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

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...

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Autores principales: Barki, Natasja, Bolognini, Daniele, Börjesson, Ulf, Jenkins, Laura, Riddell, John, Hughes, David I, Ulven, Trond, Hudson, Brian D, Ulven, Elisabeth Rexen, Dekker, Niek, Tobin, Andrew B, Milligan, Graeme
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887895/
https://www.ncbi.nlm.nih.gov/pubmed/35229717
http://dx.doi.org/10.7554/eLife.73777
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author Barki, Natasja
Bolognini, Daniele
Börjesson, Ulf
Jenkins, Laura
Riddell, John
Hughes, David I
Ulven, Trond
Hudson, Brian D
Ulven, Elisabeth Rexen
Dekker, Niek
Tobin, Andrew B
Milligan, Graeme
author_facet Barki, Natasja
Bolognini, Daniele
Börjesson, Ulf
Jenkins, Laura
Riddell, John
Hughes, David I
Ulven, Trond
Hudson, Brian D
Ulven, Elisabeth Rexen
Dekker, Niek
Tobin, Andrew B
Milligan, Graeme
author_sort Barki, Natasja
collection PubMed
description 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.
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spelling pubmed-88878952022-03-02 Chemogenetics defines a short-chain fatty acid receptor gut–brain axis Barki, Natasja Bolognini, Daniele Börjesson, Ulf Jenkins, Laura Riddell, John Hughes, David I Ulven, Trond Hudson, Brian D Ulven, Elisabeth Rexen Dekker, Niek Tobin, Andrew B Milligan, Graeme eLife Medicine 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. eLife Sciences Publications, Ltd 2022-03-01 /pmc/articles/PMC8887895/ /pubmed/35229717 http://dx.doi.org/10.7554/eLife.73777 Text en © 2022, Barki et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Medicine
Barki, Natasja
Bolognini, Daniele
Börjesson, Ulf
Jenkins, Laura
Riddell, John
Hughes, David I
Ulven, Trond
Hudson, Brian D
Ulven, Elisabeth Rexen
Dekker, Niek
Tobin, Andrew B
Milligan, Graeme
Chemogenetics defines a short-chain fatty acid receptor gut–brain axis
title Chemogenetics defines a short-chain fatty acid receptor gut–brain axis
title_full Chemogenetics defines a short-chain fatty acid receptor gut–brain axis
title_fullStr Chemogenetics defines a short-chain fatty acid receptor gut–brain axis
title_full_unstemmed Chemogenetics defines a short-chain fatty acid receptor gut–brain axis
title_short Chemogenetics defines a short-chain fatty acid receptor gut–brain axis
title_sort chemogenetics defines a short-chain fatty acid receptor gut–brain axis
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887895/
https://www.ncbi.nlm.nih.gov/pubmed/35229717
http://dx.doi.org/10.7554/eLife.73777
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