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PubMed2002

Enhanced production of IL-18 in butyrate-treated intestinal epithelium by stimulation of the proximal promoter region.

Expression of IL-18 in intestinal epithelial cells (IEC) has been implicated in Th1 cell-mediated chronic intestinal inflammation and anti-tumor immunity. However, physiological regulatory factors have not been identified. Besides their effects on proliferation and restitution, immunomodulatory functions have been attributed to short chain fatty acids (SCFA). We investigated the effect of SCFA (butyrate, propionate, acetate) on expression of IL-18 in IEC in vitro and in vivo. Expression of IL-18 mRNA and protein in human carcinoma-derived HT-29 and Caco-2 cells was analyzed by reverse transcription-PCR and Western blot. Transcriptional regulation of IL-18 gene expression was determined by transient transfection of wild-type and mutated IL-18 promoter. Further, in vivo expression of IL-18 in the intestine from butyrate-treated and untreated mice was assessed by immunohistochemistry. IL-18 mRNA and the IL-18 protein were expressed in IEC, while IL-18 secretion was not observed. Butyrate and acetate increased intracellular IL-18 content in a time- and dose-dependent fashion. In contrast to proinflammatory stimuli butyrate potently activated the IL-18 promoter, indicating that IL-18 is regulated at the transcriptional level by SCFA. Furthermore, a 108-bp sequence in the proximal region was identified to be essential for IL-18 promoter activation by butyrate. As proof of principle butyrate effects were confirmed in vivo by demonstration of increased IL-18 protein expression in IEC from butyrate-treated mice. In conclusion, SCFA up-regulate IL-18 protein expression in IEC, suggesting a potential regulatory contribution of these luminal constituents to T cell mediated inflammatory and neoplastic intestinal conditions.

Acetates↗
PubMed2005

Butyrate suppresses tumor necrosis factor alpha production by regulating specific messenger RNA degradation mediated through a cis-acting AU-rich element.

OBJECTIVE: To study the capacity of butyrate to inhibit production of tumor necrosis factor alpha (TNFalpha) in macrophage-like synoviocytes (MLS) from patients with rheumatoid arthritis (RA), in human peripheral monocytes, and in murine RAW264.7 macrophages. METHODS: The concentrations of TNFalpha in culture supernatants of these cells were measured using enzyme-linked immunosorbent assay. The expression levels of various messenger RNAs (mRNA), such as those for TNFalpha, the mRNA-binding protein TIS11B, and luciferase, were measured using real-time quantitative polymerase chain reaction. The in vitro effects of butyrate on transcriptional regulation were evaluated by transfection with various reporter plasmids in RAW264.7 macrophages. The effects of TIS11B on TNFalpha expression were examined using an overexpression model of TIS11B in RAW264.7 cells. RESULTS: Butyrate suppressed TNFalpha protein and mRNA production in MLS and monocytes, but paradoxically enhanced transactivation of the TNFalpha promoter. Expression of the AU-rich element (ARE)-binding protein TIS11B was up-regulated by butyrate. Induction of TNFalpha mRNA by lipopolysaccharide was significantly inhibited when TIS11B was overexpressed. Butyrate facilitated the degradation of luciferase transcripts containing the 3'-untranslated region (3'-UTR) of TNFalpha, and this effect was dependent on the ARE in the 3'-UTR that is known to be involved in the regulation of mRNA degradation. CONCLUSION: These results indicate that butyrate suppresses TNFalpha expression by facilitating mRNA degradation mediated through a cis-acting ARE. Butyrate has the ability to regulate TNFalpha at the mRNA level and is therefore a potential therapeutic drug for RA patients.

3' Untranslated Regions↗
PubMed2005

Construction and characterization of pta gene-deleted mutant of Clostridium tyrobutyricum for enhanced butyric acid fermentation.

