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

Bermudez-Martin, Patricia; Becker, Jérôme A.J.; Caramello, N.; Fernandez, Sebastian P.; Campos, Renan Costa; Canaguier, J.; Barbosa, Susana; Martinez‐Gili, Laura; Myridakis, Antonis; Dumas, Marc; Bruneau, Aurélia; Cherbuy, Claire; Langella, Philippe; Crinon, Jacques; Launay, Jean Marie; Chabry, Joëlle; Barik, Jacques; Merrer, Julie Le; Glaichenhaus, Nicolas; Davidovic, Laetitia

doi:10.1186/s40168-021-01103-z

Cited by 91 publications

(72 citation statements)

References 99 publications

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“…Thus, a possible link between gut microbiota and ASD has been proposed. Moreover, changes in the composition of the gut microbiota and metabolites have been found in both ASD patients and animal models ( Kushak et al, 2016 ; Bermudez-Martin et al, 2021 ). Meanwhile, toxins produced by abnormal gut microbiota can increase intestinal permeability and aggravate ASD symptoms, for example, Fusobacterium produces some nerve factors and exerts systemic effects.…”

Section: Introductionmentioning

confidence: 99%

Fecal Microbiota Transplantation Relieves Gastrointestinal and Autism Symptoms by Improving the Gut Microbiota in an Open-Label Study

Chen²,

Cheng

et al. 2021

Front. Cell. Infect. Microbiol.

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Autism spectrum disorder (ASD) is a severe brain development disorder that is characterized by deficits in social communication and restricted, repetitive and stereotyped behaviors. Accumulating evidence has suggested that gut microbiota disorders play important roles in gastrointestinal symptoms and neurodevelopmental dysfunction in ASD patients. Manipulation of the gut microbiota by fecal microbiota transplantation (FMT) was recently shown to be a promising therapy for the treatment of various diseases. Here, we performed a clinical trial to evaluate the effect of FMT on gastrointestinal (GI) and ASD symptoms and gut microbiota alterations in children with ASD. We found that there was a large difference in baseline characteristics of behavior, GI symptoms, and gut microbiota between children with ASD and typically developing (TD) control children. FMT could improve GI symptoms and ASD symptoms without inducing any severe complications. Similarly, FMT significantly changed the serum levels of neurotransmitters. We further observed that FMT could promote the colonization of donor microbes and shift the bacterial community of children with ASD toward that of TD controls. The abundance of Eubacterium coprostanoligenes pre-FMT was positively correlated with high GSRS scores, whereas a decrease in Eubacterium coprostanoligenes abundance induced by FMT was associated with the FMT response. Our data suggest that FMT might be a promising therapeutic strategy to improve the GI and behavioral symptoms of patients with ASD, possibly due to its ability to alter gut microbiota and highlight a specific microbiota intervention that targets Eubacterium coprostanoligenes that can enhance the FMT response. This trial was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn) (trial registration number ChiCTR1800014745).

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Section: Introductionmentioning

confidence: 99%

Fecal Microbiota Transplantation Relieves Gastrointestinal and Autism Symptoms by Improving the Gut Microbiota in an Open-Label Study

Chen²,

Cheng

et al. 2021

Front. Cell. Infect. Microbiol.

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“…The influence of p-Cresol on behavior was associated with the gut microbial composition, as microbial transplantation from p-Cresol-treated mice to control mice can stimulate behavioral defects. However, microbial transplantation from normal mice to p-Cresol-treated mice was found to restore normal social behaviors [58]. This report suggested that a microbial metabolite such as p-Cresol could provoke ASD-like behavior in mice.…”

Section: The Metabolic Pathwaymentioning

confidence: 81%

“…C. difficile can induce the p-hydroxyphenylacetate (p-HPA) enzyme and therefore stimulate the fermentation of tyrosine for the production of p-Cresol [97]. Notably, mice given p-Cresol in drinking water for four weeks exhibited an altered gut microbiota composition and social-behavioral defects [58]. The p-Cresol intervention also decreases the excitability of dopamine neurons in the ventral tegmental area (VTA) of these mice, a circuit implicated in the social reward system [98].…”

