Activating of alpha2-adrenergic receptor signaling on ISCs by microbial tyramine suppresses cell proliferation and promote colitis. (PRJCA019703)
Disorders of inflammatory bowel disease (IBD) covers dysfunction of intestinal stem cells(ISCs) and dysbiosis of gut microbiota, but so far there has been little (or none) specific validation of this link. Here we reported that, in mice, Enterococcus derived tyramine activates alpha-2A adrenergic receptor to suppress ISCs proliferation and exacerbate DSS-induced colitis. Using a combination of analysis of ISCs RNA-seq data and immunostaining of intestinal sections, we found alpha-2A adrenergic receptor (Adra2a) is a highly expressed G-protein-coupled receptor (GPCR) in apical side of ISCs. We screened a custom library of microbial metabolites against ADRA2A and identified that tyramine which is converted from tyrosine, activates ADRA2A and suppress ISCs proliferation through, mechanically, decreased cell cycle genes. Microbiome sequencing and metabolite quantification revealed that both tyramine and tyramine-producing commensal Enterococcus are enriched in IBD patients. Deletion of tyramine biosynthetic gene, tyrosine decarboxylase (TyrDC) in an Enterococcus strain or targeting Adra2a with specific inhibitor, Yohimbine, disrupted tyramine- Adra2a mediated suppression on ISCs and ameliorated DSS-induced colitis. Collectively, our works reveal a role for an IBD-enriched Enterococcus-tyramine- Adra2a axis in ISCs that exacerbates colitis, and provide therapeutic potentials to target this axis to alleviate colitis on preclinical and clinical trials.