Role of Endogenous Lipopolysaccharides in Neurological Disorders

Abstract

Lipopolysaccharide (LPS) is a cell-wall immunostimulatory endotoxin component of Gram-negative bacteria. A growing body of evidence reveals that alterations in the bacterial composition of the intestinal microbiota (gut dysbiosis) disrupt host immune homeostasis and the intestinal barrier function. Microbial dysbiosis leads to a proinflammatory milieu and systemic endotoxemia, which contribute to the development of neurodegenerative diseases and metabolic disorders. Two important pathophysiological hallmarks of neurodegenerative diseases (NDDs) are oxidative/nitrative stress and inflammation, which can be initiated by elevated intestinal permeability, with increased abundance of pathobionts. These changes lead to excessive release of LPS and other bacterial products into blood, which in turn induce chronic systemic inflammation, which damages the blood-brain barrier (BBB). An impaired BBB allows the translocation of potentially harmful bacterial products, including LPS, and activated neutrophils/leucocytes into the brain, which results in neuroinflammation and apoptosis. Chronic neuroinflammation causes neuronal damage and synaptic loss, leading to memory impairment. LPS-induced inflammation causes inappropriate activation of microglia, astrocytes, and dendritic cells. Consequently, these alterations negatively affect mitochondrial function and lead to increases in oxidative/nitrative stress and neuronal senescence. These cellular changes in the brain give rise to specific clinical symptoms, such as impairment of locomotor function, muscle weakness, paralysis, learning deficits, and dementia. This review summarizes the contributing role of LPS in the development of neuroinflammation and neuronal cell death in various neurodegenerative diseases.

Keywords: endotoxemia; gut microbiota; gut–brain axis; lipopolysaccharide; neurodegeneration; neuroinflammation.

Figure 1

Structure of LPS embedded in the cell membrane of Gram-negative bacteria.

Figure 2

Mechanisms of lipopolysaccharide (LPS-induced neurodegeneration). LPS, with the help of lipopolysaccharide binding (LBP), binds to a different family of receptors viz NOD-like receptors and toll-like receptors (TLRs) to generate TLR-MD2 complex. The downstream signaling cascades include increased production of proinflammatory cytokines, free radicals, and chemokines, all of which contribute to synaptic loss, neuroinflammation, and neurodegeneration.

Figure 3

Lipopolysaccharide (LPS) induces neuroinflammation in Alzheimer’s disease (AD) brains. LPS enters the brain through the vagal nerve and systemic circulation and impairs the BBB further by binding to CD14 and TLR4 receptors. This causes microglial polarization, which further increases free radical stress, defective autophagy with elevated proteinopathy, and aggravated neuroinflammation accompanied by neuronal cell death in AD.

Figure 4

Lipopolysaccharide (LPS)-induced endotoxemia causes dopaminergic neuronal death. LPS binds to CD14 and potently activates microglial cells. In addition, LPS binds to neuronal cells and down-regulates tyrosine hydroxylase gene expression. Both pathways stimulate mitochondrial dysfunction with increased free radical production, leading to dopaminergic neuronal cell loss.