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<p>Autism spectrum disorder (ASD) is associated with altered gut microbiota and elevated levels&#xa0;of the microbial metabolite <i>p</i>-cresol. We previously demonstrated that -cresol induces social deficits in male mice, alongside reduced excitability of dopamine neurons in the ventral tegmental area, a key catecholamine region in the reward circuit known to control social behavior. Here, we explore the molecular mechanisms underlying these effects. We investigated <i>p</i>-cresol and its host&#xa0;conjugate,&#xa0;<i>p</i>-cresol sulfate, biodistribution in peripheral and central matrices. We show that both metabolites accumulate in the brainstem and impair catecholamine biosynthesis by inhibiting tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH). In silico docking predicts competitive binding of both metabolites to the catalytic pockets of TH and DBH. DBH inhibition alone was sufficient to recapitulate <i>p</i>-cresol-induced social deficits. These findings identify inhibition of host enzymes as a mechanism by which microbial metabolites alter brain function and behavior, linking gut microbiota to ASD-relevant social impairments.</p>

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The autism-linked gut microbial metabolite p-cresol inhibits host catecholamine biosynthesizing enzymes to elicit social deficits

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月22日

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  • Geoffroy Mallaret,
  • Juliette Canaguier,
  • Jacques Callebert,
  • Nicolas Caramello,
  • David Fabregat-Safont,
  • Nicolas Glaichenhaus,
  • Oscar J. Pozo,
  • Jean-Marie Launay,
  • Laetitia Davidovic

摘要

Autism spectrum disorder (ASD) is associated with altered gut microbiota and elevated levels of the microbial metabolite p-cresol. We previously demonstrated that -cresol induces social deficits in male mice, alongside reduced excitability of dopamine neurons in the ventral tegmental area, a key catecholamine region in the reward circuit known to control social behavior. Here, we explore the molecular mechanisms underlying these effects. We investigated p-cresol and its host conjugate, p-cresol sulfate, biodistribution in peripheral and central matrices. We show that both metabolites accumulate in the brainstem and impair catecholamine biosynthesis by inhibiting tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH). In silico docking predicts competitive binding of both metabolites to the catalytic pockets of TH and DBH. DBH inhibition alone was sufficient to recapitulate p-cresol-induced social deficits. These findings identify inhibition of host enzymes as a mechanism by which microbial metabolites alter brain function and behavior, linking gut microbiota to ASD-relevant social impairments.