Dietary Red Raspberry Reduces Colorectal Inflammation and Carcinogenic Risk in Mice with Dextran Sulfate Sodium-Induced Colitis

Background: Ulcerative colitis causes recurring intestinal mucosal injury and sustained inflammation, increasing the likelihood of colorectal cancer (CRC) development. Dietary red raspberry (RB) is a rich source of phytonutrients known to have anti-inflammatory activity; however, the role of RB on CRC prevention in chronic colitis has not been examined. Objective: This study examined the effects of dietary RB supplementation on inflammation, epithelium repair, and oncogenic signaling in dextran sulfate sodium (DSS)-induced chronic colitis in mice. Methods: Six-week-old male C57BL/6J mice were fed a control or RB (5% of dry feed weight; n = 12/group) diet for 10 wk. Starting from the fourth week, mice were administered 2 repeated cycles of 1% DSS (7-d DSS treatment plus 14-d recovery) and were monitored daily for disease activity index (DAI) score. Colonic tissues were collected at the end of the study for histochemical, immunohistochemical, and biochemical analysis of inflammation, differentiation and proliferation markers. Results: RB supplementation reduced the DAI score and histologic damage (by 38.9%; P <= 0.01), expression of inflammatory mediators (by 20-70%; P <= 0.01), infiltration of CD4 T cells (by 50%; P <= 0.05), and alpha 4 beta 7 integrin and related adhesion molecules (by 33.3%; P <= 0.01). Furthermore, RB supplementation facilitated epithelium repair, as evidenced by enhanced goblet cell density, expression of transcription factors including Kruppel-like factor 4 (Klf4) and Hairy and enhancer of split 1 (Hes1), terminal differentiation markers, mucin 2 (Muc2), and intestinal alkaline phosphatase (by 20-200%; P <= 0.01). Conversely, proliferating cell nuclear antigen (by 70%; P <= 0.01), ) beta-catenin, and signal transducer and activator of transcription 3 (STAT3) signaling (by 19-33%; P <= 0.05) were reduced by RB supplementation. In addition, RB supplementation enhanced p53 stability (by 53%) and reduced oncogenic gene expression (by 50-60%). Conclusion: RB supplementation reduced DAI score and the risk of CRC development during recurring colitis in mice, suggesting that RB is a possible dietary supplement for patients with ulcerative colitis and related gut inflammatory diseases.