New research published in Gastroenterology This suggests that stress during childhood may increase the risk of gastrointestinal diseases later in life. Researchers found that these effects were associated with changes in both the gut and sympathetic nervous system.
“Our study shows that these stressors have real effects on children’s development and can have long-term effects on gut problems. Understanding the mechanisms involved will help us develop more targeted treatments,” said study author Kara Margolis, director of the New York University Center for Pain Research and professor of molecular pathology at New York University School of Dentistry and of pediatrics and cell biology at New York University Grossman School of Medicine.
How early stress shapes brain and gut development
Experiences such as emotional neglect and other adversities can have a significant impact on a child’s development. Research shows that stress during pregnancy and early childhood can affect brain development and increase the risk of mental health conditions such as anxiety and depression.
To better understand this connection, researchers at the New York University School of Dentistry Center for Pain Research investigated how early stress affects communication between the brain and the gut. This connection plays an important role in digestion, and disturbances can cause symptoms such as irritable bowel syndrome, abdominal pain, and movement disorders (such as constipation and diarrhea).
“If the brain is affected, the gut is likely to be affected as well. These two systems are communicating 24 hours a day, seven days a week,” Margolis said. “There is some data showing that early life stress may be associated with gut disease, but we wanted to take a closer look at the mechanisms and how the gut-brain pathways work.”
Mouse study reveals lasting effects of early stress
The research team used mouse models to investigate stress in childhood, along with two large studies in children.
In this animal study, newborn mice were separated from their mothers for several hours each day to simulate early stress. When examined several months later (an age comparable to young adults), these mice showed increased anxiety-like behavior, intestinal pain, and problems with bowel movements. The types of mobility problems vary by gender, with women more likely to develop diarrhea and men more likely to experience constipation.
Further experiments showed that different biological pathways appear to control different symptoms. Inhibiting sympathetic signaling improved mobility problems but did not reduce pain. In contrast, sex hormones affected pain but not exercise. Serotonin-related pathways were involved in both pain and bowel movements.
“This suggests that there is no one-size-fits-all approach to treating disorders of gut-brain interaction, and that if patients experience different symptoms, different pathways may need to be targeted,” Margolis said.
Human study confirms link between stress and digestive disorders
The results of the animal study were supported by two large-scale human studies. One study followed more than 40,000 children in Denmark from birth until age 15. About half were born to mothers whose depression was not treated during or after pregnancy.
Children of mothers with untreated depression were at higher risk of developing gastrointestinal disorders such as nausea and vomiting, functional constipation, colic, and irritable bowel syndrome. These results build on previous research showing that children of mothers who took antidepressants during pregnancy were more likely to be diagnosed with functional constipation.
“If maternal depression is left untreated, children appear to have more severe gastrointestinal problems, suggesting that mothers with depression should be treated during pregnancy. This may include non-medical measures such as therapy, but some pregnant women may require medication to treat depression,” Margolis said. “This discovery also strengthens our efforts to develop antidepressants that do not reach the placenta, which is currently the focus of much of our research.”
The second study analyzed data from approximately 12,000 children in the United States participating in the NIH-funded Adolescent Brain Cognitive Development (ABCD) study. Researchers looked at adverse childhood experiences, such as abuse, neglect, and parental mental health challenges, and compared them with gastrointestinal symptoms at ages 9 and 10. They found that all forms of early stress are associated with increased gastrointestinal disorders.
Interestingly, unlike the mouse studies, the human data showed no differences in digestive outcomes between men and women. This suggests that early stress can affect gut and gut-brain health similarly in both genders during critical stages of development.
Towards more targeted treatments for intestinal diseases
Overall, this study shows that early life stress can affect gut-brain communication and contribute to long-term digestive problems such as pain and movement disorders. The discovery that different biological pathways cause different symptoms may guide more precise treatments for disorders of gut-brain interactions.
“When a patient comes in with a gut problem, we shouldn’t just ask if they’re feeling stressed now. What happened in their childhood is also a very important question to consider,” Margolis said. “This developmental history may ultimately provide a way to understand how some disorders of gut-brain interactions develop and how to 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 of New York University Dentistry (co-senior author). Ardessia Talati, Priscilla Dib Gonsalves, Andrew Del Colle, Narek Israelian, Marguerite Bernard, Ruxandra Tonaire, Roy Ringel, and Michael Gershon of Columbia University; Helen Kildegaard, Mette Bridal, and Martin Thomsen-Ernst from the University of Southern Denmark;
This study was supported by the National Institutes of Health (R01 DK130517, R01MH119510, K01DA057389, F32DK132810, K01DK144656, R01DK130518, R01DK126644) and the Department of Defense (W911NF-21-S-0008, PR160365), and NARSAD/Brain Behavioral Research Foundation. Alpha Omega Alpha. North American Pediatric Gastroenterology, Hepatology, and Nutrition Society. and American Gastroenterological Association Research Foundation (AGA2024-51-02).
