Commensal bacteria make GPCR ligands that mimic human signalling molecules.

Area of Science:

• Microbiology
• Metabolomics
• Synthetic Biology

Background:

• Commensal bacteria play vital roles in human health, with bacterial metabolites mediating host interactions.
• Mechanisms of host-microbe interactions are poorly understood, highlighting the need to identify bioactive microbial compounds.

Purpose of the Study:

• To identify N-acyl amides produced by the human microbiota that interact with G-protein-coupled receptors (GPCRs).
• To investigate the potential of these microbial metabolites in regulating host physiology, particularly gastrointestinal tract functions and metabolic homeostasis.

Main Methods:

• Bioinformatic analysis of the human microbiota to identify N-acyl amide synthase genes.
• Synthetic biology approaches to characterize the function of identified microbial genes and their encoded lipids.
• In vitro cell-based assays and in vivo mouse models to assess the interaction of microbial N-acyl amides with host GPCRs and their physiological effects.

Main Results:

• N-acyl amide synthase genes are enriched in gastrointestinal bacteria.
• Microbiota-derived N-acyl amides were found to interact with GPCRs involved in gastrointestinal physiology.
• Commensal GPR119 agonists effectively regulate metabolic hormones and glucose homeostasis in mouse and cell models.

Conclusions:

• Commensal bacteria may employ chemical mimicry of eukaryotic signaling molecules for host interactions.
• Microbiota genes encoding host-interactive metabolites represent a potential target for microbiome-biosynthetic gene therapy.
• Further research is needed to elucidate the precise physiological roles of these microbial metabolites in humans.