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PubMed2006

Role of nuclear hormone receptors in butyrate-mediated up-regulation of the antimicrobial peptide cathelicidin in epithelial colorectal cells.

BACKGROUND AND AIMS: The human cathelicidin (LL-37) is one of the major antimicrobial peptides of the non-specific innate immune system in the intestinal tract. Altered expression has been associated with gastrointestinal disease. Recent studies demonstrated that butyrate induces LL-37 mRNA in colonic epithelial cells, however the underlying molecular mechanisms have not been elucidated. The objective of this study was to investigate the regulatory pathways involved in butyrate-induced up-regulation of LL-37. METHODS AND RESULTS: Treatment of Caco-2 and HT-29 cells with butyrate led to a time-dependent up-regulation of LL-37 mRNA expression as determined by semi-quantitative RT-PCR. Up-regulation of LL-37 mRNA by butyrate was subsequently followed by an increase in LL-37 protein expression as observed by immunofluorescence. Co-incubation of butyrate with a VDR, p38 MAPK, ERK 1/2 and TGF-beta1 receptor kinase inhibitor all reduced butyrate-mediated LL-37 mRNA up-regulation. In contrast, transfection of Caco-2 cells with a dominant-negative PPARgamma mutant vector did not affect butyrate-mediated up-regulation of LL-37 mRNA. CONCLUSION: Our results clearly demonstrate that butyrate-mediated up-regulation of LL-37 is influenced by several signalling pathways and receptors including MAPKs as well as VDR and TGF-beta1, but not by PPARgamma. These data may provide new opportunities in the treatment of gastrointestinal diseases.

Antimicrobial Cationic Peptides↗
PubMed2006

Acquisition of resistance to butyrate induces resistance to luminal components and other types of stress in human colon adenocarcinoma cells.

Butyrate, naturally produced by anaerobic fermentation of diet-fiber, is the major nutrient of colonocytes and also an important regulator of colonic epithelium renewal and physiology. Other luminal components, such as bile acids or bacterial products, influence these processes. The model system we used to analyze the influence of several luminal stressors is composed of a previously established cell line resistant to the apoptotic effects of butyrate and their parental butyrate-sensitive cells. Viability of butyrate-resistant cells is unaffected by mild heat-shock (2h, 42 degrees C) and only slightly reduced by severe heat-shock (2h, 45 degrees C) in contrast to their butyrate-sensitive counterparts. The higher constitutive expression of HSP70 and HSP60 could contribute to this resistance. In addition, expression of HSP70 follows a different pattern after heat-shock in both cell lines. Butyrate-resistant cells are quite unaffected by treatment with deoxycholic acid but apoptosis is induced by chenodeoxycholic acid although to a lower extent than in butyrate-sensitive cells. These resistant cells are also less sensitive to lipopolysaccharide and show differences regarding the activation of ERK following osmotic stress. Thus, the cell model herein reported is a useful tool for investigating the molecular mechanisms of resistance to apoptosis, as well as to analyze specific targets for butyrate-resistant tumors.

Adenocarcinoma↗
PubMed2006

In vitro models for the study of the effect of butyrate on human colon adenocarcinoma cells.

The effect of butyrate has been analyzed on human colon adenocarcinoma cell lines with different properties regarding tumorigenicity, differentiation and resistance to apoptosis induced by this agent. Butyrate reduces cell proliferation, induces differentiation (according to alkaline phosphatase activity) and apoptosis, being these effects time- and concentration-dependent. The susceptibility to the cytotoxic effects of butyrate depends on the cell line considered and it is not directly related to tumorigenicity or differentiation. We show that 2mM butyrate treatment of non-tumorigenic BCS-TC2 cells for four days strongly influences the transcriptional activity, causing extensive modification in gene expression patterns (69 up-regulated and 109 down-regulated genes). Some of these genes are involved in the modulation of cell cycle progression, apoptosis and differentiation. We have analyzed the effect of butyrate in spontaneous or induced multicellular spheroids. The more stable spheroids (spontaneous or induced from butyrate-resistant cells) increase the resistance of cells to the effects of butyrate probably due to an impaired accessibility. This in vitro model could be useful to study the resistance of tumors to the effect of natural regulators (i.e. butyrate) as well as to develop and test new therapeutic approaches.

Adenocarcinoma↗
PubMed2002

Butyrate reduces colonic paracellular permeability by enhancing PPARgamma activation.

