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PubMed2003

Effects of acetate and butyrate on the expression of leptin and short-form leptin receptor in bovine and rat anterior pituitary cells.

The effects of acetate and butyrate on leptin and leptin receptor (OB-R) expression in bovine and rat anterior pituitary were examined. In bovine tissues, leptin gene expression using RT-PCR was observed in fat and anterior pituitary but not in liver. Isolated anterior pituitary cells cultured in Dulbecco's modified Eagle's medium (DMEM) for 3 days were further cultured for 48 h in DMEM containing 10 mM acetate or butyrate or without any fatty acids as control. Western blot analysis revealed that the abundance of leptin protein was greater in the presence of acetate and butyrate than that for the control culture. Leptin abundance was increased in a dose- and time-dependent manner in bovine anterior pituitary cells. However, leptin expression in rat cells, of which the basal level was much greater than that in ovine cells, was significantly decreased by the culture with butyrate. In addition, we studied the effects of both fatty acids on OB-R mRNA expression using semi-quantitative RT-PCR. The results showed that butyrate significantly decreased the expression in both bovine and rat cells. These findings indicate that acetate and butyrate enhance leptin expression in bovine, but not in rat anterior pituitary cells while butyrate suppresses OB-Ra expression in both rat and bovine pituitaries.

Acetates↗
PubMed2001

Butyrate increases production of human chimeric IgG in CHO-K1 cells whilst maintaining function and glycoform profile.

The influence of sodium butyrate on the production and glycosylation of recombinant mouse/human chimeric antibody by transfected CHO-K1 cells was investigated. We selected cells expressing 'wild-type' antibody with a human IgG3 heavy chain and a mutant of this molecule in which Phe 243 is replaced by Ala. These proteins have previously been shown to exhibit very different glycoform profiles with the mutant IgG being comprised of glycoforms having a high galactose and sialic acid content. Cell culture with 0-5 mM butyrate was shown to effect a 2-4-fold increase in antibody production whilst the induction of apoptosis was observed in a dose-dependent manner. The optimal butyrate concentration was observed to be 2 mM. The glycoform profile of each antibody produced in the presence of butyrate was analyzed by HPAEC-PAD and shown to be unchanged, relative to that produced in the absence of butyrate. Biological activity was evaluated by the ability of the antibodies to trigger superoxide generation, through Fc gamma RI, and shown to be independent of production in the presence or absence of butyrate. A similar increase in production was observed for a high antibody-producing cell line when expanded in a hollow fibre bioreactor under low-serum conditions (1%). These results demonstrated that butyrate is of value for increasing the productivity of CHO-K1 for recombinant IgG and does not compromise either glycosylation or biological activity.

Animals↗
PubMed1998

Role of butyric acid and its derivatives in the treatment of colorectal cancer and hemoglobinopathies.

Butyric acid, a short chain fatty acid (SCFA), is a natural component of the animal metabolism. Physiological concentrations induce multiple and reversible biological effects. They concern regulatory mechanisms of gene expression conducing to promote markers of cell differentiation, apoptosis and cell growth control. The described hyperacetylation of histones and the induction of several immune or non-immune cell-activating mediators are consistent with the pleiotropic stimulatory effect of the agent. Butyric acid is considered as a biological response modifier (BRM) and is an interesting tool for biological studies. The history of butyric acid as a putative medication in human health is spanning since 60 years and is confusing in part because of conflicting data between exciting experimental results and clinical trials. In light of minimal impact of systemic therapy and the short half-life of the saline molecule used, it is evident that continuous infusions of butyrate are required to improve the efficacy of the treatment. Butyric acid has been viewed with skepticism because of less convenient for long-term chronic therapy. New experimental data from several studies conduced within the past decade with butyric derivatives, delivery systems, and long-acting prodrugs, have demonstrated the practical value of the therapeutic concept. To support issues regarding clinical development, it was of interest to evaluate the recent information, showing butyric acid currently considered as therapeutic purposes in the treatment of colorectal cancer and hemoglobinopathies.

