New research points to gut serotonin as a potential way to treat depression and anxiety

A new study published in Gastroenterology provides evidence that serotonin in the gut lining may play a key role in regulating mood—and could open the door to safer antidepressant treatments, especially for pregnant women. In a series of experiments with mice and a large human birth cohort, researchers found that increasing serotonin in the intestinal lining reduced anxiety- and depression-like behaviors. But they also discovered that exposing developing babies to serotonin-targeting antidepressants in utero was linked to a much higher risk of constipation in early life.

The research team, led by Mark Ansorge at Columbia University and Kara Margolis at New York University, was motivated by a longstanding puzzle in mental health care. While drugs like Prozac and Zoloft are widely used and effective for many people with anxiety and depression, they can cause unwanted side effects—especially gastrointestinal issues. And when used during pregnancy, they cross the placenta and affect fetal brain and gut development. Despite this, exactly where in the body these medications work to improve mood has remained unclear.

To investigate whether the gut might be a key player in the antidepressant response, the researchers used genetic techniques to delete a specific serotonin transporter protein (SERT) only in the intestinal lining of mice. This transporter is responsible for clearing serotonin, a chemical that helps regulate mood, from the space between cells. Removing the transporter boosts serotonin levels in the gut. The team created two groups of mice: one with SERT removed from birth, and another where SERT was deleted only in adulthood using an inducible system.

The researchers then put these mice through a battery of behavioral tests designed to assess anxiety- and depression-like behaviors, including how much time they spent exploring new environments, their willingness to eat in unfamiliar situations, and how much time they spent immobile when suspended by the tail—a common sign of despair in rodents.

Mice lacking intestinal SERT, whether from birth or adulthood, showed less anxious and less depressive behaviors. They explored more, showed fewer signs of hesitation, and were more active than control mice. Importantly, this mood-improving effect depended on communication between the gut and brain. When the researchers surgically disrupted the vagus nerve—the main information highway between the gut and brain—the benefits disappeared. This suggested that serotonin in the gut lining influences mood by sending signals to the brain via the vagus nerve.

At the same time, the researchers wanted to understand whether reducing serotonin in the gut might have the opposite effect. In another set of experiments, they used genetically modified mice that couldn’t make serotonin in the gut and also tested a drug that blocks serotonin production without being absorbed into the bloodstream. In both cases, the animals showed more anxiety-like behavior. This further confirmed the role of gut serotonin in regulating mood.

Interestingly, targeting serotonin in the gut did not appear to harm cognition or gut motility, which are often affected by systemic antidepressant use. The researchers found no major changes in learning and memory tests, and gut function remained mostly normal—though there were subtle changes in the speed of intestinal movements when the transporter was deleted from birth.

The human part of the study involved over 400 mother-child pairs enrolled in a Canadian birth cohort. The researchers followed up with mothers who either used antidepressants during pregnancy, experienced depression without medication, or had no mental health issues. They found that babies exposed to antidepressants in the womb were about three times more likely to develop functional constipation in their first year of life compared to babies who were not exposed. Constipation is a common type of gut-brain interaction disorder, and the finding adds to concerns about how these drugs may affect the developing gut.

These results are consistent with earlier animal studies showing that systemic serotonin blockers can lead to abnormal development of the nervous system in both the brain and the gut. By focusing on the gut lining specifically, the new study offers a potential workaround: targeting serotonin only in the intestine may relieve symptoms of depression and anxiety without causing unwanted side effects or affecting fetal development during pregnancy.

“Antidepressants like Prozac and Zoloft that raise serotonin levels are important first-line treatments and help many patients but can sometimes cause side effects that patients can’t tolerate. Our study suggests that restricting the drugs to interact only with intestinal cells could avoid these issues,” said Ansorge, an associate professor of clinical neurobiology at Columbia University Vagelos College of Physicians and Surgeons.

While these findings are promising, the authors stress that pregnant individuals should not stop taking prescribed antidepressants without consulting a doctor. Untreated depression and anxiety can pose serious risks to both the mother and child. Instead, the researchers hope their findings will lead to new antidepressant medications that work only in the gut and avoid entering the bloodstream—especially during pregnancy.

Larissa Takser, a pediatrician and co-author based in Quebec, noted the implications: “At the age of one, 63% of children exposed to antidepressants during pregnancy experienced constipation, compared with 31% of children whose mothers did not take medication. This finding suggests a potential connection between serotonin levels in utero and gut development, and opens new doors to examine SSRI properties not previously studied.”

The researchers are already working on next-generation antidepressants that would be delivered in a way that keeps the drug in the intestine, reducing systemic exposure. “Our findings indicate that we may be able to treat a mother’s depression or anxiety effectively without exposing the child,” Ansorge said, “and we are working on drug delivery technology that will hopefully help us achieve that.”

Margolis emphasized that the study is not intended to change clinical practice today. Instead, it is a call for more research on how antidepressants affect the gut, especially during development. “These are not clinical guidelines,” she said. “Rather, they are a call that more research is needed on the connection between SSRIs, serotonin, and the gut. It’s recommended that mothers and providers together consider treatment options that have been shown to be successful, including medications and cognitive behavioral therapy.”

This research adds to growing interest in the gut-brain connection—a field that has revealed how gut bacteria, immune signals, and hormones interact with the nervous system. The idea that mood can be regulated from the gut opens new opportunities to improve mental health with fewer risks. If future clinical trials confirm these findings, we may see a new class of antidepressants designed to work where most of the body’s serotonin is made—not in the brain, but in the gut.

The study, “Intestinal epithelial serotonin as a novel target for treating disorders of gut-brain interaction and mood,” was authored by Lin Y. Hung, Nuno D. Alves, Andrew Del Colle, Ardesheer Talati, Sarah A. Najjar, Virginie Bouchard, Virginie Gillet, Yan Tong, Zixing Huang, Kirsteen N. Browning, Jialiang Hua, Ying Liu, James O. Woodruff, Daniel Juarez, Melissa Medina, Jonathan Posner, Raquel Tonello, Nazli Yalcinkaya, Narek Israelyan, Roey Ringel, Letao Yang, Kam W. Leong, Mu Yang, Ji Ying Sze, Tor Savidge, Jay Gingrich, Robert J. Shulman, Michael D. Gershon, Annie Ouellet, Larissa Takser, Mark S. Ansorge, and Kara Gross Margolis.