N-acyl glycines produced by commensal bacteria potentiate GLP-1 secretion as GPCR ligands

Abstract

Commensal microbiota is crucial for nutrient digestion and production of biologically active molecules, many of which mimic endogenous ligands of human GPCRs. Bacteroides spp. are among the most abundant bacteria residing in the human gut and their absence has been positively correlated with metabolic disorders. In the present study, we focused on N-acylated glycines (NAGlys) as products of Bacteroides spp. and potential GPCR ligands modulating GLP-1 secretion. Representative strains of the most abundant commensal Bacteroides were cultured in either yeast- or animal-based nutrient broths. The broths post-culture were investigated in terms of the contents of NAGlys and stimulatory effects towards GLP-1 production in GLUTag and NCI-H716 cell lines. Pure preparations of the detected NAGlys were further studied to evaluate stimulation of GLP-1 production and related cellular signalling evoked. The most potent NAGlys were also tested as ligands of key lipid GPCRs involved in the regulation of carbohydrate metabolism: GPR40/FFAR1, GPR55, GPR119, and GPR120/FFAR4. We found that Bacteroides potentiate GLP-1 production, depending on the strain and provided nutrient mix. Long-chain unsaturated oleoyl and arachidonoyl glycines, produced by B. thetaiotaomicron and B. intestinalis in the animal-based broth, were particularly effective in stimulation of GLP-1 secretion. They served as agonists of all the receptors under study expressed in GLP-1-producing cells. The obtained results broaden the knowledge of microbial signalling molecules and their role in regulation of carbohydrate homeostasis. They also emphasise the importance of balanced diet as a source of building blocks for commensal bacteria to produce efficient agonists of lipid GPCRs.