Updated on December 22, 2022
An increasingly detailed and interconnected body of scientific literature is establishing the connection between the pathology of autism spectrum disorder (ASD) and the gut microbiome, leading many to wonder whether manipulation of the gut microbiome can alleviate ASD symptoms. In recent years, a number of studies have clarified the mechanisms behind the gut microbiome’s role in ASD presentation, which has spurred researchers to investigate possible treatment options specifically targeting the gut microbiome. This growing body of research is now opening the door to more effective therapies, potentially allowing individuals with ASD to find relief from symptoms that conventional treatments have not resolved.
Between 2015 and 2016, Drs. Richard Frye, John Slattery, and Derrick MacFabe of the Arkansas Children’s’ Hospital Autism Research Program published a trio of studies that sought to clarify the relationship between ASD and the gut microbiome. A number of researchers had examined this relationship prior to Frye, Slattery, and MacFabe’s experiments, producing promising data indicating that the proportions of bacterial populations within the GI tract of ASD patients could impact ASD symptoms. However, the underlying mechanism of this phenomenon remained unclear. As such, Frye, Slattery, and MacFabe sought to further elucidate the links between bacterial population proportions, mitochondria, and ASD symptoms and examine potential therapeutic avenues based on their findings.
In 2015, the group examined the mitochondria within the GI tracts of children with and without ASD to determine whether there were observable differences in mitochondrial function between them. Their study successfully established several specific metabolic mechanisms by which gut microbiota might cause mitochondrial changes and thus cause physiological changes. Not only were the associations between mitochondrial dysfunction, ASD, and GI pathologies confirmed, the researchers also found these associations are due to an overrepresentation of the Clostridia genus of bacteria in the gut microbiomes of ASD patients.
The Clostridia genus of bacteria produces the fatty acid propanoic acid (PPA) as a result of fermentation, one of the processes by which bacteria metabolize nutrients. GI-tract mitochondria are negatively influenced by high concentrations of PPA, possibly explaining some of the GI issues commonly experienced by ASD patients. This is because PPA acts as a regulator for a wide variety of mitochondrial genes, meaning that exposure to PPA causes mitochondria to function at lower efficiencies, thus causing adverse physiological changes in the GI tract. By connecting Clostridia over-representation and mitochondrial dysfunction, the study clarifies that the microbiome’s proportion of Clostridia is an important clinical factor for ASD symptoms.
Subsequent to these findings in the clinical trial cohort of children with ASD, the researchers then shifted their attention to experiments using animal models of ASD to further investigate the relationship between PPA and ASD symptomatology. Prior to initiation of their investigations, Frye, Slattery, and MacFabe had worked for more than 15 years to develop and validate these animal models so they could follow up on the results of experiments performed using human subjects more invasively. Through their animal model experiments, the researchers found that:
As a result, Frye, Slattery, and MacFabe identified a set of potential PPA producers within the gut microbiota that might be responsible for ASD-related GI issues via their influence on mitochondria.
As a result of their experiments, the research group added further confirmation to what is known in the ASD research community as “the PPA hypothesis.” The PPA hypothesis is a core theory that explains the relationship between gut microbiota and ASD GI symptoms. As described by Frye, Slattery, and MacFabe in their 2016 paper, “the PPA theory of ASD suggests that ASD may be a result of disturbances in the enteric microbiome resulting in the production of elevated levels of PPA in genetically susceptible individuals during a critical neurodevelopmental period.” Although the PPA hypothesis predates the Frye and Slattery experiments, their findings filled critical holes in the hypothesis and contributed invaluable evidence in support of it.
To investigate further, Frye, Slattery, and MacFabe used the PPA hypothesis as an investigational framework to review currently used, but not comprehensively understood, therapies that manipulate the microbiome in ASD patients. These included:
PPA concentrations were used as core metrics indicating whether a therapy might be clinically useful. As a result of their investigation, they suggested several therapies that should be examined further. In particular, FMT and probiotics were singled out as the two most promising—but least investigated—avenues for addressing ASD-related GI issues by altering the gut microbiome to remove PPA-producing colonies.
Frye, Slattery, and MacFabe’s results piqued the interest of the research community, including a clinical trial group led by Dr. D.W. Kang. To further investigate the effects of microbiome manipulation on ASD symptoms, Dr. Kang’s group conducted a study in which the entire gut microbiome of pediatric ASD patients would be removed and then replaced with a probiotic and fecal transplant product. Referred to as Microbiota Transfer Therapy (MTT), the protocol incorporates probiotics into a customized and replicable fecal transplant product with the goal of providing long-lasting relief from ASD symptoms.
Following MTT, ASD patients’ parents reported their children experienced reduction of abdominal pain and other GI symptoms by as much as 82 percent over the course of the treatment protocol, with 89 percent of the study cohort responding positively to the treatment. However, symptom reduction was not confined to GI symptoms; parents also reported improvements in ASD-related behavioral disturbances. Although Dr. Kang’s study wasn’t blinded, controlled, or randomized, it nonetheless suggests that ASD might be treatable via GI interventions designed to manipulate the microbiome and that these interventions can possibly alleviate a broad spectrum of symptoms.
While MTT is a promising treatment, it is also an intensive one. There is, however, evidence that suggests that less invasive means of microbiome manipulation could produce similar results. In 2014, a study by Dr. MacFabe found that certain biologically-produced molecules like butyric acid can act as regulators of critical genes within the cells of the GI tract. This can cause behavioral changes that could mitigate the effects of PPA. However, butyric acid can also have additional benefits. MacFabe found that in vitro butyric acid exposure altered cells’ genetic regulation of a critical protein, tyrosine hydroxylase, an enzyme that is responsible for making many of the precursors to the neurotransmitters implicated in ASD symptomatology, such as dopamine. As such, butyric acid’s impact on cells in vivo in the GI tract might mean that butyric acid supplementation can beneficially impact multiple behavioral ASD symptoms.If butyric acid’s impact on tyrosine hydroxylase can be clarified via future research, then it might be possible to identify which symptoms supplementation can most effectively target. As the research stands, butyric acid supplementation is an intriguing intervention that could provide symptom relief similar to that of the more invasive MTT and FMT, making therapeutic microbiome manipulation far more accessible and comfortable.
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