Clostridium tyrobutyricum ATCC 25755 is an acidogenic bacterium, producing butyrate and acetate as its main fermentation products. In order to decrease acetate and increase butyrate production, integrational mutagenesis was used to disrupt the gene associated with the acetate formation pathway in C. tyrobutyricum. A nonreplicative integrational plasmid containing the phosphotransacetylase gene (pta) fragment cloned from C. tyrobutyricum by using degenerate primers and an erythromycin resistance cassette were constructed and introduced into C. tyrobutyricum by electroporation. Integration of the plasmid into the homologous region on the chromosome inactivated the target pta gene and produced the pta-deleted mutant (PTA-Em), which was confirmed by Southern hybridization. SDS-PAGE and two-dimensional protein electrophoresis results indicated that protein expression was changed in the mutant. Enzyme activity assays using the cell lysate showed that the activities of PTA and acetate kinase (AK) in the mutant were reduced by more than 60% for PTA and 80% for AK. The mutant grew more slowly in batch fermentation with glucose as the substrate but produced 15% more butyrate and 14% less acetate as compared to the wild-type strain. Its butyrate productivity was approximately 2-fold higher than the wild-type strain. Moreover, the mutant showed much higher tolerance to butyrate inhibition, and the final butyrate concentration was improved by 68%. However, inactivation of pta gene did not completely eliminate acetate production in the fermentation, suggesting the existence of other enzymes (or pathways) also leading to acetate formation. This is the first-reported genetic engineering study demonstrating the feasibility of using a gene-inactivation technique to manipulate the acetic acid formation pathway in C. tyrobutyricum in order to improve butyric acid production from glucose.

Amino Acid Sequence↗
PubMed1995

Butyrate regulates gene expression of the plasminogen activating system in colon cancer cells.

Butyrate is a potent differentiating agent present in high concentrations in colonic lumen as a result of metabolic breakdown of dietary fibre and, as such, may directly influence colonic cancer progression. We have investigated the effects of butyrate on an enzyme system important in colonic tumour progression, the plasminogen-activating system, in a poorly differentiated colon cancer cell. Butyrate was found to induce a rapid and transient increase in plasminogen activator inhibitor type 1 (PAI-1) mRNA while concomitantly suppressing the constitutive production of both urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) mRNA transcripts. We have investigated the mechanisms involved in mediating these effects by run-on transcription and RNA stability analyses. Our data show that PAI-1 mRNA induction occurs through both regulation of the stability of the alternately spliced 3.3 kb PAI-1 mRNA transcript and induction of the 2.4 kb PAI-1 mRNA transcript. Studies using modulators of signal transduction pathways demonstrate that induction of PAI-1 mRNA synthesis is independent of protein kinase C but dependent on the activation of protein kinase A. Suppression of uPA mRNA by butyrate was found to occur by down-regulation of gene transcription through a process independent of de novo protein synthesis. The transcription rate of the uPAR gene was not modulated by butyrate, but rapid turnover of the uPAR gene by butyrate was dependent on ongoing protein synthesis. Our results demonstrate that butyrate can effect rapid changes in the expression of genes of the plasminogen-activating system through several different mechanisms in a gene-specific manner.

Adenocarcinoma↗
PubMed1989

Effects of butyric acid and analogues on amylase release from pancreatic segments of sheep and goats.

The specificity of the structural elements of a short-chain fatty acid for stimulating amylase release was investigated in superfused pancreatic segments of sheep and goats in vitro using butyric acid and analogues. Monocarboxylic (cyclohexanecarboxylic and benzoic) acids were as effective as butyric acid, whilst 4-phenyl-n-butyric and dicarboxylic (succinic and phthalic) acids were weak stimulants. The amylase release evoked by butyric acid was markedly reduced in the presence of these compounds. Replacement of hydrogens by a hydroxyl group or amino group or reduction of the carboxyl group to alcohol diminished, while replacement of hydrogen by chloride at the 3 carbon position did not change, the ability to stimulate amylase release. The dose-response curve for butyric acid was shifted to the right in parallel in the solution containing succinic acid at 8 x 10(-4) mol/l. The maximal increment (but not ED50) of amylase release evoked by ACh was severely reduced in the solution simultaneously containing butyric acid at 10(-3) mol/l. These results suggest that short-chain fatty acids are required to possess both carboxyl (hydrophilic) group and hydrophobic tails in order to have the ability to stimulate amylase release, and that amylase release evoked by butyrate is caused through specific recognizing sites for short-chain fatty acids which might be different from ACh receptors, in the pancreatic segments of sheep and goats.

