Alterations in the Gut Microbiome May Contribute to Autism Spectrum Disorder Pathogenesis

By contributing to changes in metabolism, immunity, and neurophysiology, alterations in the gut microbiome influence developmental processes in the brain and are potentially involved in the development of Autism Spectrum Disorder.

By Sree Yellanki


Autism spectrum disorder (ASD) is a common condition resulting from abnormal brain development that leads to deficits in nonverbal communication, difficulty socializing, and repetitive and obsessive patterns of interest and behavior [1]. Since this disorder often starts as early as pregnancy, understanding the importance of environmental factors to the onset and development of this disorder could reveal opportunities for clinical intervention [2, 3]. One critical player may be the gut microbiome, which by interacting with the immune system, metabolism, and neurophysiology, may be involved in the regulation of ASD.

Abnormalities in the composition of the microbiome could account for some of the symptoms experienced by children with ASD. One study found that, among children experiencing gastrointestinal problems, children with ASD were more likely to bear the Sutterella species than those without the disorder [4]. Since previous research has demonstrated that changes in the colonization of a few microbial species may lead to behavioral problems, this alteration could account for some of the symptoms associated with ASD [5]. Microorganisms impact the relative balance of molecules absorbed from the diet and also secrete chemicals in a species-specific manner, both of which affect organs including the brain when passed into the bloodstream. For example, Bacteroides thetaiotaomicron produce acetate and propionate which influence the permeability of the blood-brain barrier, potentially impacting the functionality of the brain [6].

Although pregnancy is normally associated with an elevated inflammatory state, both in the mother and in the placenta, further increases in inflammation, such as due to maternal infection, can enhance the risk of autism in the offspring [7]. Animal studies have demonstrated that this additional immune responsiveness within the mother, known as maternal immune activation (MIA), increases the expression of inflammatory cytokines in the fetal environment during important periods of embryonic development, ultimately leading to ASD-like symptoms [8]. Additional research has shown that alteration of the gut microbiota causes metabolic disturbances in the MIA model, modulating ASD-related behavior [5]. For example, treatment of the MIA model with the human commensal Bacteroides fragilis led to a significant improvement in gut permeability, microbial composition, and ASD-related behaviors [5,7]. This finding suggests that the gut bacteria has an important effect on the behavior of the host.

Environmental influences may also critically impact the development of ASD. Studies have shown that children born through the cesarean section have a different gut microbe pattern than children born through the vagina and are also more likely to have ASD [9]. Additionally, maternal exposure to pesticides, certain fungicides, and particular food during pregnancy has been associated with neurodevelopmental disorders such as ASD [10,11]. These chemicals can cause changes in gene transcription in vitro, altering the production of free radicals and disrupting the expression of microtubules in neurons, traits similar to those observed in brain samples from individuals with autism [12].

Although therapies capable of alleviating symptoms associated with ASD are currently available, further research is needed to develop preventative measures or curative interventions. After 18 weeks of using certain psychotropic drugs, including risperidone and aripiprazole which treat repetitive behaviors and hyperactivity, children with autism can demonstrate improved social interaction and communication [13,14]. However, these changes are not permanent, since symptoms return following the cessation of drug use. Future treatments should take into account the relationship between the intestinal microbiome and the nervous system and possibly involve microbiome-focused therapies. Influencing the gut microbiota using Microbiota Transfer Therapy and Microbiota Transplantation could alter the ecosystem of the gut and potentially lead to a longer-lasting improvement in ASD-related symptoms [15]. Indeed, the treatment of the offspring of MIA mice with a single bacterial species, Bacteroides fragilis, was shown to lead to an improvement of ASD-related symptoms. However, this treatment also carries the risk of adverse events including diarrhea, abdominal discomfort, and even death [16,17].

The mechanisms by which diversity in the composition of the microbiome influences the health of the host are not yet fully understood. Therefore, further research is needed to determine which microbes are important to the normal function of the intestine and other organs, including the brain. Increased focus in this area could lead to improved therapies for ASD symptoms.

References:

  1. Frith, U. (2003). Autism: Explaining the enigma. Blackwell Publishing.
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  3. Jiang HY, Xu LL, Shao L, Xia RM, Yu ZH, Ling ZX, et al. Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis. Brain Behav Immun. 2016; 58:165-72.
  4. Benach JL, Li E, McGovern MM. A microbial association with autism. MBio. 2012; 3(1):e00019-12.
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  9. Magne F, Puchi Silva A, Carvajal B, Gotteland M. The elevated rate of cesarean section and its contribution to non-communicable chronic diseases in Latin America: the growing involvement of the microbiota. Front Pediatr. 2017; 5:192.
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  12. Singh K, Connors SL, Macklin EA, Smith KD, Fahey JW, Talalay P, et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci U S A. 2014; 111 (43):15550-5.
  13. McDougle CJ, Scahill L, McCracken JT, Aman MG, Tierney E, Arnold LE, et al. Research units on pediatric psychopharmacology (RUPP) autism network. Background and rationale for an initial controlled study of risperidone. Child Adolesc Psychiatr Clin N Am. 2000; 9(1):201-24.
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  15. Kang DW, Adams JB, Gregory AC, Borody T, Chittick L, Fasano A, et al. Microbiota transfer therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017; 5(1):10.
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  17. Hourigan SK, Oliva-Hemker M. Fecal microbiota transplantation in children: a brief review. Pediatr Res. 2016; 80 (1):2-6.

Kuokuo L, Zhengmao H, Ou J, Xia K. (2019) Altered Gut Microbiome in Autism Spectrum Disorder: Potential Mechanism and Implications for Clinical Intervention. Glob Clin Transl Res, 1(1), 45-52. https://pdfs.semanticscholar.org/ba3f/3ef5d19427added242b9092c6f4ca3ef3fb3.pdf

Autistic Child. Description: Having these social skill impediments makes it very difficult for people with ASD to have simple conversations with others, make friends, have close relationships, and even keep a job. All of these issues stem from cognitive impairments throughout the brain and neurons that cause these difficulties for the thought process. Date: 31 July 2010. Source: https://www.flickr.com/photos/wactout81/4846821544/in/photolist-8oiebG-9nRyWV-29jiFj-6c4Zeb-9wohTJ-8of3YZ-uUfJtW-8tU1Gb-fwJWW8-dWdwy6-dmmsT3-dRWXw1-gokfXF-dSQvTd-8oie65-dPgJ9Y-5Dbypf-dPgHTW-RWNej3-bo5Jfi-6fwaFg-5oJEgd-dWdwx8-dRRn6F-dRRmtX-qgx9wL-dRRmY2-dSQvKS-e25i6V-dRWWRu-dWdwtB-p1XW9k-dSQw2f-dRWXoA-dRWX1m-dSQwbb-qy1GdJ-dSJWQ2-dNtPka-fWWUK-dctidp-dNtPhv-7VF5cV-7TtxFe-7VJj45-7VF5VV-nAb3ac-dWjamh-dWdwsn-7VF7sa Author: Lance Nellson. https://commons.wikimedia.org/wiki/File:Autistic_Child.jpg

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