Abstract 2134: Black raspberries and protocatechuic acid protectively alter gut bacteria and bile acid metabolism in ApcMin/+ mice
Authors: Kuo Chieh-Ti , Wang Hsin-Tzu , Chen Jo-Hsin , Siddiqui Jibran , Young Matthew R. , Saud Shakir , Stoner Gary , Wang Li-Shu 
Published: May 2015

Abstract
Black raspberries (BRBs) and their component anthocyanins have been evaluated for chemopreventive potential against colorectal cancer. Because the anthocyanins are not well absorbed, more attention is being focused on protocatechuic acid (PCA), a metabolite of BRB anthocyanins produced by gut microflora. It has been known for some time that PCA exhibits preventative effects on the development of colorectal cancer in rodents. Metabolic reprograming which refers to altered nutrient uptake and use is thought to be essential for rapid cancer cell proliferation. Primary bile acids (BAs) are synthesized in the liver from the metabolism of cholesterol via cholesterol 7 alpha-hydroxylase (CYP7A1), a microsomal cytochrome p450 enzyme. The majority of primary bile acids are recycled through enterohepatic circulation, and a small fraction is further metabolized to cytotoxic secondary bile acids by intestinal anaerobic bacteria. Bile acids (BAs), especially secondary BAs, have been reported as the major dietary-related risk factor in colon carcinogenesis. The present study determined if BRBs influence the development of dysplastic lesions in the colon of ApcMin mice and whether this is associated with changes in the diversity of gut bacteria and bile acid metabolism. Diets containing 5% BRBs, 500 ppm PCA or 1000 ppm PCA significantly decreased numbers of dysplastic lesions in the small intestine and colon of Min mice. 5% BRBs significantly increased lactobacillus in feces; 500 ppm PCA but not 1000 ppm PCA, significantly increased numbers of fecal bifidobacteria and lactobacillus. Metabolomic analysis showed that BRBs significantly increase cholate in plasma of the Min mice, suggesting that BRBs increased cholesterol metabolism. Further, PCA and BRBs did not alter mRNA expression of BAs-activated receptors (FXR and VDR) and their target genes (Shp, FGF15 and IBABP). In addition, PCA and BRBs significantly decreased mRNA expression of Cyclin D1 in small intestine of the Min mice. Changes in bile acid metabolism could affect fat absorption and subsequently impact fatty acid metabolism. 5% BRB diet significantly increased levels of anti-inflammatory polyunsaturated fatty acids (PUFAs; eicosapentaenoate (EPA; 20:5n3) and docosahexaenoate (DHA; 22:6n3) in the plasma. Studies are ongoing to investigate if BRBs and PCA affect the activity of CYP7A1 in the liver. In conclusion, our results suggest for the first time that one of BRBs and PCA's chemopreventive and anti-inflammatory mechanisms is through its ability to alter gut bacteria and bile acid metabolism.
Supported by R01 CA148818 to L-S Wang
Citation Format: Chieh-Ti Kuo, Hsin-Tzu Wang, Jo-Hsin Chen, Jibran Siddiqui, Matthew R. Young, Shakir Saud, Gary Stoner, Li-Shu Wang. Black raspberries and protocatechuic acid protectively alter gut bacteria and bile acid metabolism in ApcMin/+ mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2134. doi:10.1158/1538-7445.AM2014-2134