Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids

色胺 梭状芽孢杆菌 生物化学 G蛋白偶联受体 生物 脂肪酸 人体微生物群 受体 微生物群 细菌 遗传学
作者
Frank Chang,Piro Siuti,Stéphane Laurent,Thomas L. Williams,Emerson Glassey,Andreas W. Sailer,D. Benjamin Gordon,Horst Hemmerle,Christopher A. Voigt
出处
期刊:Nature microbiology 卷期号:6 (6): 792-805 被引量:25
标识
DOI:10.1038/s41564-021-00887-y
摘要

Human physiology is regulated by endogenous signalling compounds, including fatty acid amides (FAAs), chemical mimics of which are made by bacteria. The molecules produced by human-associated microbes are difficult to identify because they may only be made in a local niche or they require a substrate sourced from the host, diet or other microbes. We identified a set of uncharacterized gene clusters in metagenomics data from the human gut microbiome. These clusters were discovered to make FAAs by fusing exogenous fatty acids with amines. Using an in vitro assay, we tested their ability to incorporate 25 fatty acids and 53 amines known to be present in the human gut, from which the production of six FAAs was deduced (oleoyl dopamine, oleoyl tyramine, lauroyl tryptamine, oleoyl aminovaleric acid, α-linolenoyl phenylethylamine and caproyl tryptamine). These molecules were screened against panels of human G-protein-coupled receptors to deduce their putative human targets. Lauroyl tryptamine is found to be an antagonist to the immunomodulatory receptor EBI2 against its native oxysterol ligand (0.98 μM half-maximal inhibitory concentration), is produced in culture by Eubacterium rectale and is present in human faecal samples. FAAs produced by Clostridia may serve as a mechanism to modulate their host by mimicking human signalling molecules.
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