A recent Science Immunology study revealed that neonatal gut bacteria produce serotonin and down-regulate monoamine oxidase A (MOA) to limit serotonin breakdown, thereby promoting immune tolerance.
Study: Gut bacteria–derived serotonin promotes immune tolerance in early life. Image Credit: Tatiana Shepeleva/Shutterstock.com
Background
Bacterial colonization in the neonatal gut plays a crucial role in the development of the immune system and intestinal maturation. In comparison to the adult gut, the neonatal gut is composed of high levels of sugars and milk oligosaccharides. Children with asthma, food allergies, and neurodevelopmental defects experience altered gut microbiotas and metabolomes.
Early life is a crucial phase in establishing immune tolerance against gut commensal bacteria, as well as environmental and dietary antigens. It is imperative to understand whether the neonatal metabolome influences the development of immune tolerance in early life.
The human gut is a major site of neurotransmitters, such as serotonin and dopamine, which are produced by epithelial enterochromaffin cells (ECs). These neurotransmitters influence the enteric and central nervous systems (CNSs). Recent studies have shown that the absence of critical gut bacteria is associated with the altered availability of neurotransmitters for neuronal signaling. These studies have also shown that gut bacteria are a significant regulator of neuroinflammation that governs the incidence of neurodevelopmental disorders.
Serotonin (5-hydroxytryptamine or 5-HT) plays an important role in the regulation of gut motility, mood regulation, and platelet function. It is important to understand whether a cross-talk between serotonin and gut immune cells occurs.
About the study
The current study investigated whether the neonatal gut metabolome shapes immune tolerance in early life. The presence of neurotransmitters in mouse neonatal small intestine (SI) was evaluated. Both in vitro and in vivo experiments were conducted to evaluate immune tolerance against gut commensal bacteria and an oral antigen (OVA).
Study findings
The in vitro and in vivo experiments demonstrated that serotonin is responsible for immune tolerance in early life. In vivo experiments indicated that neonatal gut bacteria, instead of ECs, are the major source of serotonin. Multiple mechanisms have been identified to be associated with the enhancement of serotonin in the neonatal gut.
The serotonin availability in the neonatal gut was seen to be associated with the direct production of this neurotransmitter by the gut bacteria. Furthermore, the gut microbes down-regulated MAO-A to limit 5-HT breakdown.
The oral gavage of serotonin to germ-free neonates followed by OVA sensitization boosted long-term immune tolerance toward OVA in adulthood. This experimental finding indicated that serotonin directly alters T cell metabolism to boost the differentiation of regulatory T cells, which promotes long-term immune tolerance of both commensal bacteria and dietary antigens. Therefore, neonatal gut-derived serotonin plays an important role in shaping immune tolerance.
It is important to understand the evolutionary benefits of enhanced neurotransmitter availability in the neonatal gut. This study could lead to a better understanding of how elevated neurotransmitter availability in the gut influences GI disorders. Typically, GI disorders stem from imbalanced neurotransmitters during early life.
Rodentibacter was identified as a key neonatal gut bacterium associated with the production of serotonin. A significant difference in the composition of neonatal microbiota was observed in the SI and colon. It must be noted that serotonin is only produced by ECs in adults. In adult guts, short-chain fatty acids play a crucial role in the differentiation of regulatory T cells.
Conclusions
The current study highlighted that neonatal gut bacteria enhances serotonin availability through three independent mechanisms. The first mechanism is associated with the direct production of serotonin, while the second mechanism is associated with the activation of inducing host tryptophan hydroxylase 1 (TPH1) to promote the conversion of tryptophan to serotonin. The third mechanism entails a reduction in the breakdown of serotonin by monoamine oxidase A.
The experimental findings indicated that serotonin directly modifies T cell metabolism by elevating intracellular indole-3-acetaldehyde that inhibits the activation of the mammalian target of rapamycin (mTOR). Furthermore, the presence of serotonin in the neonatal gut promotes long-term immune tolerance to both gut commensal and bacteria dietary antigens. Taken together, this study emphasized the importance of serotonin in promoting immune tolerance in early life.
In the future, more research should be conducted better to understand the contribution of SI microbiota to early life. Furthermore, it is important to understand the impact of antibiotic treatment in early life on the availability of key neurotransmitters in the neonatal gut. It will also be important to investigate the presence of serotonin receptors or transporters that influence the effect of serotonin on T cells.
Journal reference:
- Sanidad, K. Z., Rager, S. L., Carrow, H. C., Ananthanarayanan, A., Callaghan, R., Hart, L. R., Li, T., Ravisankar, P., Brown, J. A., Amir, M., Jin, J. C., Savage, A. R., Luo, R., Rowdo, F. M., Martin, M. L., Silver, R. B., Guo, C.-J., Krumsiek, J., Inohara, N. and Zeng, M. Y. (2024) Science Immunology, 9(93). doi: 10.1126/sciimmunol.adj4775. https://www.science.org/doi/10.1126/sciimmunol.adj4775
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