Dysbiosis of Gut Microbiota from the Perspective of the Gut-Brain Axis: Role in the Provocation of Neurological Disorders

Abstract

The gut-brain axis is a bidirectional communication network connecting the gastrointestinal tract and central nervous system. The axis keeps track of gastrointestinal activities and integrates them to connect gut health to higher cognitive parts of the brain. Disruption in this connection may facilitate various neurological and gastrointestinal problems. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Misfolded protein aggregates that cause cellular toxicity and that aid in the collapse of cellular proteostasis are a defining characteristic of neurodegenerative proteinopathies. These disorders are not only caused by changes in the neural compartment but also due to other factors of non-neural origin. Mounting data reveal that the majority of gastrointestinal (GI) physiologies and mechanics are governed by the central nervous system (CNS). Furthermore, the gut microbiota plays a critical role in the regulation and physiological function of the brain, although the mechanism involved has not yet been fully interpreted. One of the emerging explanations of the start and progression of many neurodegenerative illnesses is dysbiosis of the gut microbial makeup. The present understanding of the literature surrounding the relationship between intestinal dysbiosis and the emergence of certain neurological diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, is the main emphasis of this review. The potential entry pathway of the pathogen-associated secretions and toxins into the CNS compartment has been explored in this article at the outset of neuropathology. We have also included the possible mechanism of undelaying the synergistic effect of infections, their metabolites, and other interactions based on the current understanding.

Keywords: gut dysbiosis; gut microbiota; gut–brain axis; neurodegenerative disease; neuroinflammation; vagus nerve.

Figure 1

Summary of the gut microbiota-associated functioning in the human body. The gut microbiota leads to enhanced lipid clearance by repressing angiopoietin-like protein 4 (Angptl4), an inhibitor of LPL, due to which energy metabolites are elevated in the serum, which is demonstrated by an increase in associated genes in the liver transcriptome. Triglyceride levels in the serum are reduced while they rise in adipose tissue and in the liver. Dietary carbohydrates are metabolized into SCFAs, a rich energy source for the host by colonic bacteria by employing a special class of enzyme, hydrolases. Furthermore, these SCFAs, especially butyrate, can provoke the GPCR 43 expressed by intestinal epithelial cells and regulate the development, differentiation, and maturation of Treg cells via epigenetic regulation, resulting in the inhibition of Th17 cell development and the reduction of colonic inflammation. Selected gut microbiota can also act as vitamin suppliers to the host, as they synthesize vitamin B complexes and vitamin K and supplies them to the host.

Figure 2

Illustrative diagram depicting the interconnection between gut and brain. The proposed bidirectional communication is firmly affected by various pathways, including the autonomic nervous system (ANS), hypothalamic–pituitary–adrenal (HPA), immune pathways, enteric nervous system (ENS), endocrine pathways, and neural pathways. Gut microbiota can produce microbial metabolites that activate the neuroenteric plexus, stimulate neuropeptide production in the brain, and increase gut–blood barrier and blood–brain barrier (BBB) permeability. The brain releases molecules that stimulate the function of the gut and neuroendocrine plexus.

Figure 3

Variation in the composition of microbial diversity at the phylum level in numerous neurological disorders (AD, MS, PD, and HD). Changes in the occurrence of gut microbial population, dominant gut phyla, including Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, Verrucomicrobia, and Fusobacteria, in neurological illnesses compared to in healthy controls.

Figure 4

Probable mechanism of gut microbial population and their metabolites to cause neuroinflammation. Intensification and accumulation of pathogenic gut microbiota due to dysbacteriosis lead to the formation of an inflamed and leaky gut. Microbes and their associated metabolites can enter the peripheral circulatory system, where they further lower the expression of tight junction proteins in brain endothelial cells and lead to the disintegration of the blood–brain barrier that promotes the entrance of pathogenic microbes, some of them carrying prions into the brain. Meanwhile, microbial metabolites stimulate the extravasation of immune cells into the brain, all of which together trigger cytokine storm, the cause of neuroinflammation, one of the important hallmarks of neurological disorders characterized by degenerated and demyelinated neurons.

Figure 5

Composition of gut microbiota in the healthy aging process. The age-related sequential change in gut microbiota composition and metabolic function from infant to centenarian.

Figure 6

Schematic diagram depicting the effect of a lone bacterial or viral infection and pathogenic coinfection in engendering neuroinflammation. The role of extracellular vesicles from bacteria-infected cells in virus reactivation via PBMC in contributing to neuroinflammation has to be explored. Meanwhile, the analysis of the combined effect of pathogens on various neurodegenerative markers and inflammation could be contemplated in the co-infection models. NB:? signifies the nonavailability of direct evidence and study needs to be done in this aspect.