Recent studies suggest that microbiome derived 3(3,4-dihydroxy-phenyl) propionic acid (DHCA) attenuates IL-6 cytokine production through downregulation of the epigenetic modifier DNA Methyltransferase 1 (DNMT1) expression and inhibition of DNA methylation at the 5'-C-phosphate-G-3' (CpG)-rich IL6 sequence introns 1 and 3 in a mouse model of depression. In this study, we extended the investigation of DHCA epigenetic mechanisms in IL-6 expression in human peripheral blood mononuclear cells (PBMC). Using Lucia Luciferase reporter gene system we identified CpG-rich sequences in which of methylation is influenced by DHCA similar to what observed in response to treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Correlation study showed that DNA methylation at select CpG motifs in the IL-6 promoter correlates with IL-6 gene expression. Our study suggests that DHCA is effective in reducing IL-6 expression in human PBMCs, in part, by regulation of methylation in the IL-6 promoter region.