How serotonin produced in the gut can influence mood and gastrointestinal disorders was the focus of a Jan. 12 NIEHS cross-divisional seminar by Kara Margolis, M.D., from Columbia University’s Irving Medical Center. Her talk centered on selective serotonin reuptake inhibitors (SSRIs) and how they affect the body’s serotonin transporter (SERT) function.

Margolis, a pediatric gastroenterologist, studies functional gastrointestinal disorders (FGIDs) and autism spectrum disorders. Her recent research focuses on peripheral serotonin (5-HT), a neurotransmitter produced in the gut. 5-HT accounts for 95% of the body’s serotonin, and it is a key influence on brain and nervous system development — particularly in gestation and, later in life, in the modulation of mood.

Margolis conducts translational research into the biological mechanisms involved in conditions such as autism spectrum disorders, with an eye toward advancing novel therapies. (Photo courtesy of Kara Margolis)

“More than 50% of people with FGIDs also have depression or anxiety conditions,” Margolis said. “It’s increasingly recognized that the gut can have profound effects on how the brain develops and functions. Gastrointestinal dysfunction is often a precursor to disturbances in mood.”

Disruption of serotonin transport

People with FGIDs often have abnormal gut motility, or movement of the digestive tract to remove waste from the body. Although it seems like a simple process, a lot must happen for normal motility to happen. Serotonin signals for contraction in the gut to push forward, while the tract ahead of that point is relaxing.

However, Margolis noted, once serotonin is active in the system, it needs to be inactivated because it is a highly charged molecule and cannot dissolve back into cells. SERT pumps serotonin back into cells to be inactivated in mitochondria. Disruption of this process — particularly during pregnancy with the use of commonly prescribed SSRIs — may play a role in FGIDs and mood disorders.

Behavior and SSRIs

She discussed how in about 8% of pregnancies, women have been prescribed SSRIs to combat depression. SSRIs can cross the placenta, and evidence shows that developmental exposure to these inhibitors has been linked to mood disorders that progress into adulthood and cause gastrointestinal issues.

Serotonergic neurons begin to develop in the human brain as early as the fifth gestational week and play a crucial role in formation of the enteric nervous system, which governs the gastrointestinal tract.

Margolis noted that using longitudinal cohort studies, her research group determined that if a person’s mother used an SSRI during pregnancy, that individual is at increased risk of having an FGID as early as the first year of life. That increased risk persisted as far as the oldest cohort members — 17 years of age.

But because gut-brain axis communication is bidirectional, Margolis and her lab could not be sure where the effects of inhibited SERT were acting to modulate positive or negative effects on mood and gastrointestinal function.

To determine location, Margolis’s team used a mouse model to study the effects of SERT removal using mice that had the transporter selectively knocked out of both the gut epithelium — the surface lining of the gastrointestinal tract — and the enteric, or intestinal, nervous system. The researchers found that when SERT was knocked out of gut epithelium, it had antidepressant effects and did not affect gut motility. Removing SERT from the enteric nervous system led to pro-depressive effects, slowed gut motility, and caused constipation.

Margolis noted that prescribing nonabsorbable SSRIs to gestating mothers could be a potential solution.

A more holistic view

That experiment demonstrates that treating the gut and the brain as totally separate systems is problematic, according to Margolis.

“The Neurobehavioral Core Facility seeks to interact with as many groups at NIEHS as possible to support neurobehavioral research,” said Cushman. (Photo courtesy of Steve McCaw / NIEHS)

“Treatment so far has been siloed even though we know the connection of the gut and brain,” she said. “In the case of probiotics and fecal transplant, there is not enough evidence to show they treat gut and the brain. It [will be] hard to target both gastrointestinal and mood disorders effectively at the same time until we understand mechanistic underpinnings.”

Jesse Cushman, Ph.D., who leads the NIEHS Neurobehavioral Core Facility, organized the cross-divisional seminar with the aim of highlighting the interconnectedness of the different systems of the body.

“We felt that a speaker focused on gut-brain interactions would encourage a more holistic view,” he noted.

“In her more recent work, Dr. Margolis also focuses on behavioral outcomes, and we thought this would highlight the utility of these sorts of measures for researchers working in other bodily systems.”

Citation: Margolis KG, Cryan JF, Mayer EA. 2021. The microbiota-gut-brain axis: from motility to mood. Gastroenterology 160(5):1486–1501.

(Kelley Christensen is a contract writer and editor for the NIEHS Office of Communications and Public Liaison.)