Butyrate may have a role in preventing ulcerative colitis, but its precise mechanism is unknown. Also, PPARgamma (peroxisome proliferator-activated receptor gamma) is expressed at high levels both in the colonic epithelium and colon cancer cell lines, but no report was shown on the relationship between PPARgamma activation and the effect of butyrate. We investigated the effects of butyrate and PPARgamma agonist on paracellular permeability. To discover whether PPARgamma expressed in the cell lines treated with butyrate was functional or not, we transfected HT-29 cells with an acyl-CoA oxidase promoter-luciferase reporter plasmid containing a PPRE (peroxisome proliferator responsive element) and analyzed the luciferase activity. Butyrate and PPARgamma agonist significantly reduced paracellular permeability of the colon cell line (p<0.05) and this effect indicated that butyrate and PPARgamma agonist decreased HT-29 cell growth and increased differentiation (p<0.01). PPRE activation treated with butyrate was approximately four and a half times that in untreated cells (p<0.01). These findings suggest that the effect of butyrate on paracellular permeability has apparently taken place through PPARgamma activation and this effect attributes to preventing inflammation of the colon.

Butyrates↗
PubMed1998

The effect of pH on the inhibition of bacterial growth by physiological concentrations of butyric acid: implications for neonates fed on suckled milk.

Butyric acid is released from milk by pre-intestinal lipases during suckling. It is also known to inhibit bacterial growth. To investigate whether butyric acid may be a significant factor in controlling bacterial growth in the stomach of pre-weaned animals, the ability of butyric acid to inhibit growth of selected bacteria was tested over physiological ranges of pH and butyric acid concentrations. Six enteric and environmental strains of bacteria were used: two strains of Escherichia coli, Klebsiella pneumoniae, Enterococcus faecium, Enterococcus faecalis, and Enterococcus casseliflavus. At pH 4.5 and 5.0, the growth of all organisms was significantly inhibited in the presence of butyrate, and in some cases growth was completely arrested. At pH 6.0, butyric acid did not affect bacterial growth until the concentration reached 40 mM. The maximum concentration of butyric acid available in cow's milk after incubation with pre-gastric lipase is approximately 16 mM, which would be sufficient to prevent growth of the organisms tested at pH values occurring in the stomach. Therefore, butyric acid inhibition of bacterial growth may explain in part, the role of pre-intestinal lipases in young animals' natural defenses against bacteria in ingested food prior to weaning.

Animals↗
PubMed2005

Production of electricity from acetate or butyrate using a single-chamber microbial fuel cell.

Hydrogen can be recovered by fermentation of organic material rich in carbohydrates, but much of the organic matter remains in the form of acetate and butyrate. An alternative to methane production from this organic matter is the direct generation of electricity in a microbial fuel cell (MFC). Electricity generation using a single-chambered MFC was examined using acetate or butyrate. Power generated with acetate (800 mg/L) (506 mW/m2 or 12.7 mW/ L) was up to 66% higher than that fed with butyrate (1000 mg/L) (305 mW/m2 or 7.6 mW/L), demonstrating that acetate is a preferred aqueous substrate for electricity generation in MFCs. Power output as a function of substrate concentration was well described by saturation kinetics, although maximum power densities varied with the circuit load. Maximum power densities and half-saturation constants were Pmax = 661 mW/m2 and Ks = 141 mg/L for acetate (218 ohms) and Pmax = 349 mW/m2 and Ks = 93 mg/L for butyrate (1000 ohms). Similar open circuit potentials were obtained in using acetate (798 mV) or butyrate (795 mV). Current densities measured for stable power outputwere higher for acetate (2.2 A/m2) than those measured in MFCs using butyrate (0.77 A/m2). Cyclic voltammograms suggested that the main mechanism of power production in these batch tests was by direct transfer of electrons to the electrode by bacteria growing on the electrode and not by bacteria-produced mediators. Coulombic efficiencies and overall energy recovery were 10-31 and 3-7% for acetate and 8-15 and 2-5% for butyrate, indicating substantial electron and energy losses to processes other than electricity generation. These results demonstrate that electricity generation is possible from soluble fermentation end products such as acetate and butyrate, but energy recoveries should be increased to improve the overall process performance.

Acetates↗
PubMed2003

Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of PKC and MAP kinases.

