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The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remain largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin, and that specific gut bacteria directly produce serotonin while down-regulating monoamine oxidase A to limit serotonin breakdown. We found that serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye and inhibit mTOR activation, thereby promoting the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice resulted in long-term T cell–mediated antigen-specific immune tolerance toward both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for specific gut bacteria to increase serotonin availability in the neonatal gut and identified a function of gut serotonin in shaping T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life. Editor's summary: The establishment of immune tolerance to commensal bacteria and dietary antigens occurs during early life and is influenced by the gut microbiome. The gut is a major site of neurotransmitters, but how these neurotransmitters regulate immune tolerance during early life is unclear. Sanidad et al. profiled metabolites in the small intestine of neonatal mice, identifying that serotonin (5-HT) was highly enriched in the neonatal intestine. 5-HT was produced by selective gut bacteria and induced gut regulatory T cell differentiation by directly altering T cell metabolism, promoting tolerance to dietary antigens and commensal bacteria. These findings demonstrate a critical role for neonatal gut bacteria–derived serotonin in early life immune tolerance. —Hannah Isles [ABSTRACT FROM AUTHOR]