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.

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“…17,48,49 Microglia-derived proinflammatory stimuli (TNF-a, IL-1b, Ab) lead to the transformation of resting astrocytes into reactive astrocytes, driven mainly through the TLR family. [50][51][52] Microglia and neurons express all TLR subtypes, while astrocytes express a more limited repertoire, including TLR2, TLR3, TLR4, TLR9, and TLR11, 53,54 which makes them capable of responding to both Ab toxicity and inflammatory mediators released in response to Ab. It is well known that LPS is a widely used stimulus for the induction of glial cell activation and neuroinflammatory changes both in vitro and in vivo.…”

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“…Exogenous threatening stimuli (e.g., omega-3 deficiency, bacterial infections, and air pollution) that trigger microglia result in immune activation and a cascade of responses, which can contribute to the impairment of learning, memory, and global cognitive function [ 37 , 38 ] at different stages of life, but are particularly pronounced if they occur during certain critical windows of human development, such as adolescence or during aging [ 39 ]. For example, recent studies show that exogenous stimuli, such as lipopolysaccharides (LPS), can have a specific impact on microglia and significantly contribute to the pathophysiology of neurological disorders through the over-expression of pro-inflammatory cytokines, causing oxidative stress, with behavioural consequences, like decreased sociality and locomotor activity in aged rodents [ 40 , 41 , 42 , 43 , 44 ].…”

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“…LPS is a component of Gram-negative bacteria, which could be found at a higher level in the brains of AD patients. 83 A variety of reports have indicated that LPS could mediate oxidative stress and inflammation in neurodegeneration diseases. 84 Excessive LPS is also associated with intestinal barrier damage and dysbiosis of the gut microbiota.…”