Animals↗
PubMed2000

Butyrate-inducible elements in the human gamma-globin promoter.

OBJECTIVE: Several agents including hydroxyurea, erythropoietin and butyric acid have been shown to reactivate gamma gene expression during adult stage development by unknown molecular mechanisms. In addition to inhibiting the enzyme histone deacetylase, butyrate may modulate transcription factor binding to specific DNA sequences defined as butyrate response elements (BREs). The purpose of this study was to identify promoter sequences involved in gamma gene activation by butyrate using truncation mutants in stable cell lines. MATERIALS AND METHODS: A detailed analysis of Agamma gene activation in the presence of alpha-aminobutyric acid and sodium butyrate was completed in stable mouse erythroleukemia (MEL) cell pools established with seven Agamma promoter truncation mutants. Functional studies were performed in a transient assay system followed by gel mobility shift assays to define protein binding patterns and to demonstrate transcription factor interactions in the gamma promoter BRE. RESULTS: Agamma promoter analysis in stable MEL cell pools revealed BREs between nucleotide-141 and -201, and nucleotide-822 and -893 (gammaBRE). The gammaBRE required the minimal Agamma promoter (-201 to +36) to stimulate gene expression. We observed a 6.1-fold (p < 0.05) increase in CAT activity for the minimal Agamma promoter alone compared with an 11.5-fold (p < 0.05) increase when the gamma promoter was combined with the -822 to -893 fragment. Protein binding studies demonstrated altered protein-DNA interactions in the gammaBRE after butyrate induction. The pattern for binding observed suggest both negative- and positive-acting transcription factors may interact in this region. CONCLUSION: The data supports the -822 to -893 region as a DNA regulatory element that contributes to Agamma gene inducibility by butyrate.

Animals↗
PubMed1999

Enhancement of butyrate production in the rat caecocolonic tract by long-term ingestion of resistant potato starch.

Some data suggest that the colonic microflora may adapt to produce more butyrate if given time and the proper substrate. To test this hypothesis, we investigated the effect of prolonged feeding of resistant potato starch on butyrate production. Rats were fed on either a low-fibre diet (basal) or the same diet supplemented with 90 g resistant potato starch/kg (PoS) for 0.5, 2 and 6 months. Short-chain fatty acid (SCFA) concentrations were determined in caecal and colonic contents at the end of each ingestion period. Total SCFA concentration increased over time throughout the caecocolonic tract with PoS, but was not modified with the basal diet. While propionate concentration was unchanged, butyrate concentration was highly increased by PoS at each time period in both the caecum and colon. Moreover, the butyrogenic effect of PoS increased over time, and the amount of butyrate was increased 6-fold in the caecum and proximal colon and 3-fold in the distal colon after 6 months compared with 0.5 months. Accordingly, the ratio butyrate:- total SCFA increased over time throughout the caecocolonic tract (12.6 (SE 2.8) v. 28 (SE 1.8)% in the caecum, 10.5 (SE 1.4) v. 26.8 (SE 0.9)% in the proximal colon, and 7.3 (SE 2.4) v. 23.9 (SE 2.7)% in the distal colon at 0.5 v. 6 months respectively), while the proportion of acetate decreased. Neither the proportion nor the concentration of butyrate was modified over time with the basal diet. Butyrate production was thus promoted by long-term ingestion of PoS, from the caecum towards the distal colon, which suggests that a slow adaptive process occurs within the digestive tract in response to a chronic load of indigestible carbohydrates.

