Flavonoids: potential impact on intestinal inflammation and colorectal cancer

P. I. OTEIZA; E. RICCIARDI; T. CONTRERAS; G. JAGGERS; S. V. VERSTRAETEN; A. G. ERLEJMAN; C. G. FRAGA

Siena

Conferencia; II International Conference on Environmental Stressors in Biology & Medicine; 2011

Universidad de Siena

Inflammatory bowel diseases and colorectal cancer (CRC) are major public health concerns.  Although genetic factors are important, environmental factors, including nutrition, play a significant role in the onset/prevention. Food extracts containing (-)-epicatechin (EC) and related procyanidins (PCA) show protective effects against colonic inflammation and colorectal cancer (CRC). Epidemiological studies in humans support an anti-inflammatory and anti-CRC action in relationship with the consumption of diets rich in EC and PCA. A diet supplemented with EC and PCA ameliorates colonic inflammation in a rat model of ulcerative colitis.  Both EC and PCA can have distinct but complementary anti-inflammatory actions.  Monomeric EC can be absorbed by intestinal epithelial cells and exert antioxidant and anti-inflammatory actions.  EC prevents tumor necrosis alpha (TNF)–induced oxidant production, and the downstream activation of transcription factors NF-êB and AP-1, and of the mitogen activated kinases (MAPK) ERK1/2 and p-38. Chronic exposure to TNF causes the permeabilization of Caco-2 monolayers differentiated into an intestinal epithelium.  EC (1 µM) prevents the permeabilization of the barrier, in part by downregulating NF-êB which underlies in part TNF-induced altered dynamics of the tight junction proteins.  PCA of more than three EC subunits, are not absorbed by intestinal cells but can exert antioxidant, anti-inflammatory, and anti-CRC actions through their interactions with the cell membrane.  Through these interactions, hexameric PCA (Hex PCA) protect Caco-2 cell monolayers from various pro-inflammatory agents (deoxycholic acid (DCA), TNF, IL-1) that exert their actions in a receptor-independent (DCA) or –dependent (TNF, IL-1) manner.  In particular, Hex PCA prevents DCA-induced membrane cholesterol redistribution, and the associated calcium influx, NADPH oxidase activation, and oxidant production.  Hex PCA also prevents DCA-mediated activation of the pro-inflammatory and oncogenic signals ERK1/2, p38, AP-1 and Akt.  Hex PCA also delays the onset of DCA-induced apoptosis in differentiated Caco-2 cells, and the permeabilization of the epithelial barrier. From the above, EC and PCA could act synergistically to promote gastrointestinal health.