Urinaryp-cresol is elevated in young French children with autism spectrum disorder: a replication study

Abstract

The aromatic compound p-cresol (4-methylphenol) has been found elevated in the urines of Italian autistic children up to 8 years of age. The present study aims at replicating these initial findings in an ethnically distinct sample and at extending them by measuring also the three components of urinary p-cresol, namely p-cresylsulfate, p-cresylglucuronate and free p-cresol. Total urinary p-cresol, p-cresylsulfate and p-cresylglucuronate were significantly elevated in 33 French autism spectrum disorder (ASD) cases compared with 33 sex-and age-matched controls (p50.05). This increase was limited to ASD children aged 8 years (p50.01), and not older (p ¼ 0.17). Urinary levels of p-cresol and p-cresylsulfate were associated with stereotypic, compulsive/repetitive behaviors (p50.05), although not with overall autism severity. These results confirm the elevation of urinary p-cresol in a sizable set of small autistic children and spur interest into biomarker roles for p-cresol and p-cresylsulfate in autism.

Urinary metabolomics of young Italian autistic children supports abnormal tryptophan and purine metabolism

“…At least some of the metabolic perturbations described here may reflect pathophysiologically meaningful abnormalities, possibly bearing functional consequences at the clinical level. Three strengths of the experimental design may have contributed to this positive outcome: (a) a focus on early infancy, by recruiting children within a relatively narrow age window precisely defined on the basis of previous urinary metabolic data [20, 21]; (b) the use of UHPLC-MS paired with HILIC, a very sensitive and reliable method ensuring maximum accuracy in the separation of small urinary solutes [26, 27]; (b) a pathway-centered approach, moving beyond the identification of single urinary ASD markers [10–17], as beautifully exemplified by urinary metabolomic studies of rodent models of ASD [35–37]. In particular, our recruitment strategy substantially differs from previous case-control study designs, minimizing age-dependent heterogeneity by setting data-driven age thresholds (i.e., 2–8 years old) [20, 21], and applying tight age and sex matching between cases and controls.…”

“…These results point toward possible negative effects on CNS function exerted by microbiome-derived metabolites. At least three examples are available, albeit with different degrees of support: (a) urinary p -cresol amounts were found correlated with ASD severity [20] or with the intensity of stereotypic behaviors in young autistic children [21]; (b) i.c.v. injection of propionic acid, an enteric-derived short chain fatty acid, produces ASD-like behaviors in the rat [61]; (c) indoxyl sulfate is a known risk factor for cognitive impairment in chronic renal disease [62]: its influx across the blood-brain barrier using the organic anion transporter 3 significantly reduces the efflux of various neurotransmitter metabolites through the same transporter, leading to their accumulation [63].…”

“…Several of these same pathways, especially tryptophan, purine, and gut microbiome metabolisms, are also abnormal in animal models of ASD and provide very interesting leads toward possible pathophysiological explanations for specific symptoms present in many autistic children, such as seizures and sleep disorders. These metabolic abnormalities may apply to young children only, as suggested by studies of urinary p -cresol [20, 21]. It will indeed be very important to now perform a similar metabolomic assessment on ASD individuals and controls older than 8 years of age.…”

“…Interethnic differences in the gut microbiota, stemming from differences in the nutrient composition of local diets, as well as age-related changes in both gut microbiota and human metabolism indeed require that case and control samples be tightly matched for these two variables. Age-related changes may be especially relevant to studies of ASD, where we have recently reported levels of urinary p -cresol to be elevated in autistic children compared to age-matched controls both in Italy and in France, but exclusively up until 8 years of age [20, 21]. Similar age-related changes in ASD have been previously described for other parameters, such as brain serotonin synthesis capacity [22, 23] and excessive head growth rates [24].…”

Can probiotics benefit children with autism spectrum disorders?

“…A number of studies have shown abnormal fecal metabolites, such as short chain fatty acids (SCFA) related to changes in microbiota[87]. Para-cresol (a phenolic compound) has been suggested to be a urinary marker for autism[88], especially in those with constipation and ASD[89]. In a mouse model of autism induced by maternal immune activation, autistic behaviors such as communication abnormalities, stereotypies, and anxiety behaviors were associated with abnormal serum metabolities produced by the microbiota, including 4-ethylphenyl sulfate (the major metabolite) and p-cresol (to a lesser extent)[57].…”