Animals↗
PubMed2000

n-Butyrate mediated inhibition of papovavirus DNA replication in vivo and in cell culture: a mechanistic approach.

n-Butyrate, an inhibitor of G1-to-S transition inhibits papovavirus DNA replication in cell culture. To explore the efficacy of n-butyrate in vivo and to better understand its mechanism, we studied the effect of n-butyrate on viral DNA replication in mice acutely infected with polyomavirus and in the papovavirus-infected cells in culture. Newborn mice treated with n-butyrate stop growing and become runted. When infected with polyomavirus, these mice show a strong overall inhibition of viral DNA. However, a notable exception to this was the continued viral DNA replication in the differentiated mouse keratinocytes and renal epithelial cells as determined by in situ hybridization. n-Butyrate significantly inhibited viral DNA replication in the cultured IDL cells, and in polyomavirus-infected C2C12 myoblasts based on Southern blot analysis and in situ hybridization. DNA polymerase alpha (but not DNA polymerase beta) and the characteristic nuclear expression of PCNA were both inhibited in the n-butyrate treated IDL and C2C12 cells. n-Butyrate, therefore, inhibited host and viral DNA synthesis in the undifferentiated cells.

Animals↗
PubMed1999

Influence of feces from patients with ulcerative colitis on butyrate oxidation in rat colonocytes.

An impaired oxidation of butyrate has been suggested as a causative factor of ulcerative colitis and, moreover, agents present in colonic luminal contents impair butyrate oxidation in both rat and human colonocytes. To evaluate the overall effect of feces on the production of CO2 and ketone bodies from butyrate oxidation in rat colonocytes, fecal homogenates from 10 healthy subjects and 10 patients with quiescent and 10 patients with active ulcerative colitis were sterile filtrated and added to rat colonocytes incubated with 2, 4, and 10 mmol/liter of stock butyrate, respectively. Addition of fecal filtrate from healthy subjects and patients with quiescent and active ulcerative colitis to colonocytes incubated with 2, 4, and 10 mmol/liter of stock butyrate, respectively, tended to decrease the production of CO2 from butyrate oxidation, whereas ketogenesis was unaffected. The decrease in CO2 production was not explained by the simultaneous addition of fecal short-chain fatty acids (SCFAs). However, a difference in the ability to decrease CO2 production was not found between filtrates from healthy subjects and patients with quiescent and active ulcerative colitis. In conclusion, feces from healthy subjects and patients with quiescent and active ulcerative colitis contain inhibitor(s) of the production of CO2 from butyrate oxidation in colonocytes. However, a specific inhibitory effect of feces from patients with ulcerative colitis on the production of CO2 could not be identified.

Adult↗
PubMed1999

Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose) polymerase (PARP).

Butyrate exerts potent anti-tumor effects by inhibiting cancer cell growth and inducing apoptosis. However, the molecular mechanisms mediating these effects remain largely unknown. Using the Caco-2 cell line, a well established model of colon cancer cells, our data show that butyrate induced apoptosis (maximum 79%) is mediated via activation of the caspase-cascade. A key event was the proteolytic activation of caspase-3, triggering degradation of poly-(ADP-ribose) polymerase (PARP). Inactivation of caspase-3 with the tetrapeptide zDEVD-FMK completely inhibited the apoptotic response to butyrate. In parallel, butyrate potently up-regulated the expression of the pro-apoptotic protein bak, without changing Caco-2 cell bcl-2 expression. Butyrate-induced Caco-2 cell apoptosis was completely blocked by the addition of cycloheximide, indicating the necessity of protein synthesis. However, when this inhibitor was added at a time point where bak expression was already enhanced (12 - 16 h after butyrate stimulation), it failed to protect Caco-2 cells against apoptosis. Taken together, these data provide evidence that the molecular events involved in butyrate induced colon cancer cell apoptosis include the caspase-cascade and the mitochondrial bcl-pathway.

Apoptosis↗
PubMed2005

Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP.

