Dietary fiber enhances TGF-β signaling and growth inhibition in the gut
Dietary fiber enhances TGF-β signaling and growth inhibition in the gut
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DOI：
10.1152/ajpgi.00362.2010
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发表时间：
2011-07-01
影响因子：
4.5
通讯作者：
Ko, Tien C.
中科院分区：
文献类型：
--
作者：
Cao, Yanna;Gao, Xuxia;Ko, Tien C.
曹勇，高旭，张伟，张刚，阮AK，刘，希门尼斯F，小考克斯CS Jr，汤森CM Jr，Ko TC。膳食纤维可增强肠道中的转化生长因子-β信号和生长抑制。Am J生理学胃肠病肝生理学301：G156-G164,2011。2011年3月31日首次出版；DOI：10.1152/ajpgi.00362.2010。-膳食纤维摄入与降低结直肠癌风险有关。其潜在机制仍不清楚。最近，我们发现丁酸盐，一种由细菌发酵膳食纤维在肠道中产生的短链脂肪酸，可以增强大鼠肠上皮细胞(RIE-1)的转化生长因子-β信号转导。此外，转化生长因子-β抑制分化抑制物(ID)，导致细胞凋亡。我们假设膳食纤维通过抑制Id2来增强转化生长因子-β对肠上皮细胞的生长抑制作用。在本研究中，Balb/c和DBA/2N小鼠分别饲喂普通鼠粮和添加膳食纤维(20%果胶)，测定肠上皮细胞中Smad3的水平。体外，用丁酸盐和转化生长因子-β(1)处理RIE-1细胞，并评价细胞功能。此外，我们还研究了IDs在丁酸盐和转化生长因子-β诱导的生长抑制中的作用。我们发现果胶喂养增加了空肠Smad3蛋白水平(Balb/c小鼠为1.47+/-0.26倍，P=0.045；Dba/2N小鼠为1.49+/-0.19倍，P=0.016)和磷酸化Smad3水平(Balb/c小鼠为1.92+/-0.27倍，P=0.009；Dba/2N小鼠为1.83+/-0.28倍，P=0.022)。丁酸盐或转化生长因子-β单独抑制细胞生长并诱导细胞周期停滞。丁酸盐和转化生长因子-β联合作用协同诱导RIE-1细胞周期停滞和凋亡，抑制Id2和Id3水平。此外，利用小干扰RNA抑制Id2基因的表达可引起细胞周期停滞和细胞凋亡。我们的结论是，膳食纤维果胶增强了Smad3在肠道中的表达和激活。丁酸盐和转化生长因子-β诱导细胞周期停滞和凋亡，这可能是通过抑制Id2介导的。我们的结果暗示了膳食纤维降低结直肠癌发生风险的新机制。
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.