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Short-chain fatty acids produced by bacterial fermentation of dietary fiber may provide a tonic stimulus to colonocyte differentiation that contributes to the protective effect of fiber against colorectal malignancy. Since brush-border enzymes are common markers of colonocytic differentiation, we compared the effects of equimolar (10 mmol/L) concentrations of the three most common short-chain fatty acids, acetate, butyrate, and propionate, on the alkaline phosphatase and dipeptidyl dipeptidase specific activity of human colonic mucosal biopsies obtained from normal volunteers. Only butyrate significantly stimulated alkaline phosphatase specific activity (50.4% +/- 18.6%, P < .05). Short-chain fatty acid stimulation of dipeptidyl dipeptidase did not achieve statistical significance. Fibers yielding high colonic butyrate levels could have different effects on human colonic mucosal differentiation.

Peptide YY (PYY) is produced by colonic mucosal endocrine cells and modulates gastrointestinal endocrine activity through specific Y-receptors. The direct effects of PYY on intestinal mucosal growth and differentiation remain uncharacterized. The abundance of PYY in colonic mucosa suggests that PYY acts locally to maintain colonocytic differentiation. We tested this hypothesis in human Caco-2 intestinal epithelial cells, which express alkaline phosphatase (AP) and dipeptidyl dipeptidase (DP), brush-border enzymes differentially concentrated in large and small intestinal mucosa, respectively. The effects of PYY on enzyme specific activity were compared with those of pancreatic polypeptide, neuropeptide-Y, vasoactive intestinal peptide, pentagastrin, bombesin, and selective Y1- and Y2-receptor agonists. Brush-border enzyme activity was assessed by AP and DP specific activity in cell lysates quantitated spectrophotometrically following synthetic substrate digestion. PYY, neuropeptide-Y, pancreatic polypeptide, and vasoactive intestinal peptide (10(-7) mol/L) stimulated AP activity. PYY brought about the greatest increase (38.0%+/-11.0%, n=48). Only PYY decreased DP specific activity (7.9%+/-2.2%, n=48). The Y2-agonist but not the Y1-agonist mimicked these PYY effects (increasing AP 28.3%+/-3.5% and decreasing DP 10.4%+/-3.6%). These data suggest that PYY promotes differentiation toward a colonocytic phenotype in Caco-2 intestinal epithelial cells and that this effect may be mediated through the Y2-receptor subtype.