Gut Serotonin Curbs the Developing Immune System

The infant gut is packed with a medley of molecules that dictate development during a critical time in a newborns’ life. But how these molecules interact with and influence immune cells early in life isn’t fully understood. Now, in a study published in Science Signaling, a team of scientists revealed how one molecule produced in the gut, the neurotransmitter serotonin, activates a subset of T cells and dampens the immune system.¹ The authors linked gut-derived serotonin to the creation of tolerance against allergens, suggesting that the pathway may play a role in the development of conditions such as asthma and food allergies.

“The body is interconnected, and everything is talking to everything else,” said Sarkis Mazmanian, a microbiologist at the California Institute of Technology who was not involved with the study. “The paper bridges gaps between those different systems of the body and is a great convergence of trying to understand how these systems are communicating with each other.”

Despite their name, neurotransmitters do not live exclusively in the brain; they also reside in the digestive system. In fact, the gut is known as the “second brain.” Despite this, Melody Zeng, an immunologist at Weill Cornell Medicine and coauthor of the study, and her team hypothesized that the immature neonatal gut, which lacks cells found in the adult gut and has a different collection of microbes, would be unable to produce neurotransmitters.

However, when Zeng and her team profiled the metabolites in the gut of neonatal mice, they found that the neonatal intestine had an unexpectedly high amount of the neurotransmitter serotonin. But the serotonin was not coming from the enterochromaffin cells, the cells that produce serotonin in adults, but rather from the gut’s resident bacteria. When they isolated bacteria from both neonatal mice and healthy human infants they found that around half of the microbes in their samples produced serotonin.

In addition to the production of serotonin, the gut also worked overtime to maintain high levels of the molecule. The small intestine of mice expressed higher levels of the enzyme that turns tryptophan into serotonin and lower levels of the enzyme that breaks down serotonin.

“When we found very high levels of serotonin, we wanted to see if there might be some immune function of serotonin in the baby's intestine,” said Zeng, who noted that neurotransmitters act on immune cells. Regulatory T cells, which are typically anti-inflammatory, could help prevent the infant immune system from overreacting to new environmental stimuli and foods, a process known as tolerance. Zeng and her team found that serotonin activated regulatory T cells, linking the dampening effects of regulatory T cells to the gut-derived serotonin.

Finally, to examine how the neurotransmitter influenced immune tolerance to antigens, the researchers gave serotonin to germ-free neonates, which lack gut microbes, and exposed the animals to dietary antigens that induce immune reactions, including proteins isolated from chicken eggs. In germ-free mice that received serotonin, regulatory T cells tolerated the antigen challenge better than those that did not.

Zeng said that serotonin seems critical for educating the immature neonatal immune system, which may be important in preventing the development of allergies. “There might be a very important reason for why [babies] have those unique bacteria that [adults] no longer have, because those bacteria will provide things like neurotransmitters, like serotonin, before the baby's intestine is mature enough to make its own,” said Zeng.

But it will be critical to see if this also happens in humans, said Mazmanian. If researchers replicate the findings in humans, it will underscore the importance of having the right types of bacterial signals during development for long-lasting impacts on immune function and disease susceptibility. Mazmanian said that it brings up an important question: What would happen if doctors inadvertently got rid of these serotonin-producing bacteria? For example, changes to the gut and microbiome composition through interventions like antibiotic use early in life may have detrimental effects on the immune system later.

Now with a biobank of stool samples collected from infant humans, Zeng’s team are measuring serotonin levels to see if it correlates with health outcomes like allergy development or neurodevelopmental conditions. She added, “If we see such interesting and strong patterns that relate bugs that produce serotonin in the gut to allergic reaction [in humans], that justifies an intervention.”

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