Acetylcholine↗
PubMed1995

Butyrate absorption and lactate secretion in ulcerative colitis.

PURPOSE: Fecal electrolytes and organic anion concentrations are altered in ulcerative colitis, presumably reflecting changes in colon epithelial transport. Information of mucosal absorption of butyrate in active ulcerative proctosigmoiditis is not available. METHODS: Dialysis bags containing 70 mmol/liter of butyrate in an isotonic electrolyte solution were placed in the rectum for 30 minutes. Net absorption or secretion rates of butyrate, lactate, and electrolytes were determined in the rectum of 12 patients with active ulcerative colitis (UC) and in 10 patients with quiescent UC and then compared with 10 healthy controls. RESULTS: Net flux rates demonstrated a considerable absorption of butyrate in patients with active inflammation of 7.5 +/- 0.4 mumol/cm2/h and quiescent colitis of 6.6 +/- 0.4 mumol/cm2/h, equal to absorption in healthy controls of 6.3 +/- 0.5 mumol/cm2/h, P = 0.12. Despite normal butyrate absorption, sodium absorption was compromised in active ulcerative colitis (11.5 +/- 1.4 mumol/cm2/h) compared with quiescent (15.4 +/- 1.0 mumol/cm2/h) and controls (18.7 +/- 0.8 mumol/cm2/h) (P = 0.0006). Mucosal secretion of L-lactate was minimal in both healthy controls and quiescent UC but significantly increased in patients with proctosigmoiditis (0.2 +/- 0.1 mumol/cm2/h, 0.2 +/- 0.1 mumol/cm2/h vs. 0.9 +/- 0.2 mumol/cm2/h; P = 0.0001). Appearance of D-lactate was negligible in all three groups. CONCLUSIONS: This study demonstrates that rectal butyrate absorption is normal in UC, and it follows that butyrate supplied in enemas can be expected to be absorbed. The inflamed colonic mucosa secretes L-lactate, and the increased fecal lactate concentrations can be explained by mucosal origin of lactate.

Adult↗
PubMed2003

Effect and comparison of sodium butyrate and trichostatin A on the proliferation/differentiation of K562.

In order to explore the molecular mechanisms of sodium butyrate and trichostatin A on K562 cell proliferation/differentiation, K562 cells were grown in the absence or presence of sodium butyrate or trichostatin A. The percentage of viable cells was determined by trypan blue exclusion. Differentiation was determined by nitro-blue tetrazolium (NBT) reduction and cell surface adhesion molecules analyzed by FACS. Cell cycle distribution was studied after DNA staining by propidium iodide. Cell cycle regulatory proteins were detected by Western blot and reverse transcription-polymerase chain reaction. The results showed that sodium butyrate blocked cells mainly at the G0/G1 phase of the cell cycle, whereas trichostatin A arrested the cells at G2 phase. Sodium butyrate could down-regulate the mRNA expression of cyclin D1, but not affect its protein expression; down-regulate the protein expression of cyclin D3, but not affect its mRNA expression. Trichostatin A showed similar effects on cyclin D1 and D3 as sodium butyrate. Both sodium butyrate and trichostatin A could stimulate p21 expression of K562 cells at mRNA and protein levels. It may be concluded that sodium butyrate and trichostatin A could promote the proliferation/differentiation of the K562 cells, which might be contributed to the induced expression of cyclin D3 and p21 proteins.

Butyrates↗
PubMed2001

Cytokine-activated degradation of inhibitory kappaB protein alpha is inhibited by the short-chain fatty acid butyrate.

