Chemogenetics defines a short-chain fatty acid receptor gut–brain axis
Natasja Barki,
Daniele Bolognini,
Ulf Börjesson,
Laura Jenkins,
John Riddell,
David I Hughes,
Trond Ulven,
Brian D Hudson,
Elisabeth Rexen Ulven,
Niek Dekker,
Andrew B Tobin,
Graeme Milligan
Affiliations
Natasja Barki
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
Daniele Bolognini
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
Ulf Börjesson
Discovery Sciences, Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden
Laura Jenkins
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
John Riddell
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken, Copenhagen, Denmark
Brian D Hudson
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
Elisabeth Rexen Ulven
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken, Copenhagen, Denmark
Niek Dekker
Discovery Sciences, Biopharmaceutical R&D, AstraZeneca, Gothenburg, Sweden
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
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.