Butyrate, produced in the colon by fermentation of dietary fibre, induces apoptosis in colon adenoma and cancer cell lines, which may contribute to protection against colorectal cancer. However, butyrate is present in the colon along with other dietary factors, including unconjugated bile acids, which are tumour promoters. We have shown previously that the proapoptotic effects of butyrate on AA/C1 human adenoma cells were reduced in the presence of bile acids. To determine the cellular basis of this interaction, we examined the effects of butyrate and the secondary bile acid ursodeoxycholic acid (UDCA) on signalling pathways known to regulate apoptosis using AA/C1 cells. Butyrate activated PKC-delta and p38 MAP (mitogen-activated protein) kinase, whereas UDCA activated PKC-alpha and p42/44 MAP kinase. Butyrate treatment also resulted in the caspase-3-mediated proteolysis of PKC-delta. Butyrate-induced apoptosis was reduced by inhibitors of PKC-delta (Rottlerin), p38 MAP kinase (SB202190) and caspase 3 (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by inhibitors of PKC-alpha (Gö6976) and MEK 1 (PD98059). The effects of butyrate and bile acids are therefore mediated by the differential activation of signalling pathways that are known to regulate apoptosis.

Adenoma↗
PubMed2006

Butyrate modulates TGF-beta1 generation and function: potential renal benefit for Acacia(sen) SUPERGUM (gum arabic)?

Anecdotal evidence suggests that high fibre supplementation of dietary intake may have health benefits in renal disease related to alterations in circulating levels of short-chain fatty acids. The aim of the study was to examine the hypothesis that dietary manipulation may increase serum butyrate and thus have potential beneficial effects in renal disease. We examined the effect of dietary supplementation with a gum arabic sample of standardized molecular characteristics, Acacia(sen) SUPERGUM EM2 (SUPERGUM), on systemic levels of butyrate in normal human subjects. In an in vitro study, we also examined the potential role of butyrate in modifying the generation of the profibrotic cytokine transforming growth factor-beta (TGF-beta1) by renal epithelial cells. Following 8 weeks of dietary supplementation with 25 g/day of SUPERGUM, there was a two-fold increase in serum butyrate (n=7, P=0.03). In vitro work demonstrated that exposure of renal epithelial cells to elevated concentrations of butyrate suppressed both basal and stimulated TGF-beta1 synthesis. The action of butyrate was mediated by suppression of the extracellular signal-regulated kinase/mitogen-activated protein kinase signalling pathway. In addition, butyrate exposures reduced the response of renal epithelial cells to TGF-beta1 as assessed by luciferase activity of a TGF-beta-responsive reporter construct. Attenuation of TGF-beta1 signalling was associated with reduced phosphorylation of Smad 3 and decreased trafficking of TGF-beta1 receptors into signalling, non-lipid raft-associated membrane fractions. In conclusion, the data demonstrate that dietary supplementation with SUPERGU increased serum butyrate, which at least in vitro has beneficial effects on renal pro-fibrotic cytokine generation.

Butyrates↗
PubMed1998

Effect of topical butyrate on rectal epithelial kinetics and mucosal enzyme activities.

1. This study aimed to determine the effect of luminal butyrate on proliferative kinetics, a differentiation marker (alkaline phosphatase), and a molecule that controls cell-substratum adhesion (urokinase) in histologically normal human rectal mucosa. 2. Ten subjects with a colonoscopically normal colon (seven had previous adenomas) were given either butyrate or saline enemas for 4 days in a double-blind cross-over manner. Rectal biopsies were taken before and after each course of enemas. Epithelial proliferative kinetics were measured immunohistochemically using antibodies to proliferating cell nuclear antigen. Urokinase and alkaline phosphatase activities were measured spectrophotometrically in biopsy homogenates. 3. Both saline and butyrate enemas were well tolerated and induced no histological change except for a significant increase in crypt length (P < 0.05). The number of proliferating cells per crypt also increased significantly after butyrate (P = 0.018). 4. Compared with saline enemas, butyrate did not affect kinetic indices nor alkaline phosphatase activities. However, mucosal urokinase activities were significantly lower in butyrate-treated patients (9.5 +/- 2.0 i.u./g) than in saline-treated patients (12.8 +/- 2.0 i.u./g; P = 0.045). 5. Delivering of extra butyrate to the distal colon in healthy subjects may stabilize cell-substratum adhesion in surface epithelium and therefore offer a potential mechanism by which elevating distal colonic luminal butyrate concentrations might be beneficial in patients with colitis or hyperproliferative large bowel epithelium.

Adult↗
PubMed2002

The ability of antigen, but not interleukin-2, to promote n-butyrate-induced T helper 1 cell anergy is associated with increased expression and altered association patterns of cyclin-dependent kinase inhibitors.

