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Adversity at a young age alters gut-nerve circuits and leads to long-term changes in pain sensitivity, disorders of gut-brain interaction (DGBI), and bowel function, according to a recent study in Gastroenterology.

While negative experiences during early life are known to disrupt gut-brain axis development, the mechanisms linking early-life stress (ELS) to long-term gastrointestinal (GI) dysmotility and pain remain unclear.

To clarify that connection, researchers led by Kara G. Margolis, MD, a pediatric gastroenterologist and a professor in the Department of Pediatrics at NYU Grossman School of Medicine in New York City, conducted a dual assessment in mice and in humans.

The animal component of the study used a maternal separation model in 8-week-old mouse pups to evaluate visceral pain sensitivity, intestinal motility, and enteric nervous system (ENS) composition. In addition, the investigators analyzed two large human pediatric population cohorts for associations between ELS and DGBI risk.

In mice, maternal separation led to visceral hypersensitivity, sex-specific motility defects, and altered ENS composition, including increased serotonergic innervation and changes in subtype-specific neuronal proportions, Margolis’s group reported. The gonadotropin-releasing hormone antagonist d egarelix suppressed separation-induced visceral pain and motility defects, thereby implicating sex hormones in long-term gut changes. Maternal separation led to enhanced sympathetic innervation of the ENS and chemical sympathectomy, suggesting sympathetic overactivity in ELS-related gut dysfunction.

In humans, significant associations between maternal mental health problems and pediatric DGBI emerged in both population cohorts and mirrored the preclinical murine findings. The results identify ELS-driven changes in enteric, sensory, and sympathetic pathways as contributors to DGBI risk and point to potential therapeutic targets, the authors wrote.

“As a physician who specializes in kids with [DGBI], I was caring for children who were really suffering with symptoms, such as constipation, diarrhea, and/or abdominal pain, so severe that they lived their lives fearing not feeling well rather than focusing on thriving at school and enjoying friends and family,” Margolis told Medscape Medical News. “The pain part of DGBI can be particularly challenging to treat, in large part because we don’t understand the precise etiologies.” 

Some children struggled with stressors in early life, for example, maternal depression, abuse, or neglect. “I have found some of these kids harder to treat than kids who come in with more acute stress,” Margolis added. “My hope was that we could first define links between ELS and DGBI and now that we have targeted some, begin to look for novel therapeutic targets.”

Two unexpected findings emerged from the human part of the research, which used copious data from a large national Danish study, 1997-2015, and the National Institutes of Health (NIH)’s ongoing Adolescent Brain Cognitive Development study.

“DGBI are thought to occur overwhelmingly in females. In our clinical studies, however, we did not detect differences between males and females,” Margolis said. Interestingly, a recent clinical study looking at adverse childhood events (ACE) and DGBI outcomes also saw no sex differences. “This suggests that ELS/ACE that occur early enough to impact development override the sex bias normally thought to occur,” she said. Her group also expected that observed pathways would overlap in terms of motility and pain-related symptoms. “We were surprised that in ELS, there seemed to be targeted pathways for pain vs dysmotility.”

A key but not well-studied link between mouse and human studies in ELS is the impact of medications, Margolis noted. “Since we showed previously that SSRIs [selective serotonin reuptake inhibitors] can impact DGBI development, and virtually all mouse studies evaluating ELS occur in animals not given SSRIs, we knew we had to look at a population susceptible to ELS that were not given SSRIs. Like the preclinical studies, abdominal pain was increased in both males and females.” Other DGBI detected in the clinical study could not be evaluated in the mouse models, but these should be addressed in future research. 

In Margolis’s view, the biggest takeaways for now are that untreated maternal depression is linked to increased risk for pediatric DGBI and needs treatment in the form of psychotherapy and lifestyle changes, but in some cases with medication. “The gut and brain communicate continuously and bidirectionally. This means that they are continuously impacting one another. Thus, when seeing patients with GI problems, particularly DGBI, it’s important to consider the role of mood.” 

In addition, it’s essential to look not only at what is currently stressing patients with DGBI but also at their life history because stressors during development have critical, long-lasting impacts on gut-brain communication, she said. “DGBI co-occur with mood disorders in over 50% of cases, so when patients come in with DGBI, mood disorders should also be evaluated for.” Conversely, doctors seeing patients for mood disorders should evaluate GI symptoms because treating one may help the other. 

Commenting on the study but not involved in it, gastroenterologist Lin Chang, MD, vice chief of the Vatche and Tamar Manoukian Division of Digestive Diseases at University of California, Los Angeles, called the study an excellent example of translational research, combining mechanistic animal studies with analyses of large human cohorts.

“It bridges the gap between basic neurogastroenterology and motility and clinical gastroenterology. Work like this helps move the field toward a more precise understanding of DGBI and ultimately toward more individualized care for patients,” Chang told Medscape Medical News.

Prior clinical and experimental studies have linked adverse childhood experiences with about twofold increased risk for conditions such as irritable bowel syndrome, she said. “What is particularly valuable about this study is that it provides mechanistic insights, showing that ELS can remodel enteric and sympathetic neural circuits that regulate motility and visceral pain. That type of biological framework strengthens the role of the brain-gut axis, which many of us in the field have been studying for years.”

The link to long-lasting changes in ENS organization and sympathetic innervation and signaling are particularly compelling, Chang added, noting that the associations were observed in both males and females, reinforcing the conclusion that ELS is a clinically relevant risk factor.

“That these neural changes were associated with sex-specific alterations in motility, and that suppression of sex hormones could modify these effects, add important insights, suggesting that developmental programming of gut function may involve interactions between stress pathways, the autonomic nervous system, and sex hormones,” she noted.

For clinicians, this study highlights the importance of taking a biopsychosocial approach that considers psychosocial history and adverse childhood experiences when evaluating patients with chronic GI symptoms, Chang added. Her group conducted a study showing that confiding in others about adverse childhood experiences at the time reduced the risk for IBS.

“Addressing stressful life events in the lifespan with behavioral interventions can help reduce stress-sensitive symptoms, like IBS symptoms and other coexisting non-GI symptoms, and improve a sense of control over the symptoms,” she said. The findings strengthen the rationale for a biopsychosocial plus mechanism-informed approach to DGBI, which may ultimately help identify biologically distinct patient subgroups who could benefit from more targeted therapies.

“These conditions are not simply functional in the sense of [impaired] biology; they often reflect complex interactions among neural, environmental, and developmental influences,” she said, recommending an integrated, holistic care approach with gastroenterologists, primary care physicians, GI dietitians, and GI psychologists.

Still to be determined is how closely the mechanisms in animal models translate to humans and whether similar neural remodeling occurs in patients with a history of early-life adversity.

“Future studies will likely focus on identifying biomarkers of these neural and autonomic alterations and determining whether they define distinct patient subgroups,” Chang said. Another key step will be to explore therapeutic strategies that modulate enteric neural circuits or autonomic signaling, potentially enabling more mechanism-based treatment approaches. “In addition to diaphragmatic breathing and other behavioral approaches to increase vagal tone to help normalize homeostasis, an emerging therapy is noninvasive vagal stimulation, but more studies are needed.”

This work was supported by grants to various authors from multiple research-funding bodies including the American Gastroenterological Association and NASPGHAN Foundation as well as government agencies such as the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases and the Department of Defense. Margolis received support from Nutrition Takeda Innovation.

The authors and Chang had no relevant conflicts of interest.