Enterococcus-derived tyramine hijacks α2A-adrenergic receptor in intestinal stem cells to exacerbate colitis

• Published in: Cell host & microbe Vol. 32; no. 6; pp. 950 - 963.e8
• Main Authors: Li, Chaoliang, Zhang, Panrui, Xie, Yadong, Wang, Shishan, Guo, Meng, Wei, Xiaowei, Zhang, Kaiguang, Cao, Dan, Zhou, Rongbin, Wang, Sheng, Song, Xinyang, Zhu, Shu, Pan, Wen
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 12.06.2024
• Subjects: ADRA2A; colitis; Enterococcus; IBD; inflammatory bowel disease; intestinal stem cells; ISCs; tyramine; yohimbine; α2A-adrenergic receptor; Enterococcus; colitis; α2A-adrenergic receptor; intestinal stem cells; ISCs; yohimbine; IBD; tyramine; inflammatory bowel disease; ADRA2A
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2024.04.020

Inflammatory bowel disease (IBD) is characterized by dysbiosis of the gut microbiota and dysfunction of intestinal stem cells (ISCs). However, the direct interactions between IBD microbial factors and ISCs are undescribed. Here, we identify α2A-adrenergic receptor (ADRA2A) as a highly expressed GPCR in ISCs. Through PRESTO-Tango screening, we demonstrate that tyramine, primarily produced by Enterococcus via tyrosine decarboxylase (tyrDC), serves as a microbial ligand for ADRA2A. Using an engineered tyrDC-deficient Enterococcus faecalis strain and intestinal epithelial cell-specific Adra2a knockout mice, we show that Enterococcus-derived tyramine suppresses ISC proliferation, thereby impairing epithelial regeneration and exacerbating DSS-induced colitis through ADRA2A. Importantly, blocking the axis with an ADRA2A antagonist, yohimbine, disrupts tyramine-mediated suppression on ISCs and alleviates colitis. Our findings highlight a microbial ligand-GPCR pair in ISCs, revealing a causal link between microbial regulation of ISCs and colitis exacerbation and yielding a targeted therapeutic approach to restore ISC function in colitis. [Display omitted] •Tyramine is a microbial ligand of α2A-adrenergic receptor (ADRA2A) in ISCs•Enterococcus-derived tyramine suppresses ISC proliferation and exacerbates colitis•Enterococcus, tyramine, and ADRA2A are enriched in geographically distinct IBD cohorts•ADRA2A antagonist yohimbine disrupts the suppression on ISCs and alleviates colitis The direct interactions between microbial factors and intestinal stem cells (ISCs) in inflammatory bowel disease are poorly understood. Li et al. now reveal that Enterococcus-derived tyramine hijacks α2A-adrenergic receptor (ADRA2A) in ISCs to suppress ISC proliferation and exacerbate colitis. ADRA2A antagonist yohimbine disrupts the ISC suppression and alleviates colitis.