Chemogenetics defines the roles of short chain fatty acid receptors within the gut-brain axis

Barki, N. et al. (2022) Chemogenetics defines the roles of short chain fatty acid receptors within the gut-brain axis. eLife, 11, e73777. (doi: 10.7554/eLife.73777) (PMID:35229717)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hughes, Dr David I and Bolognini, Dr Daniele and Milligan, Professor Graeme and Tobin, Andrew and Barki, Ms Natasja and Jenkins, Mrs Laura and Riddell, Professor John and Hudson, Dr Brian
Creator Roles:
Barki, N.Conceptualization, Data curation, Investigation, Methodology, Validation, Writing – original draft
Tobin, A.Conceptualization, Funding acquisition, Methodology, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing
Milligan, G.Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, ["credit_typename_" not defined], Writing – original draft, Writing – review and editing
Bolognini, D.Formal analysis, Investigation, Methodology
Jenkins, L.Formal analysis, Investigation, Methodology, Validation
Hughes, D. I.Investigation, Methodology, Supervision
Hudson, B.Methodology
Riddell, J.Supervision
Authors: Barki, N., Bolognini, D., Börjesson, U., Jenkins, L., Riddell, J., Hughes, D. I., Ulven, T., Hudson, B. D., Rexen Ulven, E., Dekker, N., Tobin, A. B., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN:2050-084X
ISSN (Online):2050-084X
Copyright Holders:Copyright © 2022 Barki et al
First Published:First published in eLife 11: e73777
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190801Designer Receptor Exclusively Activated by Designer Drug' to define the role of short chain fatty acids in metabolic disease and inflammation (Fatty acid DREADD)Graeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/L027887/1MCSB - Molecular Pharmacology
173799Using a Designer Receptor Exclusively Activated by Designer Drug to define the role of short chain fatty acids in metabolic disease and inflammationAndrew TobinBiotechnology and Biological Sciences Research Council (BBSRC)BB/L02781X/2MCSB - Molecular Pharmacology
302989Defining physiological and pathophysiological roles of the Free Fatty Acid Receptor 2 by analysis of novel transgenic mouse modelsGraeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/S000453/1Institute of Molecular, Cell & Systems Biology