A Forward Chemical Genetic Screen Reveals Gut Microbiota Metabolites That Modulate Host Physiology

Abstract

Highlights d Screening of gut microbiota metabolomes against hundreds of G protein-coupled receptors d Phylogenetically diverse gut microbes produce agonists for many GPCRs including orphans d Bioactivity-based screening reveals diet-microbe-host and microbe-microbe-host axes d Microbiota-derived GPCR ligands impact local and systemic host physiology

Diet‐derived microbial metabolites in health and disease

“…; Chen et al . ). Combining metagenomics and metabolomics to shed light on diet–microbiome interactions has the potential to advance nutrition by providing insights on personal responses to diets, foods and ingredients, enable precision nutrition, and ultimately improve human health.…”

“…Imidazole propionate, a microbial product of histidine, has been reported to impair insulin signalling when administered to mice (Koh et al 2018). Histidine can also be converted by microbes to histamine, which was found to increase colonic motility through activation of the histamine receptor in gnotobiotic mice (Chen et al 2019). Other biogenic amines, including serotonin, dopamine, tyramine, phenethylamine and c-aminobutyric acid (GABA), are produced by gut microbes from tryptophan, tyrosine, phenylalanine and glutamate, respectively.…”

“…Such a strategy will also enable assessment of strain-dependent microbial metabolism of nutrients. Finally, mechanistic studies linking diet-derived microbial metabolites with host receptors are needed to unravel how and which metabolites affect host physiology (Husted et al 2017;Chen et al 2019). Combining metagenomics and metabolomics to shed light on diet-microbiome interactions has the potential to advance nutrition by providing insights on personal responses to diets, foods and ingredients, enable precision nutrition, and ultimately improve human health.…”

Chemical Reporters for Exploring Microbiology and Microbiota Mechanisms

“…Moreover, the production of aromatic acids by Clostridium sporogenes has been suggested to modulate host immunity . Furthermore, targeted screening of specific microbiota species and their metabolites with different protein families such as GPCRs have revealed new commensal bacteria and metabolite interactions . These exciting studies suggest specific microbiota species might generate unique metabolites to alter host immunity or infection, but the protein targets and mechanism(s) of action for these microbiota‐derived metabolites in host cells and/or microbes have not been fully characterized, thus could benefit from future studies with chemical reporters.…”

“…[119] Furthermore, targeted screening of specific microbiota speciesa nd their metabolites with different protein families such as GPCRs have revealed new commensal bacteria and metabolite interactions. [120][121][122] These exciting studies suggests pecific microbiota speciesm ight generate unique metabolites to alter host immunity or infection, but the protein targets and mechanism(s) of action for these microbiota-derived metabolites in host cells and/or microbes have not been fully characterized, thus could benefit from future studies with chemical reporters. Indeed, photoaffinity reportersh ave been previously generated for fatty acids (Figure 10 C), [78] cholesterol [123] and bilea cids [81] (Figure 10 D) and could be readily developed for otherm icrobiota-associated metabolites.…”