Suppression of fecal phenol production by oral supplementation of sesamol: inhibition of tyrosine phenol-lyase by sesamol

Phenol is produced from dietary L-tyrosine by the action of tyrosine phenol-lyase (TPL) of gut bacteria and contributes to various physiological disorders, including skin diseases, certain cancers, and kidney dysfunction. We found that oral supplementation of sesamol (36 or 180 μg mL^-1) <i>ad libitum</i> for 14 days in mice significantly suppressed fecal phenol production. Fecal microbiota structure analysis in sesamol-supplemented and control groups revealed that their overall microbiota structures were indistinguishable. To explain the sesamol-induced suppression of fecal phenol production, we characterized inhibition of bacterial TPL by sesamol <i>in vitro</i>. Sesamol specifically inhibited bacterial TPL in a mixed-type fashion (<i>K</i>_i, 135 μM), which was rationalized by computational docking studies using the crystal structure of <i>Pantoea agglomerans</i> TPL that was determined at 1.3 Å resolution. Sesamol was detected at 0-0.295 μmol g^-1 feces in the sesamol-supplemented group. Given the <i>K</i>_i value of sesamol for TPL inhibition, these levels may not have been sufficient to fully inhibit TPL and suppress fecal phenol production. Therefore, the observed suppression of fecal phenol production upon oral sesamol supplementation arose not solely from the inhibition of TPL by sesamol, but also potentially from the effects of metabolites derived from sesamol and the antioxidant activities of sesamol and related metabolites. Nevertheless, these findings highlight the potential for using sesamol to prevent physiological disorders associated with phenol production by the gut microbiota.