PT  - JOURNAL ARTICLE
AU  - Natasja Barki
AU  - Daniele Bolognini
AU  - Ulf Börjesson
AU  - Laura Jenkins
AU  - John Riddell
AU  - David I. Hughes
AU  - Trond Ulven
AU  - Brian D. Hudson
AU  - Elisabeth Rexen Ulven
AU  - Niek Dekker
AU  - Andrew B. Tobin
AU  - Graeme Milligan
TI  - Chemogenetic analysis of how receptors for short chain fatty acids regulate the gut-brain axis
AID  - 10.1101/2020.01.11.902726
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.11.902726
4099  - http://biorxiv.org/content/early/2020/01/13/2020.01.11.902726.short
4100  - http://biorxiv.org/content/early/2020/01/13/2020.01.11.902726.full
AB  - The gut-brain axis allows bi-directional communication between the enteric and central nervous systems. Short chain fatty acids (SCFAs) generated by the gut microbiota are important regulators of this interface. However, defining mechanisms by which SCFAs do so has been challenging because, amongst various roles, they co-activate both of a pair of closely related and poorly characterized G protein-coupled receptors, FFA2 and FFA3. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) can provide an important approach in defining receptor-specific functions. By screening a library of carboxylate-containing small molecules we identified 4-methoxy-3-methyl-benzoic acid (MOMBA) as a specific agonist of a DREADD variant of FFA2 which is not activated by SCFAs. Using mice engineered to replace FFA2 with this FFA2-DREADD, whilst retaining FFA3 expression, combinations of MOMBA and the now FFA3 receptor selective SCFAs defined key, but distinct, roles of FFA2 and FFA3 in each of gut transit time, secretion of entero-endocrine hormones, and communication from the gut to each of autonomic and somatic sensory ganglion cells and the spinal cord. These studies map mechanisms and signalling pathways by which each of FFA2 and FFA3 act to link the gut and the brain and provide both animal models and novel tool compounds to further explore this interface.