Sulfur amino acid metabolism and related metabotypes of autism spectrum disorder: A review of biochemical evidence for a hypothesis

Indika, Neluwa-Liyanage Ruwan; Deutz, Nicolaas E. P.; Engelen, M.P.; Peiris, H.; Wijetunge, Swarna; Perera, Rasika

doi:10.1016/j.biochi.2021.02.018

Cited by 21 publications

(11 citation statements)

References 202 publications

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“…3f). These results support previously noted differences in amino acid metabolism in ASD patients 46; 47 and expand the analysis to new cohorts.…”

Section: Resultssupporting

confidence: 91%

Meta-analysis of the autism gut microbiome identifies factors influencing study discrepancies and machine learning classification

Chavira¹,

Wang²,

Mills³

2022

Preprint

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Autism Spectrum Disorder (ASD) is a severe neurodevelopmental disorder and accumulating evidence has suggested that dysbiosis of the gut microbiome plays an essential role. However, a body of research has investigated the ASD gut microbiome without consensus as to whether or how the ASD microbiome differs from neurotypical children. Here, we evaluate the underlying factors leading to study discrepancies by performing a meta-analysis on reprocessed 16S ribosomal RNA gene amplicon (16S) sequencing data. We compile a total of 1,740 samples across 13 carefully selected published studies together with samples from the American Gut Project, and analyze the data in aggregate and from a per-study perspective. We observed increased Bifidobacterium, Actinobacteria, and Prevotella among ASD individuals across cohorts. We further identified associations to Desulfovibrionales, Deltaproteobacteria and Prevotella that were dependent upon which 16S variable regions were sequenced. Utilizing machine learning (ML), we obtained increased accuracy in ASD classification using data collected from certain territories, on younger subjects, on unrelated age-matched rather than related controls, on samples with increased sequencing depth and when accounting for sex differences. Our work provides compelling evidence that the gut microbiome is altered in ASD patients, and highlights novel factors that are important considerations for future studies.

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“…3f). These results support previously noted differences in amino acid metabolism in ASD patients 46; 47 and expand the analysis to new cohorts.…”

Section: Resultssupporting

confidence: 91%

Meta-analysis of the autism gut microbiome identifies factors influencing study discrepancies and machine learning classification

Chavira¹,

Wang²,

Mills³

2022

Preprint

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“…3′-Phosphoadenosine-5′-phosphosulfate ( PAPS ) and adenosine-5′-phosphosulfate (APS) are important phosphosulfate compounds for sulfur metabolism that participate in assimilatory and dissimilatory sulfate reduction via sulfate-reducing bacteria ( Supplementary Figure S5 ) [ 24 , 25 ]. As shown in Figure 8 , the relative abundance of the gene that encodes for KO K01082 ( BPNT1/cycQ ) 3′(2′), 5′-bisphosphate nucleotidase, the enzyme that converts PAPS to APS, was significantly higher at Baseline and non-significantly decreased (median, p > 0.05) at MTT-10 wk, and decreased significantly at MTT-2 yr vs. Baseline (adjusted p < 0.05) and its relative abundance became more similar to TD ( Figure 8 A).…”

Section: Resultsmentioning

confidence: 99%

“…This suggests that microbes enhanced by MTT have the potential to synthesize folate for the host, and folate supplementation has been demonstrated to improve ASD symptoms. It has been hypothesized that lower levels of Prevotella and Bifidobacterium ( Figure 3 A–D and Figure 4 A) may lead to reduced levels of folate production due to diminished folate-dependent remethylation in ASD [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…Researchers have reported sulfate deficiency or altered sulfate metabolism as being linked with autism [ 8 , 24 , 58 , 59 ]. We observed differences in relative abundance in genes that encode for two KOs that participate in microbial dissimilatory sulfate reduction: K01082 ( BPNT1/cycQ ) 3′(2′), 5′-bisphosphate nucleotidase and K00395 adenylylsulfate reductase, subunit B ( aprB gene ) ( Figure 8 , Supplementary Figure S5 ).…”

Section: Discussionmentioning

confidence: 99%

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Shotgun Metagenomics Study Suggests Alteration in Sulfur Metabolism and Oxidative Stress in Children with Autism and Improvement after Microbiota Transfer Therapy

