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PubMed1997

Wheat bran diet reduces tumor incidence in a rat model of colon cancer independent of effects on distal luminal butyrate concentrations.

To investigate the effects of dietary fibers in colonic luminal physiology and their role in the prevention of colon cancer, a study was conducted using two diet groups and two treatment groups in a 2 x 2 factorial design. The two diets differed only in the type of dietary fiber, wheat bran and oat bran, and the two treatments were injection with the colon-specific carcinogen azoxymethane, or saline, as a control. There were 34 rats in the carcinogen-injected groups and 11 saline-injected rats per diet group. The goal of the study was to determine if a moderate consumption (6 g/100 g diet) of wheat bran or oat bran would alter the development of colonic tumors in this rat model of colon cancer, and if the differences in tumor incidence were correlated to luminal butyrate concentrations, luminal pH or fecal bulk. Short-chain fatty acid concentrations (SCFA) were measured in feces during the first half of the study (the promotion phase of tumor development) and again at the end of the study. Rats consuming oat bran had greater body weights (P < 0. 002), produced much larger concentrations of all SCFA, including butyrate, in both the proximal and distal colon (P < 0.0001), had more acidic luminal pH values (P < 0.0001), but also had significantly more development of colon tumors (P < 0.03). Alternatively, rats consuming wheat bran produced more typical molar ratios of the SCFA (65:10:20), had a relatively greater concentration of butyrate than propionate, and produced a larger volume (P < 0.05) and more bulky stool than the rats fed oat bran. The results of this study support other evidence that an acidic luminal pH is not protective in and of itself, and that diets containing wheat bran are protective against colon cancer development. In addition, these data show that large luminal butyrate concentrations in the distal colon alone, as were present in the rats consuming oat bran diets, are not protective of tumor development.

Animals↗
PubMed2003

Megasphaera elsdenii JCM1772T normalizes hyperlactate production in the large intestine of fructooligosaccharide-fed rats by stimulating butyrate production.

Hyperlactate production is related to disorders of the large intestine such as inflammatory bowel diseases. Lactate, an intermediate in hindgut fermentation, is metabolized to SCFA. Megasphaera elsdenii can convert lactate to butyrate, a physiologically important organic acid for the hindgut mucosa. This experiment was conducted to determine whether M. elsdenii normalizes hyperlactate production and stimulates butyrate production in the rat large intestine. Specific pathogen-free Sprague-Dawley male rats (n = 12) were fed a fructooligosaccharide (FOS)-supplemented (100 g/kg), semipurified diet to induce lactate production. Lactate excretion in all rats was >30 mmol/kg fresh feces on d 2 of FOS-feeding. The rats were divided into two groups on the morning of d 4. One group (n = 5) was dosed orally with M. elsdenii JCM1772T (1.3 x 10(13) cells) for 3 d. The other group was treated with a vehicle solution. Fecal lactate was significantly lower in rats administered M. elsdenii than in controls. An increase in fecal butyrate compensated for the decrease in lactate. The number of cecal epithelial cells was greater in rats administered M. elsdenii than in controls. M. elsdenii has the potential to normalize hyperlactate accumulation in the large intestine, and lactate-utilizing butyrate producers may be useful probiotics when hyperlactate fermentation in the large intestine is a problem.

Animals↗
PubMed2003

Acetate and butyrate are the major substrates for de novo lipogenesis in rat colonic epithelial cells.

The objective of these experiments was to investigate the source of substrates used for lipid synthesis and the pathways of substrate incorporation into lipids by epithelial cells of the colon. Within replicates, cells were exposed to all treatments evaluated in that experiment. By comparing the relative incorporation rates of several 14C-labeled substrates into lipids, acetate made a significantly larger carbon contribution to lipids than propionate, butyrate, glucose or glutamine under the in vitro conditions utilized in this study. Other major carbon contributors were butyrate and 3-hydroxybutyrate. Glucose, glutamine and propionate made only minor contributions. (-)-Hydroxycitrate did not affect the incorporation of acetate or butyrate carbon into lipids, even though it inhibited colonic ATP-citrate lyase. These data suggest that SCFA carbon used in the synthesis of lipids by colonocytes is not likely transported to the cytosol as citrate. Competition experiments suggest that ketone bodies and butyrate contribute to a single precursor pool for lipogenesis. Ketone bodies did not significantly suppress acetate incorporation into lipid, however. Incorporation of 3H2O and 14C-acetate was significantly greater into phospholipids than into free fatty acids and triacylglycerides, suggesting that the major role of lipogenesis is for membrane synthesis. In conclusion, colonocytes appear to synthesize lipids using a pathway distinct from the liver by incorporating mainly SCFA and ketone bodies into lipids, and by using citrate to a limited extent, if at all, to transport acetyl units from the mitochondria to the cytosol.

