短链脂肪酸与心脏自主神经系统

短链脂肪酸是肠道菌群的重要代谢产物,主要包括丁酸盐、乙酸盐和丙酸盐,其对心脏自主神经系统具有重要的生理、病理调节作用。短链脂肪酸可通过肠-脑轴间接调节交感神经和副交感神经系统活性发挥心血管保护作用,亦可进入循环血液后直接作用于短链脂肪酸受体影响心脏自主神经功能。     

5-氨基水杨酸和丁酸钠局部治疗顽固性远侧溃疡性结肠炎

侵及直肠和乙状结肠的溃疡性结肠炎(溃结)患者与病灶范围较广的患者相比,前者活动 期较长而对标准治疗有效率较低。基于溃结时结肠粘膜存在能量缺乏的假设,故有直肠滴注短链脂肪酸。(SCFA)的治疗方法。滴注S FA与单用丁酸盐治疗本病,具有同样的治疗作用。本文报告5-氨基水杨酸(5-ASA)-丁酸盐合并治疗9例远侧顽固性溃结患者的作用。     

丁酸盐灌肠治疗难治性溃疡性直肠乙状结肠炎

现有证据提示短链脂肪酸(SCFAs)在维持正常肠粘膜方面起重要的作用。SCFAs主要成分醋酸盐、丙酸盐、丁酸盐是由肠腔内未吸收的碳水化合物经细菌发酵而生成,且其在结肠中以相对固定的比例存在,其中丁酸盐是最易被吸收和代谢的物质。已有研究显示丁酸盐是结肠粘膜代谢的底物,能刺激结肠粘膜吸收钠、     

丁酸盐在肠道疾病中作用和机制的研究进展

丁酸盐是结肠和盲肠部位的微生物群酵解膳食纤维和部分氨基酸的主要产物,可减轻肠道炎症,调节肠道菌群平衡,改善肠黏膜屏障等。近年来国内外诸多研究表明丁酸盐在炎症性肠病、肠易激综合征、肠缺血再灌注损伤、结直肠癌、短肠综合征等肠道疾病中发挥作用。本文就丁酸盐在肠道疾病中作用和机制的研究进展作一综述。     

纤维素饮食及其代谢产物与结直肠癌的化学预防

以合成或天然物质抑制癌前病变的发展是结直肠癌化学预防的重要环节。纤维素来源于植物成分．多项流行病学调查和临床试验结果证实高纤维素饮食可降低结直肠癌的发生率。纤维素的剂量、使用时机、时间长短及其种类均可影响癌变过程。纤维素饮食预防结直肠癌的机制包括纤维素在结肠中经厌氧菌发酵产生丁酸盐等短链脂肪酸（SCFA），通过抑制组蛋白脱乙酰基酶（HDAC）而提高抑癌基因p21^WAF1相关染色体活性，从而阻滞细胞周期。本文就纤维素饮食及其代谢产物与结直肠癌化学预防的相关研究结果作一简要分析。     

丁酸类衍生物抗肿瘤作用机制的研究进展

Nkondjock〔1〕等发现不易发酵的小麦纤维经结肠细菌发酵后,在结肠内产生较高水平的丁酸,推测结肠内较高水平丁酸与结肠癌的预防有关。丁酸是一种短链脂肪酸,它作为一种非特异性的组蛋白去乙酰化酶的抑制剂,已被证实在体内外能抑制许多肿瘤细胞生长。1丁酸类衍生物的生成和化学性质丁酸类衍生物中丁酸是食物在肠道菌丛发酵作用下产生的短链脂肪酸,和乙酸、丙酸一起被认为是最主要的3种四碳短链脂肪酸(short chain fatty acids,SCFA)。三丁酸甘油酯是丁酸的甘油三酯同类物,无色油状液体,带有苦味,其分子式为C12H2506。SCFA通过氧化为结…     

短链脂肪酸对人结肠癌Caco-2细胞增殖分化的影向与临床意义

目的 离纤维素饮食对预防结肠癌有重要作用，但其具体作用环节与机制并不清楚。以人结肠癌Caco-2细胞为模型，研究3种短链脂肪酸对细胞增殖、分化和转移的影响以及高纤维素饮食抗结肠癌的作用与意义。方法 以人高分化结肠癌Caco-2为模型，分别绎细胞增殖能力对数转换法检测倍增时间、结肠癌上皮刷状缘细胞分化标忐物组蛋白酶C生化检测及转移率测定，分析短链脂肪酸对人结肠癌细胞增殖、分化与转移的影响。结果 3种短链脂肪酸均可影响人结肠癌细胞的表型，显著延长肿瘤细胞倍增时川，增强癌细胞分化标志物组蛋白酶的表达，行明显抑制癌细胞的转移。结论 高纤维素饮食所含的短链脂肪酸通过抑制癌细胞的增殖、分化及转移而起到抗肿瘤作用。提高丁酸盐／乙酸盐比率的纤维素饮食可增强其抗癌作用。     

短链脂肪酸介导的菌群-宿主互动与肠易激综合征的研究进展

肠道菌群和肠易激综合征(irritable bowel syndrome,IBS)发病密切相关,短链脂肪酸是菌群代谢的主要产物和重要信息分子,不仅起到稳定菌群结构的作用,还参与肠道免疫、动力和肠上皮屏障的调节.IBS患者肠道菌群失调,直接影响了肠道菌群-短链脂肪酸-肠上皮细胞的正常信号路径,最终导致低度炎症反应、肠上皮屏障通透性增加和动力异常.研究短链脂肪酸与I B S发病机制的关系对全面认识I B S并指导临床具有重要意义.     

