Early life stress may lead to digestive issues later in life, driven by changes in the gut and sympathetic nervous systems, according to a new study published in the journal Gastroenterology .
"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.
Emotional neglect and other adverse experiences early in life can have a profound impact on a child's development. Research shows that early life stress, both during pregnancy and after birth, may shape how the brain forms and are linked to a higher likelihood of developing mental health conditions like anxiety and depression.
Researchers at NYU College of Dentistry's Pain Research Center sought to understand how these difficulties shape the brain's two-way communication with the gut. When things go awry with this communication superhighway, people can experience digestive problems, including 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."
The researchers explored early life stress in three different ways using mouse models and two large studies of children.
In the study in mice, neonatal mice were separated from their mothers for multiple hours a day, a model for early life stress. When the researchers examined them several months later (at the equivalent of young adulthood), the mice had higher levels of anxiety-like behaviors, gut pain, and motility issues. The changes in motility differed based on sex, with female mice experiencing diarrhea and males experiencing constipation.
Additional experiments revealed that different pathways may be driving different gastrointestinal symptoms. Knocking out sympathetic signaling to the gut resolved motility issues, but not pain, while sex hormones seemed to play a role in pain, but not motility. Serotonin-based pathways appear to impact both gut pain and motility.
"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.
The link between early life stress and gastrointestinal issues found in the preclinical experiments was largely mirrored in two large human studies. In one, the researchers looked at a population-based study conducted in Denmark of more than 40,000 babies through 15 years of age, half of whom were born to mothers with untreated depression during or after pregnancy.
They found that depression during and after pregnancy among mothers not taking antidepressants was associated with children having an increased risk of being diagnosed with numerous digestive disorders, including nausea and vomiting, functional constipation, colic, and irritable bowel syndrome. This finding builds on a previous study led by Margolis that determined that mothers who take antidepressants during pregnancy are more likely to have kids who are 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."
In a second human study, the researchers analyzed data from nearly 12,000 children in the US who were part of the NIH-funded Adolescent Brain Cognitive Development (ABCD) study. They looked at adverse childhood experiences, including abuse, neglect, and parental mental health problems, and whether children had digestive issues when they were nine and 10 years old. They found that gastrointestinal symptoms increased with any type of early childhood stress.
In the human studies, the researchers did not find differences in digestive outcomes between males and females who experienced early life stress, suggesting that difficulties during this critical developmental stage may impact gut and gut-brain health, irrespective of sex.
Taken together, the studies show that early life stress may shape the development of gut-brain communication and contribute to long-term gastrointestinal symptoms, including pain and motility issues. By demonstrating that different pathways modulate different symptoms, future studies can explore how to target individual pathways to more effectively treat digestive issues, like 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).
