Chicken or Egg? The Paradox of Autism Spectrum Disorder and the Human Gut Microbiome

February 14, 2024
Science Magazine

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has received much attention in recent years. Over the past decade, diagnostic rates for ASD have increased while debates rage over what the markers, mechanisms, causes, and necessary support systems are for the condition. 

ASD can manifest in a variety of ways, with different people experiencing completely different spectra of effects. These symptoms can include a lack of interest in social interaction, unusual emotional reactions to sensory input, difficulty in language or movement, restricted and/or repetitive behavior, impulses and hyperactivity, and excessive anxiety or stress. 

Research on the gut microbiome and neuropsychiatric conditions has contributed to a greater understanding of the bidirectional relationship between the gut and brain, called the gut-brain axis. Metabolites produced by certain bacteria in the gut influence nervous system development as well as neurological signals during and after adulthood. 

Above: Diagram depicting the mechanisms of the human gut-brain axis. Image courtesy of Nature Reviews Microbiology.

Some research has found that gastrointestinal (GI) problems are surprisingly frequent among people with ASD. Scientists have also observed correlations between microbiota composition and ASD. However, the cause of this correlation remains unclear: could certain gut bacteria (or lack thereof) affect development and cause ASD? Conversely, are certain behaviors correlated with ASD causing problems in the microbiome? Or, are these two events both driven by a third unknown factor? The answer to this question could drastically change the future direction of research and treatments for ASD.

In 2019, a group of researchers in China sequenced core genes of bacterial cells in the gut microbiome of children with and without ASD, as well as their neurotypical (NT) mothers. The team found correlations between ASD diagnosis and certain bacteria genera. The most prevalent genus was Clostridium, which is known for producing the neurotoxin that causes lockjaw. This genus increased in abundance within the microbiomes of children with ASD, suggesting that Clostridium could serve as a biomarker for the condition. While the microbiomes of children with ASD still generally resembled those of their mothers as expected, the mothers’ microbiomes did not differ in Clostridium in a way that correlated to their children’s diagnosis with ASD. It is thus possible that Clostridium inhibits certain signals through the gut-brain axis that induce specific steps in CNS development.

Above: Hypotheses regarding how ASD and the gut microbiome could affect each other. Image courtesy of Digestive Diseases and Sciences Journal

A 2021 study investigated how the microbiome correlates with the strength of ASD indicators. Researchers studied the microbiomes of individuals with ASD at different time points in addition to observing various indicators of ASD, such as irritability, unusual speech patterns, lethargy, and social withdrawal. They found that shifts in behavioral indicators of ASD were correlated to microbiome composition changes. Specifically, the strength of ASD indicators correlated with large shifts in microbiome beta diversity and decreased abundance of bacterial genera Coprococcus and Prevotella. Other studies have found that a low abundance of Coprococcus in the microbiome correlates with major depressive disorder, potentially explaining increases in ASD indications like lethargy or social withdrawal. This correlation was especially strong for social withdrawal and repetitive behavior, which are considered central indicators of ASD. The team also examined whether GI problems were to blame for these results and found that there wasn’t a longitudinal correlation between GI problems and other indicators of ASD.

A 2017 clinical study used microbiota transfer therapy (MTT), which replaces the gut microbiome with one cultured from the stool of a neurotypical individual, to treat GI problems due to ASD. They found that MTT led to not only a strong reduction in GI symptoms in people with ASD, but also a decrease in other indicators of ASD, such as hyperactivity, lethargy, irritability, and stereotypy. Participants’ stool samples were then sampled before and after MTT to find increases in microbiota diversity and changes in the relative abundance of bacterial genera. The bacterial genus Desulfovibrio increased in abundance while the genera Prevotella and Bifidobacterium decreased. This is consistent with the claim that the microbiome influences ASD, as Desulfovibrio facilitates the growth of microbiota that are negatively associated with ASD and inhibits the growth of Clostridium, a driving force of the condition. The lack of Bifidobacterium could also be a contributor to ASD, as previous studies suggest that metabolites produced by Bifidobacterium participate in neuronal plasticity, improving cognition, memory, and learning in both mouse models and human clinical trials. Bifidobacterium also lessens emotions of anxiety by producing the neurotransmitter GABA, which decreases neuronal excitability. The fact that replacing the microbiome can have this strong an effect on ASD indicators suggests that the microbiota has a great influence on ASD. However, there have not been any follow-up experiments that prove that the effects of MTT did not revert after the study’s conclusion. 

Some studies have argued that observed correlations are caused by the effects that ASD has on the microbiome or even cast doubt on the correlation as a whole. A 2021 study sequenced stool sample metagenomes from participants with and without ASD and found that they did not replicate the results of the previously discussed studies regarding changes in bacterial genus abundance. Instead, the researchers found that decreased gut microbiota diversity is more associated with age and dietary habits than ASD diagnosis. Restrictive and/or repetitive dietary habits are not unique or central to ASD diagnosis, which suggests that previous correlations found in microbiome composition and ASD are not special to ASD. 

Although the microbiome appears to win this round of the “chicken or egg” question, multiple major issues should be addressed in the studies that point to this conclusion. 

For one, the paradox of the relationship between ASD and the microbiome could be fully correlative and not causative. Other researchers identify genetic and environmental factors of ASD, which simultaneously influence ASD and the gut microbiome. In other words, there could be an unidentified cause for issues experienced on both ends of the gut-brain axis.

Additionally, dietary habits, climate, social lifestyle, and varying levels of healthcare coverage (including maternal care and access to antibiotics) greatly impact the sensitive gut microbiome. In fact, many of the studies have a small and geographically restricted sample size, skewing the diversity of microbiome compositions. One 2021 longitudinal study, for example, found that while Prevotella was a biomarker in their Colorado cohort, it was almost completely absent among the Arizona cohort. 

Moreover, like any other neuropsychiatric condition, the evaluation of ASD indicators is highly subjective, variable from person to person, and vulnerable to factors such as culture, placebo effects, influences from daily life, and data collectors’ assumptions and biases. Many studies about ASD fail to address the variability of experiences that different people with ASD have. 

Above: A symbolic representation of certain indicators of autism spectrum disorder. Image courtesy of Carmen B. Pingree Autism Center of Learning

In the future, the shared complexity and diversity of ASD and the gut microbiome may provide an opportunity to better understand both the human mind and the symbiotic relationships we share with bacteria. But for now, this paradox remains unsolved. 

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