美国耶鲁大学医学院Noah W. Palm团队揭示了共生菌衍生的乙酰胆碱可增强黏膜免疫教育。相关论文于2026年6月3日发表在《自然》杂志上。

本研究采用多重GPCR筛选技术，对100株共生菌在单相关无菌小鼠体内或体外细菌培养基中生长的GPCR全基因组生物活性进行了评估。由于(1)宿主介导的代谢物降解，体内和体外的共生代谢组表现出不同的GPCR激活模式；(2)体内微生物代谢重编程；(3)饲料底物的生物转化。值得注意的是，该课题组人员发现多种共生菌株通过饮食胆碱的转化在体内产生乙酰胆碱（ACh），包括在生命早期主导微生物组的双歧杆菌菌株和一种益生菌片球菌菌株。

在机制上，该团队鉴定并鉴定了介导这种生物转化的细菌酶，并在短双歧杆菌和戊糖片球菌中产生了一种缺乏乙酰胆碱生产的短双歧杆菌等基因突变株。感染产乙酰氨基酚短芽胞杆菌的小鼠表现出肠道免疫球蛋白A （IgA）产生增强，微生物群组成改变，对肠道感染的抵抗力增强。这些发现强调了体内环境对微生物群代谢的深远影响，并揭示了饮食-微生物-宿主轴可以增强粘膜免疫防御并加强宿主-微生物群的相互作用。

研究人员表示，微生物群产生具有潜在生物活性的小分子的需求。体外共生培养物的高通量生物活性筛选揭示了微生物群代谢物，这些代谢物通过激活多种G蛋白偶联受体（GPCRs）来塑造宿主生理。然而，由于技术限制，由复杂的饮食-微生物-宿主相互作用产生的体内代谢物的全GPCR生物活性尚不清楚。

附：英文原文

Title: Commensal-derived acetylcholine enhances mucosal immune education

Author: Song, Deguang, Duncan-Lowey, Brianna, Khetrapal, Varnica, Hamchand, Randy, Deng, Tong, Brown, Hailey, Wu, Anchi, Martin, Anjelica L., Bauer, Kaylyn M., Zhao, Yanyu, Nguyen, Mytien T., Sonnert, Nicole D., Leopold, Shana R., Wu, Qihao, Crawford, Jason M., Palm, Noah W.

Issue&Volume: 2026-06-03

Abstract: The microbiota produces thousands of potentially bioactive small molecules1,2,3. High-throughput bioactivity screens of in vitro commensal cultures have exposed microbiota metabolites that shape host physiology by activating diverse G-protein-coupled receptors (GPCRs)4,5,6,7. However, owing to technical limitations, the GPCRome-wide bioactivities of in vivo metabolomes, which result from complex diet–microorganism–host interactions, remain unclear. Here we used a multiplexed GPCR screening technology to assess GPCRome-wide bioactivities of 100 commensal strains grown in vivo in monoassociated germ-free mice or in vitro in bacterial culture medium. In vivo and in vitro commensal metabolomes exhibited distinct GPCR activation patterns due to (1) host-mediated metabolite degradation; (2) in vivo microbial metabolic reprogramming; and (3) biotransformation of dietary substrates. Notably, we found that multiple commensal strains produced acetylcholine (ACh) in vivo through the conversion of dietary choline, including select Bifidobacterium strains that dominate the microbiome in early life and a probiotic Pediococcus strain. Mechanistically, we identified and characterized the bacterial enzymes that mediate this biotransformation in Bifidobacterium breve and Pediococcus pentosaceus, and generated an isogenic mutant B. breve strain lacking ACh production. Mice colonized with ACh-producing B. breve exhibited enhanced intestinal immunoglobulin A (IgA) production, altered microbiota composition and increased resistance to enteric infection. These findings underscore the profound impacts of the in vivo environment on microbiota metabolism and reveal a diet–microbiome–host axis that strengthens mucosal immune defences and reinforces host–microbiota mutualism.

DOI: 10.1038/s41586-026-10592-7

Source: https://www.nature.com/articles/s41586-026-10592-7

期刊信息

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504

官方网址：http://www.nature.com/

投稿链接：http://www.nature.com/authors/submit_manuscript.html