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

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.