In TNF-related apoptosis-inducing ligand (TRAIL)-resistant glioma cells, co-treatment with nontoxic doses of sodium butyrate and TRAIL resulted in a marked increase of TRAIL-induced apoptosis. This combined treatment was also cytotoxic to glioma cells overexpressing Bcl-2 or Bcl-xL, but not to normal human astrocytes, thus offering an attractive strategy for safely treating resistant gliomas. Cotreatment with sodium butyrate facilitated completion of proteolytic processing of procaspase-3 that was partially blocked by treatment with TRAIL alone. We also found that treatment with sodium butyrate significantly decreased the protein levels of survivin and X-linked inhibitor of apoptosis protein (XIAP), two major caspase inhibitors. Overexpression of survivin and XIAP attenuated sodium butyrate-stimulated TRAIL-induced apoptosis, suggesting its involvement in conferring TRAIL resistance to glioma cells. Furthermore, the kinase activities of Cdc2 and Cdk2 were significantly decreased following sodium butyrate treatment, accompanying downregulation of cyclin A and cyclin B, as well as upregulation of p21. Forced expression of Cdc2 plus cyclin B, but not Cdk2 plus cyclin A, attenuated sodium butyrate/TRAIL-induced apoptosis, overriding sodium butyrate-mediated downregulation of survivin and XIAP. Therefore, Cdc2-mediated downregulation of survivin and XIAP by sodium butyrate may contribute to the recovery of TRAIL sensitivity in glioma cells.

Apoptosis↗
PubMed1976

Gluconeogenesis in isolated intact lamb liver cells. Effects of glucagon and butyrate.

1. Isolated lamb liver cells were prepared from 24-h-starved animals by venous perfusion of the excised caudate lobe with buffer containing collagenase. On the basis of Trypan-Blue exclusion, rate of O2 uptake, adenine nucleotide content and retention of constitutive enzymes, these cells were judged to be intact. 2. Isolated caudate-lobe liver cells showed rates of gluconeogenesis from 10 mM-propionate and 10 mM-lactate that compared favourably with rates determined in isolated median-lobe cells and with rates determined with the isolated perfused lamb liver. 3. The gluconeogenic potential of substrates tested depended on the lamb's age. Cells prepared from suckling lambs (up to 20 days of age and essentially non-ruminant) showed highest rates from galactose, serine and alanine; those prepared from post-weaned lambs (older than 30 days of age and ruminant) showed highest rates from propionate, lactate and fructose. 4. Gluconeogenic rates from endogeneous precursors, 10 mM-propionate and 10mM-galactose, were linear for 1 h and were both stimulated by 1 muM-glucagon. Provided the endogenous rate of gluconeogenesis remained unchanged after substrate addition, glucagon caused a net stimulation of gluconeogenesis from each of these substrates. 5. Gluconeogenic capacity and glucagon sensitivity were examined in cells maintained in substrate-free oxygenated buffer at 37 degrees, 22 degrees and * degrees C. Even under the best of the three conditions of storage that were tested (i.e. at 22 degrees C in gelatin-containing buffer) deterioration of the lamb cells proceeded rapidly, and loss of glucagon responsiveness preceeded the loss of ability to convert precursor into glucose. 6. n-Butyric acid, 2-methylpropanoic acid and 3-methylbutanoic acid at concentrations comparable with those found in lamb portal-vein blood each stimulated gluconeogenesis from 10mM-galactose or 10mM-propionate; gluconeogenesis from galactose was stimulated to the greater extent. 7. The regulatory effects of glucagon and sodium butyrate on lamb liver-cell gluconeogenesis and glycogenolysis were compared. Glucagon (1 muM) and 2mM-butyrate accelerated the rate of glucose formation of liver cells of 24h-starved animals from lactate+pyruvate or fructose. Insulin (20nM) decreased both gluconeogenesis and the efficacy of 1 muM-glucagon. For lactate+pyruvate as substrate, the stimulatory effect of butyrate was additive to that of 1muM-glucagon and for both lactate+pyruvate and fructose the stimulatory effect of butyrate was not influenced by 20nM-insulin. In contrast with glucagon, which stimulated the rate of glycogenolysis in cells prepared from fed lambs, butyrate (0.1-20mM) had no effect. 8. It is concluded that glucagon and butyrate stimulate lamb liver-cell gluconeogenesis by different mechanisms.

Adenine Nucleotides↗
PubMed1999

Counter-regulatory effect of sodium butyrate on tumour necrosis factor-alpha (TNF-alpha)-induced complement C3 and factor B biosynthesis in human intestinal epithelial cells.

