Short-chain fatty acids and microbiota metabolites attenuate ghrelin receptor signaling

The gastrointestinal microbiota is emerging as a unique and inexhaustible source for metabolites with potential to modulate G-protein coupled receptors (GPCRs). The ghrelin receptor [growth hormone secretagogue receptor (GHSR)-1a] is a GPCR expressed throughout both the gut and the brain and plays a crucial role in maintaining energy balance,metabolism, and the centralmodulation of food intake,motivation, reward, andmood. To date, few studies have investigated the potential of the gastrointestinal microbiota and its metabolites to modulate GPCR signaling. Here we investigate the ability of short-chain fatty acids (SCFAs), lactate, and different bacterial strains, including Bifidobacteriumand Lactobacillus genera, tomodulateGHSR-1a signaling.We identify, forwhat is to our knowledge the first time, a potent effect ofmicrobiota-derivedmetabolites on GHSR-1a signaling with potential significant consequences for host metabolism and physiology. We show that SCFAs, lactate, and bacterial supernatants are able to attenuate ghrelin-mediated signaling through the GHSR-1a.We suggest a novel route of communication between the gut microbiota and the host via modulation of GHSR-1a receptor signaling. Together, this highlights the emerging therapeutic potential in the exploration of themicrobiota metabolome in the specific targeting of key GPCRs, with pleiotropic actions that span both the CNS and periphery.
This study was supported by Science Foundation Ireland Research Centre Grant SFI/12/RC/2273 to the Alimentary Pharmabiotic Centre (APC) Microbiome Ireland, Student/Faculty Interaction (SFI) Grant 12/RC/2276 DBP and APC Microbiome Ireland industry partner Cremo SA