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.
Free fatty acid receptor 2 (FFAR2) has been reported as a tumor suppressor in colon cancer development. The current study investigated the effects of FFAR2 signaling on energy metabolism and gut microbiota profiling in a colorectal cancer mouse model (Apc Min/+ ). Ffar2 deficiency promoted colonic polyp development and enhanced fatty acid oxidation and bile acid metabolism. Gut microbiome sequencing analysis showed distinct clustering among wild-type, Apc Min/+ , and Apc Min/+ -Ffar2 -/mice. The relative abundance of Flavobacteriaceae and Verrucomicrobiaceae was significantly increased in the Apc Min/+ -Ffar2 -/mice compared to the Apc Min/+ mice. In addition, knocking-down FFAR2 in the human colon cancer cell lines (SW480 and HT29) resulted in increased expression of several key enzymes in fatty acid oxidation, such as carnitine palmitoyltransferase 2, acyl-CoA dehydrogenase, longchain acyl-CoA dehydrogenase, C-2 to C-3 short chain, and hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit. Collectively, these results demonstrated that Ffar2 deficiency significantly altered profiles of fatty acid metabolites and gut microbiome, which might promote colorectal cancer development.
A diet supplemented with freeze‐dried black raspberries (BRBs) has been demonstrated to modulate various biochemical and physiological pathways in both colorectal cancer (CRC) patients and ApcMin/+ mice, which are utilized to model CRC. These changes have been previously shown to exert beneficial chemopreventive effects against CRC, with outcomes such as reduction of adenoma development and inflammation. This study aimed to assess whether these effects manifest in a meaningful change in survival rates by comparing these rates between ApcMin/+ mice administered a 5% BRB‐supplemented diet or a control AIN‐76A diet. Percent survival over days elapsed was assessed in order to determine a median length of survival for each group of mice. Significant increases in survival rates with consumption of the BRB diet versus the control diet were demonstrated in both male and female mouse study groups. Male and female control groups were also compared in order to reduce confounding due to the sex of the mice; the difference in survival rates between male and female mice was not significant (p = 0.07, *p < 0.05), as male mice lived for a median of 143 days and females for 194 days. The results of this study suggest that administration of a BRB‐supplemented diet may potentially prolong the lifespan and increase survival rates of colorectal cancer patients.
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