Microbially mediated phenolic catabolites exert differential genoprotective activities in normal and adenocarcinoma
Brian Óg Murphy1, Cheryl Latimer1, Sara Dobani1
1Nutrition Innovation Centre for Food and Health (NICHE), Ulster University, Coleraine, UK.
Abstract:
Age-associated decline of nuclear factor erythroid 2-related factor 2 (Nrf2) activity and DNA repair efficiency leads to the accumulation of DNA damage and increased risk of cancer. Understanding the mechanisms behind increased levels of damaged DNA is crucial for developing interventions to mitigate age-related cancer risk. Associated with various health benefits, (poly)phenols and their microbially mediated phenolic catabolites represent a potential means to reduce DNA damage. Four colonic-microbiota-derived phenolic catabolites were investigated for their ability to reduce H2O2-induced oxidative DNA damage and modulate the Nrf2-Antixoidant Response Element (ARE) pathway, in normal (CCD 841 CoN) and adenocarcinoma (HT29) colonocyte cell lines. Each catabolite demonstrated significant (p < .001) genoprotective activity and modulation of key genes in the Nrf2-ARE pathway. Overall, the colon-derived phenolic metabolites, when assessed at physiologically relevant concentrations, reduced DNA damage in both normal and adenocarcinoma colonic cells in response to oxidative challenge, mediated in part via upregulation of the Nrf2-ARE pathway.
Insights
Phenolic metabolites from gut microbes can protect colon cells from DNA damage. These compounds activate the Nrf2-ARE pathway, offering a potential strategy to reduce cancer risk associated with aging.
Area of Science:
- Cellular and Molecular Biology
- Genetics
- Cancer Research
Background:
- Aging is linked to decreased Nrf2 activity and DNA repair, increasing cancer risk.
- Accumulated DNA damage is a key factor in age-related cancer development.
- (Poly)phenols and their microbial metabolites show potential for DNA damage reduction.
Purpose of the Study:
- To investigate the genoprotective effects of four colonic-microbiota-derived phenolic catabolites.
- To determine the impact of these metabolites on the Nrf2-Antioxidant Response Element (ARE) pathway.
- To assess their efficacy in normal and cancerous colonocyte cell lines.
Main Methods:
- Utilized normal (CCD 841 CoN) and adenocarcinoma (HT29) colonocyte cell lines.
- Exposed cells to hydrogen peroxide (H2O2) to induce oxidative DNA damage.
- Assessed the ability of phenolic catabolites to reduce DNA damage and modulate Nrf2-ARE pathway genes.
Main Results:
- All four phenolic catabolites exhibited significant genoprotective activity (p < .001).
- The metabolites effectively modulated key genes within the Nrf2-ARE pathway.
- Reduced DNA damage was observed in both normal and adenocarcinoma cells at physiologically relevant concentrations.
Conclusions:
- Colon-derived phenolic metabolites demonstrate significant genoprotective effects against oxidative DNA damage.
- These metabolites upregulate the Nrf2-ARE pathway, contributing to their protective function.
- This suggests a potential therapeutic strategy for mitigating age-related DNA damage and cancer risk.
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