A Comprehensive Review on the Role of the Gut Microbiome in Human Neurological Disorders

Abstract

The human body is full of an extensive number of commensal microbes, consisting of bacteria, viruses, and fungi, collectively termed the human microbiome. The initial acquisition of microbiota occurs from both the external and maternal environments, and the vast majority of them colonize the gastrointestinal tract (GIT). These microbial communities play a central role in the maturation and development of the immune system, the central nervous system, and the GIT system and are also responsible for essential metabolic pathways. Various factors, including host genetic predisposition, environmental factors, lifestyle, diet, antibiotic or nonantibiotic drug use, etc., affect the composition of the gut microbiota. Recent publications have highlighted that an imbalance in the gut microflora, known as dysbiosis, is associated with the onset and progression of neurological disorders. Moreover, characterization of the microbiome-host cross talk pathways provides insight into novel therapeutic strategies. Novel preclinical and clinical research on interventions related to the gut microbiome for treating neurological conditions, including autism spectrum disorders, Parkinson's disease, schizophrenia, multiple sclerosis, Alzheimer's disease, epilepsy, and stroke, hold significant promise. This review aims to present a comprehensive overview of the potential involvement of the human gut microbiome in the pathogenesis of neurological disorders, with a particular emphasis on the potential of microbe-based therapies and/or diagnostic microbial biomarkers. This review also discusses the potential health benefits of the administration of probiotics, prebiotics, postbiotics, and synbiotics and fecal microbiota transplantation in neurological disorders.

Keywords: fecal-microbiota transplantation; gut microbiota; neurodegenerative disorders; neuropsychiatric disorders; probiotic.

FIG 1

Association of gut microbiome and CNS functions in neurological diseases.

FIG 2

Molecular communication pathways among the microbiota and the brain via the gut-brain axis (GBA). Several direct including, vagus nerve, and indirect pathways, such as cytokines, SCFA, and essential dietary amino acids (e.g., tyrosine, histidine, and tryptophan), have roles in modulation of the gut-brain axis by gut microbiota. The gut-brain axis is comprised of the immune pathway (including cytokines); microbial metabolites; the neuroactive pathway, such as neuroactive metabolites and neurotransmitters; and the neural pathway (spinal nerves, enteric nervous system, and vagus nerve); the endocrine pathway; and the hypothalamic-pituitary-adrenal axis. Microbes residing in gastrointestinal tract are capable of neurotransmitters synthesis, including GABA, serotonin, dopamine, and noradrenaline, locally playing an essential part of the cross talk between the host and the microbiome. Bacterial neuroactive metabolites and dietary molecules can alter the brain and behavior in several ways that are still being discovered, such as influencing epithelial cells to affect the function of the epithelial barrier, hormone release from enteroendocrine cells, and modulation of microglial and immune cells functions through dendritic cells. Abbreviations: AD, Alzheimer’s disease; ASD, autism spectrum disorder; MS, multiple sclerosis; PD, Parkinson’s disease; HDP, host defense proteins; EC, enterochromaffin cells; 5-HT, 5-hydroxytryptamine (serotonin); SCFAs, short-chain fatty acids; GABA, γ-aminobutyric acid; LPS, lipopolysaccharide; TPH, tryptophan hydroxylase.

FIG 3

Schematic presentation of molecular pathways by which the changes related to age in gastrointestinal tract (GIT) microflora and the neuro-entero-endocrine system might influence the brain’s health through dysfunction of the gut-brain signaling pathway. In healthy adult individuals, the balanced gut microflora and gut barrier integrity contribute to maintaining balanced microbial communities and their metabolites, including SCFAs. In addition, the appropriate production of neurotransmitters in the gastrointestinal tract aids in the maintenance of controlled enteric- inflammatory and immune systems via the balanced proliferation of macrophages and dendritic cells, which finally leads to controlled gut-brain communication and appropriate functioning of the CNS. However, in the senescent host, an alteration in the diversity of gastrointestinal microbial communities and disruption of gut barrier integrity contributes to the perturbation of the biochemical and microbial microenvironment of the epithelial cell lining of the GI tract through unbalanced levels of SCFA, LPS, 5-HT, histamine, secretory immunoglobin (sIgA), etc. Consequently, inducing an overactivated inflammatory environment in the intestinal environment leads to the disruption of healthy gut-brain communication. Abbreviations: SCFA, short-chain fatty acids; LPS, lipopolysaccharide; 5-HT, 5-hydroxytryptamine; TNF-α, tumor necrosis factor α; IFN-δ, interferon δ; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein 1; CNS, central nervous system.

FIG 4

Organizational structure of the main steps implicated in the bioinformatic analysis of the gastrointestinal microbiome. The general overview of the bioinformatic analysis pipelines is divided into two branches based on the type of sequencing, including 16S rRNA gene microbial profiling and shotgun metagenomics. After microbial DNA extraction and sequencing, the pipeline determines the taxonomic profiling of the gut microbiota and the genomes’ reconstruction, in addition to a functional analysis of the genes. This schematic presentation depicts the major steps and may be modified according to the analysis’ ultimate objective. ASV, amplicon sequence variant; OTU, operational taxonomic unit.

FIG 5

Modulation of gut microbiota by therapeutic microbial interventions. Microbial interventions, including probiotics, prebiotics postbiotics, synbiotics, and fecal microbiota transplant (FMT), improve the microbiota-gut-brain axis through modification of the microbial communities. Modulation of the microbial composition, regulation of their essential metabolites, or both can improve neurological complications by increasing neurochemicals and SCFAs and reducing intestinal permeability, regulation of neural, metabolic, and immune pathways. Each approach can be improved by personalized medicine for more effective management of a patient’s pathophysiology.