The Endotoxin Hypothesis of Parkinson's Disease

Abstract

The endotoxin hypothesis of Parkinson's disease (PD) is the idea that lipopolysaccharide (LPS) endotoxins contribute to the pathogenesis of this disorder. LPS endotoxins are found in, and released from, the outer membrane of Gram-negative bacteria, for example in the gut. It is proposed that gut dysfunction in early PD leads to elevated LPS levels in the gut wall and blood, which promotes both α-synuclein aggregation in the enteric neurons and a peripheral inflammatory response. Communication to the brain via circulating LPS and cytokines in the blood and/or the gut-brain axis leads to neuroinflammation and spreading of α-synuclein pathology, exacerbating neurodegeneration in brainstem nuclei and loss of dopaminergic neurons in the substantia nigra, and manifesting in the clinical symptoms of PD. The evidence supporting this hypothesis includes: (1) gut dysfunction, permeability, and bacterial changes occur early in PD, (2) serum levels of LPS are increased in a proportion of PD patients, (3) LPS induces α-synuclein expression, aggregation, and neurotoxicity, (4) LPS causes activation of peripheral monocytes leading to inflammatory cytokine production, and (5) blood LPS causes brain inflammation and specific loss of midbrain dopaminergic neurons, mediated by microglia. If the hypothesis is correct, then treatment options might include: (1) changing the gut microbiome, (2) reducing gut permeability, (3) reducing circulating LPS levels, or (4) blocking the response of immune cells and microglia to LPS. However, the hypothesis has a number of limitations and requires further testing, in particular whether reducing LPS levels can reduce PD incidence, progression, or severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; endotoxin; gut; inflammation; lipopolysaccharide; microglia; neurodegeneration; neuroinflammation.

FIG 1

The endotoxin hypothesis of Parkinson's disease. Early microbiome changes and increased intestinal permeability elevate levels of lipopolysaccharide (LPS) in the gut wall. This promotes local inflammation, which induces α‐synuclein expression and aggregation locally in the gut, with propagation via the vagus nerve to brain. Gut inflammation and permeability also increase LPS levels and inflammation in the circulating blood, which promotes activation of microglia, α‐synuclein aggregation, and neurotoxicity in the brain. Figure created with BioRender.com. [Color figure can be viewed at wileyonlinelibrary.com]

FIG 2

Structure of Escherichia coli lipopolysaccharide. The hexagons represent sugar monomers, circles with P represent phosphate groups, and wavy lines represent acyl chains (ie, fatty acids). The O‐antigen consists of a unit of four sugars repeated 0–40 times. Different bacteria have different endotoxin structures with additions or subtractions from the structure indicated.

FIG 3

A proportion of Parkinson's disease (PD) patients have elevated endotoxin levels. Serum levels of endotoxin were measured by Limulus amoebocyte lysate (LAL) assay in 41 PD patients and 41 age‐matched controls. Each data point is the measured serum endotoxin level for one PD patient or control person. The black bars are the mean endotoxin levels. P = 0.023. EU, endotoxin unit. Adapted from Wijeyekoon et al (2020). [Color figure can be viewed at wileyonlinelibrary.com]

FIG 4

Peripherally administered endotoxin causes specific loss of dopaminergic (TH⁺) neurons in the substantia nigra of mice, prevented by knockout of the P2Y6 receptor (P2ry6^−/−) required for microglial phagocytosis of neurons. LPS, lipopolysaccharide; WT, wildtype. Adapted from Milde et al (2021).