The ability of the cell cycle inhibitor n-butyrate to induce T helper 1 (Th1) cell anergy is dependent upon its ability to block the cell cycle progression of activated Th1 cells in G1. Results reported here show that although both interleukin (IL)-2 and antigen (Ag) push Th1 cells into G1 where they are blocked by n-butyrate, only the Ag-activated Th1 cells demonstrate functional anergy once the n-butyrate has been removed from the culture. Because n-butyrate-induced Th1 cell anergy has been linked to increased expression of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1, mechanistic experiments focused on the role of these inhibitors. It was found that when Th1 cells were reincubated in Ag-stimulated secondary cultures, the Th1 cells previously exposed to Ag and n-butyrate (anergic Th1 cells) demonstrated a cumulative increase in p21Cip1 and p27Kip1 when compared with Th1 cells previously exposed to recombinant (r)IL-2 and n-butyrate (non-anergic Th1 cells). p27Kip1 in the anergic Th1 cells from the secondary cultures was associated with cyclin-dependent kinases (cdks). In contrast, p21Cip1 in the anergic Th1 cells, although present at high levels, did not associate significantly with cdks, suggesting that p21Cip1 may target some other protein in the anergic Th1 cells. Taken together, these findings suggest that Th1 cell exposure to Ag and n-butyrate, rather than IL-2 and n-butyrate, is needed to induce the cumulative increase in p21Cip1 and p27Kip1 that is associated with the proliferative unresponsiveness in anergic Th1 cells. In addition, p21Cip1 may inhibit proliferation in the anergic Th1 cells by some mechanism other than suppression of cdks that is unique to the induction of Th1 cell anergy.

Animals↗
PubMed2004

Butyrate as an effective treatment of congenital chloride diarrhea.

BACKGROUND & AIMS: Many therapeutic attempts have demonstrated to be ineffective in reducing the severity of congenital chloride diarrhea and its long-term complications. The short-chain fatty acid butyrate stimulates intestinal water and ion absorption through a variety of mechanisms, including the activation of a parallel Cl-/butyrate and Na+/H+ exchanger. In this case report, we report the therapeutic efficacy of butyrate on an 11-year-old patient affected by congenital chloride diarrhea. METHODS: The efficacy of increasing doses of oral butyrate (from 50 to 100 mg/kg/day) was investigated through the daily evaluation of stool volume, bowel movements, fecal incontinence, serum, and stool electrolytes concentrations. The modifications in transepithelial intestinal ion transport elicited by butyrate were examined by rectal dialysis study. RESULTS: A butyrate dose of 100 mg/kg/day induced a normalization of stool pattern and of serum and fecal electrolytes concentration. The rectal dialysis study demonstrated a proabsorptive effect induced by butyrate on Na+, Cl-, and K+ intestinal transport. Butyrate therapy was well tolerated during the entire 12-month observation period, and the stool pattern and fecal and serum ion concentrations remained stable within the normal ranges. No clinical adverse events or episodes of dehydration requiring hospital care were observed. CONCLUSIONS: Butyrate could be effective in treating congenital chloride diarrhea. It is easily administered, useful in preventing severe dehydration episodes, and may be a promising therapeutic approach for a long-term treatment in this rare and severe condition.

Butyrates↗
PubMed2003

The stable isotope-based dynamic metabolic profile of butyrate-induced HT29 cell differentiation.

Stable isotope-based dynamic metabolic profiling is applied in this paper to elucidate the mechanism by which butyrate induces cell differentiation in HT29 cells. We utilized butyrate-sensitive (HT29) cells incubated with [1,2-13C2]glucose or [1,2-13C2]butyrate as single tracers to observe the changes in metabolic fluxes in these cells. In HT29 cells, increasing concentrations of butyrate inhibited glucose uptake, glucose oxidation, and nucleic acid ribose synthesis in a dose-dependent fashion. Glucose carbon utilization for de novo fatty acid synthesis and tricarboxylic acid cycle flux was replaced by butyrate. We also demonstrated that these changes are not present in butyrate-resistant pancreatic adenocarcinoma MIA cells. The results suggest that the mechanism by which colon carcinoma cells acquire a differentiated phenotype is through a replacement of glucose for butyrate as the main carbon source for macromolecule biosynthesis and energy production. This provides a better understanding of cell differentiation through metabolic adaptive changes in response to butyrate in HT29 cells, demonstrating that variations in metabolic pathway substrate flow are powerful regulators of tumor cell proliferation and differentiation.

Acetyl Coenzyme A↗
PubMed2004

Oncogenic Ras promotes butyrate-induced apoptosis through inhibition of gelsolin expression.

