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

Abstract

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.

The Impact of Gut Microbiota-Derived Metabolites in Autism Spectrum Disorders

“…Another study showed that p-cresol-treated mice developed social impairments and presented lower dopamine activity, these parameters were restored after faecal microbial transplantation from control mice. On the other hand, these effects were transferred by faecal microbial transplantation of p-cresol-treated mice into control mice suggesting the involvement of a microbiota-dependent mechanism [ 122 ]. Additionally, it was shown that dopamine concentrations were higher in certain brain regions, such as the nucleus accumbens, the caudate-putamen and the amygdala (prefrontal cortex and hippocampus did not show significant differences) from BTBR T + tf/J mice (model for ASD) after p-cresol administration [ 123 ].…”

Role of the Gut Microbiota in the Pathophysiology of Autism Spectrum Disorder: Clinical and Preclinical Evidence

“…P-cresol treatment also impaired excitability of dopaminergic neurons in the ventral tegmental area of those mice, a circuit involved in the social reward system [69]. Plus, the authors showed that the effect of p-cresol on behavior was dependent on microbiota composition, as fecal microbiota transplantation (FMT) from p-cresol treated mice to WT mice induced the similar behavioral impairments, and, in contrast, FMT from WT mice to p-cresol-treated mice restored normal social behaviors [68].…”

“…However, the reasons behind such an increase in this model are currently not known. Interestingly, in a recent report from Bermudez-Martin et al (2020) [68] a 4-week administration of p-cresol in the drinking water changed microbiota composition and induced impaired social behavior and increased repetitive behavior in wild-type (WT) mice. P-cresol treatment also impaired excitability of dopaminergic neurons in the ventral tegmental area of those mice, a circuit involved in the social reward system [69].…”

Microbiota‐gut‐brain axis as a regulator of reward processes

“…In rats, p-cresol administration induced changes in glutamatergic and GABAergic receptors in NAc that were reversed following oxytocin administration, suggesting that mesolimbic system may be important in the development of p-cresol-dependent neurological disorders (Tevzadze et al, 2019). Recently, it has been shown that p-cresol induced social deficits, stereotypes and perseverant behaviours (core autism symptoms) in mice associated with changes in VTA dopaminergic activity, suggesting alterations in social reward processing (Bermudez-Martin et al, 2020),…”