GI Symptoms May Herald Mental Illness in Traumatized Kids

Batya Swift Yasgur, MA, LSW

April 10, 2019

Early adversity (EA) in life is associated with increased gastrointestinal (GI) problems in children that may affect brain development and behavior, new research suggests.

Investigators conducted two studies that drew on data from a study of almost 350 children between ages 3 and 18, comparing those who were adopted from orphanages or foster care on, or before, age 2 to those raised by a biological caregiver.

Study 1 showed children who had experienced previous caregiving disruptions displayed higher levels of GI symptoms, including stomach aches, constipation, vomiting, and nausea, and that these symptoms were associated with concurrent and future anxiety and mediated the adversity-anxiety association.

Study 2 focused on a subsample of children who provided stool samples and also underwent functional magnetic resonance imaging (fMRI) of the brain while completing a task evoking fear.

EA was associated with changes in the diversity of microbial communities and bacterial levels were correlated with activation of the prefrontal cortex activation, a region of the brain that helps regulate emotions.

"We found that children who had been exposed to caregiving adversity in their early lives had higher levels of GI symptoms than their non-adversity-exposed peers and, importantly, those GI symptoms were also associated with higher levels of anxiety in each year of the study," lead author Bridget Callaghan, PhD, a postdoctoral research fellow at the Sackler institute of Psychobiology, Columbia University, New York City, told Medscape Medical News.

"We also found that the connection between the brain and gut — and the bacteria that live in the gut — might be particularly important to consider when trying to understand emotional functioning following adverse experiences," she said.

The study was published online March 28 in Development and Psychopathology.

Window Into Emotional Health

"Many children present to primary healthcare providers with unexplained GI symptoms, and in adults, we know that such 'functional' GI complaints are often associated with anxiety," Callaghan said.

"In adults, functional GI issues are also highly connected with experiences of early childhood adversity; however, there are very few studies which have established an adversity–GI symptoms–anxiety link in development," she continued, "so if we can use GI symptoms as a window into a child's emotional health, it could help us to recognize and intervene with problems early."

She noted that one of the "exciting potential ways to intervene at the level of GI symptoms is to alter GI bacteria."

In animal studies, these bacterial manipulations "show promise as a mental health treatment — particularly [for] anxiety and depression."

For this reason, the researchers also wanted to "establish proof-of-concept for a link between adversity, GI bacteria (the microbiome), and the brain," she said.

To investigate the question, the researchers conducted two related studies, the first to test whether adversity is associated with GI complaints in a large sample of youth and whether they are associated with concurrent anxiety and predictive of future anxiety.

The second study was conducted in a smaller convenience sample taken from the larger Study 1 population to establish proof-of-concept for microbiome–brain associations in middle childhood following adversity.

Higher Distress, Digestive Issues

Study 1 took a total of 344 children and adolescents (ages 3-18 years) and compared those who had been exposed to EA (ie, institutional or foster care, followed by international adoption, n = 115; 75 female) with a comparison group (COMP) who had been raised with their biological families with no adverse caregiving and no psychiatric diagnoses (n = 229; 120 female).

Parents completed the measure at up to three time points, spaced approximately 2 years apart, to provide a longitudinal assessment of child anxiety.

The first time when participants provided report of GI symptoms was considered their "Time 1" assessment, regardless of the visit in which those data had been collected.

If participants provided >1 time point of anxiety symptoms, these were labeled Time 2 for the second point, and Time 3 for the third point.

GI symptoms were divided into two factors: GI distress/digestive issues (Factor 1) and anxiety (Factor 2).

GI symptomatology (nausea, stomach aches/cramps, expulsion, vomiting, and constipation — all without known medical cause) was assessed through GI distress items included within the Child Behavior Checklist (CBCL) (1.5–5 years and 4–18 years).

The researchers used the Revised Children's Anxiety and Depression Scale-Parent version (RCADS-P) to assess GI somatic symptoms.

The Screen for Child Anxiety Related Disorders-Parent version (SCARED-P) was used to assess anxiety-related behavior.

When looking at Factor 1, the researchers found EA exposure to be associated with higher GI distress scores (β = .25, t [340] = 2.20, P = .028, 95% confidence interval [0.03, 0.47]), as was increasing child age (β = .04, t [340] = 3.22, P = .001, [0.02, 0.07]).

