Commensal-derived acetylcholine enhances mucosal immune education

Area of Science:

• Microbiome research
• Metabolomics
• Immunology

Background:

• The gut microbiota produces numerous bioactive small molecules that influence host physiology.
• G-protein-coupled receptors (GPCRs) are activated by various microbial metabolites, but their full range of activities in vivo remains largely unexplored due to technical challenges.

Purpose of the Study:

• To comprehensively assess the GPCRome-wide bioactivities of in vivo and in vitro commensal metabolomes.
• To investigate how the host environment influences microbial metabolism and metabolite bioactivity.

Main Methods:

• Utilized multiplexed GPCR screening technology to analyze 100 commensal strains.
• Compared metabolomes from bacteria grown in vivo (monoassociated germ-free mice) versus in vitro (culture medium).
• Employed mechanistic studies to identify bacterial enzymes responsible for specific metabolite production.

Main Results:

• In vivo and in vitro metabolomes showed distinct GPCR activation profiles.
• Identified that several commensal strains, including Bifidobacterium and Pediococcus, produce acetylcholine (ACh) in vivo from dietary choline.
• Demonstrated that mice colonized with ACh-producing Bifidobacterium breve exhibited enhanced IgA production, altered microbiota, and increased resistance to infection.

Conclusions:

• The in vivo environment significantly impacts microbiota metabolism and metabolite bioactivity.
• Revealed a diet-microbiome-host axis where bacterial production of acetylcholine strengthens mucosal immunity and promotes host-microbiota mutualism.