The Causes of Autism

Who are the phenomenal authors, what is the full title of the study, and what year was it published?

Authors: Mengxiang Zhang, Yanan Chu, Qingren Meng, Rui Ding, Xing Shi, Zuqun Wang, Yi He1, Juan Zhang, Jing Liu, Jie Zhang, Jun Yu, Yu Kang, Juan Wang

Title: A quasi-paired cohort strategy reveals the impaired detoxifying function of microbes in the gut of autistic children. Science Advances 2020 Oct; 6(43): eaba3760

Year: 2020

What is this study about?

This study proposes a new quasi-paired cohort strategy for metagenome analysis to investigate the impaired detoxifying function of microbes in the gut of autistic children. The study successfully identifies a conspicuous trend of impairment in detoxification in the ASD gut microbiome, which is correlated with the clinical rating of ASD and the extent of mitochondrial dysfunction. The findings suggest that impaired microbial detoxification is deeply involved in the pathogenesis of ASD and may lead to potential therapeutic strategies of rebuilding the impaired microbial detoxification for patients with ASD.

What previous research is there on this topic?

Gut Dysbiosis

Recent research suggests a strong link between autism spectrum disorder (ASD) and gut dysbiosis. ASD-associated gut dysbiosis can cause intestinal inflammation and a leaky gut-blood barrier, leading to chronic inflammation, oxidative stress, and impaired mitochondrial function.

Microbiome

Previous research has shown that gastrointestinal comorbidity is common in children with ASD, and there is clear dysbiosis in their gut microbiome, with a deficiency in Bifidobacterium longum and overgrowth of Clostridium spp. and Candida albicans. However, previous studies based on 16S rDNA sequencing-based species profiling only provide a limited understanding of ASD pathogenesis, and new strategies are needed for metagenome analysis to provide a more precise mechanism for understanding the relationship between microbiome and ASD.

Mitochondria

To better understand the causes of autism spectrum disorder (ASD), researchers have studied the role of mitochondrial dysfunction, which can be caused by both genetic defects and environmental toxins. When mitochondria are damaged, they can release molecules that trigger a low-grade inflammatory response, which is known to be associated with ASD. This systemic inflammation is characterized by high levels of cytokines, chemokines, and immune activity, and is present in many ASD patients. Previous studies have shown that environmental toxins can contribute to this dysfunction, and that mitochondrial dysfunction is a key factor in the development of ASD.

What methods were used in this study?

Metagenome Sequencing and Annotation

This study utilized metagenome sequencing and annotation to analyze the gut microbiomes of 20 ASD children and 18 healthy controls. Fecal specimens were collected, and DNA was extracted and paired-end sequenced on the Illumina HiSeq X10 platform. Quality control was performed, and reads of human origin were removed before taxonomy and metabolic function annotation using MetaPhlAn2 and HUMAnN2. Alpha diversity and beta diversity were evaluated, respectively, by the Shannon index and principal components analysis.

Construction of Quasi-Paired Cohort

The quasi-paired cohort strategy is a new analysis method that compares the activity of a specific pathway between samples of similar metabolic backgrounds. To construct the quasi-paired cohort, comparable numbers of boundary samples were selected for each group, and ASD-control pairs were constructed with one boundary sample and one of its k nearest neighbors of the opposite side. The quasi-paired cohort was constructed with these ASD-control pairs after removing redundancy. This strategy is a powerful tool for metagenome analysis that can identify disease-associated microbial features more accurately with fewer samples.

Measurement of Urine Organic Acid

In this study, morning urine samples were collected from both ASD and control children and immediately frozen for later analysis. Using an Agilent 7890A gas chromatograph-mass spectrometer, a total of 75 metabolites were measured and analyzed according to the manufacturer’s instructions with MSD ChemStation. The concentration of each metabolite was normalized by the concentration of creatine in the same sample.

What were the findings?

