Evidence indicates that children often present with unexplained gastrointestinal (GI) symptoms. Although such “functional” GI complaints have been shown to often be associated with anxiety in adults and also be highly correlated with experiences of early adversity, studies establishing adversity–GI–anxiety interactions during human development are lacking. Use of GI symptoms as a window into a child’s emotional health could allow for earlier recognition and intervention. GI bacterial manipulations have shown promise as a mental health treatment, particularly for anxiety and depression, in animal studies. For a two-part study published in Development and Psychopathology, Bridget Callaghan and colleagues sought to establish a proof-of-concept for a link between adversity, GI symptoms, GI bacteria (the microbiome), and the brain.


Two Studies in One

The researchers used data from a population of 344 children aged 3-18 who were raised with their biological parents without any report of adverse caregiving or were exposed to early adverse caregiving experiences, such as institutional or foster care followed by international adoption. For the initial study, parents of all participants completed the Child Behavior Checklist and Revised Children’s Anxiety and Depression Scale—Parent version for a baseline assessment of GI symptoms. In total, GI symptoms and anxiety were measured at three time points, spaced 2 years apart. Anxiety-related behavior was assessed through parent report on the Screen for Child Anxiety Related Disorders—Parent version, which provides a continuous measure of anxiety. “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,” explains Dr. Callaghan. “Importantly, those GI symptoms were also associated with higher levels of anxiety in each year of the study.”

In a follow-up study, Dr. Callaghan and colleagues tested a proof-of-concept association between early caregiving adversity, the GI microbiome, and brain reactivity to threat stimuli (fear faces) in a smaller convenience sample that was a subset of the initial study population. Children were selected if they had provided usable task-based MRI data when aged 5-11—as previously published data shows this to be a sensitive period for prefrontal cortex development in youth—and had agreed to donate a stool sample for microbiome data analysis. In this smaller subsample, the researchers were able to ask more targeted questions about GI symptoms and analyze each question individually (Table).

“We indeed established proof-of-concept that adversity was associated with changes in the GI microbiome, and that those bacterial differences were linked to how the brain responded to threatening stimuli, perhaps providing a biological link between GI symptoms and anxiety,” says Dr. Callaghan. “Specifically, we found that levels of a certain bacteria (which was decreased in the adversity-exposed children) were correlated with stronger activity in the prefrontal cortex—particularly involved in emotion regulation and inhibition—when viewing threat stimuli. These data suggest that the connection between the brain and gut (and the bacteria that live in the gut) might be particularly important to consider when assessing emotional functioning following adverse experiences.”

According to Dr. Callaghan, the most important finding, however, was that less than five questions on GI symptoms could be used to explain variance in concurrent and future mental health issues. “This opens the door to possibilities that we can use these GI symptoms to predict (with some degree of accuracy) whether an individual is at risk for anxiety disorders in the long term,” she adds. “Such predictive ability would be a step toward better integration between primary and mental healthcare professionals.”


More Work to Be Done

Dr. Callaghan notes a high amount of heterogeneity in the study data. “Whereas adversity was associated with elevated GI symptoms, anxiety, and changes to the microbiome at the group level, many individuals within the adversity-exposed group were not following that trajectory,” she says. “We need to explore and understand those individual differences so we can move this field toward precision medicine.”

To that end, the study team is currently working to extend their findings beyond the initial study population, testing a predictive algorithm that uses GI symptoms to classify individuals into high-risk groups for anxiety. “We would like to develop a tool that physicians can easily and quickly use in their everyday practice to help identify children who are at risk for future anxiety, and can then refer these youth onto the appropriate preventative services,” Dr. Callaghan says.

Animal studies indicate that the microbiome is associated with brain development in several regions that process threat and are therefore linked to anxiety and depression (the prefrontal cortex, amygdala, and hippocampus), explains Dr. Callaghan. “For example, bacteria in the gut help to produce several neurochemicals that assist brain development,” she adds. “Hence, it is possible that GI disruptions are linked to mental health through alterations in the microbiome and therefore brain development in the human. It will take some time to understand all of these pieces and how they fit together, but we are on that path.”