A new study published in Gastroenterology suggests that stress during early life may increase the risk of digestive problems later on. Researchers found that these effects are linked to changes in both the gut and the sympathetic nervous system.
“Our research shows that these stressors can have a real impact on a child’s development and may influence gut issues long-term. Understanding the mechanisms involved can help us to create more targeted treatments,” said study author Kara Margolis, director of the NYU Pain Research Center and professor of molecular pathobiology at NYU College of Dentistry and pediatrics and cell biology at NYU Grossman School of Medicine.
How Early Stress Shapes Brain and Gut Development
Experiences such as emotional neglect and other forms of adversity can significantly influence a child’s development. Studies indicate that stress during pregnancy and early childhood can affect how the brain develops and increase the risk of mental health conditions like anxiety and depression.
To better understand this connection, researchers at NYU College of Dentistry’s Pain Research Center examined how early stress affects communication between the brain and the gut. This connection plays a key role in digestion, and disruptions can lead to conditions such as irritable bowel syndrome, abdominal pain, and motility issues (e.g., constipation or diarrhea).
“When the brain is impacted, the gut is likely also impacted — the two systems communicate 24 hours a day, seven days a week,” said Margolis. “There’s some data showing that early life stress may be linked to gut disorders, but we wanted to take an in-depth look at the mechanisms and how these gut-brain pathways work.”
Mouse Studies Reveal Lasting Effects of Early Stress
The research team investigated early life stress using mouse models along with two large studies involving children.
In the animal study, newborn mice were separated from their mothers for several hours each day to simulate early stress. When examined months later (at the equivalent of young adulthood), these mice showed increased anxiety-like behavior, gut pain, and problems with gut movement. The type of motility issue differed by sex, with females more likely to develop diarrhea and males more likely to experience constipation.
Further experiments showed that different biological pathways appear to control different symptoms. Disrupting sympathetic nerve signaling improved motility issues but did not reduce pain. In contrast, sex hormones influenced pain but not motility. Serotonin-related pathways were involved in both pain and gut movement.
“This suggests that there’s no one-size-fits-all approach to treating disorders of gut-brain interaction, and that when patients experience different symptoms, we may have to target different pathways,” said Margolis.
Human Studies Confirm Link Between Stress and Digestive Disorders
The findings from animal experiments were supported by two large human studies. One study followed more than 40,000 children in Denmark from birth to age 15. About half were born to mothers who experienced untreated depression during or after pregnancy.
Children of mothers with untreated depression had a higher risk of developing digestive conditions, including nausea and vomiting, functional constipation, colic, and irritable bowel syndrome. These results build on earlier work showing that children of mothers who took antidepressants during pregnancy were more likely to be diagnosed with functional constipation.
“Digestive outcomes for children seem to be even more profound when a mother’s depression is left untreated, suggesting that mothers experiencing depression should be treated during pregnancy. This may include nonmedical measures like therapy, but some pregnant women may also require medications to treat their depression,” said Margolis. “This finding also reinforces our commitment to developing antidepressants that do not reach the placenta — a focus of many of our studies right now.”
A second study analyzed data from nearly 12,000 children in the US participating in the NIH-funded Adolescent Brain Cognitive Development (ABCD) study. Researchers examined adverse childhood experiences, such as abuse, neglect, and parental mental health challenges, and compared them with digestive symptoms at ages nine and 10. They found that any form of early stress was linked to an increase in gastrointestinal problems.
Interestingly, unlike the mouse studies, the human data showed no differences between males and females in digestive outcomes. This suggests that early stress may affect gut and gut-brain health similarly across sexes during key stages of development.
Toward More Targeted Treatments for Gut Disorders
Overall, the research indicates that early life stress can influence how the gut and brain communicate, contributing to long-term digestive issues such as pain and motility problems. The discovery that different biological pathways drive different symptoms could help guide more precise treatments for disorders of gut-brain interaction.
“When patients come in with gut problems, we shouldn’t just be asking them if they are stressed right now; what happened in your childhood is also a really important question and something we need to consider,” said Margolis. “This developmental history could ultimately inform how we understand how some disorders of gut-brain interaction develop and treat them based on specific mechanisms.”
Additional study authors include Sarah Najjar (first author), Zixing Huang, Yan Tong, Daniel Juarez, Rahi Shah, Erfaneh Barati, Taeseon Woo, Melissa Medina, Michelle Ovchinsky, Noa Pesner, Luisa Valdetaro, and Lin Hung (co-senior author) of NYU Dentistry; Ardesheer Talati, Priscila Dib Goncalves, Andrew Del Colle, Narek Israelyan, Marguerite Bernard, Ruxandra Tonea, Roey Ringel, and Michael Gershon of Columbia University; and Helene Kildegaard, Mette Bliddal, and Martin Thomsen Ernst of the University of Southern Denmark.
The research was supported by the National Institutes of Health (R01 DK130517, R01MH119510, K01DA057389, F32DK132810, K01DK144656, R01DK130518, R01DK126644) and Department of Defense (W911NF-21-S-0008, PR160365), as well as the NARSAD/Brain Behavior Research Foundation; Alpha Omega Alpha; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition; and the American Gastroenterological Association Research Foundation (AGA2024-51-02).