Tryptamine Metabolism and Functionalization in Gut Commensal Bacteria Expand Human Tryptamine Signaling Responses.

IF 3.5 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hyun Bong Park, Deguang Song, Mytien Nguyen, Noah W Palm, Jason M Crawford
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Abstract

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 Clostridium sporogenes, 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, 1-3, including two previously uncharacterized metabolites, which were synthesized to confirm their structures. While the structure of 1 features a urea core symmetrically disubstituted with tryptamine moieties, 2 and 3 harbor a monomeric tryptamine functionalized with methyl carbamate and N-acetyl groups, respectively. These structural characterization efforts illuminated downstream functional consequences of tryptamine metabolism in C. sporogenes. Additional GPCR screening analyses revealed that 2 activates melatonin receptors and the purinergic P2RY11 receptor, whereas 1 serves as an agonist for the semiorphan receptor GPR55. Interestingly, 1 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 1 relative to the solvent vehicle control revealed that 1 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.

肠道共生菌的色胺代谢和功能化扩展了人类色胺信号反应。
肠道微生物分泌专门的小分子,广泛影响人体生理。尽管它们具有潜在的意义,但肠道中已知的功能性小分子的种类相对有限。在这里,我们筛选了来自人类粪便细菌培养的上清,以探索它们对人类G蛋白偶联受体(gpcr),褪黑激素受体1A和1B (MTNR1A, MTNR1B)的激动剂作用。对筛选中发现的一种重要的肠道共生体芽孢梭菌的上清可溶性分子进行化学分析,确定了这两种褪黑激素受体的激动剂。具体来说,通过生物活性辅助分离和表征,我们鉴定了三个小分子,1-3,包括两个以前未表征的代谢物,合成以确认其结构。虽然1的结构特征是尿素核与色胺部分对称二取代,但2和3分别含有氨基甲酸甲酯和n -乙酰基功能化的单体色胺。这些结构表征工作阐明了孢子孢菌中色胺代谢的下游功能后果。额外的GPCR筛选分析显示,2激活褪黑素受体和嘌呤能P2RY11受体,而1作为半孤儿受体GPR55的激动剂。有趣的是,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,一半最大抑制浓度为420 nM。相对于溶剂载体对照,口服1处理小鼠肠道组织的单细胞RNA测序分析显示,1特异性降低了上皮内淋巴细胞群中表达GPR55和颗粒酶k效应样CD8 T细胞的频率。总的来说,这项研究拓宽了我们对人类-微生物界面上的色胺衍生信号的理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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