Intestinal serotonin inhibits the developing immune system

TA baby’s intestines are filled with a mixture of molecules that dictate development at a critical point in a newborn’s life. However, how these molecules interact with and influence immune cells is not fully understood. Now, in a study published in Scientific signalingteam of scientists has discovered how one molecule produced in the gut, the neurotransmitter serotonin, activates a subset of T cells and weakens the immune system.¹ The authors linked intestinal serotonin with the development of tolerance to allergens, suggesting that this pathway may play a role in the development of diseases such as asthma and food allergies.

“The body is interconnected and everything talks to everything else,” said Sarkis Mazmanian, a microbiologist at the California Institute of Technology who was not involved in the study. “The paper bridges the gaps between different body systems and is an excellent convergence of attempts to understand how these systems communicate 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 called the “second brain.” Still, Melody Zeng, an immunologist at Weill Cornell Medicine and co-author of the study, and her colleagues hypothesized that the immature guts of newborns, which lack the cells found in the adult gut and have a different set of microbes, would not be able to produce neurotransmitters. .

But when Zeng and her team profiled metabolites in the guts of newborn mice, they found that the newborns’ gut contained an unexpectedly large amount of the neurotransmitter serotonin. However, the serotonin did not come from enterochromaffin cells, the serotonin-producing cells in adults, but rather from bacteria residing in the gut. When they isolated bacteria from both newborn mice and healthy infants, they found that about half of the microbes in their samples produced serotonin.

In addition to producing serotonin, the gut also worked overtime to keep levels of this molecule high. In the mouse small intestine, there were higher levels of the enzyme that converts tryptophan into serotonin and lower levels of the enzyme that breaks down serotonin.

“When we discovered very high levels of serotonin, we wanted to see if serotonin in the baby’s gut could have an immune function,” said Zeng, who noted that neurotransmitters act on immune cells. Regulatory T cells, which typically have anti-inflammatory effects, can help prevent an infant’s immune system from overreacting to new environmental stimuli and foods, a process known as tolerance. Zeng and her team found that serotonin activates regulatory T cells, linking the suppressive effects of regulatory T cells to serotonin from the gut.

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

Zeng found that serotonin appears to be crucial in shaping newborns’ immature immune systems, which may play an important role in preventing the development of allergies. “There may be a very good reason why (children) have these unique bacteria that (adults) no longer have, because these bacteria provide neurotransmitters such as serotonin before a child’s gut is mature enough to produce its own,” Zeng said .

But it will be extremely important to see if this also happens in humans, Mazmanian said. If researchers replicate the findings in humans, it would highlight the importance of having the right types of bacterial signals during development to ensure long-lasting effects on immune function and disease susceptibility. Mazmanian said this raises an important question: What would happen if doctors inadvertently got rid of serotonin-producing bacteria? For example, changes in gut composition and microbiome caused by interventions such as antibiotic use early in life can later have deleterious effects on the immune system.

Now, with a biobank of stool samples from infants, Zeng’s team measures serotonin levels to see if they correlate with health consequences, such as the development of allergies or neurodevelopmental conditions. She added: “If we see such interesting and clear patterns that link the serotonin-producing bacteria in the gut with an allergic reaction (in humans), it warrants intervention.”