The various biological activities of butyrate have been well documented. In this study, we tested the effects of butyrate on TNF-alpha-induced complement C3 and factor B biosynthesis in human intestinal epithelial cells. The biosynthesis of C3, factor B and IL-8 was evaluated at the protein and mRNA levels. To evaluate transcriptional activation, the nuclear run-on assay was performed. The transcription factor-DNA binding activity was assessed by an electrophoretic gel mobility shift assay (EMSA). In the intestinal epithelial cell lines HT-29, T84 and Caco-2, sodium butyrate enhanced TNF-alpha-induced C3 secretion, but suppressed TNF-alpha-induced factor B and IL-8 secretion. Nuclear run-on assay revealed that transcriptional regulatory mechanisms are involved in the effects of sodium butyrate. The EMSAs indicated that sodium butyrate suppressed TNF-alpha-induced nuclear factor (NF)-kappaB- and activation protein (AP)-1-DNA binding activity, but enhanced TNF-alpha-induced activation of CCAAT/enhancer-binding protein (C/EBP)beta (NF-IL-6)-DNA binding activity. Sodium butyrate induced a counter-regulatory effect on TNF-alpha-induced C3 and factor B biosynthesis in human intestinal epithelial cells. Butyrate action has been discussed with its activity to induce histone hyperacetylation, but its counter-regulatory effect on complement biosynthesis may be closely associated with the modulation of transcription factor activation.

Blotting, Northern↗
PubMed2002

Influence of resistant starch on the SCFA production and cell counts of butyrate-producing Eubacterium spp. in the human intestine.

AIMS: The genus Eubacterium, which is the second most common genus in the human intestine, includes several known butyrate producers. We hypothesized that Eubacterium species play a role in the intestinal butyrate production and are inducible by resistant starch. METHODS AND RESULTS: In a human pilot study species-specific and group-specific 16S rRNA-targeted, Cy3 (indocarbocyanine)-labelled oligonucleotide probes were used to quantify butyrogenic species of the genera Eubacterium, Clostridium and Ruminococcus. Following the intake of RS type III a significant increase in faecal butyrate but not in total SCFA was observed. However, increase in butyrate was not accompanied by a proliferation in the targeted bacteria. CONCLUSIONS: The tested Eubacterium species have the capacity to produce butyrate but do not appear to play a major role for butyric acid production in the human intestine. SIGNIFICANCE AND IMPACT OF THE STUDY: In view of the fact that the bacteria responsible for butyrate production are largely unknown, it is still difficult to devise a dietary intervention to stimulate butyrogenic bacteria in a targeted way.

Acetates↗
PubMed2001

Sodium butyrate induces transcription from the G alpha(i2) gene promoter through multiple Sp1 sites in the promoter and by activating the MEK-ERK signal transduction pathway.

Sodium butyrate, an erythroid differentiation inducer and a histone deacetylase inhibitor, increases G alpha(i2) levels in differentiating K562 cells. Here we show that sodium butyrate induces G alpha(i2) gene transcription via sequences at -50/-36 and -92/-85 in the G alpha(i2) gene promoter. Both sequences contain core sequence motif for Sp1 binding; electrophoretic mobility shift as well as supershift assays confirmed binding to Sp1. Transcription from the G alpha(i2) gene promoter was also activated by two other histone deacetylase inhibitors, trichostatin A and Helminthsporium carbonium toxin (HC toxin), which also induce erythroblastic differentiation in K562 cells. However, hydroxyurea, a potent erythroid differentiation inducer in these cells, did not activate transcription from this gene promoter, indicating that promoter activation is inducer-specific. Mutations within the Sp1 sites at -50/-36 and -92/-85 in the G alpha(i2) gene promoter substantially decreased transcriptional activation by sodium butyrate, trichostatin A, or HC toxin. Transfection with constitutively activated ERKs indicated that this promoter can be activated through the MEK-ERK signal transduction pathway. Inhibition of the MEK-ERK pathway with U0126 or reduction in the expression of endogenous ERK with an antisense oligonucleotide to ERK significantly inhibited sodium butyrate- and HC toxin-induced transcription but had no effect on trichostatin A-induced transcription. Inhibition of the JNK and p38 MAPKs, using selective inhibitors, had no effect on sodium butyrate-induced transcription. In cells in which sodium butyrate induction of promoter activation had been inhibited by various concentrations of U0126, constitutively activated ERK2 reversed this inhibition. These results show that the MEK-ERK signal transduction pathway is important in butyrate signaling, which eventually converges in the cell nucleus.

