Study points to possible role of microbial metabolite in ASD

A new study adds to evidence that alterations of the gut microbiome may play a key role in autism spectrum disorders (ASD).

Noting that urinary and fecal levels of the microbial metabolite p-Cresol are more abundant in individuals with ASD than in neurotypical individuals, and that urinary p-Cresol levels correlate with the severity of ASD, Patricia Bermudez-Martin and colleagues exposed mice to p Cresol to see if the metabolite induced ASD-like behavior. The researchers exposed the mice to p-Cresol for four weeks, placing it in their drinking water.

Bermudez-Martin and her team found that the exposed mice exhibited social deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. “This suggests,” they say, “a possible causal relationship between elevated p-Cresol levels and ASD core symptoms.” They also determined that the abnormal social behaviors detected in the experimental mice were associated with decreased activity of dopamine neurons in the ventral tegmental area (VTA), which is part of the brain’s social reward circuit.

The researchers next transferred microbiota from the p-Cresol-exposed mice to control mice. They found that the mice receiving the transplants developed social deficits and stereotypy and exhibited increased fecal excretion of p-Cresol compared to mice receiving transplants from control mice.

Finally, the researchers transplanted microbiota from control mice into the experimental mice. They report, “The microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol treated mice.”

They conclude, “[T]he ability of a control microbiota to normalize p-Cresol levels, VTA dopamine neurons excitability, and social behavior when transplanted to p-Cresol treated mice provides a rationale for clinical trials aimed at studying the beneficial impact of microbiota interventions targeting p-Cresol production to alleviate core social deficits in ASD.”

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“The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota,” Patricia Bermudez-Martin, Jérôme A. J. Becker, Nicolas Caramello, Sebastian P. Fernandez, Renan Costa-Campos, Juliette Canaguier, Susana Barbosa, Laura Martinez-Gili, Antonis Myridakis, Marc-Emmanuel Dumas, Aurélia Bruneau, Claire Cherbuy, Philippe Langella, Jacques Callebert, Jean-Marie Launay, Joëlle Chabry, Jacques Barik, Julie Le Merrer, Nicolas Glaichenhaus, and Laetitia Davidovic, Microbiome, 2021 (free online). Address: Laetitia Davidovic, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université Côte d’Azur, 660 route des Lucioles, 06560 Valbonne, France, davidovic@pmc.cnrs.fr.

This article originally appeared in Autism Research Review International, Vol. 35, No. 3, 2021