Chemogenetics defines a short-chain fatty acid receptor gut–brain axis

Abstract

Volatile small molecules, including the short-chain fatty acids (SCFAs), acetate and propionate, released by the gut microbiota from the catabolism of nondigestible starches, can act in a hormone-like fashion via specific G-protein-coupled receptors (GPCRs). The primary GPCR targets for these SCFAs are FFA2 and FFA3. Using transgenic mice in which FFA2 was replaced by an altered form called a Designer Receptor Exclusively Activated by Designer Drugs (FFA2-DREADD), but in which FFA3 is unaltered, and a newly identified FFA2-DREADD agonist 4-methoxy-3-methyl-benzoic acid (MOMBA), we demonstrate how specific functions of FFA2 and FFA3 define a SCFA–gut–brain axis. Activation of both FFA2/3 in the lumen of the gut stimulates spinal cord activity and activation of gut FFA3 directly regulates sensory afferent neuronal firing. Moreover, we demonstrate that FFA2 and FFA3 are both functionally expressed in dorsal root- and nodose ganglia where they signal through different G proteins and mechanisms to regulate cellular calcium levels. We conclude that FFA2 and FFA3, acting at distinct levels, provide an axis by which SCFAs originating from the gut microbiota can regulate central activity.

Communication of gut microbiota and brain via immune and neuroendocrine signaling

“…In addition, it was shown that oral supplementation of the three major SCFAs (acetate, propionate, and butyrate) in C57BL/6J mice undergoing psychosocial stress reduced disturbance in food-seeking behavior as well as reducing anti-depressant and anti-anxiety effects ( van de Wouw et al, 2018 ). SCFAs are presumed to affect the host nervous system in a hormone-like fashion via specific G-protein coupled receptors (GPCRs) ( Barki et al, 2022 ), which also include many metabotropic neurotransmitter receptors. On the other hand, emotional disorders such as chronic stress not only affect the metabolism of neurotransmitters but also have strong implications on the composition of the gut microbiota ( Yang et al, 2021 ).…”

Short chain fatty acids: key regulators of the local and systemic immune response in inflammatory diseases and infections

“…Interestingly, acetate can even reduce liver steatosis by suppressing appetite by acting on enteroendocrine cells and glutamate-glutamine and GABA neuroglial cycles associated with increasing hypothalamic lactate [ 159 ]. Mechanistically, FFAR2 and FFAR3 expressed by enteroendocrine cells mediate the release of peptide YY and GLP-1 [ 160 ], both important mediators of satiety [ 161 , 162 ]. In another study, butyrate supplementation was associated with reduced food uptake, promoted FAO and activation of brown adipose tissue with increased utilization of plasma triglyceride-derived fatty acids, which prevented diet-induced obesity, hyperinsulinemia, hypertriglyceridemia and hepatic steatosis [ 163 ].…”

Probiotic supplement as a promising strategy in early tau pathology prevention: Focusing on GSK-3β?

“…However, L. plantarum has been shown to increase the abundance of butyrate-producing bacteria Anaerotruncus and Faecalibacterium ( Wang et al, 2018 ). Therefore, it could mediate the brain effect through SCFAs circulating in the blood and binding to GPR43 receptors ( Brown et al, 2003 ; Barki et al, 2022 ; Tang et al, 2022 ), TLR ( Dang et al, 2018 ; Mohseni et al, 2021 ; Paveljsek et al, 2021 ), or IGF-1R via elevated serum IGF-1 ( Endo et al, 2013 ; Yan et al, 2016 ; Mohseni et al, 2021 ). IGF-1R is widely expressed in the brain such as the hippocampus ( Lin J. Y. et al, 2020 ).…”