P-cresol Alters Brain Dopamine Metabolism and Exacerbates Autism-Like Behaviors in the BTBR Mouse

Pascucci, Tiziana; Colamartino, Marco; Fiori, E.; Sacco, Roberto; Coviello, Annalisa; Ventura, Rossella; Puglisi-Allegra, Stefano; Turriziani, Laura; Persico, Antonio M.

doi:10.3390/brainsci10040233

Cited by 59 publications

(53 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…C. difficile and Pseudomonas stutzeri are the main sources of p -cresol in humans [ 58 ]; this organic aromatic compound acts as a neuroactive uremic toxin and is increased in autistic subjects [ 59 ]. Our results confirm that the magnitude of the p -cresol increase was proportional to the severity of ASD core symptoms, as previously demonstrated in both humans and animal models [ 60 , 61 ], and is associated with slow bowel transit due to the decrease of gut motility [ 62 ].…”

Section: Discussionsupporting

confidence: 91%

The Urine Metabolome of Young Autistic Children Correlates with Their Clinical Profile Severity

et al. 2020

View full text Add to dashboard Cite

Autism diagnosis is moving from the identification of common inherited genetic variants to a systems biology approach. The aims of the study were to explore metabolic perturbations in autism, to investigate whether the severity of autism core symptoms may be associated with specific metabolic signatures; and to examine whether the urine metabolome discriminates severe from mild-to-moderate restricted, repetitive, and stereotyped behaviors. We enrolled 57 children aged 2–11 years; thirty-one with idiopathic autism and twenty-six neurotypical (NT), matched for age and ethnicity. The urine metabolome was investigated by gas chromatography-mass spectrometry (GC-MS). The urinary metabolome of autistic children was largely distinguishable from that of NT children; food selectivity induced further significant metabolic differences. Severe autism spectrum disorder core deficits were marked by high levels of metabolites resulting from diet, gut dysbiosis, oxidative stress, tryptophan metabolism, mitochondrial dysfunction. The hierarchical clustering algorithm generated two metabolic clusters in autistic children: 85–90% of children with mild-to-moderate abnormal behaviors fell in cluster II. Our results open up new perspectives for the more general understanding of the correlation between the clinical phenotype of autistic children and their urine metabolome. Adipic acid, palmitic acid, and 3-(3-hydroxyphenyl)-3-hydroxypropanoic acid can be proposed as candidate biomarkers of autism severity.

show abstract

Section: Discussionsupporting

confidence: 91%

The Urine Metabolome of Young Autistic Children Correlates with Their Clinical Profile Severity

et al. 2020

View full text Add to dashboard Cite

show abstract

“…p-Cresol (an alcohol) is produced from tyrosine [ 137 , 138 ] by 4-hydroxyphenylacetate decarboxylases [ 139 ]. It increases anxiety-like behaviors in mice [ 140 ], has cell toxicity [ 141 ] and acts as an insect attractant [ 142 ]. Moreover, 3-vinyl-1-cyclobutene is an unsaturated cyclic hydrocarbon found in the extract of Cornus officinalis (Japanese cornel), a traditional Chinese herbal medicine [ 66 ].…”

Section: Resultsmentioning

confidence: 99%

Production of Plant-Associated Volatiles by Select Model and Industrially Important Streptomyces spp.

et al. 2020

View full text Add to dashboard Cite

The Streptomyces produce a great diversity of specialized metabolites, including highly volatile compounds with potential biological activities. Volatile organic compounds (VOCs) produced by nine Streptomyces spp., some of which are of industrial importance, were collected and identified using gas chromatography–mass spectrometry (GC-MS). Biosynthetic gene clusters (BGCs) present in the genomes of the respective Streptomyces spp. were also predicted to match them with the VOCs detected. Overall, 33 specific VOCs were identified, of which the production of 16 has not been previously reported in the Streptomyces. Among chemical classes, the most abundant VOCs were terpenes, which is consistent with predicted biosynthetic capabilities. In addition, 27 of the identified VOCs were plant-associated, demonstrating that some Streptomyces spp. can also produce such molecules. It is possible that some of the VOCs detected in the current study have roles in the interaction of Streptomyces with plants and other higher organisms, which might provide opportunities for their application in agriculture or industry.

show abstract

“…However, the causal relationship between social behavior and p-Cresol levels was not investigated. Also, a recent study showed that a single acute intravenous injection of p-Cresol exacerbated anxiety and reduced social preference in the BTBR idiopathic model of ASD 47 . Nonetheless, the intravenous administration of p-Cresol did not recapitulate chronic intestinal exposure and the broad observed effects may have resulted from acute activity of the compound.…”

Section: P-cresol Induces Asd Core Behavioral Deficitsmentioning

confidence: 98%

The microbial metabolitep-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

Bermudez-Martin

Becker

Caramello

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Perturbations of the microbiota-gut-brain axis have been identified in autism spectrum disorders (ASD), suggesting that the microbiota could be involved in the development or maintenance of abnormal social and stereotyped behaviors in ASD patients.Yet, the underlying mediators and mechanisms remain unclear. We hypothesized that microbial metabolites produced by the gut microbiota contribute to behavioral deficits in ASD.We focused on p-Cresol, a microbial metabolite previously described as abnormally elevated in ASD patients. Methods:Wild-type mice were chronically treated with p-Cresol in drinking water to mimic intestinal exposure. We combined behavioral phenotyping, electrophysiology, microbiota 16S sequencing and fecal microbiota transplantations to decipher the consequences of p-Cresol exposure. Results:We showed that p-Cresol selectively induced behavioral alterations reminiscent of ASD core symptoms: social behavior deficits, stereotypies and perseverative behaviors, but no changes in anxiety, locomotion or cognition. We further showed that p-Cresol decreases the activity of dopamine neurons in the ventral tegmental area (VTA), a key brain region for social reward processing. In addition, we reveal that p-Cresol remodels the intestinal microbiome, impacting specific bacterial taxa associated with social behavior deficits and stereotypies. We further demonstrated that social behavior deficits are transferred to control mice after transplantation of microbiota from p-Cresol-treated mice. Finally, both social interactions and VTA dopamine neurons activity were normalized in p-Cresol treated mice after transplant of microbiota from control mice. Conclusions:Our study suggests that the microbial metabolite p-Cresol could be involved in the development of autistic behaviors through remodeling of the gut microbiota.

show abstract

P-cresol Alters Brain Dopamine Metabolism and Exacerbates Autism-Like Behaviors in the BTBR Mouse

Cited by 59 publications

References 66 publications

The Urine Metabolome of Young Autistic Children Correlates with Their Clinical Profile Severity

The Urine Metabolome of Young Autistic Children Correlates with Their Clinical Profile Severity

Production of Plant-Associated Volatiles by Select Model and Industrially Important Streptomyces spp.

The microbial metabolitep-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

Contact Info

Product

Resources

About