结直肠癌患者血清叶酸和粪便短链脂肪酸的变化及意义

目的探讨结直肠癌患者血清叶酸和粪便短链脂肪酸的变化及意义。方法收集400例经肠镜检查结果正常者、58例结直肠癌和56例腺瘤性息肉病人的血液和大便标本,用磁性颗粒化学发光免疫法检测血清叶酸水平,高压液相色谱法检测大便短链脂肪酸,非秩和检验方法进行数据分析。结果从总体上看,正常组、腺瘤性息肉组、结直肠癌组血清叶酸、大便短链脂肪酸浓度无显著性差异（叶酸P=0.199,短链脂肪酸P=0.214）,提示两者与结直肠癌和腺瘤性息肉发生风险无关。经多独立样本两两比较法（Nemenyi法）检验,结直肠癌组的异丁酸值要显著高于正常组（P=0.002）,而与腺瘤性息肉组无显著性差异（P=0.194）;腺瘤性息肉组和结直肠癌组的异戊酸值显著高于正常组（P=0.016和P=0.000）,而腺瘤性息肉组与结直肠癌组的异戊酸值无显著性差异。结论血清叶酸和粪便纤维素的代谢产物-大便短链脂肪酸与结直肠癌和腺瘤性息肉的发生无关。     

丁酸盐灌肠对远段溃结时结肠粘膜的作用

由大肠内细菌分解碳水化合物及蛋白质所产生的短链脂肪腹(SCFAs;主要为乙酸盐、丙酸盐和丁酸盐),是结肠内环境的重要调节剂。丁酸盐是结肠细胞肠炎主要能源物,可影响人与鼠粘膜细胞增殖。溃疡性结肠炎(UC)病人的大便SCFAs浓度减低。本作者观察丁酸盐灌肠来治疗10例UC病人的疗效。材料和方法:10例急性UC病人,男女各5例。平均38.8±3.9岁。病变范围从直肠至结肠脾曲,对标准治疗无效。研究期间用口服药物和丁酸钠/安剂慰(氯化钠)灌肠,采用随机、单盲、交叉方案进行研究。直肠滴注,每天2次,滴注后嘱病人平卧30min。除3例连用4周外,其余均用丁酸钠灌肠2周。治疗前后用清水灌肠后作乙状肠镜检查,在直肠与乙状结肠交接处和直肠壶腹部作活检。将炎症分为无、轻、中、重4级。用~3H胸腺嘧啶掺入法检测直肠上皮细胞增殖情况。结果:10例远段UC病人持续腹泻至少3周,用丁酸盐灌肠后每天大便次数明显减少,便血由9例减为     

Short-Chain Fatty Acids Induce Cytoskeletal and Extracellular Protein Modifications Associated with Modulation of Proliferation on Primary Culture of Rat Intestinal Smooth Muscle Cells

Short-chain fatty acids are the main end products of bacterial fermentation of carbohydrates. Their role on the metabolism and biology of colonocytes is now well characterized. However, the functional consequences of their presence on intestinal smooth muscle cells remain poorly studied. We aimed to assess the effect of different short-chain fatty acids on ileal and colonic smooth muscle cells in primary culture and on A7R5 line. Butyrate (above 0.1 mM) inhibited A7R5 cell proliferation, while at low concentration (0.05 to 0.5 mM) butyrate significantly stimulated the proliferation of ileal and colonic myocytes in primary culture. An inhibition was observed at higher concentrations. Collagenous and noncollagenous protein synthesis was stimulated by butyrate. Moreover, butyrate stimulated actin and myosin expression. Thus, butyrate, which is produced by dietary fiber fermentation, may affect intestinal muscles by directly acting at the molecular level on myocytes.     

