What is the Relationship Between Gut-microbiome and ASD?

We coexist with vast populations of microorganisms on and inside our bodies. Microbiome is the collection of these microbes and their genetic material. It is estimated that the human gastro-intestinal (GI) tract contains approximately 1014 bacteria from 1000 species (Neish, 2009). Gut-microbiome benefits us in many ways, including metabolizing indigestible dietary compounds, defending against pathogens, and contributing to our intestinal barrier.

Conversely, when the balance of gut-microbiome is tipped, there could be negative impacts on human health. Considering the gut-brain axis – the bidirectional biochemical communication between the GI tract and the nervous system likely mediated by neural, endocrine, and immune pathways – an imbalance of gut-microbiome potentially disrupts the smooth communication between the gut and the brain. Consequently, the production, expression, and turnover of biochemicals, neurotoxins, and neurotransmitters is also disrupted, influencing cognitive and behavioural functions.

Given that ASD is characterised by social deficits, repetitive behaviours, and cognitive inflexibility, it would be unsurprising if these could be contributed by microbial dysbiosis in the gut. Reinforcing this point, evidence from many studies have established that children with autism are three times more likely to suffer from GI problems, such as bloating, constipation, and diarrhea, than their neurotypical counterparts (e.g. Chaidez, Hansen, & Hertz-Picciotto, 2015; Lefter, Ciobica, Timofte, Stanciu, & Trifan, 2020; McElhanon, McCraken, Karpen, & Sharp, 2014). Could the composition of gut-microbiome be a biomarker for ASD? Here, we review two of the most promising evidence suggesting an association between gut-microbiome and ASD.

1. ASD children have altered gut microbiome

The composition of gut microbiome in children with ASD has been found to be significantly different from that of neurotypical children. More specifically, those with ASD possess less diverse gut microbial compositions and decreased levels of several genera, such as Prevotella, Corprococcus, and Veilonellaceae, and an overrepresemtaion of Desulfovibrio and Clostridium species (Li et al., 2019; Parracho, Bingham, Gibson

& McCartney, 2005; Tomova et al., 2015).

Interestingly, the abundance of Desulfovibrio has been found to be associated with ASD severity, with higher concentrations linked to higher prevalence of restricted and repetitive behaviours based on scores on the Autism Diagnostic Interview (Tomova et al., 2015). Consequently, these correlations between gut microflora composition and ASD symptomatology raise the question of whether altered gut microbiome could be an effect of ASD, or if they play a pathophysiological role in the manifestation of ASD.

2. Manipulation of gut microflora impacts prevalence of ASD pathology

The most convincing evidence thus far that attempts to establish the directional link between ASD and gut microflora described above, involves the manipulation of specific microbiome groups found to be associated with behaviours characteristic and symptomatic of ASD. Bolte (1998) and Sandler et al. (2000) obtained converging results demonstrating ASD children’s reduction in rigid behaviour and displaying smoother social communication and interactions after being administered oral vancomycin – an antibiotic that controls the growth of Clostridium. Importantly, these core behavioural symptoms relapsed after discontinuing antibiotic administration – suggesting that gut microbiota could be involved in a more causal role in ASD.

One possible mechanism for autism pathogenesis through altered gut microbiome is that some species produce neurotoxin which transits through the vagus nerve linking the digestive system to the brain, consequently blocking neurotransmitter delivery that leads to abnormal behaviour. In the case of Clostridium, its abundance leads to an overproduction of short-chain fatty acids, including propionic acid that is commonly used as a food preservative, which could be harmful to our bodies. This is supported by studies that found restricted behavioural interest and impaired social behaviours and cognition, the key characteristics of ASD, in rats treated with propionic acid (Shultz et al., 2008; 2009).

Conclusion: What do all this mean?

Much remains to be answered regarding the relationship between gut microbiome and ASD. However, there has been consistent evidence that they could be much more closely connected than previously thought. Further investigation into this link could possibly establish gut microbiota as a biomarker for ASD, allowing for early detection and intervention, and potentially lead to the development of novel therapy or even treatment for ASD.

Written by: Rachel Yam

References:

Bolte, E. R. (1998). Autism and Clostridium tetani. Medical hypotheses, 51(2), 133-144.

Chaidez, V., Hansen, R. L., & Hertz-Picciotto, I. (2014). Gastrointestinal problems in children with autism, developmental delays or typical development. Journal of autism and developmental disorders, 44(5), 1117-1127.

Lefter, R., Ciobica, A., Timofte, D., Stanciu, C., & Trifan, A. (2020). A descriptive review on the prevalence of gastrointestinal disturbances and their multiple associations in autism spectrum disorder. Medicina, 56(1), 11-28.

Li, N., Yang, J., Zhang, J., Liang, C., Wang, Y., Chen, B., ... & Zhao, G. (2019). Correlation of gut microbiome between ASD children and mothers and potential biomarkers for risk assessment. Genomics, proteomics & bioinformatics, 17(1), 26-38.

McElhanon, B. O., McCracken, C., Karpen, S., & Sharp, W. G. (2014). Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics, 133(5), 872-883.

Neish, A. S. (2009). Microbes in gastrointestinal health and disease. Gastroenterology, 136(1), 65-80.

Parracho, H. M., Bingham, M. O., Gibson, G. R., & McCartney, A. L. (2005). Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. Journal of medical microbiology, 54(10), 987-991.

Sandler, R. H., Finegold, S. M., Bolte, E. R., Buchanan, C. P., Maxwell, A. P., Väisänen, M. L., ... & Wexler, H. M. (2000). Short-term benefit from oral vancomycin treatment of regressive-onset autism. Journal of child neurology, 15(7), 429-435.

Shultz, S. R., MacFabe, D. F., Ossenkopp, K. P., Scratch, S., Whelan, J., Taylor, R., & Cain, D. P. (2008). Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat: implications for an animal model of autism. Neuropharmacology, 54(6), 901-911.

Shultz, S. R., MacFabe, D. F., Martin, S., Jackson, J., Taylor, R., Boon, F., ... & Cain, D. P. (2009). Intracerebroventricular injections of the enteric bacterial metabolic product propionic acid impair cognition and sensorimotor ability in the Long–Evans rat: further development of a rodent model of autism. Behavioural brain research, 200(1), 33-41.

Tomova, A., Husarova, V., Lakatosova, S., Bakos, J., Vlkova, B., Babinska, K., & Ostatnikova, D. (2015). Gastrointestinal microbiota in children with autism in Slovakia. Physiology & behavior, 138, 179-187.

Picture Reference:

Interactive Autism Network (2019) [Child clutching stomach] [Photograph] Retrieved from https://iancommunity.org/ssc/curious-link-between-gi-symptoms-mental-health-and-autism