Butyrate, a short-chain fatty acid, is generated by anaerobic fermentation within the colon. Clinical trials suggest that short-chain fatty acids ameliorate inflammation in ulcerative colitis. Nuclear factor (NF) kappaB, an inducible transcription factor that is activated in inflamed colonic tissue, is sequestered to the cytoplasm by its inhibitory IkappaB proteins. The anti-inflammatory effects of butyrate are associated with an inhibition of NF-kappaB nuclear translocation. To investigate the mechanism of NF-kappaB inhibition we examined the effects of butyrate on IkappaBalpha. Human adenocarcinoma cells (SW480, SW620, and HeLa229) were treated with butyrate for up to 48 h followed by tumor necrosis factor (TNF) alpha stimulation. NF-kappaB was detected by immunofluorescence staining with an antibody against its p65 subunit. Levels of IkappBalpha and phosphorylated IkappaBalpha were determined by western blot. Stimulation with TNFalpha resulted in rapid phosphorylation and degradation of IkappaBalpha followed by NF-kappaB nuclear translocation. Butyrate pretreatment successfully inhibited NF-kappaB activation. Pretreatment of adenocarcinoma cells with butyrate is associated with inhibition of TNFalpha-mediated phosphorylation and degradation of IkappaBalpha and effective blocking of NF-kappaB nuclear translocation. The anti-inflammatory effects of butyrate may at least in part be mediated by an inhibition of IkappaBalpha mediated activation of NF-kappaB.

Adenocarcinoma↗
PubMed2006

Exposure to sodium butyrate leads to functional downregulation of calcium-activated potassium channels in human airway epithelial cells.

Cystic fibrosis (CF) is caused by genetic mutations that lead to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. The most common mutation, DeltaF508, causes inefficient trafficking of mutant CFTR protein from the endoplasmic reticulum to the cell membrane. Therapeutic efforts have been aimed at increasing the level of DeltaF508-CFTR protein in the membrane using agents such as sodium butyrate. In this study, we investigated the effects of culturing a human airway epithelial cell line, Calu-3, in the presence of 5 mM sodium butyrate. Within 24 h, butyrate exposure caused a significant decrease in the basal, as well as Ca(2+)-activated, anion secretion by Calu-3 cell monolayers, determined by the change in transepithelial short-circuit current in response to the Ca(2+)-elevating agent thapsigargin. The secretory response to 1-ethyl-2-benzimidazolinone, an activator of the basolateral Ca(2+)-activated K(+) channel KCNN4, was similarly reduced by butyrate treatment. Quantitative PCR revealed that these functional effects were associated with dramatic decreases in mRNA for both KCNN4 and CFTR. Furthermore, the KCNQ1 K(+) channel was upregulated after butyrate treatment. We suggest that prolonged exposure to sodium butyrate downregulates the expression of both KCNN4 and CFTR, leading to a functional loss of Ca(2+)-activated anion secretion. Thus, butyrate may inhibit, rather than stimulate, the anion secretory capacity of human epithelial cells that express wild-type CFTR, particularly in tissues that normally exhibit robust Ca(2+)-activated secretion.

Benzimidazoles↗
PubMed2005

The gut fermentation product butyrate, a chemopreventive agent, suppresses glutathione S-transferase theta (hGSTT1) and cell growth more in human colon adenoma (LT97) than tumor (HT29) cells.

PURPOSE: The gut fermentation product of dietary fiber, butyrate, inhibits growth of HT29, an established tumor cell line. It also induces detoxifying enzymes belonging to the glutathione S-transferase family (GSTs), namely hGSTM2, hGSTP1, hGSTA4, but not of hGSTT1 . Here we investigated kinetics of effects in HT29 and compared sensitivities with preneoplastic LT97 colon adenoma cells, to assess mechanisms of colon cancer chemoprevention in two stages of cell transformation. METHODS: We determined cell growth after butyrate treatment by quantifying DNA, GST expression by Northern/Western Blotting or biochemical analysis and butyrate consumption by measuring the residual concentrations in the cell culture supernatants. Stability of GST-theta (hGSTT1) mRNA was assessed in HT29 cells after inhibition of transcription with actinomycin D. RESULTS: LT97 adenoma cells consumed twofold more butyrate and were more sensitive to growth inhibition than HT29 (EC(50)1.9 mM and 4.0 mM, respectively). Butyrate did not induce GSTs, but instead reduced hGSTT1 in LT97 and HT29. CONCLUSIONS: Butyrate has suppressing-agent activities in human colon cells by inhibiting two survival factors, namely hGSTT1 and cell growth, with LT97 more sensitive than HT29. These findings indicate that butyrate formation in the gut lumen of humans could be protective by reducing survival of transformed colon cells.

