Scientists reveal the biological pathways linking childhood trauma to chronic gut pain

Two recent studies published in Gastroenterology provide evidence that events in early life shape the long-term health of the gut and brain. The research suggests that early stress and fetal exposure to certain medications increase the risk of digestive and mood disorders. Together, these findings point to new ways to treat conditions that involve both the brain and the digestive system.

Disorders of gut-brain interaction are digestive conditions that often occur alongside mood disorders like anxiety and depression. These conditions affect up to 40 percent of people worldwide and include issues like irritable bowel syndrome and functional constipation. Scientists recognize that the physical connection between the gut and brain tends to dictate how these diseases develop.

“As a physician who specializes in kids with disorders of gut-brain interaction (DGBI), I was caring for a number of children who were really suffering with symptoms (constipation, diarrhea and/or abdominal pain) so severe that they lived their lives in fear of not feeling well rather than focusing on thriving at school and enjoying friends and family, as they should have been able to do,” explained study author Kara G. Margolis.

Margolis is the director of the NYU Pain Research Center and a professor in the Department of Molecular Pathobiology at the NYU College of Dentistry. She is also a professor in the Departments of Cell Biology and Pediatrics at the NYU Grossman School of Medicine. Her laboratory explores the mechanisms underlying these conditions.

“The pain part of DGBI can be particularly challenging to treat, in large part because we don’t understand their precise etiologies. My impetus in studying DGBI was to try and understand underlying mechanisms in order to develop novel therapeutic targets,” she added. “It breaks my heart to see children in pain and this is my way to try and make them better.”

Margolis also noticed a pattern in her clinic regarding childhood trauma. “Along the same lines, I was seeing a lot of children in the clinic who struggled with stressors in early life. For example, abuse or neglect. I have found some of these kids harder to treat than kids who come in with more acute stress,” she noted.

“While we know that adverse childhood events (ACEs) or early-life stressors are linked to DGBI development, the mechanisms have not been well-studied,” she said. “My hope was that we could first define links between early life stress (ELS) and DGBI and, now that we have targeted some, begin to look for novel therapeutic targets, which we are currently exploring.”

Many people treat these combined mood and digestive issues with common medications known as selective serotonin reuptake inhibitors. These drugs block the reabsorption of a chemical messenger called serotonin, which increases its availability in the body. Because these medications are absorbed systemically into the entire body, they can cause unintended side effects like anxiety and digestive problems.

When taken during pregnancy, these widespread medications cross the placenta and affect the developing nervous systems of the fetus. The researchers wanted to understand exactly where serotonin acts to improve or worsen physical and emotional symptoms. They designed a 2025 study to test whether targeting serotonin specifically in the gut could offer a safer treatment.

The scientists used genetically modified mice to isolate the effects of serotonin in the gastrointestinal tract. They deleted the serotonin transporter protein specifically in the intestinal epithelium, which is the innermost cell lining of the gut. This approach allowed them to increase serotonin signaling in the digestive tract without altering serotonin levels in the brain or blood.

The researchers assessed the mice using various behavioral tests, such as placing them in open fields or elevated mazes to measure their anxiety levels. They found that deleting the serotonin transporter in the gut lining reduced both anxiety and depression-like behaviors. This targeted approach did not cause the negative digestive or cognitive side effects typically seen when the transporter is removed from the entire body.

To understand how the gut sent signals to the brain, the scientists injected a chemical to sever the vagus nerve in some of the mice. The vagus nerve is a major neural highway that connects the digestive tract directly to the brainstem. Disabling this nerve eliminated the anti-anxiety benefits, which suggests that the vagus nerve carries mood-altering signals from the gut to the brain.

The scientists also conducted a human study to observe the effects of systemic serotonin medications during fetal development. They tracked a group of 408 pregnant women and their infants through the first year of life. The mothers were categorized by whether they experienced depression and whether they took serotonin-altering medications during pregnancy.

The results showed that infants exposed to these medications in the womb had a much higher risk of developing functional constipation. This increased risk of severe constipation remained high regardless of the severity of the mother’s depressive symptoms. This provides evidence that systemic exposure to these drugs during early development directly impacts the human digestive system.