Impaired Microbial Detoxification

The study has found that children with ASD have a deficiency in the detoxification pathways of the intestinal microbiome, which impairs the ability of microbes to detoxify the gut environment. This deficiency is correlated with the clinical rating of ASD and the extent of mitochondrial dysfunction, which may explain why ASD children are more vulnerable to environmental toxins. The study suggests that impaired microbial detoxification plays a protective role in the body and may be involved in the pathogenesis of ASD. The study also proposes potential therapeutic strategies of rebuilding the impaired microbial detoxification for patients with ASD.

Glutathione

The study reveals that impaired detoxification pathways related to the generation of glutathione (GSH) are involved in ASD. Specifically, the pathways of the 𝛾-glutamyl cycle and biosynthesis of l-glutamate and l-glutamine, which are essential precursors of GSH, are affected. Enzymes such as glutamate-cysteine ligase (gshA), GSH synthase (gshB), and 𝛾-glutamyltransferase (ggt) were all found to be deficient in ASD samples. This deficiency may play a previously unknown role in toxin accumulation and mitochondrial dysfunction, two core components of ASD pathogenesis.

L-Glutamine & L-Glutamate

The study revealed that children with autism spectrum disorder (ASD) have a deficiency in the biosynthesis of l-glutamine and l-glutamate, which are precursors of glutathione (GSH), an important antioxidant and detoxifier. As GSH generated by intestinal microbes adds an essential contribution to local detoxification, the deficiency in GSH biosynthesis implicates impaired intestinal microbial detoxification in the pathogenesis of ASD. The study suggests that rebuilding the impaired microbial detoxification could be a potential therapeutic strategy for patients with ASD.

What other research does this study relate to?

Toxicant exposure is a confirmed factor in the development of autism spectrum disorder (ASD), with patients often displaying clinical signs of intoxication. Organic toxicants, particularly aromatic and halogenated compounds, are implicated in ASD, including polycyclic aromatic hydrocarbons, automotive exhaust, organochlorine pesticides, and heavy metals.

Glyphosate, the world’s most widely used herbicide, is known for its nuclear and mitochondrial toxicity. Mitochondrial dysfunction is a key pathological feature of ASD, making it vulnerable to organic toxicants that are lipophilic and tend to accumulate in fatty tissues. The study concludes that impaired microbial detoxification is deeply involved in the pathogenesis of ASD and suggests that rebuilding the impaired microbial detoxification may be a potential future therapeutic strategy for patients with ASD.

What conclusions can be drawn from the study?

The study proposes a new strategy for analyzing the gut microbiome of children with autism spectrum disorder (ASD) and highlights that impaired detoxifying function of microbes plays a key role in ASD pathogenesis. The study suggests rebuilding the impaired microbial detoxification as a potential therapeutic strategy for ASD. The study identifies significant deficiencies in detoxifying enzymes and pathways in ASD children, which strongly correlate with biomarkers of mitochondrial dysfunction. The study also found that a diagnostic model based on microbial markers accurately distinguished ASD individuals from controls with an AUC of 88%. The study highlights the need for personalized treatment for ASD children based on identified microbial markers.

What other research within the library does this study relate to?

This study relates strongly to the study by Volkova et al. (2021) which found that early-life exposure to low doses of penicillin can significantly disrupt the development of the intestinal microbiota in mice, with significant effects observed in the small intestine and cecum. The antibiotic treatment selectively targeted certain bacteria taxa, such as Lactobacillus, and promoted the growth of others, including Corynebacterium, Lachnospiraceae, Sphingomonaceae, Enterococcus, Pseudomonas, and Stenotrophomonas. The alterations in the microbiota were associated with changes in the expression of specific genes in the CNS. This research highlighted the potential long-term effects of early-life antibiotic exposure on the gut-brain axis and the importance of judicious use of antibiotics during infancy.

Can I read the full study somewhere?

Sure, and please do so quietly. It’s right here.