Potential Therapeutic Effects of Short-Chain Fatty Acids on Chronic Pain

Abstract

The intestinal homeostasis maintained by the gut microbiome and relevant metabolites is essential for health, and its disturbance leads to various intestinal or extraintestinal diseases. Recent studies suggest that gut microbiome-derived metabolites short-chain fatty acids (SCFAs) are involved in different neurological disorders (such as chronic pain). SCFAs are produced by bacterial fermentation of dietary fibers in the gut and contribute to multiple host processes, including gastrointestinal regulation, cardiovascular modulation, and neuroendocrine-immune homeostasis. Although SCFAs have been implicated in the modulation of chronic pain, the detailed mechanisms that underlie such roles of SCFAs remain to be further investigated. In this review, we summarize currently available research data regarding SCFAs as a potential therapeutic target for chronic pain treatment and discuss several possible mechanisms by which SCFAs modulate chronic pain.

Keywords: Short-chain fatty acids; chronic pain; gut microbiome; gut-brain communication; intestinal diseases.; metabolites.

Fig. (1)

Schematic diagram showing potential mechanisms by which SCFAs modulate chronic pain. SCFAs could contribute to pain modulation through the following mechanisms: histone acetylation-mediated epigenetic mechanism, neurotransmitter regulation, enteroendocrine signaling, vagus nerve activation, and microglial activation. (Abbreviations: CNS, central nervous system; FFAR, free fatty acid receptor; GAD65, glutamic acid decarboxylase 65; GLP1, glucagon-like peptide 1; 5-HT, serotonin; mGlu2, metabotropic glutamate receptor 2; MOR, μ-opioid receptor; PYY, peptide YY).

Fig. (2)

Mechanisms underlying SCFAs-mediated epigenetic regulation of chronic pain. SCFAs function as an inhibitor of HDACs to mediate epigenetic regulation of chronic pain. As shown in the figure, by inhibiting HDACs, SCFAs epigenetically modulate chronic pain through the following mechanisms: 1) inhibiting the PI3K/Akt/GSK-3β signal pathway; 2) diminishing inflammatory response in microglia; 3) up-regulating the expression of mGlu2, GAD65 and MOR in the CNS. Together, SCFAs can produce pain relief. (Abbreviations: GAD65, glutamic acid decarboxylase 65; HDAC, histone deacetylase; mGlu2, metabotropic glutamate receptor 2; MOR, μ-opioid receptor; SCFAs, short-chain fatty acids).

Fig. (3)

Vagus nerve activation induced by SCFAs for pain modulation. SCFAs can directly or indirectly activate vagal afferents to contribute to pain modulation. SCFA receptor FFAR3 is expressed in the nodose ganglia's vagal sensory neurons, and SCFAs can bind to FFAR3 to produce vagal afferent activation. SCFAs can also promote the release of serotonin or gut hormones from intestinal ECCs. Together, these direct and indirect mechanisms underlie SCFAs-caused vagus nerve activation during chronic pain. (Abbreviations: 5-HT, serotonin; ECCs, enterochromaffin cells; FFAR3, free fatty acid receptor 3; SCFAs, short-chain fatty acids).