Adenoma↗
PubMed1996

Withdrawal of butyrate from the colonic mucosa triggers "mass apoptosis" primarily in the G0/G1 phase of the cell cycle.

Butyrate exerts a trophic effect on the colonocytes and plays a protective role in ulcerative colitis. In the present study, we investigated the effect of butyrate withdrawal on the colonic mucosa of the guinea-pig. The samples were mounted in Ussing chambers and bathed for 45, 60, 90 and 150 min with standard Ringer solution with or without sodium butyrate. Light and electron microscopy for morphology, electrophysiological methods for testing tissue function, histochemistry using the TUNEL method for localization of apoptotic cells and flow cytometry for cell cycle analysis were applied. Morphological observations revealed that butyrate deprivation caused a time-dependent hypoplasia and a rapid triggering of massive apoptosis as substantiated by the TUNEL assay. The epithelium, however, did not show discontinuities at any time. Electrophysiological data confirmed that no leakage of the epithelium had occurred. In the control specimens, the mucosa underwent a moderate reduction in height; apoptotic epithelial cells were infrequently observed. Cell cycle analysis of colonocytes isolated from the mucosa deprived of butyrate revealed a decrease in the percentage of cells occupying each phase of the cycle, especially the G0/G1 phase. Thus, in the absence of butyrate, apoptosis was enhanced and cell renewal reduced. The trophic protective action exerted by butyrate in both physiological and pathological conditions could derive from its capacity to modulate survival and death of colonocytes.

Animals↗
PubMed2005

The influence of specific luminal factors on the colonic epithelium: high-dose butyrate and physical changes suppress early carcinogenic events in rats.

INTRODUCTION: Although luminal delivery of butyrate is one putative mechanism by which biology of the colonic epithelium might be influenced by changes in luminal contents, there is a paucity of supportive cause-effect evidence. This study aimed to directly establish whether distal colonic butyrate delivery is able to alter the response of the distal colonic epithelium to a carcinogen. METHODS: Groups of male Sprague-Dawley rats with chronically intubated colons received infusions of 80 mM butyrate or 0.9 percent saline into distal colon two or five times daily. Three weeks after exposure to azoxymethane (15 mg/kg subcutaneously), the density of aberrant crypts was quantified in distal colon. RESULTS: Infusions of 0.5 ml twice daily, whether containing saline or butyrate, decreased the number of aberrant crypt foci by 45 percent compared with rats receiving no infusions (P = 0.004, analysis of variance). Similar results were obtained when infusions were restricted to the post-initiation phase. When infusions were increased to 1 ml five times daily, saline infusions similarly suppressed aberrant crypt formation (38 percent), but butyrate infusions suppressed it to a greater degree (by 64 percent; P = 0.02 compared with saline infusion, t-test). CONCLUSIONS: High levels of butyrate delivery to the distal colonic lumen alter the epithelial response to a carcinogen in otherwise healthy rats. This finding directly supports the notion that the effects of butyrate on cells in vitro do occur in vivo provided a sufficient dose is delivered. The effect of infusion of liquid per se on the epithelial response highlights the potential impact physical changes alone can have on the colonic epithelium.

Animals↗
PubMed1987

Comparison of the butyrate effects on neurotransmitter receptors in neurohybrids NG108-15 and NCB-20 cells.

