Markers in Saliva Tied to Gut Disorders in Children With Autism

Pauline Anderson

March 04, 2022

Dr David Q. Beversdorf

Researchers have identified markers in saliva that are differentially expressed in children with autism spectrum disorder (ASD) who have gastrointestinal (GI) disturbances.

These findings mark the beginning of an understanding of the biological differences separating kids with ASD with, and without, GI disturbances, study investigator David Q. Beversdorf, MD, professor of radiology, neurology and psychology, Department of Psychological Sciences, University of Missouri, Columbia, told Medscape Medical News.

"The hope is this will lead us in future to markers that help guide targeted precision treatments of gastrointestinal disorders" in children with autism, with the ultimate goal of improving their quality of life, said Beversdorf.

The study was published online January 20 in Frontiers in Psychiatry.

Anxiety a Key Driver?

GI disorders, particularly constipation, are common in children with ASD. Previous research by Beversdorf and colleagues suggest anxiety may be driving the relationship between gut disturbances and autism.

Research shows some children with ASD respond well to traditional treatments such as laxatives, while others do not. However, the reasons for this are unclear.

"It would be great to know who those great responders are," said Beversdorf. "Subtyping and using biomarkers might be biologically meaningful" because this could identify distinct groups.

The case-control study included 898 children aged 18-73 months recruited from outpatient pediatric clinics affiliated with seven academic medical centers across the United States. The average age of the sample was 44 months and participants were mainly White (76%), non-Hispanic (89%), and male (73%).

The children fell into three neurodevelopmental categories: ASD (n = 503), non-ASD developmental delay (DD, n = 205), and typical development (TD, n = 190).

ASD was diagnosed using standardized assessment tools including the Autism Diagnostic Observation Scale, second edition (ADOS-2). DD participants had delays in gross motor skills, fine motor skills, language, or cognitive development, but did not meet criteria for ASD.

Including children with DD could address whether biological markers are specific to autism or to developmental disorders in general, noted Beversdorf.

TD participants, recruited at the time of their annual well-child visit, did not exhibit developmental delays.

Links to GI Disturbance, Behavior

Researchers subdivided participants into those with GI disturbances (n = 184) and those without these disturbances (n = 714). This was based on medical record review and parental report of disorders such as constipation, reflux, chronic diarrhea or abdominal pain, and food intolerance.

As expected, investigators found more children with ASD reported GI disturbance (22%) than with TD (10%). In children with ASD, rates of constipation (11%) and reflux (6%) were higher than rates among those with TD (3% and 0.5%, respectively).

However, rates of GI disturbances in children with ASD were similar to those with DD.

Investigators used a swab to obtain a saliva sample from participants in a nonfasting state. Saliva is a feasible and often favored source for sampling GI-related biology. Unlike stool microbiome, the saliva microbiome can be repeatedly sampled on demand and has shown resilience to antibiotics.

Researchers examined numerous RNAs, which are "incredibly biologically relevant," said Beversdorf.

Investigators compared levels of 1821 micro-transcriptome features across neurodevelopmental status and the presence or absence of GI disorders.

They also examined micro-transcriptome levels among GI subgroups (constipation, reflux, food intolerance, other GI condition, no GI condition). In addition, they identified RNAs that differed among children taking three common GI medications. These included probiotics, reflux medication, or laxatives.

The investigators found five piwi-interacting RNAs, which are small noncoding RNA molecules and three microbial RNAs in saliva that displayed an interaction between developmental status and GI disturbance. Fifty-seven salivary RNAs differed between GI subgroups, with microRNA differences found between food intolerance and reflux groups being the most common.

The analysis identified 12 microRNAs that displayed relationships with GI disturbance, behavior, and GI medication use.

First Exploration

However, Beversdorf cautioned about the medication finding. "I can't speak confidently about what we see there because with each group you get much, much smaller sample sizes with each individual treatment approach."

The researchers looked at downstream targets of the 12 microRNAs and found involvement with 13 physiologic pathways. These included long-term depression, metabolism, and digestion pathways

The metabolism and digestion pathways make sense, but it's unclear why an addiction-related pathway would be involved, said Beversdorf. However, he noted children with autism do display obsessive features.

Experts don't know if RNA changes are a cause of, or a response to, GI problems. "It could be the pain of constipation is triggering, say, these addiction pathway changes," said Beversdorf.

The study is the "first exploration" into possible specific targets for treating GI disturbances in autism, said Beversdorf. "We hope these biomarkers will eventually give us an indication of which patients are going to respond to the individual approach to treating their constipation, their diarrhea, or whatever it is."

The investigators plan to study whether RNA biomarkers determine which patients respond to different treatments targeting constipation, said Beversdorf.

A study limitation was that GI disturbances were not assessed by physicians. In addition, the term "GI disturbance" groups together loosely related pathology occurring in the GI tract, although there are important physiologic differences between conditions such as constipation and reflux.

The study received funding from the National Institutes of Health.

Front Psychiatry. Published online January 20, 2022. Full text

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