Gut bacteria-derived serotonin promotes immune tolerance in early life through regulation of neonatal gut T cells III

The gut microbiota promotes immune system development in early life, but the interactions between the gut metabolome and immune cells in the neonatal gut remains largely undefined. Here, we demonstrate that the neonatal gut is uniquely enriched with neurotransmitters, including serotonin; specific gut bacteria produce serotonin directly while downregulating monoamine oxidase A to limit serotonin breakdown. Serotonin directly signals to T cells to increase intracellular indole-3-acetaldehdye to inhibit mTOR activation and thereby promotes the differentiation of regulatory T cells, both ex vivo and in vivo in the neonatal intestine. Oral gavage of serotonin into neonatal mice leads to long-term T cell-mediated antigen-specific immune tolerance towards both dietary antigens and commensal bacteria. Together, our study has uncovered an important role for unique gut bacteria to increase serotonin availability in the neonatal gut and a novel function of gut serotonin to shape T cell response to dietary antigens and commensal bacteria to promote immune tolerance in early life. Overall design: GF WT neonatal mice were given 50 µL of 5-HT (12.5 µg/mL) or vehicle (PBS) at P8 and P9 via oral gavage. The mice were then sacrificed at P14 and small intestine tissue was harvested. Total RNA was isolated and bulk RNA-seq performed using an Illumina NovaSeq 6000 sequencer. LEfSe followed by multiple hypotheses correction using signal-to-noise rate and false discovery rate analyses was used to discover genes with differential abundance. Differences at LEfSe p < 0.05 and FDR < 0.05 were considered significant.