Elevated levels of one or more microbially derived metabolites (MDMs) detected in a simple urine test were found in up to 90% of children with autism spectrum disorder (ASD) raising the possibility of a simple, noninvasive screening test for the disorder.
The multi-site pilot study showed that children with ASD had significantly higher levels of MDMs than typically developing peers, including several metabolites not previously investigated in the disorder.
Although the results need to be validated, they support the use of a noninvasive screening test for ASD, study investigator James B. Adams, PhD, President’s Professor, Autism Research Program, Arizona State University, Tempe, Arizona, told Medscape Medical News.
“We’re saying we now have a test which says these kids with autism have high levels of microbial metabolites, some of which we know are harmful, and others which we suspect are harmful.”
With this latest study adding to a growing body of evidence, Adams questioned how many more studies are needed to establish a clear link between elevated metabolites and autism.
The findings were published on May 26 in Molecular Psychiatry.
Gastrointestinal Link
Once considered relatively rare, ASD now affects an estimated 323 per 10,000 children in the US, up from about 1 per 10,000 in 1980.
Behavioral interventions initiated within the first 2 years of life can reduce ASD symptoms and improve outcomes. However, the average age at diagnosis in the US remains about 5 years, Adams said.
The gap highlights the need for a simple, noninvasive screening tool that could identify children at an increased risk for ASD and facilitate earlier diagnosis and intervention, he added.
ASD is thought to result from a complex interplay of genetic and environmental factors. Research has also implicated the gut-brain axis, with chronic gastrointestinal symptoms reported in about 40% of individuals with the disorder.
Growing evidence supports a role for the gut-brain axis in ASD. Multiple studies have identified elevated levels of specific microbial metabolites in individuals with autism; p-cresol alone has been linked to ASD in at least 17 studies. Research in mouse models has shown that fecal microbiota transplantation from healthy donors can improve autism-related behaviors.
The investigators believe that the current evidence base supports the hypothesis that gut microbiome disruption may influence neurodevelopment through the gut-brain axis and that a subset of individuals with ASD may represent a distinct dysbiosis-associated phenotype.
The multi-site study included 99 children aged 2-11 years — 52 with ASD and 47 age-matched typically developing control individuals — recruited from centers in Arizona, Massachusetts, Tennessee, and Texas.
Elevated Gut Metabolites
Urine samples were analyzed using the MDM System, which quantifies MDM and compares results with a reference population of typically developing children. Roughly half of the metabolites assessed have previously been linked to elevated levels in children with ASD.
Results showed that 23 of 24 MDMs were significantly elevated in children with ASD compared with typically developing control individuals, pointing to a potentially important biological signature of the disorder, Adams said. N-formyl methionine was the only metabolite that did not differ significantly between groups, although it approached statistical significance, he said.
Between 80% and 90% of children with ASD had elevated levels of one or more MDMs, with some metabolites present at concentrations 100- to 1000-fold higher than those seen in their typically developing counterparts.
The metabolites fell into three broad categories — tryptophan-derived, phenylalanine- (or tyrosine-) derived, and yeast/fungi-derived. Metabolites in the first two categories may interfere with neurotransmitter metabolism, potentially influencing ASD-related symptoms.
“What’s interesting is that almost all of those metabolites are very similar chemically to dopamine and serotonin, and those neurotransmitters are made mostly in your gut. For example, 90% of serotonin is made in the gut and 50% of dopamine is also made in the gut,” said Adams.
Adams highlighted p-cresol as a potentially important metabolite, noting that it can affect dopamine pathways involved in mood, cognition, and learning. Disturbances in dopamine and serotonin signaling may contribute to core ASD symptoms, he said.
Yeast-derived metabolites may be markers of gastrointestinal fungal overgrowth. While not thought to be directly toxic, they could indicate increased levels of yeast or fungi that produce other harmful metabolites.
Adams pointed to earlier research showing that antifungal treatment lowered concentrations of yeast-related metabolites and to survey findings in which many parents rated antifungals as more beneficial for ASD symptoms than any other medication.
Adams said he suspects that the number of elevated metabolites may be linked to ASD severity. However, he cautioned that the study only provides a cross-sectional snapshot of children. He said that children with more severe ASD tend to remain more severely affected over time, whereas those with milder symptoms tend to have a milder trajectory.
The urine-based metabolite panel classified children with ASD and typically developing control individuals with 90% sensitivity and 100% specificity.
Adams said the findings suggest a urine-based screening test could help identify children at risk for ASD much earlier than is currently possible.
Cost Saving?
Such a screening tool could help reduce the substantial economic burden of ASD, with lifetime care costs estimated at roughly $3.5 million per individual.
“If we could get children diagnosed earlier — and it’s widely accepted that earlier intervention leads to better outcomes, earlier behavioral therapies, earlier medical therapy, speech therapy, etc. Then we could really cut down on that lifetime cost, not to mention get a much better quality of life for people,” Adams said.
If validated, the urine screen test could be integrated into routine screening at around age 2, particularly for children with gastrointestinal symptoms, Adams said.
Beyond ASD, the researchers are evaluating whether the test may have applications in adults with the disorder as well as in attention-deficit/hyperactivity disorder and other childhood psychiatric conditions, such as anxiety and depression, Adams said.
The screening test is now available in the UK, and Adam is working on making it available in the US.
The study excluded participants with known single-gene disorders, such as Fragile X syndrome. Other limitations included the lack of data on BMI, diet, and medication use, all of which could influence metabolite levels.
Although the sample size was sufficient to demonstrate proof-of-concept diagnostic performance, the investigators noted that larger cohorts will be needed to validate the findings and assess the test’s utility at the population level.
Promising but Preliminary
Despite the need for further validation, the findings drew a positive response from at least one outside expert.
The study’s methodology was solid and yielded reliable results with very high sensitivity and specificity, said Iliyan Ivanov, MD, professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York City, and a member of the American Psychiatric Association Council on Research, who was not involved in the study. Most striking, he said, was the consistency of the findings across sites.
One of the study’s more novel observations, Ivanov said, is the possibility that a subset of children with ASD may represent a distinct MDM-associated phenotype. The substantially elevated MDM levels detected in young children could have important clinical implications and appear to represent a new finding, he added.
Applying the findings in clinical practice will depend on whether the testing is widely available, affordable, and covered by insurance, as well as how quickly results can be delivered to clinicians, Ivanov said.
A key next step, Ivanov said, will be to determine how sustained elevations in these metabolites affect brain function and behavior over time in children with ASD. He acknowledged, however, that answering that question is likely to be difficult.
