Production of -cresol by Decarboxylation of -HPA by All Five Lineages of Provides a Growth Advantage

is the leading cause of antibiotic-associated diarrhea and is capable of causing severe symptoms, such as pseudomembranous colitis and toxic megacolon. An unusual feature of is the distinctive production of high levels of the antimicrobial compound -cresol. -Cresol production provides with a competitive colonization advantage over gut commensal species, in particular, Gram-negative species. -Cresol is produced by the conversion of -hydroxyphenylacetic acid (-HPA) the actions of HpdBCA decarboxylase coded by the operon. Host cells and certain bacterial species produce -HPA; however, the effects of -HPA on the viability of and other gut microbiota are unknown. Here we show that representative strains from all five clades are able to produce -cresol by two distinct mechanisms: (i) fermentation of -tyrosine and (ii) uptake and turnover of exogenous -HPA. We observed strain-specific differences in -cresol production, resulting from differential efficiency of tyrosine fermentation; representatives of clade 3 (CD305) and clade 5 (M120) produced the highest levels of -cresol tyrosine metabolism, whereas the toxin A-/B+ isolate from clade 4 (M68) produced the lowest level of -cresol. All five lineages share at least 97.3% homology across the operon, responsible for decarboxylation of -HPA to -cresol, suggesting that the limiting step in -cresol production may result from tyrosine to -HPA conversion. We identified that elevated intracellular -HPA, modulated indirectly CodY, controls -cresol production inducing the expression of HpdBCA decarboxylase ubiquitously in populations. Efficient turnover of -HPA is advantageous to as -HPA has a deleterious effect on the growth of and other representative Gram-negative gut bacteria, transduced potentially by the disruption of membrane permeability and release of intracellular phosphate. This study provides insights into the importance of HpdBCA decarboxylase in pathogenesis, both in terms of -cresol production and detoxification of -HPA, highlighting its importance to cell survival and as a highly specific therapeutic target for the inhibition of -cresol production across species.