The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication

Abstract

A substantial body of evidence supports that the gut microbiota plays a pivotal role in the regulation of metabolic, endocrine and immune functions. In recent years, there has been growing recognition of the involvement of the gut microbiota in the modulation of multiple neurochemical pathways through the highly interconnected gut-brain axis. Although amazing scientific breakthroughs over the last few years have expanded our knowledge on the communication between microbes and their hosts, the underpinnings of microbiota-gut-brain crosstalk remain to be determined. Short-chain fatty acids (SCFAs), the main metabolites produced in the colon by bacterial fermentation of dietary fibers and resistant starch, are speculated to play a key role in neuro-immunoendocrine regulation. However, the underlying mechanisms through which SCFAs might influence brain physiology and behavior have not been fully elucidated. In this review, we outline the current knowledge about the involvement of SCFAs in microbiota-gut-brain interactions. We also highlight how the development of future treatments for central nervous system (CNS) disorders can take advantage of the intimate and mutual interactions of the gut microbiota with the brain by exploring the role of SCFAs in the regulation of neuro-immunoendocrine function.

Keywords: central nervous system; gut microbiota; gut-brain axis; neuroinflammation; short-chain fatty acids.

Figure 1

Potential pathways through which SCFAs influence gut-brain communication. Short-chain fatty acids (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 receptor 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. SCFA 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 γ-aminobutyric acid (GABA), and serotonin (5-HT). Colon-derived SCFAs reaches 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 T regulatory cells (Treg) differentiation and by regulating the secretion of interleukins. SCFAs can cross the blood-brain barrier (BBB) via monocarboxylate transporters located on endothelial cells and influence BBB integrity by upregulating the expression of tight junction proteins. Finally, in the central nervous system (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 emotion, cognition, and pathophysiology of brain disorders. Figure of this review was created with BioRender (https://biorender.com/).