Short-chain fatty acids induce cell cycle inhibitors in colonocytes

Background & Aims: We tested the hypothesis that short-chain organic acids in the colon derived from dietary pectin, wheat bran, and oat bran are protective against the development of colon cancer because they induce transforming growth factor (TGF)-beta 1, which in turn inhibits cell growth by inducing cyclin-directed kinase (cdk) inhibitors. Methods: U4 human colon carcinoma cells differentiate into water-and salt-transporting columnar enterocytes and therefore model normal colonocytes. The composition and kinase activity of cdk/cyclin complexes were determined by immunoprecipitation and Western blotting studies in U4 cells treated in vitro with short-chain fatty acid (SCFA) mixtures that mimic the digestion products of wheat bran, oat bran, pectin, and cellulose las control), which is largely unfermentable. Results: Induction of the cdk inhibitors p21cip1 and p27kip1 by fiber-mimicking SCFA mixtures occurs much more rapidly and is manyfold greater than their induction by TGF-beta 1. The SCFA mixtures most effective in causing growth inhibition and cdk inhibitor production mimicked those from wheat bran > oat bran > pectin. Conclusions: cdk inhibitor induction by SCFA mixtures is not mediated by TGF-beta 1. The SCFA mixture mimicking digested wheat bran fiber was the most effective of all mixtures tested in inhibiting cell growth through induction of cdk inhibitors.