Targeting Gut Dysbiosis and Microbiome Metabolites for the Development of Therapeutic Modalities for Neurological Disorders

Abstract

The gut microbiota, composed of numerous species of microbes, works in synergy with the various organ systems in the body to bolster our overall health and well-being. The most well-known function of the gut microbiome is to facilitate the metabolism and absorption of crucial nutrients, such as complex carbohydrates, while also generating vitamins. In addition, the gut microbiome plays a crucial role in regulating the functioning of the central nervous system (CNS). Host genetics, including specific genes and single nucleotide polymorphisms (SNPs), have been implicated in the pathophysiology of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD). The gut microbiome dysbiosis also plays a role in the pathogenesis of these neurodegenerative disorders, thus perturbing the gut-brain axis. Overproduction of certain metabolites synthesized by the gut microbiome, such as short-chain fatty acids (SCFAs) and p-cresyl sulfate, are known to interfere with microglial function and trigger misfolding of alpha-synuclein protein, which can build up inside neurons and cause damage. By determining the association of the gut microbiome and its metabolites with various diseases, such as neurological disorders, future research will pave the way for the development of effective preventive and treatment modalities.

Keywords: Alzheimer’s disease; Autism spectrum disorder.; Gut microbiome; Parkinson’s disease; gut dysbiosis; gut metabolite; neurological disorders; therapeutic modalities.

Fig. (1)

A graphical representation highlighting the role of gut dysbiosis, microbiome metabolites and host genetics in predisposition to neurological disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and autism spectrum disorder (ASD).

Fig. (2)

Potential pathways through which short-chain fatty acids (SCFAs) influence gut-brain communication. SCFAs are the main metabolites produced by the microbiota in the large intestine through the anaerobic fermentation of indigestible polysaccharides, such as dietary fiber and resistant starch. SCFAs might influence gut-brain communication and brain function directly or indirectly. Following their production, SCFAs are absorbed by colonocytes, mainly via H⁺-dependent monocarboxylate transporters (MCTs) or sodium-dependent monocarboxylate transporters (SMCTs). Through binding to G protein-coupled receptors (GPCRs), such as free fatty acid receptors 2 and 3 (FFAR2 and FFAR3), as well as GPR109a/HCAR2 (hydrocarboxylic acid receptor) and GPR164 or by inhibiting histone deacetylases, SCFAs influence intestinal mucosal immunity, and barrier integrity and function. SCFAs interaction with their receptors on enteroendocrine cells promotes indirect signaling to the brain via the systemic circulation or vagal pathways by inducing the secretion of gut hormones, such as glucagon-like peptide 1 (GLP1) and peptide YY (PYY), as well as GABA and serotonin (5-HT). Colon-derived SCFAs reach the systemic circulation and other tissues, leading to brown adipose tissue activation, regulation of liver mitochondrial function, increased insulin secretion by β-pancreatic cells, and whole-body energy homeostasis. Peripherally, SCFAs influence systemic inflammation mainly by inducing Treg cell differentiation and regulating the secretion of interleukins. SCFAs can cross the BBB via monocarboxylate transporters located on endothelial cells and influence BBB integrity by upregulating the expression of tight junction proteins. Finally, in the CNS, SCFAs also influence neuroinflammation by affecting glial cell morphology and function as well as by modulating the levels of neurotrophic factors, increasing neurogenesis, contributing to the biosynthesis of serotonin, and improving neuronal homeostasis and function. Together, the interaction of SCFAs with these gut-brain pathways can directly or indirectly affect the emotion, cognition, and pathophysiology of brain disorders. A figure of this review was created with BioRender (https://biorender.com/). Taken from Silva et al., 2020, which is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) [25]. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice.