Slow intestinal transit contributes to elevate urinary p‐cresol level in Italian autistic children

Abstract

The uremic toxin p-cresol (4-methylphenol) is either of environmental origin or can be synthetized from tyrosine by cresol-producing bacteria present in the gut lumen. Elevated p-cresol amounts have been previously found in the urines of Italian and French autism spectrum disorder (ASD) children up until 8 years of age, and may be associated with autism severity or with the intensity of abnormal behaviors. This study aims to investigate the mechanism producing elevated urinary p-cresol in ASD. Urinary p-cresol levels were thus measured by High Performance Liquid Chromatography in a sample of 53 Italian ASD children assessed for (a) presence of Clostridium spp. strains in the gut by means of an in vitro fecal stool test and of Clostridium difficile-derived toxin A/B in the feces, (b) intestinal permeability using the lactulose/mannitol (LA/MA) test, (c) frequent use of antibiotics due to recurrent infections during the first 2 years of postnatal life, and (d) stool habits with the Bristol Stool Form Scale. Chronic constipation was the only variable significantly associated with total urinary p-cresol concentration (P < 0.05). No association was found with presence of Clostridium spp. in the gut flora (P = 0.92), augmented intestinal permeability (P = 0.18), or frequent use of antibiotics in early infancy (P = 0.47). No ASD child was found to carry C. difficile in the gut or to release toxin A/B in the feces. In conclusion, urinary p-cresol levels are elevated in young ASD children with increased intestinal transit time and chronic constipation. Autism Res 2016, 9: 752-759. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Biological plausibility of the gut–brain axis in autism

“…13,14 The fact that HPHPA and p-cresol are produced in the gastrointestinal tract and are measurable in urine provides evidence of their systemic absorption and distribution; in autism, gut dysfunction correlates with elevated urinary p-cresol, which correlates with behavioral abnormalities and autism severity. 15 Relatively elevated dopamine and reduced norepinephrine are consistent with monoamine models of psychopathology, and evidence supports a role of dopaminergic dysfunction in autism. 16 Furthermore, elevated dopamine is converted to aminochrome, 17 which promotes mitochondrial dysfunction and forms adducts that compromise neuronal structure and function, thereby further contributing to neuropsychopathology.…”

“…Also consistently reported by research groups is elevated fecal production of p‐cresol in autistic subjects; p‐cresol can be produced by microbial degradation of tyrosine and—similarly to HPHPA—interferes with the conversion of dopamine to norepinephrine via covalent inactivation of dopamine beta‐hydroxylase . The fact that HPHPA and p‐cresol are produced in the gastrointestinal tract and are measurable in urine provides evidence of their systemic absorption and distribution; in autism, gut dysfunction correlates with elevated urinary p‐cresol, which correlates with behavioral abnormalities and autism severity . Relatively elevated dopamine and reduced norepinephrine are consistent with monoamine models of psychopathology, and evidence supports a role of dopaminergic dysfunction in autism .…”

Enteric Ecosystem Disruption in Autism Spectrum Disorder: Can the Microbiota and Macrobiota be Restored?

“…Interestingly, the authors noted that the mice with ASD-like symptoms had markedly elevated levels of the phenolic derivative 4-ethylphenylsulfate (4EPS) at 46 times higher concentration than the control cohort mice. The chemical properties of 4EPS are structurally similar to the analogous compound found in humans, p-cresol (4-methylphenol), which alters cellular membrane permeability, redox activity and ion channels, and has been shown to be elevated in urine from individuals with ASD [26][27][28][29][30].…”

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

“…However, there was no significant relationship between these levels and severity of GI disease, including the presence of antineutrophil cytoplasmic antibodies (ANCA) [347]. Also, slow intestinal transit contributes to elevate urinary p-cresol level in autistic children [348]. But metabolomics studies in ASD are far to be definitive and univocal [349].…”