Autism, (lack of) Detoxification, and the Altered Microbiome

Last week, on the Biome Buzz’ Facebook page,  I posted a story about new research showing that microbiome alterations seem to cause detoxification issues that play a role in the parthenogenesis of autism.[i]  Many of you asked me to explain the story in detail so, by popular demand, here goes…

To summarize the general idea:  the researchers matched subjects with autism and without by metabolic pathways inferred from the metagenomic data of their microbiomes.  This method allowed the researchers to accomplish their purposes: to track down pathways disrupted by altered gut bacteria.

We know from years of past research that toxin exposure (both from external and internal sources) has already been identified as one of the main factors in the etiology of autism, and impaired detoxification has long been suspected as a major problem in the population.  Because most toxins enter through the nose and mouth, the gut bacteria has evolved to be one of the most important elements in normal detoxification:  “…the impaired detoxification capability of the intestinal microbiome suggests a previously unknown mechanism to explain why patients with ASD are more vulnerable to toxicant exposure and how the intestinal microbiome contributes to the pathogenesis of ASD.”

The researchers collected fecal and morning urine samples from 79 age and gender matched children (39 with ASD, 40 without), aged 3 to 8 years old, and compared microbiome features including metabolic pathways.  209 species of bacteria were identified in total, of which 18 showed significant differences between the two groups:  Veillonella parvula and Lactobacillus rhamnosus were higher in those with ASD while B. Longum and Prevotella copri were higher in controls, which is consistent with previous studies.  However, this information does not tell us mechanisms of action.  And so, these researchers delved further.

They looked at the actual metabolic pathways involving the gut bacteria and found some significant differences.  Firstly, there were 3 pathways that were enriched in those with autism compared to controls.  Since none of this provided clear information on how the microbiome contributes to autism, they continued their studies, pairing the cohort down to 20 with autism and 18 controls.  From comparing this cohort, they identified 5 complete pathways that were at markedly decreased levels in those with autism, two of which are involved in the generation of glutathione, the main anti-oxidant in the body and one of the most important in detoxification:  they point out that glutathione is a “…key cofactor for many detoxifying enzymes…” and is “…essential in degrading organic toxicants and expelling heavy metals…”  Deficiencies in glutathione in those with autism were identified many years ago by Dr. Jill James, at the University of Arkansas, and that work has been replicated many times since.  These two pathways also are important in the synthesis of glutamate and l-glutamine, the precursors of glutathione, as well as being important amino acids, including in maintaining the health of the epithelial barrier of the gut.  The other 3 pathways identified are involved in the degradation of organic toxins:  all the microbial enzymes involved in the pathways were significantly decreased.

The researchers then looked more closely at all enzymes involved in the degradation of various kinds of toxins and found that none were at higher levels than normal controls while another 8 were significantly deficient in autism and these eight are involved in detoxifying a wide range of toxins:  “The deficiency in these critical enzymes suggests a wider range of impairment in the detoxification in ASD…”

To try to assess some of the results of the faulty detoxification, they analyzed metabolites in the urine.  The most significant was in organic acids involved in the Krebs cycle (energy production in the cell), and these might be released into the circulation when mitochondria are damaged, “…thus serving as biomarkers of damage or dysfunction in mitochondria.”  (Mitochondria are the powerhouses of every cell in the body.)  These biomarkers were negatively correlated with the abundance of most of the detoxification enzymes deficient in the ASD subjects, implying that these microbial enzymes involved in detoxification have a protective role for the mitochondria.  That is, the loss of these enzymes, from an altered microbiome, lead to mitochondrial dysfunction, “…one of the major pathological alterations in various tissues of ASD children, including the brain.” 

There are two more major findings:  firstly, using this model (i.e. looking for deficiencies in these particular microbial enzymes) proved highly accurate in differentiating those with autism from those without.  Looking at levels of these 5 deficient enzymes enabled them to distinguish those with autism with an 88% accuracy!  Secondly, there was a correlation between the abundance of these detoxification enzymes and the severity of autism.

We know that autism appears to be the results of certain genetic fragilities that only become relevant because of environmental exposures.  What these environmental exposures are has yet to be definitively determined.  As these scientists point out, autism continues to become more and more prevalent – something in our environment is causing a massive problem of epidemic proportions: “…toxicant exposure has been epidemic, logically confirmed as an important etiological factor of ASD, and patients often show some clinical manifestations of intoxication.”  The ability to detoxify both external sources, like glyphosates, or internal ones (such as those produced by certain gut bacteria) is “essential for life.”  Other environmental toxins that are suspect, according to this paper, include hydrocarbons, automotive exhaust and heavy metals. The gut microbiota act as our first line of defense by degrading or expelling toxins, as the digestive tract is “…the major route by which we ingest toxins.  In this way, microbial detoxification serves as an essential constituent of the host’s detoxification system.”

We know that those on the autism spectrum have major dysfunction of the mitochondria, which themselves are extremely prone to damage from toxins.  Thus, these scientists state, their “…finding of impaired microbial detoxification helps explain why ASD children are so vulnerable to environmental toxins and suggests that impairment in microbial detoxification might be involved in the pathogenesis of ASD.”  

To sum up then, “Here we reported a protective effect of the microbiome on mitochondrial structural and functional integrity, which is illustrated by the close correlation between impaired microbial  detoxification and mitochondrial dysfunction…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.”  So there you have it:  dysbiosis leads to the loss of protective enzymes and impaired detoxification pathways which, in turn, allow toxins to damage mitochondria.  These findings are not yet replicated, of course, but it may very well turn out that this is among the more important papers in autism in the last number of years.

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[i] Mengxiang Zhang et al. A quasi-paired cohort strategy reveals the impaired detoxifying function of microbes in the gut of autistic children, Science Advances (2020). DOI: 10.1126/sciadv.aba3760