Chemogenetics defines a short-chain fatty acid receptor gut-brain axis
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
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.
In: eLife, Vol. 11, e73777, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - 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
N1 - Publisher Copyright: © 2022, Barki et al.
PY - 2022
Y1 - 2022
N2 - 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.
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 - gut–brain axis
KW - medicine
KW - mouse
KW - short-chain fatty acids
U2 - 10.7554/eLife.73777
DO - 10.7554/eLife.73777
M3 - Journal article
C2 - 35229717
AN - SCOPUS:85125559473
VL - 11
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e73777
ER -
ID: 300064404