Impaired Microbial Detoxification May Be Involved in Pathogenesis of Autism Spectrum Disorder

Gut bacteria , gut flora, microbiome. Bacteria inside the small intestine, concept, representation. 3D illustration. Gut bacteria , gut flora, microbiome. Bacteria inside the small intestine, concept, representation. 3D illustration.
Investigators used a quasi-paired cohort strategy to study how the microbiome, specifically microbial detoxification, might contribute to the pathogenesis of autism spectrum disorder.

Impaired microbial detoxification may be involved in the pathogenesis of autism spectrum disorder (ASD), according to research recently reported in Science Advances.

The study population comprised 79 patients, including 39 children with ASD and 40 age- and gender-matched neurotypical controls (mean age, 5.59 years; 82% male). Metagenome sequencing and stool sample analysis identified 209 species in all samples (each sample, 101 ± 14 species).

The investigators developed a quasi-paired cohort strategy for metagenomic analysis, in which they paired ASD samples with control samples of similar metabolic backgrounds. “This approach allowed us to transform the original group cohort into a paired cohort, which not only controls for individual diversity but also increases statistical power,” the study authors noted.

The investigators created 65 ASD-control pairs, which encompassed 20 patients with ASD and 18 controls from the original groups based on the metabolic profiles of samples. A comparison between the paired samples led the study authors to identify 96 ASD-associated pathways (Wilcoxon signed-rank test, P <.05).Thirty-nine over-represented and 57 deficient pathways were found to be involved in many metabolic categories.

“Among the list of the ASD-associated pathways, we identified a conspicuous trend in the deficiencies in the metabolic category of detoxification in ASD samples. A total of 5 complete pathways in this category exhibited obviously decreased abundance in ASD subjects when compared to their control counterparts,” the study authors said.

The investigators further scrutinized all enzymes involved in the degradation of various kinds of toxins in patients with ASD and the controls (Wilcoxon signed-rank test, P < .05). None of the enzymes demonstrated significant over-representation. However, eight were found to be significantly deficient in ASD and play roles in the degradation of a wide range of toxicants, including chloroalkane/ chloroalkene, aminobenzoate, benzamide, styrene, naphthalene, xylene, and benzoate, which are commonly used as insecticides and food additives.

“The deficiency in these critical enzymes suggests a wider range of impairment in detoxification in ASD, although the corresponding pathways that contained these enzymes were not significantly different between the paired samples,” the investigators observed.

Although the study authors did not explicitly identify study limitations, they noted that at present, there is “no suitable method” to concurrently measure the absolute concentrations of the metabolites relative to pathogenesis, toxicant exposure, and detoxification in ASD. Therefore, “novel methods of toxicant measurement” are needed to aid not only toxicant accumulation identification efforts, but also the clinical evaluation of individual etiological factors.

“The impaired microbial detoxification is correlated with the clinical rating of ASD and the extent of mitochondrial dysfunction, one of the main pathological alterations of ASD, which strongly suggests that impaired microbial detoxification is deeply involved in the pathogenesis of ASD,” the researchers concluded. “Such a previously unknown protective role of intestinal microbes suggests potential future therapeutic strategies of rebuilding the impaired microbial detoxification for patients with ASD.”

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Zhang M, Chu Y, Meng Q, et al. A quasi-paired cohort strategy reveals the impaired detoxifying function of microbes in the gut of autistic children. Sci Adv. 2020;6(43):eaba3760. doi: 10.1126/sciadv.aba3760