Regulation of para-cresol production in Clostridioides difficile

The human pathogen Clostridioides difficile colonises the gastrointestinal tract following antibiotic exposure, which causes perturbations in the beneficial microbiome. An unusual feature of C. difficile among the gut microbiota is its ability to produce high concentrations of the antimicrobial compound para-cresol, which selectively targets Gram-negative bacteria. Production of p-cresol occurs either by: (a) tyrosine fermentation via the intermediate para-hydroxyphenylacetate (p-HPA), or (b) direct turnover of exogenous p-HPA in the human gut. p-HPA is decarboxylated to produce p-cresol, by the action of HpdBCA decarboxylase encoded by the hpdBCA operon. HpdBCA decarboxylase production is induced at the transcriptional level by elevated p-HPA, which causes elevated p-cresol production, that significantly reduces microbiome diversity and richness. This deleterious effect of p-cresol on the beneficial gut microbiome is advantageous for C. difficile pathogenesis and infection relapse. Inhibiting this pathway would provide a highly specific therapeutic.