Dietary fiber enhances TGF-β signaling and growth inhibition in the gut

Cao Y, Gao X, Zhang W, Zhang G, Nguyen AK, Liu X, Jimenez F, Cox CS Jr, Townsend CM Jr, Ko TC. Dietary fiber enhances TGF-beta signaling and growth inhibition in the gut. Am J Physiol Gastrointest Liver Physiol 301: G156-G164, 2011. First published March 31, 2011; doi:10.1152/ajpgi.00362.2010.-Dietary fiber intake links to decreased risk of colorectal cancers. The underlying mechanisms remain unclear. Recently, we found that butyrate, a short-chain fatty acid produced in gut by bacterial fermentation of dietary fiber, enhances TGF-beta signaling in rat intestinal epithelial cells (RIE-1). Furthermore, TGF-beta represses inhibitors of differentiation (Ids), leading to apoptosis. We hypothesized that dietary fiber enhances TGF-beta's growth inhibitory effects on gut epithelium via inhibition of Id2. In this study, Balb/c and DBA/2N mice were fed with a regular rodent chow or supplemented with a dietary fiber (20% pectin) and Smad3 level in gut epithelium was measured. In vitro, RIE-1 cells were treated with butyrate and TGF-beta(1), and cell functions were evaluated. Furthermore, the role of Ids in butyrate-and TGF-beta-induced growth inhibition was investigated. We found that pectin feeding increased Smad3 protein levels in the jejunum (1.47 +/- 0.26-fold, P = 0.045, in Balb/c mice; 1.49 +/- 0.19-fold, P = 0.016, in DBA/2N mice), and phospho-Smad3 levels (1.92 +/- 0.27-fold, P = 0.009, in Balb/c mice; 1.83 +/- 0.28-fold, P = 0.022, in DBA/2N mice). Butyrate or TGF-beta alone inhibited cell growth and induced cell cycle arrest. The combined treatment of butyrate and TGF-beta synergistically induced cell cycle arrest and apoptosis in RIE-1 cells and repressed Id2 and Id3 levels. Furthermore, knockdown of Id2 gene expression by use of small interfering RNA caused cell cycle arrest and apoptosis. We conclude that dietary fiber pectin enhanced Smad3 expression and activation in the gut. Butyrate and TGF-beta induced cell cycle arrest and apoptosis, which may be mediated by repression of Id2. Our results implicate a novel mechanism of dietary fiber in reducing the risk of colorectal cancer development.