Section: The Metabolic Pathwaymentioning

confidence: 99%

The Human Gut Microbiome as a Potential Factor in Autism Spectrum Disorder

Al-Harthi

Alhazmi

Alburae

et al. 2022

IJMS

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The high prevalence of gastrointestinal (GI) disorders among autism spectrum disorder (ASD) patients has prompted scientists to look into the gut microbiota as a putative trigger in ASD pathogenesis. Thus, many studies have linked the gut microbial dysbiosis that is frequently observed in ASD patients with the modulation of brain function and social behavior, but little is known about this connection and its contribution to the etiology of ASD. This present review highlights the potential role of the microbiota–gut–brain axis in autism. In particular, it focuses on how gut microbiota dysbiosis may impact gut permeability, immune function, and the microbial metabolites in autistic people. We further discuss recent findings supporting the possible role of the gut microbiome in initiating epigenetic modifications and consider the potential role of this pathway in influencing the severity of ASD. Lastly, we summarize recent updates in microbiota-targeted therapies such as probiotics, prebiotics, dietary supplements, fecal microbiota transplantation, and microbiota transfer therapy. The findings of this paper reveal new insights into possible therapeutic interventions that may be used to reduce and cure ASD-related symptoms. However, well-designed research studies using large sample sizes are still required in this area of study.

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“…Of interest is the recent finding that microbiota transfer therapy lowered enhanced fecal p CS levels in ASD similar to those of the typically developing controls ( Kang et al, 2020 ). Furthermore, mice chronically exposed to p -cresol in the drinking water demonstrated an ASD-like behavioral phenotype which was shown to be dependent on p -cresol-induced changes in the intestinal microbiota composition ( Bermudez-Martin et al, 2021 ). This highlights p -cresol and p CS as intriguing ASD-associated molecules with possible implications in the microbiota–gut–brain axis in ASD.…”

Section: Autism Spectrum Disorder-associated Bacterial Metabolites P -Cresyl Sulfate and 4-ethylphenyl Sulfatementioning

confidence: 99%

The Role of Bacterial-Derived Aromatic Amino Acids Metabolites Relevant in Autism Spectrum Disorders: A Comprehensive Review

et al. 2021

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In recent years, the idea of the gut microbiota being involved in the pathogenesis of autism spectrum disorders (ASD) has attracted attention through numerous studies. Many of these studies report microbial dysregulation in the gut and feces of autistic patients and in ASD animal models. The host microbiota plays a large role in metabolism of ingested foods, and through the production of a range of metabolites it may be involved in neurodevelopmental disorders such as ASD. Two specific microbiota-derived host metabolites, p-cresol sulfate and 4-ethylphenyl sulfate, have been associated with ASD in both patients and animal models. These metabolites originate from bacterially produced p-cresol and 4-ethylphenol, respectively. p-Cresol and 4-ethylphenol are produced through aromatic amino acid fermentation by a range of commensal bacteria, most notably bacteria from the Clostridioides genus, which are among the dysregulated bacteria frequently detected in ASD patients. Once produced, these metabolites are suggested to enter the bloodstream, pass the blood–brain-barrier and affect microglial cells in the central nervous system, possibly affecting processes like neuroinflammation and microglial phagocytosis. This review describes the current knowledge of microbial dysbiosis in ASD and elaborates on the relevance and synthesis pathways of two specific ASD-associated metabolites that may form a link between the microbiota and the brain in autism. While the two discussed metabolites are promising candidates for biomarkers and (nutritional) intervention targets, more research into the role of these metabolites in ASD is required to causally connect these metabolites to ASD pathophysiology.

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

Cited by 91 publications

References 99 publications

Fecal Microbiota Transplantation Relieves Gastrointestinal and Autism Symptoms by Improving the Gut Microbiota in an Open-Label Study

Fecal Microbiota Transplantation Relieves Gastrointestinal and Autism Symptoms by Improving the Gut Microbiota in an Open-Label Study

The Human Gut Microbiome as a Potential Factor in Autism Spectrum Disorder

The Role of Bacterial-Derived Aromatic Amino Acids Metabolites Relevant in Autism Spectrum Disorders: A Comprehensive Review

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