Activation of Ras promotes oncogenesis by altering a multiple of cellular processes, such as cell cycle progression, differentiation, and apoptosis. Oncogenic Ras can either promote or inhibit apoptosis, depending on the cell type and the nature of the apoptotic stimuli. The response of normal and transformed colonic epithelial cells to the short chain fatty acid butyrate, a physiological regulator of epithelial cell maturation, is also divergent: normal epithelial cells proliferate, and transformed cells undergo apoptosis in response to butyrate. To investigate the role of k-ras mutations in butyrate-induced apoptosis, we utilized HCT116 cells, which harbor an oncogenic k-ras mutation and two isogenic clones with targeted inactivation of the mutant k-ras allele, Hkh2, and Hke-3. We demonstrated that the targeted deletion of the mutant k-ras allele is sufficient to protect epithelial cells from butyrate-induced apoptosis. Consistent with this, we showed that apigenin, a dietary flavonoid that has been shown to inhibit Ras signaling and to reverse transformation of cancer cell lines, prevented butyrate-induced apoptosis in HCT116 cells. To investigate the mechanism whereby activated k-ras sensitizes colonic cells to butyrate, we performed a genome-wide analysis of Ras target genes in the isogenic cell lines HCT116, Hkh2, and Hke-3. The gene exhibiting the greatest down-regulation by the activating k-ras mutation was gelsolin, an actin-binding protein whose expression is frequently reduced or absent in colorectal cancer cell lines and primary tumors. We demonstrated that silencing of gelsolin expression by small interfering RNA sensitized cells to butyrate-induced apoptosis through amplification of the activation of caspase-9 and caspase-7. These data therefore demonstrate that gelsolin protects cells from butyrate-induced apoptosis and suggest that Ras promotes apoptosis, at least in part, through its ability to down-regulate the expression of gelsolin.

Alleles↗
PubMed2001

Effect of sodium butyrate on reactive oxygen species generation by human neutrophils.

BACKGROUND: Short-chain fatty acids enema has been shown to be effective in the treatment of ulcerative colitis (UC). However, the mechanisms that lead to this response have not been well characterized. The aims of this study were to investigate the effect sodium butyrate has on reactive oxygen species (ROS) generation by human neutrophils, which are responsible for mucosal injury. METHODS: Human neutrophils incubated with or without sodium butyrate were stimulated with opsonized zymosan (OZ) or phorbol myristate acetate (PMA). ROS generation was largely differentiated with flow cytometry assays of hydroethidine oxidation and dichlorofluorescein oxidation for superoxide anion and hydrogen peroxide respectively, and luminol-dependent chemiluminescence for myeloperoxidase-mediated oxidants. RESULTS: Sodium butyrate (up to 50 mM) did not alter hydroethidine oxidation upon stimulation of the OZ or PMA. However, sodium butyrate at a concentration of 25 mM elevated dichlorofluorescein oxidation to 125 + 8% (P = 0.028) of control upon stimulation of OZ and to 191 +/- 30% (P = 0.0016) upon stimulation of PMA. Contrary to these results, sodium butyrate greatly inhibited chemiluminescence responses in a dose-dependent manner. The inhibition by 50 mM sodium butyrate was 61 +/- 6% upon OZ and 71 +/- 9% upon PMA, respectively. CONCLUSIONS: These data indicate that sodium butyrate up-regulates hydrogen peroxide generation but down-regulates generation of myeloperoxidase-mediated oxidants, the latter being more potent in killing microorganisms and in inducing tissue injury. A possible mechanism is suggested whereby sodium butyrate may inhibit myeloperoxidase activity and hence attenuate the destructive activities of neutrophils in UC.

Butyrates↗
PubMed2000

Inhibition of repair of X-ray-induced DNA double-strand breaks in human lymphocytes exposed to sodium butyrate.

