Apoptosis Cascade Proteins Are Regulated In Vivo by High Intracolonic Butyrate Concentration: Correlation With Colon Cancer Inhibition

Abstract

The present study was aimed at evaluating the effect of high intracolonic butyrate concentrations, either through fermentation of a soluble fiber-enriched diet or via intracolonic butyrate instillation, on colon cancer in a chemically induced (dimethylhydrazine) rat model. The effects were tested in four groups of dimethylhydrazine-treated rats: (i) rats fed a standard diet, (ii) rats fed a diet enriched with 15% citrus pectin, a soluble fiber that ferments and produces a high concentration of intracolonic butyrate, (iii) rats fed a standard diet and intrarectally instilled with a sodium butyrate solution (50 mM), (iv) rats fed a standard diet and intrarectally instilled with sodium butyrate vehicle solution (100 mM NaCl). The apoptotic index in the distal colon of rats fed pectin was higher than in colonic tissue from rats fed a standard diet. The expression of caspase-1, a cysteine protease implicated in the regulation of programmed cell death, as detected by both Northern and Western analysis, showed the highest mRNA and protein levels in colonic tissue from rats intrarectally instilled with butyrate. Immunohistology confirmed the Western blot findings. Expression of the cleaved poly(ADPribose) polymerase product, a downstream nuclear substrate for caspase-3 in the apoptotic pathway, was elevated in both the pectin-fed and butyrate-instilled groups. Expression of the antiapoptotic protein Bcl-2 was significantly reduced following pectin feeding as well as butyrate instillation. The highest expression of Bcl-2 was observed in tumor tissue. A marked reduction in aberrant crypt number was observed in colonic tissue obtained from both the pectin-fed and butyrate-instilled groups relative to rats from the standard diet group. The average tumor volume per rat in both the pectin-fed and butyrateinstilled groups was significantly lower than in rats from the standard diet and the sodium butyrate vehicle-instilled groups. We conclude that high butyrate levels, either instilled or obtained following fermentation of soluble dietary fibers, inhibit early and late events in colon tumorigenesis by controlling the transcription expression and activity of key proteins involved in the apoptotic cascade.

Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug

“…Butyric acid causes the upregulation of genes involved in cellular differentiation by inhibiting histone deacetylase activity 41 and has previously been reported to induce hepatocyte differentiation in human hepatoma cells. 42 Despite BA treatment having been considered for patients with leukemia and colon cancer, 6,7 its effective use as chemotherapeu- tic or chemopreventive agent is compromised 8 due to its short half-life. 6 To circumvent the problem of fast metabolism of butyrate monomers, analogues have been tested.…”

Butyrate induced Caco-2 cell apoptosis is mediated via the mitochondrial pathway

“…In contrast, we did not observe any effect of butyrate on expression of any caspases, in contrast with a recent report in a rat colon cancer model. 5 Several inhibitory proteins have recently been described which block the caspase cascade at specific levels. The molecules XIAP as well as cIAP1 and 2 selectively block caspases-3 and -9.…”

Impact of pH on Lactate Formation and Utilization by Human Fecal Microbial Communities

“…The end products of bacterial fermentation are diet dependent, with acetate, propionate, and butyrate being major fermentation products that can provide up to 10% of the energy requirements of humans (35,40). Butyrate, in particular, is the preferred energy source for colonocytes (20,46) and is considered to protect against colorectal disease (3,39,43,53). Lactate is also produced by many species of gut bacteria but does not normally accumulate in the colon.…”