Gut microbiome regulates serotonin production in the neonatal intestine to promote immune tolerance in early life

Abstract The gut microbiome in neonates is vastly different from that in adults due to dietary changes and gut maturation. However, the neonatal gut metabolome, largely shaped by gut bacteria, remains largely undefined. Using high-throughput metabolomics, we compared >500 metabolites in the ileum of specific pathogen-free (SPF) wild-type neonatal and adult mice. We found that most metabolites at significantly higher levels in neonates were neurotransmitters, including serotonin (5-HT), a neurotransmitter critical in the regulation of gut motility and mood stabilization. SPF neonates had significantly higher 5-HT levels in the ileum compared to both SPF adults and germ-free (GF) neonates, suggesting the gut microbiome as a key driver of generation in the neonatal intestine. Gut bacteria in neonates modulate the enzymes TPH-1 and MAO-A involved in the synthesis and breakdown of 5-HT. In addition, unlike in the adult intestine where 5-HT is produced primarily by enterochromaffin cells, gut bacteria are major producers of 5-HT in the neonatal intestine. The immunomodulatory role of 5-HT in the neonatal intestine has not been explored. We demonstrate that 5-HT directly promotes the differentiation regulatory T cells while diminishing interferon gamma and interleukin-17 produced in CD4 T cells, ex vivo and in vivo, in the neonatal intestine. Oral gavage of 5-HT into neonatal mice enhanced immune tolerance toward both commensal bacteria and dietary antigens. Our study has elucidated unique mechanisms by gut microbiota to regulate 5-HT generation in the neonatal intestine, and a novel immunomodulatory role for intestinal 5-HT to promote immune tolerance towards both dietary antigens and commensal bacteria during the early developmental stage.