PURPOSE: Sodium butyrate is known to inhibit histone deacetylase enzymes and to enhance the frequencies of X-ray-induced dicentrics and rings in human lymphocytes. In this study an investigation was made of the mechanisms underlying this enhancement by assessing the effect of sodium butyrate on the extent of X-ray-induced DNA damage and its repair in human peripheral blood lymphocytes. METHODS AND MATERIALS: Unstimulated G0 lymphocytes were pretreated for 24h with sodium butyrate at a final concentration of 5 mM, irradiated with different doses of X-rays and then analysed for different endpoints either immediately or after different repair periods. The frequencies of DNA strand breaks were determined biochemically using nucleoid sedimentation, alkaline elution and immunochemical analysis as well as cytogenetically using the premature chromosome condensation (PCC) technique. RESULTS: The results show that sodium butyrate pretreatment does not lead to a significant increase of DNA double- or single-strand breaks nor to an increase of alkali labile base damage in G0 lymphocytes. Moreover, sodium butyrate treatment had no effect on the initial frequency of chromosome breaks. However, PCC analysis clearly showed that the presence of sodium butyrate post-irradiation severely inhibited DNA double-strand break (DSB) repair, which most likely accounts for the increase in X-ray-induced chromosome aberrations. CONCLUSIONS: Sodium butyrate treatment leading to changes in histone acetylation and increased accessibility of chromatin had no effect on the initial levels of X-ray-induced DNA damage. However, sodium butyrate may affect either the chromatin configuration or the enzymatic activities that play a key role in the repair of DSB.

Animals↗
PubMed2000

Butyric acid is synthesized by piglets.

We hypothesized that there is no synthesis of butyric acid within organs or tissues not drained by the portal vein (PV). Two experiments were performed. In six piglets, the colonic vasculature was clamped (n = 4) or the entire colon resected while [1-13C]-butyric acid (99% enriched) was infused into a jejunal vein for 120 min; 13C enrichment of butyric acid was measured in the PV and carotid artery (ART) during the last 30 min of the infusion. In a second experiment, butyric acid tracer and unlabeled disaccharide were infused into the cecum for 120 min, and blood again was sampled from the PV and ART. For the four piglets studied during ligation of the colonic vasculature, the mean (+/- SD) ratio of the butyric acid enrichment in the ART to that in the PV (ART/PV) was 0.80+/-0.05 (ART vs. PV, P = 0.002) and for all six piglets in expt. 1, the ART/PV ratio was 0.74+/-0.1 (ART vs. PV, P = 0.001). The enrichment of butyric acid in the PV averaged 96.0% for the six studies, implying that splanchnic tissues other than the colon did not produce a substantial amount of butyric acid. For the second experiment, the ART/PV ratio was 0.80+/-0.15 (ART vs. PV, P = 0.03). These studies provide the first evidence for endogenous synthesis of butyric acid by piglets.

Animals↗
PubMed2002

Resveratrol enhances the differentiation induced by butyrate in caco-2 colon cancer cells.

Butyrate, a short-chain fatty acid produced in the colon by microbial fermentation of fiber, inhibits growth of colonic carcinoma cells while inducing differentiation. Resveratrol, a plant polyphenol found in red wine and peanuts, has been shown to exert chemopreventive properties on colon cancer cells. The aim of this study was to determine whether resveratrol modulates the effects of butyrate on Caco-2, a colonic adenocarcinoma cell line. The growth inhibitory effect of resveratrol (50 micromol/L) was more powerful than that of butyrate (2 mmol/L). Butyrate did not intensify the inhibition of proliferation exerted by resveratrol. Although the polyphenol enhanced the differentiation-inducing effect of butyrate, it did not elevate alkaline phosphatase activity or E-cadherin protein expression, markers of epithelial differentiation, when applied alone. Butyrate-induced transforming growth factor-beta1 secretion was inhibited by resveratrol. Treatment with the combination of resveratrol and butyrate attenuated levels of p27(Kip1), whereas resveratrol enhanced butyrate's effect on the induction of p21(Waf1/Cip1) expression. These data demonstrate a possible combined chemopreventive effect of two substances naturally occurring in the colonic lumen after ingestion of fibers and resveratrol-containing food.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Microbial degradation products influence colon cancer risk: the butyrate controversy.

All dietary fiber, by definition, escapes digestion in the small intestine and thus arrives relatively intact in the large intestine. Its fate in the large intestine depends upon the type of fiber and the colonic microflora. Highly fermentable fibers result in short chain fatty acids including butyrate, which is thought by some to be protective against colon cancer. However, not all studies support a chemopreventive effect for butyrate and the lack of agreement (particularly between in vivo and in vitro studies) on butyrate and colon cancer has been termed the "butyrate paradox." There are a number of reasons for this discrepant effect including differences between the in vitro and in vivo environments, the timing of butyrate administration, the amount of butyrate administered, the source of butyrate (usually dietary fiber) as a potential confounder, and an interaction with dietary fat. Collectively, the studies suggest that the chemopreventive benefits of butyrate depend in part on amount, time of exposure with respect to the tumorigenic process, and the type of fat in the diet.

Butyrates↗