Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism
The metabolic pathways most distinctive of young Italian autistic children largely overlap with those found in rodent models of ASD following maternal immune activation or genetic manipulations. These results are consistent with the proposal of a purine-driven cell danger response, accompanied by overproduction of epileptogenic and excitotoxic quinolinic acid, large reductions in melatonin synthesis, and gut dysbiosis.
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The “metabolome overview” obtained through metabolic pathway analysis (MetPA) shows tryptophan metabolism, purine metabolism, vitamin B6 metabolism, and phenylalanine-tyrosine-tryptophan biosynthesis as the four most perturbed metabolic pathways in ASD (Fig. 3).
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Given the relevance of tryptophan-derived compounds in many neural functions, tryptophan metabolism was assessed in greater detail at the level of specific intermediates (Fig. 4):
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- The kynurenine pathway displays increases in xanthurenic acid and especially in quinolinic acid, paralleled by a considerable decrease in kynurenic acid...
- The serotonin pathway shows a significant decrease in melatonin and its catabolite N-acetyl-5-methoxytryptamine...
- Bacterial degradation of tryptophan yields in ASD, compared to controls, prominently larger urinary concentrations of indoxyl sulfate and other indole derivatives, including indolyl-3-acetic acid and especially indolyl lactate...
Purine metabolites are also well represented in the urines of ASD children, which display a large excess of inosine, hypoxanthine, and xanthosine (Figs. 3 and 5). This pattern bears an interesting resemblance to the excess of urinary inosine and hypoxanthine detected in Fmr1 knock-out mice, an animal model of fragile-X syndrome [35]. Also, mice exposed prenatally to MIA triggered by poly(I:C) injected at E12.5 and E17.5 show an excess of urinary inosine [36].
This excess of urinary purinergic metabolites has been interpreted as part of a “cell danger metabolic response” involving mitochondrial dysfunction, adenosine triphosphate (ATP), and adenosine diphosphate (ADP) release, activation of a variety of purinergic receptors yielding microglial activation, innate, and adaptive immunity responses and leukocyte chemotactics [65]. Inborn errors of purine metabolism are associated with behavioral abnormalities including autistic features [66]. Strikingly, inhibition of purine metabolism by suramin, a competitive antagonist at P2X and P2Y purinergic receptors, reverses behavioral, neurochemical, transcriptional, and metabolomics abnormalities both in the Fmr1 knock-out mouse and in MIA mice exposed to poly(I:C) during pregnancy [35, 36, 37]. Conceivably, this metabolic abnormality, shared between human ASD and genetic/immunological rodent models could thus represent a valuable biomarker to help guide therapeutic interventions.
In addition, the cell danger response also yields relative vitamin B6 deficiency and the enzyme kynureninase is B6 dependent [65]; hence, a cell danger metabolic response in the presence of adequate tryptophan intake could also explain the decreased kynurenine and increased xanthurenic and quinolinic acid observed here (Fig. 4). Interestingly, these abnormalities have been sometimes overcome with vitamin B6 supplementation [67], a therapeutic approach initially proposed for ASD in conjunction with magnesium supplementation [68]. In light of the present data, B6-Mg++ supplementation in ASD may deserve further scrutiny in urinary biomarker-driven therapeutic trials
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