Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging

Abstract

It has been noticed in recent years that the unfavorable effects of the gut microbiota could exhaust host vigor and life, yet knowledge and theory are just beginning to be established. Increasing documentation suggests that the microbiota–gut–brain axis not only impacts brain cognition and psychiatric symptoms but also precipitates neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). How the blood–brain barrier (BBB), a machinery protecting the central nervous system (CNS) from the systemic circulation, allows the risky factors derived from the gut to be translocated into the brain seems paradoxical. For the unique anatomical, histological, and immunological properties underpinning its permeable dynamics, the BBB has been regarded as a biomarker associated with neural pathogenesis. The BBB permeability of mice and rats caused by GM dysbiosis raises the question of how the GM and its metabolites change BBB permeability and causes the brain pathophysiology of neuroinflammation and neurodegeneration (NF&ND) and brain aging, a pivotal multidisciplinary field tightly associated with immune and chronic systemic inflammation. If not all, gut microbiota-induced systemic chronic inflammation (GM-SCI) mainly refers to excessive gut inflammation caused by gut mucosal immunity dysregulation, which is often influenced by dietary components and age, is produced at the interface of the intestinal barrier (IB) or exacerbated after IB disruption, initiates various common chronic diseases along its dispersal routes, and eventually impairs BBB integrity to cause NF&ND and brain aging. To illustrate the immune roles of the BBB in pathophysiology affected by inflammatory or “leaky” IB resulting from GM and their metabolites, we reviewed the selected publications, including the role of the BBB as the immune barrier, systemic chronic inflammation and inflammation influences on BBB permeability, NF&ND, and brain aging. To add depth to the bridging role of systemic chronic inflammation, a plausible mechanism indispensable for BBB corruption was highlighted; namely, BBB maintenance cues are affected by inflammatory cytokines, which may help to understand how GM and its metabolites play a major role in NF&ND and aging.

Dual-Hit Model of Parkinson’s Disease: Impact of Dysbiosis on 6-Hydroxydopamine-Insulted Mice—Neuroprotective and Anti-Inflammatory Effects of Butyrate

“…Recent advances strongly suggested the correlation between neuroinflammation, neurodegeneration, and gut microbiota alteration [ 14 ], sustained by host genomics, lifestyle, age, sex, comorbidity, and polypharmacy [ 15 ]. Hence, prolonged dysbiosis leads to gut immune dysregulation, intestinal barrier disruption, and local and/or systemic inflammation, with the potential to perturb brain homeostasis [ 16 ].…”

Effects of a Mealworm (Tenebrio molitor) Extract on Metabolic Syndrome-Related Pathologies: In Vitro Insulin Sensitivity, Inflammatory Response, Hypolipidemic Activity and Oxidative Stress

“…Inflammation is a common cellular response in many diseases, as well as a defense response against pathogens. In particular, the chronic inflammation of the central nervous system (CNS) was related to peripheral metabolic alterations including those associated with obesity, insulin resistance and type 2 diabetes [ 39 , 40 ]. Therefore, the ability of the mealworm extract to counteract LPS-mediated proinflammatory effects in resident macrophages of the CNS was investigated in immortalized murine microglial cells.…”

Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)

“…LPS core-OSs often contain highly immunogenic non-carbohydrate components including amino acids, phosphate groups and/or ethanolamine substituents that are highly variable in composition amongst all Gram-negative bacterial species and even within strains of the same species [ 5 , 6 , 7 , 9 , 10 , 11 , 12 ]. Together as a group, (i) LPSs are highly varied in their basic structure, organization and immunogenicity; (ii) they are classified as pathogen-associated molecular pattern (PAMP) molecules containing microbial-conserved molecular motifs recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs); (iii) they activate cells of the innate-immune system, such as macrophages and neutrophils, which synthesize pro-inflammatory factors that include cytokines, chemokines (chemotactic cytokines) and adipokines such as interleukin-1β (IL-1β), tumor necrosis factor (TNF), free radicals and reactive oxygen species (ROS); (iv) they act as prototypical endotoxins that promote the efflux of nitric oxides and eicosanoids; (v) because of their amphipathic character, they relatively easily pass through GI-tract biophysical barriers into the systemic circulation, especially when these barriers are damaged, diseased or ‘leaky’, such as in ‘ leaky gut syndrome ’ [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]; (vi) they invariably lead to significant innate-immune and pro-inflammatory responses in the infected host tissue; (vii) they strongly induce pro-inflammatory transcription factor signaling, which includes an up-regulation of NF-kB (p50/p65)-DNA binding and the transactivation of pro-inflammatory gene expression, especially in neuroglia and other related brain cell types; (viii) they up-regulate the abundance of NF-kB (p50/p65)-sensitive microRNAs, such as miRNA-30b, miRNA-34a, miRNA-146a and miRNA-155; (ix ) which is followed by a significant down-regulation of the expression of neuron-specific messenger RNA (mRNA) targets, including those that encode synaptic (SYN), neurofilament (NF) and other structural and cytoarchitectural components of the neuron [ 9 , 10 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…The genus Bacteroidetes , and in particular Gram-negative anaerobe, non-spore -forming bacillus Bacteroides fragilis , which is especially abundant in deeper regions of the GI-tract, is among the most studied and genetically understood of all human GI-tract resident microbes [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 31 , 32 , 33 , 37 ]. B. fragilis exhibits a significant amount of intra-species genomic diversity and associated range and variety of potential biochemical functions, and as a prominent Genus species , it has significant potential to secrete: (i) both a ‘generic’ form of LPS and a unique, exceptionally potent, pro-inflammatory LPS subtype, BF-LPS [ 30 , 38 ]; (ii) a zinc-metalloproteinase known as B. fragilis toxin (BFT) or fragilysin; (iii) truncated LPS molecules known as lipooligosaccharides ( LOSs ) [ 8 , 19 , 20 ]; and (iv) bacterial-derived miRNA-like small non-coding RNAs (sncRNAs) [ 18 , 19 , 20 , 21 ]. Bacterial-derived sncRNAs are important microbial regulators that often act to transmit environmental signals when cells encounter suboptimal or stressful growth conditions and whose functions remain incompletely understood [ 29 , 30 , 37 , 38 ].…”