Nguyen KA et al. (2006) Dietary fiber enhances a tumor suppressor signaling pathway in the gut. Ann Surg 243: 619–627

A high intake of dietary fiber is associated with a substantially reduced risk of colorectal cancer, but the mechanisms behind this association are far from clear. Nguyen et al. hypothesized that the beneficial effects of dietary fiber might be mediated by butyrate, one of the principal short-chain fatty acids produced by microbial fermentation of fiber in the gut. Butyrate is known to have anticancer effects in vitro that resemble the tumor-suppressive effects of transforming growth factor β (TGF-β).

Nguyen and colleagues' in vitro study examined the effects of butyrate in a non-neoplastic rat intestinal epithelial cell line (RIE-1), as well as in transformed RIE-1 cells and six human colorectal cancer cell lines. The authors showed that even low levels of butyrate potentiated some tumor-suppressive actions of TGF-β. This effect of butyrate on TGF-β signaling resulted from selectively increased expression and activation of SMAD3 (but not SMAD2) protein. Butyrate strongly inhibits histone deacetylases and, thus, modulates transcription by inducing conformational changes in chromatin; the authors suggest that this mechanism could explain the increased SMAD3 expression. Butyrate also increases activation of SMAD3 and, therefore, upregulates transcription of TGF-β-responsive genes after activated SMAD3 translocates to the nucleus.

Paradoxically, TGF-β also has tumor-promoting effects. The authors noted that butyrate inhibited one tumor-promoting effect of TGF-β, namely the induction of cyclo-oxygenase 2 expression. Further in vitro and in vivo studies by the same team are underway.