The neurotransmitter serotonin plays a central role in animal behavior and physiology, and many of its functions are regulated via evolutionarily conserved biosynthesis and degradation pathways. Here we show that in Caenorhabditis elegans, serotonin is abundantly produced in nonneuronal tissues via phenylalanine hydroxylase, in addition to canonical biosynthesis via tryptophan hydroxylase in neurons. Combining CRISPR–Cas9 genome editing, comparative metabolomics and synthesis, we demonstrate that most serotonin in C. elegans is incorporated into N-acetylserotonin-derived glucosides, which are retained in the worm body and further modified via the carboxylesterase CEST-4. Expression patterns of CEST-4 suggest that serotonin or serotonin derivatives are transported between different tissues. Last, we show that bacterial indole production interacts with serotonin metabolism via CEST-4. Our results reveal a parallel pathway for serotonin biosynthesis in nonneuronal cell types and further indicate that serotonin-derived metabolites may serve distinct signaling functions and contribute to previously described serotonin-dependent phenotypes.

神经递质血清素在动物行为和生理学中发挥着核心作用，其许多功能是通过进化上保守的生物合成和降解途径来调节的。在这里，我们表明，在秀丽隐杆线虫中，除了通过神经元中的色氨酸羟化酶进行典型的生物合成之外，还通过苯丙氨酸羟化酶在非神经元组织中大量产生血清素。结合 CRISPR-Cas9 基因组编辑、比较代谢组学和合成，我们证明线虫中的大多数血清素被整合到N-乙酰血清素衍生的糖苷中，这些糖苷保留在蠕虫体内并通过羧酸酯酶 CEST-4 进一步修饰。 CEST-4 的表达模式表明血清素或血清素衍生物在不同组织之间转运。最后，我们证明细菌吲哚的产生通过 CEST-4 与血清素代谢相互作用。我们的结果揭示了非神经元细胞类型中血清素生物合成的平行途径，并进一步表明血清素衍生的代谢物可能具有不同的信号传导功能，并有助于先前描述的血清素依赖性表型。