Protocatechuic Acid, a Gut Bacterial Metabolite of Black Raspberries, Inhibits Adenoma Development and Alters Gut Microbiome Profiles in Apc(Min/+) Mice

Administration of black raspberries (BRBs) and their anthocyanin metabolites, including protocatechuic acid (PCA), has been demonstrated to exert chemopreventive effects against colorectal cancer through alteration of innate immune cell trafficking, modulation of metabolic and inflammatory pathways, etc. Previous research has shown that the gut microbiome is important in the effectiveness of chemoprevention of colorectal cancer. This study aimed to assess the potency of PCA versus BRB dietary administration for colorectal cancer prevention using an Apc(Min/+) mouse model and determine how bacterial profiles change in response to PCA and BRBs. A control AIN-76A diet supplemented with 5% BRBs, 500 ppm PCA, or 1,000 ppm PCA was administered to Apc(Min/+) mice. Changes in incidence, polyp number, and polyp size regarding adenomas of the small intestine and colon were assessed after completion of the diet regimen. There were significant decreases in adenoma development by dietary administration of PCA and BRBs in the small intestine and the 5% BRB-supplemented diet in the colon. Pro-inflammatory bacterial profiles were replaced with anti-inflammatory bacteria in all treatments, with the greatest effects in the 5% BRB and 500 ppm PCA-supplemented diets accompanied by decreased COX-2 and prostaglandin E(2) levels in colonic mucosa. We further showed that 500 ppm PCA, but not 1,000 ppm PCA, increased IFN-γ and SMAD4 levels in primary cultured human natural killer cells. These results suggest that both BRBs and a lower dose PCA can benefit colorectal cancer patients by inhibiting the growth and proliferation of adenomas and promoting a more favorable gut microbiome condition.