For a newer 2026 study, the scientists sought to explain how adverse experiences during early childhood alter the gut-brain connection. Early life stress is a known risk factor for long-term digestive and emotional problems. The researchers designed this second study to uncover the exact biological pathways that link childhood adversity to ongoing gut pain and movement issues.

The scientists used a mouse model of maternal separation to mimic the type of childhood adversity that humans sometimes face. They separated newborn mice from their mothers for three hours a day between their second and twelfth days of life.

When the mice reached young adulthood, the researchers tested their sensitivity to visceral pain, which is pain originating from the internal organs. They placed a tiny pressure sensor inside the colons of the awake mice to measure their physical responses to inflation. The mice that experienced maternal separation displayed significantly heightened sensitivity to gut pain compared to mice that stayed with their mothers.

The researchers also measured how quickly food moved through the digestive tracts of the adult mice. They fed the mice a harmless red dye and tracked the time it took to pass through their systems. The maternal separation caused distinct digestive movement issues that varied significantly by sex.

Male mice exposed to early stress experienced much slower overall digestive transit times. Female mice that experienced the same early stress showed faster colon movement times. The scientists also measured the rhythmic muscle contractions of isolated intestinal tissue in an organ bath and found similar sex-based differences.

To see if physical changes in the gut nerves explained these symptoms, the researchers analyzed the enteric nervous system. The enteric nervous system is a vast network of neurons embedded directly in the walls of the digestive tract. They found that mice exposed to early stress developed an increased number of serotonin-producing nerve fibers.

The scientists then investigated the role of sex hormones in these distinct symptoms. They injected both male and female mice with a drug called degarelix to temporarily suppress their natural sex hormone production. Suppressing these hormones eliminated the gut pain and reversed the movement abnormalities in the stressed mice.

The researchers also looked at the sympathetic nervous system, which controls the body’s emergency fight or flight response. They observed that the early life stress increased the density of sympathetic nerve fibers within the intestinal walls. To test this pathway, they gave the mice a chemical that temporarily disabled these sympathetic nerves.

Disabling the sympathetic nerves restored normal gut movement in both male and female mice. This chemical intervention did not reduce the heightened gut pain that the mice experienced.

“We expected that the pathways we looked at would overlap in terms of motility and pain-related symptoms,” Margolis told PsyPost. “We were surprised that, in ELS, there seemed to be targeted pathways for pain versus dysmotility.”

To bridge their laboratory findings with human health, the scientists analyzed two massive sets of pediatric health data. The first dataset came from a Danish national registry featuring over one million children. The researchers compared 20,055 children born to mothers with untreated depression against 1,093,263 children of mothers without depression.

They defined maternal depression using medical records and prescription histories, making sure to exclude mothers who took antidepressants during pregnancy. The analysis showed that children born to mothers with untreated depression faced an elevated risk for several digestive disorders. These included conditions like infant colic, abdominal pain, and functional constipation.

The scientists also evaluated the effects of postpartum depression in the Danish registry. They found that maternal depression in the first six months after birth similarly increased the risk of infant digestive issues like regurgitation and nausea.

“We were amazed that untreated maternal pre- and/or post-partum depression led to an increased risk of developing so many different DGBI, this really shows that these conditions, when untreated, impact gut-brain communication,” Margolis observed.

The second human dataset came from the Adolescent Brain Cognitive Development study in the United States. The researchers reviewed baseline data from 11,868 children aged nine and ten from diverse socioeconomic backgrounds. They assessed various forms of childhood adversity, such as parental mental health struggles, neglect, and lifetime abuse.

The scientists found that any form of early life stress more than doubled the odds of a child experiencing ongoing gastrointestinal symptoms. These symptoms included stomachaches, nausea, and severe constipation. Unlike the mouse experiments, the human data did not show major differences between boys and girls.

“DGBI are thought to occur overwhelmingly in females. In our clinical studies, however, we did not detect differences between males and females,” Margolis explained. “Interestingly a clinical study came out at the same time looking at adverse childhood events (ACEs) and DGBI outcomes and also did not see sex differences. This suggests that ELS/ACEs, that occur early enough to impact development, override the sex bias normally thought to occur.”

