Do Bacterial Outer Membrane Vesicles Contribute to Chronic Inflammation in Parkinson's Disease?

Abstract

Parkinson's disease (PD) is an increasingly common neurodegenerative disease. It has been suggested that the etiology of idiopathic PD is complex and multifactorial involving environmental contributions, such as viral or bacterial infections and microbial dysbiosis, in genetically predisposed individuals. With advances in our understanding of the gut-brain axis, there is increasing evidence that the intestinal microbiota and the mammalian immune system functionally interact. Recent findings suggest that a shift in the gut microbiome to a pro-inflammatory phenotype may play a role in PD onset and progression. While there are links between gut bacteria, inflammation, and PD, the bacterial products involved and how they traverse the gut lumen and distribute systemically to trigger inflammation are ill-defined. Mechanisms emerging in other research fields point to a role for small, inherently stable vesicles released by Gram-negative bacteria, called outer membrane vesicles in disease pathogenesis. These vesicles facilitate communication between bacteria and the host and can shuttle bacterial toxins and virulence factors around the body to elicit an immune response in local and distant organs. In this perspective article, we hypothesize a role for bacterial outer membrane vesicles in PD pathogenesis. We present evidence suggesting that these outer membrane vesicles specifically from Gram-negative bacteria could potentially contribute to PD by traversing the gut lumen to trigger local, systemic, and neuroinflammation. This perspective aims to facilitate a discussion on outer membrane vesicles in PD and encourage research in the area, with the goal of developing strategies for the prevention and treatment of the disease.

Keywords: Extracellular vesicles; Parkinson’s disease; bacteria; bacterial outer membrane vesicles; endotoxin; inflammation; innate immune response; lipopolysaccharide; membrane particles; microbiota-gut-brain axis; spread.

Fig. 1

The proposed hypothesis for the pro-inflammatory role of outer membrane vesicles (OMVs) in Parkinson’s disease (PD). A) In states of microbial dysbiosis, OMVs and other microbial factors can cause damage to epithelial barriers, causing the translocation of OMVs past the epithelium, where immune cells can be activated to promote gastrointestinal inflammation which increases intestinal permeability. Information about gastrointestinal inflammation can be directly communicated to the brain via the autonomic nervous system (ANS), by altering neural signaling or retrograde transport of pathogenic proteins (for example α-synuclein) or OMVs. B) OMVs reach the systemic circulation whereby they promote systemic inflammation. OMVs could promote neuroinflammation indirectly via increasing systemic inflammation, leading to weakening of the blood-brain barrier, entry of immune cells into the brain and increased cytokine signaling. OMVs could also promote neuroinflammation directly by infiltrating the brain and activating microglia. This chronic inflammation can contribute to neurodegeneration.