Acetic Acid↗
PubMed2003

ZBP-89 mediates butyrate regulation of gene expression.

Inducible p53-independent regulation of the cyclin-dependent kinase inhibitor p21(Waf1) transcription is mediated through its proximal GC-rich sites. Prior studies have shown that Sp1, Sp3 and the histone acetyltransferase coactivator p300 are components of the complexes that bind to these sites. Although Sp1 and Sp3 collaborate with p300, a direct interaction between Sp1 and p300 does not occur. Zinc-finger binding protein-89 (ZBP-89, also known as BFCOL1, BERF-1 and ZNF-148) is a Krüppel-type zinc-finger transcription factor that binds to the same GC-rich sequences as Sp1. We sought to determine whether ZBP-89 is a target of p300 during butyrate induction of p21(Waf1). This review summarizes the evidence that supports a crucial role for ZBP-89 in butyrate regulation of p21(Waf1). Adenovirus-mediated expression of ZBP-89 in HT-29 cells reveals that ZBP-89 potentiates butyrate induction of endogenous p21(Waf1) gene expression. DNA-protein interaction assays demonstrate that Sp1, Sp3 and ZBP-89 bind the p21(Waf1) promoter at -245 to -215. Coprecipitation assays reveal that p300 preferentially binds to the N-terminus of ZBP-89. ZBP-89 also induces p21(Waf1) through stabilization of p53. Although ZBP-89 binds mutant and wild-type p53, only wild-type p53 is stabilized. Moreover, mutant p53 shifts the subnuclear location of ZBP-89 to the nuclear periphery, which is a domain rich in heterochromatin. This finding led to the conclusion that mutant p53 exerts a dominant negative effect on ZBP-89. We propose that gene silencing by mutant p53 might be mediated by sequestering ZBP-89 within heterochromatin regions at the nuclear periphery. Overall, ZBP-89 is a butyrate-regulated coactivator of p53 and is able to induce p21(Waf1) gene expression through both p53-dependent and -independent mechanisms to inhibit cell growth.

Apoptosis↗
PubMed2004

Dietary sodium gluconate protects rats from large bowel cancer by stimulating butyrate production.

Butyrate has an antitumorigenic effect on colorectal cancer cell lines. Dietary sodium gluconate (GNA) promotes butyrate production in the large intestine. Accordingly, we examined the effect of dietary GNA on tumorigenesis in the large intestine in rats. Male Fisher-344 rats (n = 32) were divided into 4 groups: 2 diets (with or without 50 g GNA/kg basal diet) x 2 treatments (with or without carcinogen administration). Colonic tumors were induced by 3 intraperitoneal injections of azoxymethane (15 mg/kg body wt, 1 time/wk) and dietary deoxycholic acid (2 g/kg basal diet). The experiment was conducted for 33 wk except for a few rats. Ingestion of GNA increased cecal butyrate concentration at the end of experiment (P < 0.01). No tumor development occurred in the untreated groups. Ingestion of GNA decreased the incidence of tumors in rats administered the carcinogen (37.5 vs. 100%, P < 0.05). Ingestion of GNA also decreased the mean number of tumors per rat (0.5 +/- 0.8 vs. 2.8 +/- 1.5, P < 0.01). beta-Catenin accumulation and TdT-mediated dUTP nick end labeling (TUNEL) positive cells in tumors were histochemically examined. The results of this study suggested that the antitumorigenic effect of GNA may involve the stimulation of apoptosis through enhanced butyrate production in the large intestine.

Adenocarcinoma↗
PubMed2005

Oral administration of butyrivibrio fibrisolvens, a butyrate-producing bacterium, decreases the formation of aberrant crypt foci in the colon and rectum of mice.

Butyrivibrio fibrisolvens, a butyrate-producing ruminal bacterium, was evaluated for use as a probiotic to prevent colorectal cancer. Oral administration to Jcl:ICR mice of a new strain of B. fibrisolvens (MDT-1) that produces butyrate at a high rate (10(9) cfu/dose) increased the rate of butyrate production by fecal microbes, suggesting that MDT-1 can grow in the gut. The number of colorectal aberrant crypt foci (ACF), putative preneoplastic lesions induced by 1,2-dimethylhydrazine, was reduced after MDT-1 administration (10(9) cfu/dose, 3 times/wk for 4 wk). The number of aberrant crypts (ACs), number of foci having 3 or 4 ACs per focus, and the percentage of mice having 3 or 4 ACs per focus were also reduced, suggesting that the progress of lesions was suppressed by MDT-1. Interestingly, the MDT-1 cell homogenate did not have a similar beneficial effect. MDT-1 had low beta-glucuronidase activity, and administration of MDT-1 reduced the beta-glucuronidase activity in the colorectal contents. The numbers of natural killer (NK) and NKT cells in the spleen were markedly enhanced in response to MDT-1. Decreased beta-glucuronidase activity and increased numbers of NK and NKT cells and butyrate production may explain in part why MDT-1 administration suppressed ACF formation. These results suggest that colorectal cancer may be prevented or suppressed by the utilization of MDT-1 as a probiotic. Administration of MDT-1 had no harmful effect on the health of mice at least for 3 mo.

Administration, Oral↗
PubMed2001

Butyrate and propionate downregulate ERK phosphorylation in HT-29 colon carcinoma cells prior to differentiation.

We have characterized the effects of different short-chain fatty acids (SCFAs) on cell growth and differentiation as well as the phosphorylation state of ERK1 and 2 in the human colon adenocarcinoma cell line HT-29. Of the five SCFAs tested, only butyrate and propionate impaired cellular proliferation. Moreover, butyrate and propionate specifically resulted in a decrease in ERK1 and 2 phosphorylation at 3 and 6 hours post-treatment, suggesting a correlation between the ability of these SCFAs to inhibit cellular proliferation and decrease ERK phosphorylation. Notably, the decrease in ERK phosphorylation was observed prior to the induction of the differentiation markers alkaline phosphatase (AP) and carcinoembryonic antigen (CEA) by butyrate and propionate from days 6 to 18 post-treatment. In the case of butyrate- and propionate-induced differentiation, ERK phosphorylation is a marker and may play a role in the proliferation and/or differentiation states of this cell line.

Alkaline Phosphatase↗
PubMed2004

Butyrate inhibits leukocyte adhesion to endothelial cells via modulation of VCAM-1.

BACKGROUND: Leukocyte recruitment to areas of inflammation depends on Integrin-VCAM/ICAM interaction. Blocking the vascular cell adhesion molecule (VCAM-1) and the intracellular adhesion molecule (ICAM-1) may have therapeutic benefit for the inflammatory component of bowel disease. Notably, the induction of ICAM and VCAM is mediated by a nuclear factor kappaB (NF-kappaB)-dependent mechanism. We investigated whether the anti-inflammatory properties of butyrate are mediated via the modulation of VCAM and ICAM on human endothelial cells. METHODS: VCAM-1 and ICAM-1 expression on human endothelial cells upon tumor necrosis factor-alpha (TNF-alpha) stimulation was assessd by FACS analysis. A monocyte adhesion assay was performed to evaluate the relevance of a modulated CAM-expression. Electrophoretic mobility shift assays were applied to investigate NF-kappaB activation. RESULTS: The observed butyrate-associated inhibition of monocyte adhesion to endothelial cells is associated with an inhibition of NF-kappaB activation in human endothelial cells. In this context, the observed suppression of the TNF-alpha induced VCAM-1 expression is likely to play an essential role. CONCLUSIONS: Butyrate inhibits VCAM-1 mediated leukocyte adhesion to human endothelial cells. This inhibition may contribute to the anti-inflammatory effects of butyrate in patients with distal ulcerative colitis.

Butyrates↗
PubMed2006

The histone deacetylase inhibitor sodium butyrate protects against cisplatin-induced hearing loss in guinea pigs.

OBJECTIVE: There is a need for otoprotective agents that can be administered systemically without compromising cancer treatment. Histone deacetylase inhibitors are anticancer agents that act by upregulating the expression of cell-cycle control genes. They are also neuroprotective, leading us to hypothesize that they might be otoprotective. The goal of this study was to determine if the antitumor agent sodium butyrate (a histone deacetylase inhibitor) protects against cisplatin ototoxicity when administered systemically. STUDY DESIGN: This was an animal study. METHODS: : Cisplatin was administered to guinea pigs who received either 12 days of sodium butyrate (7 d before and 5 d after cisplatin) or equivolume saline injections. Hearing was tested with distortion product otoacoustic emission (DPOAE) analysis before the start of the study and 2 weeks after cisplatin treatment. RESULTS: Guinea pigs given a single intraperitoneal injection of 14 mg/kg cisplatin experience a mean hearing loss of 8 dB across the frequencies of 3.5, 5, 7, 10, 14, and 20 kHz. Intraperitoneal injection of 1.2 mg/kg sodium butyrate per day for 7 days before and 5 days after cisplatin almost completely eliminates this threshold shift (P=.0011). CONCLUSIONS: The histone deacetylase inhibitor sodium butyrate gives almost complete protection in a single-dose model of cisplatin ototoxicity in guinea pigs. Because histone deacetylase inhibitors are anticancer agents with very few side effects, they may be candidates for clinical use during cisplatin chemotherapy.

Animals↗
PubMed1980

Enhanced production of interferon from human lymphoblastoid (Namalwa) cells pre-treated with sodium butyrate.

Pre-treatment of Namalwa cells with 1 mM-sodium butyrate enhanced interferon production induced by Sendai virus. This enhancement was reversed if the cells were incubated in butyrate-free medium. Butyrate treatment increased the rate of interferon production but not its duration. Yields of interferon from Namalwa cells were also enhanced in response to other inducers including the synthetic dsRNA, poly(rI) . poly(rC). Butyrate pre-treatment also increased interferon yields from cells of the vervet monkey kidney cell line, V3, but cells of the human diploid fibroblast line, MRC-5, did not respond.

Butyrates↗
PubMed1991

Divergent effect of the anaerobic bacteria by-product butyric acid on the immune response: suppression of T-lymphocyte proliferation and stimulation of interleukin-1 beta production.

The effects of short-chain fatty acids (SCFA) produced by anaerobic bacteria, namely propionic, butyric and iso-butyric on T-cell proliferation was investigated. A dose-dependent inhibition of both phytohemagglutinin-induced blastogenesis and mixed lymphocyte culture was observed in the millimolar range of SCFA concentrations. The tested SCFA displayed different levels of suppression. The degree of activity was in the following order: butyrate greater than propionate greater than isobutyrate. T-cell inhibition was partially reversed, at least for propionic and isobutyric acids, by increasing the concentration of macrophages in the assay system. Furthermore, butyric acid displayed an interesting biphasic stimulation of monocyte interleukin-1 beta production, a cytokine with a powerful bone-resorbing activity. Since millimolar concentrations of SCFA are present in gingival fluid from periodontal pockets, the observed results support the role of these by-products of anaerobic metabolism in the pathogenesis of periodontal diseases.

Alveolar Bone Loss↗
PubMed2006

Butyrate- and propionate-degrading syntrophs from permanently cold marine sediments in Skan Bay, Alaska, and description of Algorimarina butyrica gen. nov., sp. nov.

Two anaerobic, psychrotolerant, syntrophic strains were enriched from permanently cold, shallow anoxic marine sediments in Skan Bay, Alaska. One strain, AK-B(T), oxidized butyrate syntrophically and was isolated in defined coculture with a H(2)-using methanogen or in a dixenic coculture that also contained an acetate-scavenging methanogen. The other enrichment culture syntrophically oxidized propionate. The growth of these syntrophic cultures was very slow: approximately 1 year for cocultures of strain AK-B(T) to form colonies and >1 year for the propionate-oxidizing enrichment to form colonies. Neither culture grew axenically when supplied with the catabolic substrates crotonate, pyruvate, malate, or sulfate plus butyrate or propionate. Strain AK-B(T) catabolized iso-butyrate in syntrophic coculture but did not catabolize valerate or caproate. Phylogenetic analyses of the 16S rRNA gene sequence suggested that strain AK-B(T) was only distantly related to cultivated sulfate-reducing bacteria, and that this strain represented a new genus. We propose Algorimarina butyrica, with strain AK-B(T) (=OCM 842(T)), as the type strain. This report is the first description of psychrotolerant as well as marine butyrate--and propionate-oxidizing syntrophic organisms.

Alaska↗
PubMed2000

Chemostat enrichments of human feces with resistant starch are selective for adherent butyrate-producing clostridia at high dilution rates.

Resistant starch (RS) enrichments were made using chemostats inoculated with human feces from two individuals at two dilution rates (D = 0.03 h(-1) and D = 0.30 h(-1)) to select for slow- and fast-growing amylolytic communities. The fermentations were studied by analysis of short-chain fatty acids, amylase and alpha-glucosidase activities, and viable counts of the predominant culturable populations and the use of 16S rRNA-targeted oligonucleotide probes. Considerable butyrate was produced at D = 0. 30 h(-1), which corresponded with reduced branched-chain fatty acid formation. At both dilution rates, high levels of extracellular amylase activity were produced, while alpha-glucosidase was predominantly cell associated. Bacteroides and bifidobacteria predominated at the low dilution rate, whereas saccharolytic clostridia became more important at D = 0.30 h(-1). Microscopic examination showed that within 48 h of inoculation, one particular bacterial morphotype predominated in RS enrichments at D = 0.30 h(-1). This organism attached apically to RS granules and formed rosette-like structures which, with glycocalyx formation, agglomerated to form biofilm networks in the planktonic phase. Attempts to isolate this bacterium in pure culture were repeatedly unsuccessful, although a single colony was eventually obtained. On the basis of its 16S rDNA sequence, this RS-degrading, butyrate-producing organism was identified as being a previously unidentified group I Clostridium sp. A 16S rRNA-targeted probe was designed using this sequence and used to assess the abundance of the population in the enrichments. At 240 h, its contributions to total rRNA in the chemostats were 5 and 23% at D = 0.03 and 0.30 h(-1), respectively. This study indicates that bacterial populations with significant metabolic potential can be overlooked using culture-based methodologies. This may provide a paradigm for explaining the discrepancy between the low numbers of butyrate-producing bacteria that are isolated from fecal samples and the actual production of butyrate.

Amylases↗
PubMed1979

Enzymology of butyrate formation by Butyrivibrio fibrisolvens.

Butyrivibrio fibrisolvens is a major butyrate-forming species in the bovine and ovine rumen. The enzymology of butyrate formation from pyruvate was investigated in cell-free extracts of B. fibrisolvens D1. Pyruvate owas oxidized to acetylcoenzyme A (CoA) in the presence of CoA.SH and benzyl viologen or flavin nucleotides. The bacterium uses thiolase, beta-hydroxybutyryl-CoA dehydrogenase, crotonase, and crotonyl-CoA reductase to form butyryl-CoA from acetyl-CoA. Reduction of acetoacetyl-CoA to beta-hydroxybutyryl-CoA was faster with NADH than with NADPH. Crotonyl-CoA was reduced to butyryl-CoA by NADH, but not by NADPH, only in the presence of flavin nucleotides. Reduction of flavin nucleotides by NADH was much slower than the flavin-dependent reduction of crotonyl-CoA. This indicates that flavoproteins rather than free flavin participated in the reduction of crotonyl-CoA. Butyryl-CoA was converted to butyrate by phosphate butyryl transferase and butyrate kinase.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1995

Pathway of butyrate catabolism by Desulfobacterium cetonicum.

Desulfobacterium cetonicum 480 oxidized butyrate to 1 mol of acetate and 2 mol of CO2; this reaction was coupled to reduction of sulfate to sulfide. Butyrate was activated by coenzyme A (CoA) transfer from acetyl-CoA, and butyryl-CoA was oxidized to acetyl-CoA by a classical beta-oxidation pathway. Acetyl-CoA was oxidized through the acetyl-CoA/carbon monoxide dehydrogenase pathway. There was a rapid exchange of 14CO2 into the intermediate CoA esters and into acetate and butyrate, showing that all of the steps involved in the oxidation of butyrate to acetyl-CoA are reversible.

Acyl Coenzyme A↗
PubMed1981

Effect of sodium butyrate on induction of cellular and viral DNA syntheses in polyoma virus-infected mouse kidney cells.

Sodium butyrate inhibited initiation of viral and cellular DNA replication in polyoma virus-infected mouse kidney cells. Ongoing viral or cellular DNA replication, however, was not affected by the presence of the substance. Butyrate had no effect on T-antigen synthesis and on the stimulation of transcription, one of the earliest reactions of the infected cells to the appearance of T-antigen, nor did it inhibit expression of late viral genes (synthesis of viral capsid proteins). In addition to blocking the onset of DNA synthesis, butyrate also inhibited stimulation of the activities of enzymes involved in DNA synthesis. When butyrate was removed, viral and cellular DNA syntheses were induced in parallel after a lag period of approximately 4 h. At the same time, the activities of enzymes involved in DNA synthesis increase. If protein synthesis was inhibited during part of the lag period, the initiation of DNA synthesis was retarded for the same time interval, suggesting that the proteins involved in the initiation of DNA replication had to be made. We have developed an in vitro system for measuring DNA synthesis in crude nuclear preparations which mimics the status of DNA replication in intact cells and may help in future experiments to study the requirements for initiation of cellular and viral DNA synthesis and the possible involvement of T-antigens in this reaction.

Animals↗
PubMed1988

Short chain fatty acid distributions of enema samples from a sigmoidoscopy population: an association of high acetate and low butyrate ratios with adenomatous polyps and colon cancer.

We investigated the distribution of short chain fatty acids (SCFA) in enema samples taken from subjects before sigmoidoscopy as an indicator of possible microbial community differences between subjects subsequently diagnosed as normal or having colonic disorders. The major SCFA in all groups were acetic, propionic, and butyric acids. A significantly higher ratio of acetate to total SCFA and lower ratio of butyrate to total SCFA was found for polyp-colon cancer subjects than for normal subjects. There were no significant differences in the ratios of acetate, propionate, or butyrate between the diverticulosis or inflammatory bowel groups and the normal group. There were no significant sex differences nor were there correlations with the ratios of acetate, propionate or butyrate and age, subject weight, or dry weights of samples. Significant differences in concentrations of individual acids were found between normal and certain diagnostic groups. The difference in proportions of individual SCFA between groups suggest differences in fermentation patterns of the colonic microflora.

Acetates↗
PubMed2005

Butyric acid prodrugs are histone deacetylase inhibitors that show antineoplastic activity and radiosensitizing capacity in the treatment of malignant gliomas.

Histone modification has emerged as a promising approach to cancer therapy. We explored the efficacy of a novel class of histone deacetylase inhibitors in the treatment of malignant gliomas. Treatment of glioma cell lines with two butyric acid derivatives, pivaloylomethyl butyrate (AN-9) and butyroyloxymethyl butyrate (AN-1), induced hyperacetylation, increased p21(Cip1) expression, inhibited proliferation, and enhanced apoptosis. Histone deacetylase inhibitor-induced apoptosis was mediated primarily by caspase-8. Treatment of cells with AN-1 or AN-9 for 24 hours before exposure to gamma-irradiation potentiated further caspase-8 activity and resultant apoptosis. Clonogenic survival curves revealed marked reductions in cell renewal capacity of U251 MG cells exposed to combinations of AN-1 and radiation. Preliminary in vivo experiments using human glioma cell lines grown as xenografts in mouse flanks suggest in vivo efficacy of AN-9. The data suggest that novel butyric acid prodrugs provide a promising treatment strategy for malignant gliomas as single agents and in combination with radiation therapy.

Antineoplastic Agents↗