EA exposure was also associated with higher scores on Factor 2 (digestive issues factor, β=0.41, t [340] = 3.57, P = .0004, [0.18, 0.63]).

No association with age or sex was found in both factors.

GI distress, sex, and caregiving group (but not age) were, however, significantly associated with Time 1 anxiety scores — an association that was confirmed even when the researchers included only children older than age 8.

Digestive issues (Factor 2) were not significantly associated with variance in SCARED-P anxiety scores (β = 0.03, t [325] = 1.83, P = .068, [0.00, 0.05]).

The authors, however, acknowledge that digestive issues had a "generally low incidence overall."

Elevated GI scores explained the variance in the association between EA and concurrent anxiety.

The mediation was found to be significant in several paths: between caregiving group and scores on the GI Distress measure; between GI distress and anxiety, and between EA caregiving history and anxiety (all Ps < .0001).

Adversity's Impact on the Gut

The second study tested a "proof of concept" between EA the GI microbiome, and brain reactivity to threat stimuli in a small "convenience sample," which was a subset of the Study 1 population (n = 16; mean age 8 (range, 5–11 years).

Participants were selected if they had provided usable task-based MRI data during childhood (between 5–11 years) and agreed to donate a stool sample, which was analyzed for its bacterial content.

Parents completed a daily diary of the child's food intake during the 2 days preceding stool sample collection, and the amount of protein, carbohydrate, and fat — which can influence bacterial composition — for each meal were averaged across 2 days and included as potential confounding factors.

Parents also answered questions to assess the presence/frequency of children's GI symptoms and pain.

During the fMRI task, the children completed two runs of an emotional faces task designed to assess brain activity when children reacted to a fearful face.

Across all the samples, bacteria from the genus Bacteroides were the most abundantly expressed, and their level did not differ between the groups, after controlling for age, sex, and GI symptom factor scores.

However, two biomarkers — including an unknown genus from the family Lachnospiraceae — were higher in children from the COMP than from the EA group.

When the researchers considered the microbial "community structure," they found that EA children had lower counts of bacteria, alpha diversity, and observed richness, compared to the COMP children, as well as changes in beta diversity.

Moreover, bacteria levels (adversity-associated and adversity-independent) were correlated with prefrontal cortex activation to emotional faces.

Callaghan noted that animal studies have demonstrated that the microbiome is associated with brain development in several regions that process threat (the prefrontal cortex, amygdala, and hippocampus).

"Hence, it is possible that GI disruptions are linked to mental health through alterations in the microbiome and therefore brain development in the human," she suggested.

However, she cautioned, "it will take us a while to unwind all of these pieces and understand how they all work together, but we are on that path."

Adversity may play a role in influencing the microbiome.

"Trauma is tightly tied to every level of the brain–gut–microbiome axis," she stated.

"We are well aware that stress hormones can influence brain development, but they are also intricately connected with the gastrointestinal system — high levels of stress can change our intestinal transit time, make our immune system overreact to bacteria in our gut, and are associated with what bacteria survive and flourish in the gut."

Microbiome Established Early

Commenting on the study for Medscape Medical News, Sara C. Campbell, PhD, associate professor, Department of Kinesiology and Health, Rutgers University, New Brunswick, New Jersey, who was not involved with the study, said that it "is suggested that the microbiome is molded early in life, perhaps even established by 2 to 3 years old, so early adverse events in a child's life may contribute to this established microbiome, making it tougher to change later in life."

She expressed concern that "diversity and richness are measures that microbiome scientists are moving away from, and it is also tough, given that the authors only looked at such a 'high' taxonomic level — generally now, lower taxonomic resolution is better."

Moreover, although the associations between the genus Lachnospiraceae and activated brain regions during fMRI during a fear face presentation is new, "more should be done to see what this actually means and what species and strains within that family are microbes are changed, compared to the children raised more 'conventionally.' "

Callaghan added that her group is "currently working on testing our model of GI symptoms in other samples of adversity-exposed youth to examine how well it predicts anxiety, and therefore how generalizable the findings are."

This research was supported by the National Institute of Mental Health, the Dana Foundation, the National Health and Medical Research Council, and the American Australian Association Fellowship. The authors and Campbell have disclosed no relevant financial relationships.

Development and Psychopathology. Published online March 28, 2019. Abstract

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