Park Hyun Bong, Song Deguang, Nguyen Mytien, Palm Noah W, Crawford Jason M
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.
Institute of Biomolecular Design & Discovery, Yale University, West Haven, Connecticut 06516, United States.
ACS Chem Biol. 2025 Jul 18;20(7):1775-1782. doi: 10.1021/acschembio.5c00313. Epub 2025 Jun 27.
Gut microbes secrete specialized small molecules that broadly influence human physiology. Despite their potential significance, the variety of functional small molecules known in the gut is relatively limited. Here, we screened the supernatants from human fecal-derived bacterial cultures to explore their agonist effects on the human G protein-coupled receptors (GPCRs), melatonin receptor types 1A and 1B (MTNR1A, MTNR1B). Chemical analysis of the supernatant-soluble molecules of , a prominent gut commensal identified in the screen, led to the characterization of agonists for these two melatonin receptors. Specifically, through bioactivity-assisted isolation and characterization, we identified three small molecules, -, including two previously uncharacterized metabolites, which were synthesized to confirm their structures. While the structure of features a urea core symmetrically disubstituted with tryptamine moieties, and harbor a monomeric tryptamine functionalized with methyl carbamate and -acetyl groups, respectively. These structural characterization efforts illuminated downstream functional consequences of tryptamine metabolism in . Additional GPCR screening analyses revealed that activates melatonin receptors and the purinergic P2RY11 receptor, whereas serves as an agonist for the semiorphan receptor GPR55. Interestingly, also exhibits significant inhibitory activity against inflammatory soluble epoxide hydrolase with a half-maximal inhibitory concentration of 420 nM. Single-cell RNA sequencing analysis of the gut tissue from mice orally treated with relative to the solvent vehicle control revealed that specifically decreased the frequency of GPR55- and granzyme K-expressing effector-like CD8 T cells in the intraepithelial lymphocyte population. Overall, this study broadens our understanding of tryptamine-derived signaling at the human-microbe interface.
肠道微生物分泌的特殊小分子对人体生理机能有广泛影响。尽管它们具有潜在的重要意义，但已知的肠道功能性小分子种类相对有限。在此，我们筛选了源自人类粪便的细菌培养物的上清液，以探究其对人类G蛋白偶联受体（GPCR）——褪黑素1A和1B型受体（MTNR1A、MTNR1B）的激动作用。对筛选中鉴定出的一种主要肠道共生菌的上清液可溶性分子进行化学分析，从而确定了这两种褪黑素受体的激动剂。具体而言，通过生物活性辅助分离和鉴定，我们确定了三种小分子，即[具体名称1]、[具体名称2]，其中包括两种此前未被表征的代谢物，并通过合成来确认其结构。[具体名称1]的结构以尿素核心对称地被色胺部分取代，而[具体名称2]和[具体名称3]分别含有用氨基甲酸甲酯和[具体基团名称]乙酰基官能化的单体色胺。这些结构表征工作揭示了色胺在[具体细菌名称]中代谢的下游功能后果。额外的GPCR筛选分析表明，[具体名称1]激活褪黑素受体和嘌呤能P2RY11受体，而[具体名称2]作为半孤儿受体GPR55的激动剂。有趣的是，[具体名称1]对炎性可溶性环氧化物水解酶也表现出显著的抑制活性，半数最大抑制浓度为420 nM。对口服[具体名称1]的小鼠肠道组织相对于溶剂载体对照进行单细胞RNA测序分析发现，[具体名称1]特异性降低了上皮内淋巴细胞群体中表达GPR55和颗粒酶K的效应样CD8 T细胞的频率。总体而言，这项研究拓宽了我们对人-微生物界面色胺衍生信号传导的理解。