Our previous study demonstrated that long term treatment of NCB-20 cells with sodium butyrate resulted in a marked increase in the density of delta-opioid receptors with a much lesser effect on muscarinic cholinergic and no effect on alpha 2-adrenergic receptors. In the present study we investigated the effect of sodium butyrate on these three types of receptors in NG108-15 cells whose neuroblastoma parent is the same as that of NCB-20 cells. Long term treatment of NG108-15 cells with sodium butyrate (0.5 mM) induced a 2-fold increase in the density of the specific binding of 3H-clonidine. A comparable increase in the number of binding sites was detected when 3H-yohimbine was used as the receptor ligand. The butyrate-induced increase in the alpha 2-adrenergic receptor binding could be totally abolished by treatment with a protein synthesis inhibitor, cycloheximide, suggesting that synthesis of receptor protein is involved. The same butyrate treatment had no significant effect on opioid and muscarinic cholinergic receptor bindings. Thus, butyrate effects on the expression of these three types of receptors in NG108-15 and NCB-20 cells are dramatically different. These data suggest that induction by butyrate of neurotransmitter receptors requires concerted action of genetic factors of both parents of the neurohybrids.

Animals↗
PubMed1978

Sodium butyrate inhibits histone deacetylation in cultured cells.

Sodium butyrate in millimolar concentrations causes an accumulation of acetylated histone species in a variety of vertebrate cell lines. In all lines tested, butyrate caused hyperacetylation of H3 and H4, and in rat IRC8 cells, H2A and H2B were also affected. In Friend erythroleukemic cells, butyrate also induces the synthesis of a nonhistone chromosomal protein, IP25. butyrate does not affect the rate of histone acetylation in cell-free extracts of nuclei of Friend cells. Rather, this fatty acid inhibits histone deacetylation. Cell-free extracts of either control cells or butyrate-grown cells contain comparable levels of histone-deacetylating activity. This in vitro activity is inhibited by the addition of butyrate to the extracts. Thus butyrate appears to be an inhibitor of histone deacetylases both in vivo and in vitro.

Acetylation↗
PubMed2004

Sodium butyrate induces apoptosis in human hepatoma cells by a mitochondria/caspase pathway, associated with degradation of beta-catenin, pRb and Bcl-XL.

Butyrate can promote programmed cell death in a number of tumour cells in vitro. This paper provides evidence that butyrate induces apoptosis in human hepatoma HuH-6 and HepG2 cells but is ineffective in Chang liver cells, an immortalised non-tumour cell line. In both HuH-6 and HepG2 cells, apoptosis appeared after a lag period of approximately 16 h and increased rapidly during the second day of treatment. In particular, the effect was stronger in HuH-6 cells, which were, therefore, chosen for ascertaining the mechanism of butyrate action. In HuH-6 cells, beta-catenin seemed to exert an important protective role against apoptosis, since pretreatment with beta-catenin antisense ODN reduced the content of beta-catenin and anticipated the onset of apoptosis at 8 h of exposure to butyrate. Moreover, in HuH-6 cells, butyrate induced loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, activation of caspase 9 and caspase 3, and degradation of poly(ADP-ribose) polymerase. In addition, during the second day of treatment, beta-catenin, pRb, and cyclins D and E were diminished and the phosphorylated form of pRb disappeared. Also, the content of the anti-apoptotic factor Bcl-XL fell markedly during this period, while that of the pro-apoptotic factor Bcl-Xs increased. These effects were accompanied by an increase in both Bcl-XL and Bcl-Xs mRNA transcripts, as ascertained by reverse transcriptase-polymerase chain reaction. Our results suggest that caspases have a crucial role in butyrate-induced apoptosis. This conclusion is supported by the observation that the inhibitors of caspases, benzyloxy carbonyl-Val-Ala-Asp-fluoromethylketone and benzyloxy carbonyl-Asp-Glu-Val-Asp-fluoromethylketone, prevented apoptosis and the decrease in Bcl-XL, pRb, cyclins and beta-catenin. These effects were most probably responsible for the increased sensitivity of the cells to butyrate-induced apoptosis, which was observed on the second day of treatment.

