PT - JOURNAL ARTICLE AU - Akhil A. Vinithakumari AU - Piyush Padhi AU - Belen Hernandez AU - Susanne Je-Han Lin AU - Aaron Dunkerson-Kurzhumov AU - Lucas Showman AU - Mattew Breitzman AU - Caroline Stokes AU - Yousuf Sulaiman AU - Chandra Tangudu AU - Deepa Ashwarya Kuttappan AU - Muhammed Shafeekh Muyyarikkandy AU - Gregory J. Phillips AU - Vellareddy Anantharam AU - Ann Perera AU - Brett Sponseller AU - Anumantha Kanthasamy AU - Shankumar Mooyottu TI - <em>Clostridioides difficile</em> infection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism and other neurologic disorders? AID - 10.1101/2021.10.22.465382 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.10.22.465382 4099 - http://biorxiv.org/content/early/2021/10/24/2021.10.22.465382.short 4100 - http://biorxiv.org/content/early/2021/10/24/2021.10.22.465382.full AB - Gastrointestinal illnesses are one of the most common comorbidities reported in patients with neurodevelopmental diseases, including autism spectrum disorders (ASD). Gut dysbiosis, overgrowth of C. difficile in the gut, and gut microbiota-associated alterations in central neurotransmission have been implicated in ASD, where the dopaminergic axis plays an important role in the disease pathogenesis. Human C. difficile strains produce a significant amount of the toxic metabolite p-cresol, an inhibitor of dopamine beta-hydroxylase (DBH), which catalyzes the conversion of dopamine (DA) to norepinephrine (NE). p-cresol is known to precipitate and exacerbate autistic behavior in rodents by increasing DA levels and altering DA receptor sensitivity in brain regions relevant to ASD. Therefore, we hypothesized that C. difficile infection dysregulates dopaminergic metabolism in the brain by increasing p-cresol levels in the gut and circulation and by inhibiting DBH, ultimately leading to elevated DA in the brain. For testing this hypothesis, we induced antibiotic-associated C. difficile in mice and determined the gut and serum p-cresol levels, serum DBH activity, and dopamine and its metabolite levels in different brain regions relevant to ASD. The results showed that C. difficile infection causes significant alterations in the dopaminergic axis in mice (p &lt; 0.05). In addition, significantly increased circulating p-cresol levels and reduced DBH activity was observed in C. difficile infected animals (p &lt; 0.05). Therefore, the results from this study suggest a potential link between C. difficile infection and alterations in the dopaminergic axis implicated in the precipitation and aggravation of ASD.Competing Interest StatementThe authors have declared no competing interest.