![]() Over the course of evolution genes encoding many ancestral forms of GPCRs have multiplied and diversified to provide enhanced flexibility of signaling and integration of responses to either the same or closely related ligands. Although a range of their key effects are believed to be produced by activation of G protein-coupled receptors (GPCRs), both locally in the lower gut and following uptake into the systemic circulation, which of these roles are generated directly by individual receptors and via which signaling pathways and circuits remains undefined. SCFAs play central roles in homeostasis at the interface between metabolism and immunity ( Alvarez-Curto and Milligan, 2016 Tan et al., 2014) and within the gut–brain axis ( van de Wouw et al., 2018 Dalile et al., 2019). ![]() Among these short-chain fatty acids (SCFAs), particularly acetate (C2) and propionate (C3), are generated in prodigious amounts by fermentation of fiber and other nondigestible carbohydrates in the lower gut. The microbiota produces a wide array of metabolites that can modulate host cells and their functions ( Chen et al., 2019 Nicolas and Chang, 2019). Growing evidence highlights the role that the intestinal microbiota may play in such interactions ( Bienenstock et al., 2015) and in the development of disease ( Luca et al., 2019). The gut–brain axis allows bidirectional communication between the enteric and central nervous systems. 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. 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. 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. 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. ![]() The primary GPCR targets for these SCFAs are FFA2 and FFA3. 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). ![]()
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