Apoptosis↗
PubMed2005

Repression of interferon-gamma-induced inducible nitric oxide synthase (iNOS) gene expression in microglia by sodium butyrate is mediated through specific inhibition of ERK signaling pathways.

We have reported recently that sodium butyrate suppressed IFN-gamma, but not the LPS-mediated induction of nitric oxide and TNF-alpha in microglia via the specific inhibition of NF-kappaB. In order to further determine the upstream signaling mechanism involved in the IFN-gamma-specific down-regulation of iNOS by sodium butyrate in microglia, this study investigated the effect of sodium butyrate on the MAP kinase activities. Sodium butyrate significantly repressed the phosphorylation of ERK induced by IFN-gamma, but had little effect on that induced by LPS. This suggests that sodium butyrate suppresses the IFN-gamma-induced iNOS expression by inhibiting the ERK to NF-kappaB pathway. In addition, it was found that sodium butyrate suppressed the IFN-gamma-induced interferon regulatory factor 1 (IRF-1) expression via the inhibition of ERK. Therefore, the ERK signaling pathway appears to play a key role in the sodium butyrate-mediated down-regulation of iNOS in the IFN-gamma-stimulated microglia.

Analysis of Variance↗
PubMed2003

Degradation of arginine and other amino acids by butyrate-producing asaccharolytic anaerobic Gram-positive rods in periodontal pockets.

The use of 20 amino acids by butyrate-producing asaccharolytic anaerobic Gram-positive rods (AAGPRs) in periodontal pockets, i.e. Eubacterium minutum, Filifactor alocis, E. infirmum, E. sulci and E. saphenum, was studied. E. minutum used only arginine and lysine, and produced substantial amounts of butyrate and ammonia as the main metabolic products from arginine, and acetate, butyrate and ammonia from lysine. Fi. alocis used arginine alone and produced butyrate and ammonia. E. infirmum, E. sulci and E. saphenum used lysine alone and produced acetate, butyrate and ammonia. The growth of these bacterial species was supported and enhanced by arginine and/or lysine enriched to culture media, but not by the other amino acids. Arginine deiminase, ornithine carbamoyltransferase and carbamate kinase activity were detected in the cell-free extract of E. minutum, suggesting that arginine was metabolised to citrulline initially, and subsequently to ornithine and carbamoyl phosphate. Ornithine and carbamoyl phosphate were further converted to butyrate, and carbon dioxide and ammonia, respectively. Enzymatic activity of arginine deiminase and ornithine carbamoyltransferase was not detected in Fi. alocis, indicating that Fi. alocis converted arginine to ornithine directly, not via citrulline, and further to butyrate.

Ammonia↗
PubMed2003

Butyrate impairs intestinal tumor cell-induced angiogenesis by inhibiting HIF-1alpha nuclear translocation.

Butyrate is known to stimulate proliferation of normal crypt cells, whereas it inhibits growth and induces apoptosis in colon cancer cells. We examined the effects of butyrate on colon cancer (Caco-2) cell-induced angiogenesis. HUVEC proliferation was significantly inhibited when incubated with medium conditioned by butyrate-treated Caco-2 cells. Simultaneously, levels of the proangiogenic vascular endothelial growth factor (VEGF) were reduced. HIF-1alpha protein, a transcription factor known to be a key regulator in hypoxia-induced angiogenesis, was upregulated by butyrate. This is in contrast to its importance as a VEGF regulating component. However Western blot of nuclear extracts revealed a downregulation of HIF-1alpha protein. HIF-1alpha DNA-binding activity was also decreased by butyrate. Our findings indicate that HIF-1alpha nuclear sequestration is repressed by butyrate, through inhibition of nuclear translocation. We postulate that diminished HIF-1alpha nuclear presence and activity in butyrate-treated Caco-2 cells could be responsible for decreased VEGF expression and antiangiogenic effects.

Active Transport, Cell Nucleus↗