Clostridioides difficile para -Cresol Production Is Induced by the Precursor para -Hydroxyphenylacetate

Clostridioides difficile infection results from antibiotic-associated dysbiosis. para -Cresol, a phenolic compound produced by C. difficile , selectively targets gammaproteobacteria in the gut, facilitating dysbiosis. Here, we demonstrate that expression of the hpdBCA operon, encoding the HpdBCA decarboxylase which converts p -HPA to p -cresol, is upregulated in response to elevated exogenous p -HPA, with induction occurring between >0.1 and ≤0.25 mg/ml. We determined a single promoter and an inverted palindromic repeat responsible for basal and p -HPA-inducible hpdBCA expression. We identified turnover of tyrosine, a p -HPA precursor, does not induce hpdBCA expression above basal level, indicating that exogenous p -HPA was required for p -cresol production. Identifying regulatory controls of p -cresol production will provide novel therapeutic targets to prevent p -cresol production, reducing C. difficile ’s competitive advantage.