Butyrates↗
PubMed2003

Butyrate is only one of several growth inhibitors produced during gut flora-mediated fermentation of dietary fibre sources.

Dietary fibre sources are fermented by the gut flora to yield short-chain fatty acids (SCFA) together with degraded phytochemicals and plant nutrients. Butyrate, a major SCFA, is potentially chemoprotective by suppressing the growth of tumour cells and enhancing their differentiation. Conversely, it could lead to a positive selection pressure for transformed cells by inducing glutathione S-transferases (GST) and enhancing chemoresistance. Virtually nothing is known about how butyrate's activities are affected by other fermentation products. To investigate such interactions, a variety of dietary fibre sources was fermented with human faecal slurries in vitro, analysed for SCFA, and corresponding SCFA mixtures were prepared. HT29 colon tumour cells were treated for 72 h with individual SCFA or complex samples. The growth of cells, GST activity, and chemoresistance towards 4-hydroxynonenal were determined. Fermentation products inhibited cell growth more than the corresponding SCFA mixtures, and the SCFA mixtures were more active than butyrate, probably due to phytoprotectants and to propionate, respectively, which also inhibit cell growth. Only butyrate induced GST, whereas chemoresistance was caused by selected SCFA mixtures, but not by all corresponding fermentation samples. In summary, fermentation supernatant fractions contain compounds that: (1) enhance the anti-proliferative properties of butyrate (propionate, phytochemical fraction); (2) do not alter its capacity to induce GST; (3) prevent chemoresistance in tumour cells. It can be concluded that fermented dietary fibre sources are more potent inhibitors of tumour cell growth than butyrate alone, and also contain ingredients which counteract the undesired positive selection pressures that higher concentrations of butyrate induce in tumour cells.

Aldehydes↗
PubMed2002

Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis.

BACKGROUND: In ulcerative colitis (UC) the activation (i.e. nuclear translocation) of nuclear factor kappa B (NF-kappaB) is an important step in the regulation of cytokines secreted by lamina propria macrophages. Clinical trials suggest anti-inflammatory effects of locally administered butyrate in UC. The potential effects of butyrate on NF-kappaB activation in lamina propria macrophages of UC patients were investigated. METHODS: Eleven patients with distal UC were treated for up to 8 weeks with butyrate at 100 mM (n = 6) or placebo (n = 5) enemas. At entry and after 4 and 8 weeks, clinical status was noted and intestinal inflammation was graded endoscopically and histologically. Double-staining with antibodies against NF-kappaB (p65) and CD68 was employed to detect NF-kappaB and macrophages, respectively. RESULTS: In untreated patients, nuclear translocation of NF-kappaB was detectable in virtually all macrophages. Butyrate treatment for 4 and 8 weeks resulted in a significant reduction in the number of macrophages being positive for nuclear translocated NF-kappaB. In addition, butyrate significantly reduced both the number of neutrophils in crypt and surface epithelia and of the lamina propria lymphocytes/plasma cells. These findings correlated with a significant decrease in the Disease Activity Index (DAI). CONCLUSIONS: The decrease in DAI and mucosal inflammation in butyrate-treated patients is associated with a reduction of NF-kappaB translocation in lamina propria macrophages. Since the inflammatory process in UC is mainly sustained by macrophage-derived cytokines, the known anti-inflammatory effects of butyrate may in part be mediated by an inhibition of NF-kappaB activation in these macrophages.

Adult↗
PubMed1999

Butyrate hastens restoration of barrier function after thermal and detergent injury to rat distal colon in vitro.

