Serotonin’s double life: From gut to brain, unlocking new possibilities for treating anxiety, depression, and digestive health.

New links between the gut and the brain that could lead to more focused treatments for depression and anxiety have been discovered by researchers. This could also help prevent digestive disorders in children by restricting antidepressant transmission during pregnancy.

The study, published in the journal Gastroenterology, found that boosting serotonin in the gut epithelium- the thin layer of cells lining the small and large intestines- improves anxiety and depression symptoms in animals. The researchers also discovered that in people, using antidepressants during pregnancy increased the likelihood of newborns getting constipation in their first year of life.

“Our findings suggest that there may be an advantage to targeting antidepressants selectively to the gut epithelium, as systemic treatment may not be necessary for eliciting the drugs’ benefits but may be contributing to digestive issues in children exposed during pregnancy,” said Kara Margolis, director of the NYU Pain Research Center and associate professor of molecular pathobiology at NYU College of Dentistry, who co-led the study with Mark Ansorge, associate professor.

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Mental Health Disorders in the US

Anxiety and depression are among the most common mental health disorders in the United States, with one in every five persons having symptoms. Many persons with mood disorders also have gut-brain interaction disorders (DGBI), as well as digestive concerns like irritable bowel syndrome and functional constipation, which are caused by communication breakdowns between the gut and brain.

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Antidepressants for Treating Depression and Anxiety

Antidepressants, notably selective serotonin reuptake inhibitors, or SSRIs, are commonly recommended for depression, anxiety, and DGBIs. While these drugs are generally thought to be safe, they can cause side effects such as gastrointestinal problems and anxiety- “the very symptoms they are sometimes designed to treat,” according to Ansorge- especially early in treatment with an SSRI, which may lead people to discontinue the medication.

Antidepressants can potentially create complications during and after pregnancy due to their ability to transfer via the placenta and breast milk. Some studies demonstrate that children exposed to SSRIs during pregnancy have a higher frequency of mood and cognitive impairments, whereas others produce inconsistent results. Untreated depression and anxiety during pregnancy pose proven dangers to both the mother and the baby, so expectant moms must balance the potential risks of medicine with their mental health needs.

SSRIs act by inhibiting a protein called the serotonin transporter, which raises serotonin levels in the brain. However, the stomach produces the great majority of the body’s serotonin, and the intestines also contain the serotonin transporter.

“For psychiatric medications that act on receptors in the brain, many of those same receptors are in the gut, so you have to consider the effects on gut development and function,” says Margolis, an associate professor of pediatrics and cell biology at NYU Grossman School of Medicine.

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Understanding the Gut-brain Link

To better understand the link between serotonin in the gut and mood and gastrointestinal diseases, the researchers investigated numerous mice models in which the serotonin transporter was deleted or inhibited. Previous research led by Margolis discovered that mice bred to lack the serotonin transporter throughout the body, as well as mice exposed to SSRIs during and after pregnancy, exhibited alterations in the development of the digestive tract and disruption in motility in the gut.

In the Gastroenterology study, the researchers looked at the role of serotonin in the gut specifically by studying mice that lacked the serotonin transporter in the gut epithelium either during development (similar to pregnancy exposure to an SSRI) or in young adulthood (similar to adult SSRI use).

Removing the serotonin transporter from the gut epithelium boosted serotonin levels and reduced anxiety and depression symptoms in both groups of mice. It also protected them against the negative effects on digestion and motility discovered in previous studies in which the serotonin transporter was absent or inhibited throughout the body.

“This adds a critical perspective to the long-held idea that the therapeutic effects of SSRIs come from directly targeting the central nervous system and suggests a role for the gut,” Ansorge said.

The researchers also discovered that serotonin in the gut epithelium influences mood via the vagus nerves, which are a critical communication pathway between the digestive system and the brain. Cutting down communication in mice from the gut to the brain eliminated benefits in anxiety and despair.

Using Antidepressants During Pregnancy

The researchers also investigated the usage of antidepressants during pregnancy to see if inhibiting the serotonin transporter in humans causes comparable digestive difficulties as in mice. They monitored more than 400 mothers and their babies during pregnancy and the first year of life, with a quarter of them using antidepressants (SSRIs or SNRIs).

The use of antidepressants throughout pregnancy dramatically raised a child’s likelihood of developing functional constipation, a frequent and potentially painful DGBI, during their first year of life.

“We discovered that, at the age of one, 63% of children exposed to antidepressants during pregnancy experienced constipation, compared to 31% of children whose mothers did not take medication,” said Larissa Takser, a professor of pediatrics at the Université de Sherbrooke in Quebec and one of the study’s authors. “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.”

Given the known consequences of untreated maternal depression and anxiety, the researchers strongly advise that these findings do not modify clinical practice or influence whether mothers continue to take SSRIs throughout pregnancy due to the risk of constipation in their children.

“These are not clinical guidelines- rather, they are a call that more research is needed on the connection between SSRIs, serotonin, and the gut,” Margolis tweeted. “It’s recommended that mothers and providers together consider treatment options that are successful, including medications and cognitive behavioral therapy.”

The findings from mice and people suggest a promising direction for future research: the gut epithelium as a novel and perhaps safer target for treating mood disorders, particularly in pregnant women.

“Systemic inhibition of the serotonin transporter appears to have a role in the development of digestive problems in both mice and humans. However, limiting an antidepressant to inhibit the serotonin transporter just in the gut epithelium may avoid these side effects and limit the drug’s transmission during pregnancy and lactation,” added Margolis.

References:

1. Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood
   (Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood
   Hung, Lin Y. et al.
   Gastroenterology, Volume 0, Issue 0)

Source-Medindia