity, and their potential to promote systemic and neural inflammation that typifies PD.

Methods: OMVs were isolated from Escherichia coli in culture and from faeces and characterized by density, size and morphology and LPS content and ability to stimulate immune cells in vitro. E. coli OMVs or LPS were orally administered to a PD neurotoxin murine model to determine if OMVs could accelerate and/or exacerbate Parkinson’s disease motor and gastrointestinal dysfunction and inflammation.

Results: OMVs from E. coli cultures are shown to be more potent at promoting immune activation than an equivalent dosage of LPS in vitro. OMVs orally administered to PD model mice promote gastrointestinal dysfunction (reduced faecal pellet output and stool weight) and inflammation (increased ileal proinflammatory cytokines). OMV treated PD model mice had increased motor dysfunction compared to sham or LPS treated mice, indicating that OMVs can cause impairments in the gastrointestinal tract which directly/indirectly promotes neurodegeneration.

Summary: This study is a first in uncovering a role for OMVs in PD related neurodegeneration and inflammation. We have shown that OMVs are potent immune stimulators in vitro and can exacerbate gastrointestinal dysfunction, inflammation and motor deficits in a PD mouse model. Our data has implications in discovering a functional link between microbiotic dysbiosis, inflammation and neurological dysfunction in many diseases, in particular PD.