BACKGROUND: Epithelial migration restores barrier function after superficial injury to any mucosa. The present study aimed to determine whether butyrate, important to colonic epithelial physiology in diverse ways, influences restoration of barrier function in the injured rat colon. METHODS: Rat distal colon was transiently exposed in vitro to heat (55 degrees C for 10 sec) or to detergent (deoxycholic acid, 7.5 mM, for 15 min), and tissue damage was verified histologically. Epithelial barrier function was assessed, in colon tissue mounted in Ussing chambers, by measuring electric resistance and passive serosa-to-mucosa fluxes of 22Na and of 14C PEG 4000 under voltage clamp conditions. Studies were done in the absence and presence of 25 mM butyrate in the bathing solutions. RESULTS: Heat exposure induced superficial epithelial damage, and the electric resistance decreased significantly. This was accompanied by increase in flux of 14C PEG and increased passive flux of 22Na. Electric resistance was significantly higher, and PEG flux significantly lower, in tissues bathed with butyrate. Exposure to deoxycholic acid also induced superficial epithelial damage, reduced tissue electric resistance, and increased passive flux of Na and PEG. Electric resistance was significantly higher, and PEG flux significantly lower, in injured tissues bathed in butyrate, than in injured tissues bathed in butyrate-free solution. The effect of butyrate on restoration of electric resistance towards normal was seen in colon both from adult rats and from younger rats that were 2 or 6 weeks old. CONCLUSIONS: Butyrate enhanced restoration of mucosal barrier function in rat distal colon in response to heat and detergent injury.

Animals↗
PubMed2006

Microarray analysis of butyrate regulated genes in colonic epithelial cells.

Butyrate is a naturally occurring product of colonic microbial fermentation of dietary carbohydrates that escape hydrolysis in the small intestine. Butyrate plays a significant role in the maintenance of colonic tissue homeostasis by regulating the expression of genes associated with the processes of proliferation, differentiation, and apoptosis. Using microarray analysis, we assessed changes in the expression of 19,400 genes in response to butyrate in a human colonic epithelial cell line. Among these, we have identified 221 potentially butyrate- responsive genes specifically associated with the processes of proliferation, differentiation, and apoptosis. Of these genes, 59 are upregulated and 162 downregulated, in accordance with the known modes of action of butyrate. The changes in the expression levels (up- or downregulation) of many of these genes were found to be opposite to that reported in colon cancer tissue, where the intracellular concentration of butyrate would be reduced due to the decline in expression of the colonic butyrate transporter, MCT1.

Apoptosis↗
PubMed2004

Sodium butyrate sensitizes TRAIL-mediated apoptosis by induction of transcription from the DR5 gene promoter through Sp1 sites in colon cancer cells.

Sodium butyrate, a short-chain fatty acid naturally present in the human colon, is able to induce cell cycle arrest, differentiation and apoptosis in various cancer cells. Sodium butyrate is most probably related to the inhibition of deacetylases leading to hyperacetylation of chromatin components such as histones and non-histone proteins and to alterations in gene expression. In this study, we demonstrate for the first time that sodium butyrate selectively up-regulated DR5 but had no effect on the expression of the other TNF-alpha-related apoptosis-inducing ligand (TRAIL) receptor, DR4. Sodium butyrate-induced expression of DR5 involves the putative Sp1 site within the DR5 promoter region. Using a combination of the electrophoretic mobility shift assay and the luciferase reporter assay, we found that a specific Sp1 site (located at -195 bp relative to the transcription start site) is required for sodium butyrate-mediated activation of the DR5 promoter. When HCT116 cells were incubated with sodium butyrate and TRAIL, enhanced TRAIL-mediated apoptosis was observed. The enhanced apoptosis was measured by fluorescent activated cell sorting analysis, DNA fragmentation, poly (ADP-ribose) polymerase cleavage, down-regulation of XIAP and caspase activity. Taken together, the present studies suggest that sodium butyrate may be an effective sensitizer of TRAIL-induced apoptosis.

Apoptosis↗