Nirmalkar

Qureshi

Kang

et al. 2022

IJMS

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Links between gut microbiota and autism spectrum disorder (ASD) have been explored in many studies using 16S rRNA gene amplicon and shotgun sequencing. Based on these links, microbiome therapies have been proposed to improve gastrointestinal (GI) and ASD symptoms in ASD individuals. Previously, our open-label microbiota transfer therapy (MTT) study provided insight into the changes in the gut microbial community of children with ASD after MTT and showed significant and long-term improvement in ASD and GI symptoms. Using samples from the same study, the objective of this work was to perform a deeper taxonomic and functional analysis applying shotgun metagenomic sequencing. Taxonomic analyses revealed that ASD Baseline had many bacteria at lower relative abundances, and their abundance increased after MTT. The relative abundance of fiber consuming and beneficial microbes including Prevotella (P. dentalis, P. enoeca, P. oris, P. meloninogenica), Bifidobacterium bifidum, and a sulfur reducer Desulfovibrio piger increased after MTT-10wks in children with ASD compared to Baseline (consistent at genus level with the previous 16S rRNA gene study). Metabolic pathway analysis at Baseline compared to typically developing (TD) children found an altered abundance of many functional genes but, after MTT, they became similar to TD or donors. Important functional genes that changed included: genes encoding enzymes involved in folate biosynthesis, sulfur metabolism and oxidative stress. These results show that MTT treatment not only changed the relative abundance of important genes involved in metabolic pathways, but also seemed to bring them to a similar level to the TD controls. However, at a two-year follow-up, the microbiota and microbial genes shifted into a new state, distinct from their levels at Baseline and distinct from the TD group. Our current findings suggest that microbes from MTT lead to initial improvement in the metabolic profile of children with ASD, and major additional changes at two years post-treatment. In the future, larger cohort studies, mechanistic in vitro experiments and metatranscriptomics studies are recommended to better understand the role of these specific microbes, functional gene expression, and metabolites relevant to ASD.

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“…Reduced SAMe production and transmethylation pathways are associated with delayed brain development and severe neuropsychiatric diseases [85]. Elevated levels of SAMe in the peripheral nerves are characterized by DNA hypermethylation at the promoter and enhancer regions of several genes involved in lipid synthesis, leading to peripheral myelin defects [86].…”

Section: Same As An Epigenetic Modulatormentioning

confidence: 99%

SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies

Ornoy

Weinstein-Fudim²,

Becker

2022

Pharmaceuticals

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In this review, we discuss the functions and main effects on pregnancy outcomes of three agents that have the ability to induce epigenetic modifications: valproic acid (VPA), a well-known teratogen that is a histone deacetylase inhibitor; S-adenosylmethionine (SAMe), the most effective methyl donor; and choline, an important micronutrient involved in the one methyl group cycle and in the synthesis of SAMe. Our aim was to describe the possible effects of these compounds when administered during pregnancy on the developing embryo and fetus or, if administered postnatally, their effects on the developing child. These substances are able to modify gene expression and possibly alleviate neurobehavioral changes in disturbances that have epigenetic origins, such as autism spectrum disorder (ASD), depression, Rett syndrome, and fetal alcohol spectrum disorder (FASD). Valproic acid and SAMe are antagonistic epigenetic modulators whether administered in utero or postnatally. However, VPA is a major human teratogen and, whenever possible, should not be used by pregnant women. Most currently relevant data come from experimental animal studies that aimed to explore the possibility of using these substances as epigenetic modifiers and possible therapeutic agents. In experimental animals, each of these substances was able to alleviate the severity of several well-known diseases by inducing changes in the expression of affected genes or by other yet unknown mechanisms. We believe that additional studies are needed to further explore the possibility of using these substances, and similar compounds, for the treatment of ”epigenetic human diseases”.

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Sulfur amino acid metabolism and related metabotypes of autism spectrum disorder: A review of biochemical evidence for a hypothesis

Cited by 21 publications

References 202 publications

Meta-analysis of the autism gut microbiome identifies factors influencing study discrepancies and machine learning classification

Meta-analysis of the autism gut microbiome identifies factors influencing study discrepancies and machine learning classification

Shotgun Metagenomics Study Suggests Alteration in Sulfur Metabolism and Oxidative Stress in Children with Autism and Improvement after Microbiota Transfer Therapy

SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies

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