TPH1 (tryptophan hydroxylase 1) catalyzes the rate-limiting step of serotonin biosynthesis by oxidizing L-tryptophan to 5-hydroxytryptophan (5-HTP) 1. TPH1 is primarily expressed in enterochromaffin (EC) cells of the gastrointestinal tract and non-neuronal cells including adipocytes 2, where it regulates peripheral serotonin production distinct from the central nervous system pool. TPH1 expression is dynamically regulated by gut microbiota through short-chain fatty acid production, with microbiota-derived signals increasing both Tph1 mRNA and protein levels alongside colonic 5-HT concentrations 3. Dysbiosis-associated reductions in commensal bacteria correlate with altered TPH1 expression in depression 4, while beneficial bacteria restore TPH1 expression and ameliorate depressive behaviors. Clinically, TPH1-derived peripheral serotonin has divergent roles in disease. In cancer, elevated TPH1 expression and serotonin production promote tumor progression by enhancing PD-L1 expression on cancer cells and impairing CD8+ T cell function 5, with TPH1−/− mice showing enhanced anti-tumor immunity. Additionally, TPH1-mediated 5-HT activates a positive feedback loop with NLRP3 inflammasome signaling in colorectal cancer 6. Conversely, IL-2-induced TPH1 expression drives T cell exhaustion in tumor microenvironments 7. These findings establish TPH1 as a critical metabolic regulator with therapeutic potential as a pharmacological target.