TY - JOUR TI - Chemogenetics defines a short-chain fatty acid receptor gut–brain axis AU - Barki, Natasja AU - Bolognini, Daniele AU - Börjesson, Ulf AU - Jenkins, Laura AU - Riddell, John AU - Hughes, David I AU - Ulven, Trond AU - Hudson, Brian D AU - Ulven, Elisabeth Rexen AU - Dekker, Niek AU - Tobin, Andrew B AU - Milligan, Graeme A2 - Karsenty, Gérard A2 - Zaidi, Mone VL - 11 PY - 2022 DA - 2022/03/01 SP - e73777 C1 - eLife 2022;11:e73777 DO - 10.7554/eLife.73777 UR - https://doi.org/10.7554/eLife.73777 AB - 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. KW - Designer Receptor Exclusively Activated by Designer Drugs KW - short-chain fatty acids KW - gut–brain axis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -