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PubMed1999

Butyrate inhibits and Escherichia coli-derived mitogen(s) stimulate DNA synthesis in human hepatocytes in vitro.

Bacterial constituents and products of the bacterial metabolism pass from the gut lumen to the portal vein and may influence the homeostasis of the liver. Our aim is to examine whether DNA synthesis of human hepatocyte cell lines is affected by constituents of Escherichia coli species as well as by intracolonic products of bacterial fermentation that reach the liver via the portal vein. Supernatant solutions and bacterial cell fractions (containing either whole dead bacteria, cell walls, cytosol or non-soluble intracellular components) of E. coli K12 and of E. coli species from rat fecal flora were separated by multi-step centrifugation, French press, and microfiltration. The supernatant solution and the cell fractions were incubated with a human hepatoma cell line (Hep-G2) and with a cell line derived from non-malignant human liver cells (Chang cells) for 24 h. The cells were labeled with tritiated thymidine before processing to autoradiography. DNA synthesis was estimated by the labeling index (LI%). DNA synthesis was also estimated following incubation of Hep-G2 cells with short chain fatty acids (acetic, propionic, butyric and succinic acid), acetaldehyde, and ammonium chloride. Epidermal growth factor and a water extract of Helicobacter pylori were used as references. The fractions of E. coli from rat fecal flora containing cytosol and non-soluble intracellular components significantly increased the labeling index in both Hep-G2 and Chang cells (p < 0.05). In addition, the supernatant solution significantly increased the LI in Chang cells (p < 0.05). Epidermal growth factor increased the LI of Hep-G2 cells dose-dependently (p < 0.05). Butyric acid reduced DNA synthesis at 10(-4) M (p < 0.05). The highest doses of acetaldehyde were cytotoxic and reduced the LI. Escherichia coli species contain mitogenic factors to human hepatocytes. The mitogen(s) are present in the supernatant solution, in the cytosol and in non-soluble intracellular components. Butyrate, which is a product of bacterial fermentation of colonic substrates inhibit DNA synthesis in the hepatocyte cell lines. Our findings suggest that soluble mitogen(s) that diffuse from the microorganism to the outer environment, intracellular bacterial constituents, and products of the bacterial metabolism that reach the liver via the portal vein may influence the cell kinetic steady-state of hepatic cells.

Acetaldehyde↗
PubMed2003

Butyric acid derivative induces allospecific T cell anergy and prevents graft-versus-host disease.

Graft-versus-host-disease (GVHD) is a common and potentially fatal complication following bone marrow transplantation. This study was initiated to test whether MEB [n-butyrate 2-(4-morpholinyl) ethyl butyrate hydrochloride], a derivative of the G1 blocker butyric acid, could specifically inactivate the alloantigen-specific T cells that mediate GVHD. MEB was shown to inhibit proliferation in a one-way mixed lymphocyte reaction (MLR) in which spleen cells from C57BL/6 mice (H-2b) were stimulated with spleen cells from DBA/2 mice (H-2d). The addition of MEB to the MLR prevented the expansion of alloantigen-stimulated CD8+ and CD4+ T cells in association with decreased IL-2 production. In addition, MEB inhibited the CTL activity of CD8+ T cells from the MLR. Most importantly, T cells from the MEB-treated MLR, unlike T cells from an untreated MLR, were unable to induce the splenomegaly and increased serum TNF-alpha levels characteristic of acute GVHD when injected into B6D2F1 mice. The splenomegaly found in the B6D2F1 mice injected with T cells from an untreated MLR encompassed the expansion and activation of CD8+ T cells, CD4+ T cells, B cells and macrophages. In contrast, the spleens of mice injected with T cells from MEB-treated MLR looked essentially identical to those of control B6D2F1 mice in terms of the numbers and activation state of the spleen cell populations. Similarly, the increase in IFN-gamma and TNF-alpha production by CD4+ and CD8+ T cells from the spleens of mice undergoing acute GVHD was not observed if the mice were injected with T cells from an MEB-treated MLR instead of an untreated MLR. The use of MEB to inactivate host-specific T cells ex vivo underlines the potential clinical importance of this compound in the prevention and treatment of unwanted immune responses such as GVHD.

Animals↗
PubMed1980

Effects of sodium butyrate on the membrane glycoconjugates of murine sarcoma virus-transformed rat cells.

The temporal relationship between butyrate-induced cellular flattening of murine sarcoma virus-transformed rat cells (MSV-NRK) and alterations in certain surface-associated biochemical markers of transformation, e.g., surface glycopeptides, glycolipids, fibronectin, hexose uptake, and cell-substrate adhesion was examined. The induction of elevated levels of the ganglioside GM3 and of a GDla-like ganglioside were observed to precede or to parallel cellular flattening. Likewise, enhanced incorporation of radioisotopically labeled fucose into a novel fucose-containing component, i.e., glucopyranosyl (1 leads to 3) fucopyranosyl-threonine, was also observed to occur at an early stage of cellular flattening. In contrast, a shift in the molecular weight distribution of trypsin-sensitive, surface fucopeptides was observed to occur at a late stage of cellular flattening. Moreover, surface fibronectin was not detectable in the butyrate-flattened MSV-NRK cells despite the fact that the cells manifested significantly enhanced cell-substrate adhesion. Thus, butyrate appears to be a useful tool for understanding the sequential changes associated with expression of the transformed phenotype of MSV-NRK cells.

Animals↗
PubMed1980

Effects of sodium butyrate on a human lymphoblastoid cell line (Namalwa) and its interferon production.

Treatment of lymphoblastoid cells with sodium butyrate before infection with Sendai virus increases the subsequent yield of interferon and of its messenger RNA. This treatment caused almost complete inhibition of cellular DNA synthesis and consequently cell division, and some inhibition of cellular RNA and protein synthesis. It also caused increased acetylation of histones and alterations in the plasma membrane. There was no decrease in cell viability or change in cell morphology but the cells were smaller than untreated cells and were all in the G1 phase. Sodium butyrate treatment had no effect on the course of Sendai virus infections. The observed increase in interferon yields after butyrate treatment did not correlate with its effects on DNA synthesis, size, cell division and histone acetylation, but did with its effects on RNA and protein synthesis.

Acetylation↗
PubMed1982

Links between effects of butyrate on histone hyperacetylation and regulation of interferon synthesis in Namalva and FS-4 cell lines.

The human Namalva lymphoma cell line being an established producer, predominantly of alpha interferon, has been reported to enhance interferon synthesis after a preincubation in butyrate containing media. We have performed the corresponding experiments with FS-4 fibroblast cells and show that the synthesis of human beta interferon is adversely affected by this treatment. Both cell types are hyperacetylated by the fatty acid to a comparable extent. However, after the withdrawal of butyrate, the persistence of highly acetylated forms of histone H4 is insufficient in the case of FS-4 to endure the interferon induction period. Concerning fibroblasts, deacetylation proceeds to a hypoacetylated state which is reversed only slowly. With lymphoid cells on the other hand, acetylated H4 specimens are much more stable and persist for more than eight hours in the absence of butyrate. Moreover, the acetylation reactions are supported by other Friend cell stimulators which by themselves are no inhibitors of deacetylase activities.

Acetamides↗
PubMed2000

In vitro fermentation of swine ileal digesta containing oat bran dietary fiber by rat cecal inocula adapted to the test fiber increases propionate production but fermentation of wheat bran ileal digesta does not produce more butyrate.

This experiment evaluated three hypotheses: i) production of propionate is increased during fermentation of substrate containing oat bran (OB)(6); ii) production of butyrate is increased during fermentation of substrate containing wheat bran (WB) and iii) results of in vitro fermentations using physiological substrates and inocula agree with in vivo data. Ileal digesta collected from swine fed OB and WB were the substrates. Digesta was fermented for 0-96 h in an anaerobic in vitro system using inocula prepared from ceca of rats fed the same fiber sources. Carbohydrate and short-chain fatty acid (SCFA) contents in the fermentations were measured by gas chromatography. Fermentation of WB digesta did not produce more n-butyrate (P > 0.05) and was significantly slower (P < 0.05) than fermentation of OB digesta. OB digesta fermentation produced a significantly greater (P < 0.05) molar proportion of SCFA as propionate. Bacterial mass increased more and was maintained longer during fermentation of OB digesta than the WB digesta. Our results indicate that dilution of undigested WB fiber and not n-butyrate production is one mechanism by which WB may protect colonic mucosa; propionate production is increased during fermentation of beta-glucan in OB; and an in vitro system using physiological sources of inoculum and substrate containing WB and OB yields results that agree with in vivo findings in humans and rats.

Analysis of Variance↗
PubMed2001

Tributyrin, a stable and rapidly absorbed prodrug of butyric acid, enhances antiproliferative effects of dihydroxycholecalciferol in human colon cancer cells.

Tributyrin, a prodrug of natural butyrate, has been evaluated with an aim to overcome pharmacokinetic drawbacks of natural butyrate as a drug, i.e., its rapid metabolization and inability to achieve pharmacologic concentrations in neoplastic cells. We studied the effects of tributyrin on growth, differentiation and vitamin D receptor expression in Caco-2 cells, a human colon cancer cell line. Tributyrin was more potent in inhibiting growth and inducing cell differentiation than natural butyrate. The effect was further enhanced after addition of physiologic concentrations of dihydroxycholecalciferol [(OH)2D3]. The synergistic effect of tributyrin and (OH)2D3 in Caco-2 cells was due to tributyrin-induced overexpression of the vitamin D receptor, as measured by reverse transcriptase-polymerase chain reaction. Treatment with tributyrin increased binding of (OH)2D3 to its receptor 1.5-fold, without any change in receptor affinity. We conclude that tributyrin may, at least in part, exert its growth-reducing and differentiation-inducing effect in Caco-2 cells by an upregulation of the vitamin D receptor; this may provide a useful therapeutic approach in chemoprevention and treatment of colorectal cancer by the two nutrients occurring naturally in human diet.

Alkaline Phosphatase↗
PubMed2003

Butyrate impairs lipid transport by inhibiting microsomal triglyceride transfer protein in Caco-2 cells.

Recently, the idea was advanced that short-chain fatty acids (SCFA) may potentially regulate intestinal fat absorption. The aim of this investigation was to examine the effects of butyrate on the intracellular events governing the assembly of triglyceride-lipoproteins in enterocytes. To this end, differentiated human Caco-2 cells were exposed to 10 or 20 mmol/L butyrate for 20 h. The incubation of Caco-2 cells with butyrate decreased cholesteryl ester (P < 0.005) export in the basolateral medium, probably due to reduced activity of DL-3-hydroxy-3-methyl-glutaryl-CoA reductase (P < 0.02), the rate-limiting enzyme in cholesterol synthesis. Furthermore, a drop was noted in the protein expression of microsomal triglyceride transfer protein (P < 0.03), concomitant with the inhibition of de novo apolipoprotein B-48 synthesis (P < 0.02) and triglyceride-rich lipoprotein output (P < 0.03). Our results support the hypothesis that SCFA can influence lipoprotein concentrations by limiting lipid release from the small intestine into the circulation.

Biological Transport↗
PubMed1977

Induction of globin gene expression in cultured erythroleukemia cells by butyric acid.

Butyric acid induces erythroid differentiation of cultured Friend leukemia cells when added to the culture medium. A high level of globin messenger RNA (mRNA) was detected in Friend leukemia cells treated with butyric acid by a liquid hybridization method using radioactive DNA complementary to reticulocyte globin mRNA. The content of globin mRNA molecules induced in the cytoplasm of the butyric acid-treated Friend leukemia cells paralleled the hemoglobin content determined by the benzidine staining method. Therefore, this hemoglobin synthesis may be most reasonably explained in terms of transcriptional activation of globin genes, as previously proposed in the case of dimethylsulfoxide, another inducer of erythroid differentiation. Induced accumulation of globin mRNA in the nuclei also supports this interpretation.

Animals↗
PubMed1978

Butyrate-binding protein from rat and mouse liver.

A novel component which specifically binds butyrate was found in rat and mouse liver. This component, termed butyrate binding protein (BBP), is localized in the cytosolic fraction and exhibits protein characteristics, such as heat- and protease-sensitivity. The size of BBP was found to be 7.6S, while it was converted to subunits of 45,000--48,000 dalton by treatment with sodium dodecyl sulfate. The dissociation constant of the binding of BBP with butyrate was 2.22 X 10(-6) M in the standard assay. 30-Fold purification of BBP was achieved by batch-wise adsorption and elution from CM-cellulose and hydroxylapatite column chromatography. BBP is clearly distinguishable from the fatty acid-binding protein found previously on the basis of its size and binding specificity.

Animals↗
PubMed2003

Butyrivibrio hungatei sp. nov. and Pseudobutyrivibrio xylanivorans sp. nov., butyrate-producing bacteria from the rumen.

Two novel Gram-negative, anaerobic, non-spore-forming, butyrate-producing bacterial species, strains Mz 5T and JK 615T, were isolated from the rumen fluid of cow and sheep. Both strains were curved rods that were motile by means of single polar or subpolar flagellum and common in the rumen microbial ecosystem. Strain Mz 5T produced high xylanase, proteinase, pectin hydrolase and DNase activities; 1,4-beta-endoglucanase was also detected in the culture medium. The bacterium utilized a wide range of carbohydrates. Glucose was fermented to formate, butyrate, lactate, succinate and ethanol. The DNA G + C content was 42.1 mol%. The complete 16S rDNA sequence was obtained and phylogenetic relationships were determined. Strain Mz 5T and related isolates were located in clostridial cluster XIVa and were closely related to Pseudobutyrivibrio ruminis, Butyrivibrio crossotus, Roseburia cecicola and Eubacterium rectale. The name proposed for this novel bacterium is Pseudobutyrivibrio xylanivorans; the type strain is Mz 5T (=DSM 14809T =ATCC BAA-455T). Strain JK 615T produced no fibrolytic activity, but utilized a wide range of carbohydrates. Glucose was fermented to formate, acetate, butyrate and ethanol. The DNA G + C content was 44-8 mol%. The complete 16S rDNA sequence was obtained and phylogenetic relationships were determined. Strain JK 615T was located in clostridial cluster XIVa and was closely related to Clostridium proteoclasticum, Butyrivibrio fibrisolvens and Eubacterium halii. The name proposed for this novel bacterium is Butyrivibrio hungatei; the type strain is JK 615T (=DSM 14810T =ATCC BAA-456T).

Animals↗
PubMed1999

Propionate and butyrate esters of camptothecin and 9-nitrocamptothecin as antileukemia prodrugs in vitro.

Six camptothecin (CPT) alkyl esters and four 9-nitrocamptothecin (9NC) alkyl esters were assayed for ability to inhibit proliferation and induce programmed cell death (apoptosis) in human leukemia HL-60 and U-937 cells, which exhibit differential sensitivity to CPT and 9NC. In general, CPT-propionate and CPT-butyrate demonstrated activities, while the other esters were practically inactive. Similarly, 9NC-propionate and 9NC-butyrate were active, while the other 9NC esters exhibited little or no activity. The biologically active esters required metabolic conversion (i.e., de-esterification) to their parental compounds as demonstrated by the conversion of CPT-propionate to CPT in mouse liver homogenate, and the topoisomerase I-inhibition assay. In conclusion, the propionate and butyrate esters of CPT and 9NC are CPT and 9NC prodrugs, that can develop to important chemotherapeutic agents for the effective treatment of human leukemias and other malignancies.

Animals↗
PubMed1998

Cellular and molecular effects of a pulse butyrate regimen and new inducers of globin gene expression and hematopoiesis.

Cooley's anemia is characterized by a deficiency of beta-globin chains, a relative excess of alpha-globin chains, and consequent accelerated programmed death of developing erythroid cells in the bone marrow. Increasing expression of the gamma-globin genes to adequately balance excess alpha-globin chains can ameliorate this disorder. Butyrates induce gamma-globin experimentally, but can also cause cell growth arrest with prolonged exposure or high concentrations, which in turn can accelerate apoptosis. To determine if these potentially opposing effects can be balanced to enhance therapeutic efficacy, an intermittent "pulsed" regimen of butyrate was evaluated. Following induction of gamma-globin mRNA and protein synthesis, total hemoglobin increased in beta-thalassemia patients by more than 2 g/dl above baseline, and Hb F increased above 20% in 5/8 sickle cell patients from baseline levels of 2% Hb F. Specific regulatory regions were identified in the gamma- and beta-globin gene promoters to which new binding of transcription factors, including alpha CP2 (an activator of gamma globin) occur during therapy solely in the butyrate-responsive patients. Other compounds which induce gamma globin, derivatives of acetic, phenoxyacetic, propionic, and cinnamic acids, and dimethylbutyrate, are under investigation. Some of these newer gamma-globin inducers (designed hemokines) provide better potential as therapeutics by also acting to increase hematopoietic cell viability and proliferation. Pharmacologic induction of expression of the endogenous gamma-globin genes is a realistic approach to therapy of the beta-globin disorders for many patients, with some effective agents available now and new therapeutics, with enhanced activities, under development.

Adult↗
PubMed1981

Syntrophic association of a butyrate-degrading bacterium and methanosarcina enriched from bovine rumen fluid.

An anaerobic butyrate-degrading bacterium, morphologically similar to Syntrophomonas wolfei, was isolated in coculture with Desulfovibrio strain G11 from an enrichment of bovine rumen fluid. A Methanosarcina species was the major H2-using organism in the enrichment. The results are discussed in relationship to the absence of Methanospirillum hungatei, the H2-using methanogen usually found in association with S. wolfei, and the finding of Methanosarcina rather than Methanobrevibacter ruminantium as the major H2-using bacterium in the enrichments. The finding of butyrate degraders in the rumen suggests that, if the retention time of the rumen contents becomes more prolonged, butyrate and longer-chained fatty acids might be significantly degraded.

Animals↗
PubMed2003

Oligonucleotide probes that detect quantitatively significant groups of butyrate-producing bacteria in human feces.

16S rRNA-targeted oligonucleotide probes were designed for butyrate-producing bacteria from human feces. Three new cluster-specific probes detected bacteria related to Roseburia intestinalis, Faecalibacterium prausnitzii, and Eubacterium hallii at mean populations of 2.3, 3.8, and 0.6%, respectively, in samples from 10 individuals. Additional species-level probes accounted for no more than 1%, with a mean of 7.7%, of the total human fecal microbiota identified as butyrate producers in this study. Bacteria related to E. hallii and the genera Roseburia and Faecalibacterium are therefore among the most abundant known butyrate-producing bacteria in human feces.

Adult↗
PubMed2004

Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product.

The microbial community of the human colon contains many bacteria that produce lactic acid, but lactate is normally detected only at low concentrations (<5 mM) in feces from healthy individuals. It is not clear, however, which bacteria are mainly responsible for lactate utilization in the human colon. Here, bacteria able to utilize lactate and produce butyrate were identified among isolates obtained from 10(-8) dilutions of fecal samples from five different subjects. Out of nine such strains identified, four were found to be related to Eubacterium hallii and two to Anaerostipes caccae, while the remaining three represent a new species within clostridial cluster XIVa based on their 16S rRNA sequences. Significant ability to utilize lactate was not detected in the butyrate-producing species Roseburia intestinalis, Eubacterium rectale, or Faecalibacterium prausnitzii. Whereas E. hallii and A. caccae strains used both D- and L-lactate, the remaining strains used only the d form. Addition of glucose to batch cultures prevented lactate utilization until the glucose became exhausted. However, when two E. hallii strains and one A. caccae strain were grown in separate cocultures with a starch-utilizing Bifidobacterium adolescentis isolate, with starch as the carbohydrate energy source, the L-lactate produced by B. adolescentis became undetectable and butyrate was formed. Such cross-feeding may help to explain the reported butyrogenic effect of certain dietary substrates, including resistant starch. The abundance of E. hallii in particular in the colonic ecosystem suggests that these bacteria play important roles in preventing lactate accumulation.

Adult↗
PubMed2006

Butyrate specifically down-regulates salmonella pathogenicity island 1 gene expression.

Invasion of intestinal epithelial cells by Salmonella enterica is decreased after exposure to butyric acid. To understand the molecular mechanisms of this phenomenon, a comparative transcriptomic analysis of Salmonella enterica serovar Enteritidis and Salmonella enterica serovar Typhimurium grown in medium supplemented with butyrate was performed. We found that butyrate down-regulated the expression of 19 genes common to both serovars by a factor of twofold or more, and 17 of these genes localized to the Salmonella pathogenicity island 1 (SPI1). These included the SPI1 regulatory genes hilD and invF. Of the remaining two genes, ampH has 91% homology to an Escherichia coli penicillin-binding protein and sopE2 encodes a type III-secreted effector protein associated with invasion but located at a separate site on the chromosome from SPI1.

Animals↗
PubMed1981

Butyrate and propionate: important components of toxic dental plaque extracts.

Extracts of in vitro-cultured human dental plaque contain factors toxic to mammalian cells. Previous studies demonstrated that those toxic factors most readily released from cultured plaque had very low molecular weights and were heat stable. Studies reported here demonstrate that metabolic end products including short-chain fatty acids were present in fractions containing the low-molecular-weight, heat-stable factors. The salts of two of these acids, butyrate and propionate, inhibited proliferation of both mouse L929 cells and human gingival fibroblasts. Furthermore, when tested at concentrations present in plaque extracts, the inhibitory effects of butyrate and propionate accounted for essentially all the inhibitory potential of the extracts. These findings, taken together with those of other groups, suggest that butyrate and propionate, end products of dental plaque metabolism, may have an etiological role in periodontal disease.

Animals↗