The Gut Feeling: GPCRs Enlighten the Way

Abstract

Host-microbiome interactions affect host physiology, but the underlying mechanisms are not well understood. Recent papers from Chen et al. (2019) and Colosimo et al. (2019) in this issue of Cell Host & Microbe demonstrate that metabolites produced by several members of the gut microbiota can efficiently activate host G protein-coupled receptors and influence host physiology.

Figure 1. Microbiota Metabolites Influence Host Physiology through G Protein-Coupled Receptors

(A)Screening of metabolites produced by the individual members of human gut microbiota identifies several GPCR agonists. Chen et al. used culture supernatants from 144 unique bacterial isolates to measure the activation of non-olfactory GPCRs using GPCR-βarr interaction as readout. Microbiota metabolites activate a diverse spectrum of GPCRs with a predominant effect on aminergic receptors. Interestingly, some of the metabolites exhibit receptor subtype selectivity as well as functional selectivity. Moreover, bacterial metabolites such as L-Phe (phenylalanine) also activate orphan GPCRs belonging to the adhesion subfamily such as GPR56 and GPR97. (B)The ability of isolated bacterial cultures to produce GPCR agonists is recapitulated in vivo. Germ-free mice colonized with Morganella morganii (M. morganii) display enhanced levels of histamine and L-Phe (phenylalanine). Feeding M. morganii monocolonized mice with L-His(histidine), a precursor of histamine, further substantiates histamine levels and results in increased colonic motility in mice. Furthermore, M. morganii colonization also results in enhanced level of PEA and leads to lethargic behavior in mice treated with MAO (monoamine oxidase) inhibitor. (C)Metabolic exchange between two bacterial isolates is observed in mice colonized with defined bacterial species. Germ-free mice were colonized with Bacteroides thetaiotaomicron (B. theta) and Morganella morganii (M. morganii). L-Phe (pheylalanine) produced by B. theta can be processed into PEA (phenethylamine), a dopamine receptor agonist, by M. morganii and leads to lethargic behavior in mice treated with monoamine oxidase (MAO) inhibitor. This figure is designed based on the findings described recently by Chen et al. (2019).