Alterations in the Gut Microbiome and Suppression of Histone Deacetylases by Resveratrol Are Associated with Attenuation of Colonic Inflammation and Protection Against Colorectal Cancer

Abstract

Inflammatory bowel disease (IBD) is known to significantly increase the risk for development of colorectal cancer (CRC), suggesting inflammation and cancer development are closely intertwined. Thus, agents that suppress inflammation may prevent the onset of cancer. In the current study, we used resveratrol, an anti-inflammatory stilbenoid, to study the role of microbiota in preventing inflammation-driven CRC. Resveratrol treatment in the azoxymethane (AOM) and dextran sodium sulphate (DSS) CRC murine model caused an increase in anti-inflammatory CD4 + FOXP3 + (Tregs) and CD4 + IL10 + cells, a decrease in proinflammatory Th1 and Th17 cells, and attenuated CRC development. Gut microbial profile studies demonstrated that resveratrol altered the gut microbiome and short chain fatty acid (SCFA), with modest increases in n-butyric acid and a potential butyrate precursor isobutyric acid. Fecal transfer from resveratrol-treated CRC mice and butyrate supplementation resulted in attenuation of disease and suppression of the inflammatory T cell response. Data also revealed both resveratrol and sodium butyrate (BUT) were capable of inhibiting histone deacetylases (HDACs), correlating with Treg induction. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed increased expression of Treg-specific transcription factor FoxP3 or anti-inflammatory IL-10 resulted in an increase in 5-year survival of patients with CRC. These data suggest that alterations in the gut microbiome lead to an anti-inflammatory T cell response, leading to attenuation of inflammation-driven CRC.

Resveratrol Suppresses Cross-Talk between Colorectal Cancer Cells and Stromal Cells in Multicellular Tumor Microenvironment: A Bridge between In Vitro and In Vivo Tumor Microenvironment Study

“…Moreover, several lines of evidence have shown that the influence of T-lymphocyte phenotypes on the tumor depends mostly on the type of tumor together with its severity status and whether the cancer is a chronic inflammatory disease, which may explain the contradictory statements. In the case of CRC, which is associated with chronic inflammation, an anti-inflammatory response might be more beneficial, at least in the early stages of the disease, which may explain why resveratrol is seen to be an effective treatment for CRC cancer in vitro and in vivo [ 36 , 79 ], and thus, partly due to the ability of the resveratrol/Sirt1 axis to change from a pro-inflammatory T-lymphocyte response to an anti-inflammatory effect in the multicellular-TME.…”

Resolving the Contradictory Functions of Lysine Decarboxylase and Butyrate in Periodontal and Intestinal Diseases

“…More recently, in a different approach, investigators used resveratrol to activate the sirtuin 1 deacetylase. The investigators found that this activation of sirtuin 1 inactivates HDACs ( Section 3.3 ) and enhances the butyrate-mediated HDACi/HMBG1 necrosis of colorectal cancer in mice [ 184 ].…”

Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

“…136 Expression of many pro-inflammatory mediators like tumor necrosis factor-a and NOS2, and anti-inflammatory mediator IL-10 are tightly controlled by deposition of activating histone modification H3K9ac and its erasure by histone deacetylase in many tissues, including the gastrointestinal track. [182][183][184] In mouse models of microbial dysbiosis and related colitis, histone deacetylase inhibition caused induction of antiinflammatory Tregs along with suppression of proinflammatory Th1 and Th17 cells. 183,184 These reports highlight the molecular and cellular impact of microbiome modulation and the underlying involvement of epigenetic changes.…”