The Gut Microbial Metabolite Pyrogallol Is a More Potent Inducer of Nrf2-Associated Gene Expression Than Its Parent Compound Green Tea (-)-Epigallocatechin Gallate

Abstract

(-)-Epigallocatechin gallate (EGCG) has been associated with multiple beneficial effects. However, EGCG is known to be degraded by the gut microbiota. The present study investigated the hypothesis that microbial metabolism would create major catechol-moiety-containing microbial metabolites with different ability from EGCG to induce nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated gene expression. A reporter gene bioassay, label-free quantitative proteomics and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) were combined to investigate the regulation of Nrf2-related gene expression after exposure of U2OS reporter gene or Hepa1c1c7 cells in vitro to EGCG or to its major microbial catechol-moiety-containing metabolites: (-)-epigallocatechin (EGC), gallic acid (GA) and pyrogallol (PG). Results show that PG was a more potent inducer of Nrf2-mediated gene expression than EGCG, with a 5% benchmark dose (BMD5) of 0.35 µM as compared to 2.45 µM for EGCG in the reporter gene assay. EGC and GA were unable to induce Nrf2-mediated gene expression up to the highest concentration tested (75 µM). Bioinformatical analysis of the proteomics data indicated that Nrf2 induction by PG relates to glutathione metabolism, drug and/or xenobiotics metabolism and the pentose phosphate pathway. Taken together, our findings demonstrate that the microbial metabolite PG is a more potent inducer of Nrf2-associated gene expression than its parent compound EGCG.

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“…Additionally, the medicinal plant should over-express secondary metabolites that are able to facilitate nuclear translocation of NRF2 to upregulate the cytoprotective genes that provide the beneficial effect. Green tea catechins are one class of polyphenols that can induce the NRF2-KEAP1 defense mechanism via nuclear translocation of NRF2, transcribing cytoprotective genes such as glutathione S-transferases (GSTs) and glutathione reductases (GRs), to name a few (Yamamoto, Kensler and Motohashi, 2018;Talebi et al, 2021;Liu et al, 2022).…”

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“…Previous studies have shown that urolithins disrupt the regulatory mechanisms in the G1 phase of the cell cycle upregulating apoptosis, control proliferation of epithelial cells, and decrease serum concentrations of prostate-specific antigen (PSA) as well as androgen receptor (AR) levels within prostate cells [ 216 , 217 ]. Moreover, the gut microbial metabolite pyrogallol is a more potent inducer of Nrf2-associated gene expression compared to its parent green tea compound EGCG [ 218 ], which suggests strong antioxidant and detoxifying effects. Recently, secondary polyphenol metabolites such as urolithins have been reported as anticancer compounds that can mediate cell cycle arrest, inhibit estrogen biosynthesis via the aromatase enzyme, induce apoptosis, promote autophagy, reduce oxidative stress, enhance antioxidant activities, and regulate growth factors [ 219 ].…”