Gut Bacterial Metabolites from Tryptophan and Phenylalanine Induce Melatonin Synthesis and Extend Sleep Duration in Mice

The human gut microbiota significantly influences various physiological systems, including immune, nervous, and metabolic systems. Recent studies suggest that gut microbiota may affect sleep quality with certain bacteria and metabolites being linked to sleep patterns. However, the underlying chemical signaling pathway remains unclear. In this study, we investigated the effect of four gut bacteria-derived metabolites, tryptamine (1), indolokine A5 (2), 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE, 3), and phenethylamine (PEA, 4), on sleep characteristics in mice and melatonin biosynthesis pathways in zebrafish. Their sleep-promoting effects were evaluated in a pentobarbital-induced sleep mouse model, revealing significant increases in sleep duration and blood melatonin levels, particularly with ITE (3) and PEA (4). Further tests in zebrafish embryos showed that ITE (3) and PEA (4) increased the expression of genes for melatonin biosynthesis (Aanat1, Aanat2, Tph1a, and Hiomt) in a concentration-dependent manner, indicating their potential as therapeutic agents for sleep disorders.