These findings rely in part on observational human data, which cannot definitively prove that early stress directly causes digestive disorders. The mouse models of maternal separation capture only one specific type of early life stress.

“The pathways we specifically identified to cause pain or motility changes are based on studies done in mice and need to be confirmed in humans,” Margolis cautioned.

The research carries important implications for maternal health. “Maternal mental health conditions need to be treated because even though there are potential interactions between SSRIs and gut-brain axis development, we actually saw more DGBIs with untreated maternal health conditions,” Margolis advised.

“Furthermore, untreated mental health conditions may not only affect the baby but can have a significant impact on the mom, which is a critical consideration. Treatments need not be medications in every case,” she added. “For some pregnant women even exercise, sleep, stress relief, healthy eating and therapy can help. In fact, all of those things should be considered as a part of treatment. But if a pregnant person needs medication I wholly support that as well!”

When treating patients, Margolis emphasizes looking at the whole picture. “When you have gut symptoms, it is important not only to look at what is currently stressing you but also to look at your life history because stressors during development induce critical, long-lasting impacts on gut-brain communication,” she said. “But, it is also important to recognize that not all people who are exposed to early life stressors develop gut symptoms!”

“An important takeaway message for primary care doctors and gastroenterologists and other medical specialists: The gut and brain communicate continuously and bidirectionally. This means that they are continuously impacting one another,” Margolis told PsyPost.

“Thus, when seeing patients with GI problems, particularly DGBI (but others as well), it is important to consider the role of mood. Similarly, if doctors are seeing patients for mood disorders it’s important to evaluate GI symptoms, because treating one may help the other,” she noted. “DGBI co-occur with mood disorders in over 50% of cases so when you have a DGBI, consider whether you might also have a mood disorder and vice versa.”

Despite the challenges, Margolis offered a message of hope. “Optimism! Gut symptoms associated with early life stress can be treated,” she emphasized. “The amazing thing about the nervous systems in the gut and the brain is that they are plastic.”

“This means that even if development is different because of early life stress, nerve cell connections and communication can be altered in beneficial ways through therapy and/or other habit or lifestyle changes like sleep, diet and exercise, as well as potential medications,” she said. “All of these options should be discussed with your care provider.”

Looking ahead, the research team aims to apply these insights to new treatments. “Our major long-term goal is to translate the findings of this study and our prior study showing that gut serotonin can influence mood, to develop gut-focused drugs that treat mood disorders,” Margolis concluded. “These studies, in tandem, suggest potential paradigm-shifting ways in which we may be able to treat anxiety and depression in the future.”

The study, “Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood,” was authored by Lin Y. Hung, Nuno D. Alves, Andrew Del Colle, Ardesheer Talati, Sarah A. Najjar, Virginie Bouchard, Virginie Gillet, Yan Tong, Zixing Huang, Kirsteen N. Browning, Jialiang Hua, Ying Liu, James O. Woodruff, Daniel Juarez, Melissa Medina, Jonathan Posner, Raquel Tonello, Nazli Yalcinkaya, Narek Israelyan, Roey Ringel, Letao Yang, Kam W. Leong, Mu Yang, Ji Ying Sze, Tor Savidge, Jay Gingrich, Robert J. Shulman, Michael D. Gershon, Annie Ouellet, Larissa Takser, Mark S. Ansorge, and Kara Gross Margolis.

The study, “Enteric and Sympathetic Nervous System Pathways Mediate Early Life Stress Effects on Gut Motility and Pain: Mechanistic Findings With Human Correlation,” was authored by Sarah A. Najjar, Helene Kildegaard, Ardesheer Talati, Priscila Dib Goncalves, Andrew Del Colle, Zixing Huang, Yan Tong, Daniel Juarez, Rahi Shah, Erfaneh Barati, Taeseon Woo, Melissa Medina, Narek Israelyan, Marguerite Bernard, Ruxandra Tonea, Michelle Ovchinsky, Noa Pesner, Roey Ringel, Luisa Valdetaro, Mette Bliddal, Martin Thomsen Ernst, Michael D. Gershon, Lin Y. Hung, and Kara G. Margolis.