Utilization of short-chain fatty acids by colonic mucosal tissue strips. A new method of assessing colonic mucosal metabolism

BACKGROUND: Previous metabolic studies of the colonic mucosa have been done using isolated cells or small biopsy specimens. METHODS: A new method for assessing the utilization of short-chain fatty acids in human colonic mucosal tissue strips considerably larger than routine samples was evaluated and compared with the method of isolated colonocytes. Human colonic mucosal strips and isolated human and rat colonocytes were incubated with acetate (C2), butyrate (C4), and hexanoate (C6), and oxidation rates obtained by quantifying the production of CO2. RESULTS: The wet weight of strips was highly correlated with the production of CO2, and intersample coefficient of variance was <10%. The production of CO2 from the oxidation of C2, C4, and C6 was in the order of C2 > C4 > C6 for both strips and isolated human and rat colonocytes. The production of adenosine triphosphate (ATP) in strips and isolated human and rat colonocytes was in the order of C2 < or = C4 < or = C6. The Km value for the oxidation of butyrate to CO2 in strips (1.8 mmol/l) was several times higher than previously reported for isolated human and rat colonocytes (0.1-0.3 mmol/l). CONCLUSIONS: This new method is highly reproducible and able to assess the metabolic activity of the colonic mucosa. The high Km value of butyrate oxidation in mucosal strips seems to reflect the in vivo Km value of colonocytes and shows the importance of a preserved anatomic structure in metabolic studies of the colonic epithelium. The low Km value for isolated colonocytes probably reflects the intracellular ability to oxidize butyrate. We propose that both isolated colonocytes and mucosal strips be used in studies of colonic mucosal metabolism. This method is relevant in disease states of the colon in which a disagreement prevails as to the ability to oxidize butyrate by colonocytes, such as in ulcerative colitis.     

Influence of Feces from Patients with Ulcerative Colitis on Butyrate Oxidation in Rat Colonocytes

An impaired oxidation of butyrate has beensuggested as a causative factor of ulcerative colitisand, moreover, agents present in colonic luminalcontents impair butyrate oxidation in both rat and human colonocytes. To evaluate the overall effect offeces on the production of CO₂ and ketonebodies from butyrate oxidation in rat colonocytes, fecalhomogenates from 10 healthy subjects and 10 patients with quiescent and 10 patients with activeulcerative colitis were sterile filtrated and added torat colonocytes incubated with 2, 4, and 10 mmol/literof stock butyrate, respectively. Addition of fecal filtrate from healthy subjects and patientswith quiescent and active ulcerative colitis tocolonocytes incubated with 2, 4, and 10 mmol/liter ofstock butyrate, respectively, tended to decrease theproduction of CO₂ from butyrate oxidation,whereas ketogenesis was unaffected. The decrease inCO₂ production was not explained by thesimultaneous addition of fecal short-chain fatty acids(SCFAs). However, a difference in the ability todecrease CO₂ production was not found betweenfiltrates from healthy subjects and patients withquiescent and active ulcerative colitis. In conclusion, feces from healthy subjects and patients withquiescent and active ulcerative colitis containinhibitor(s) of the production of CO₂ frombutyrate oxidation in colonocytes. However, a specific inhibitory effect of feces from patients withulcerative colitis on the production of CO₂could not be identified.     

Effect of structural analogues of propionate and butyrate on colon cancer cell growth

The aim of this study was to evaluate the effects of natural short-chain fatty acids (butyrate, propionate, valerate, acetate) and structural analogues of butyrate and propionate on cell growth and apoptosis in three human colonic adenocarcinoma cell lines (HT-29, Colo-320, and SW-948). We have previously shown that mercapto- and bromo-analogues of butyrate and propionate compete with natural short-chain fatty acids for uptake in the colonocyte. Among naturally occurring short-chain fatty acids, butyrate was the most potent inhibitor of proliferation in all three cell lines. Propionate exhibited a weaker antiproliferative effect, while other short-chain fatty acids (valerate, acetate) were ineffective. Bromo-analogues of butyrate and propionate were more potent proapoptotic agents than butyrate. In contrast to butyrate, the analogues induced strand breaks on isolated supercoiled DNA, the effect being completely reversed by a DNA-protecting agent, spermine. We conclude that bromo-analogues of butyrate and propionate are more potent proapoptotic agents than butyrate in colon cancer cells in culture. Their effect may be a result of direct DNA damage.     

Luminal fermentation and colonocyte metabolism in a rat model of enteral nutrition

Large intestinal fermentation and nutrient metabolism in colonocytes were investigated in a rat model of enteral feeding. Male Wistar rats (240–280 g) were submitted to 7 or 14 days of treatment: intragastric feeding (elemental formula) versus oral feeding (isocaloric and isonitrogenous diet, containing 5% purified cellulose) in the control group. Fermentation products and bacterial populations were analyzed in cecal contents. Colonic cells were isolated and tested for their capacities to metabolize [1-¹⁴C] butyrate and [U-¹⁴C]glutamine. After 7 days of enteral nutrition, short-chain fatty acid concentrations represented 52% of those measured in the control group, but colonocyte metabolism remained unchanged. After 14 days of enteral nutrition, short-chain fatty acid concentrations were still decreasing, although bacterial counts remained unchanged. In parallel, ammonia and lactate concentrations were significantly increased. The capacities to utilize butyrate and glutamine in colonocytes were only slightly affected. However, there was a dramatic increase in the ratio of -OH-butyrate to acetoacetate fluxes, suggesting a more reduced redox mitochondrial state associated with enteral feeding.     

Dietary resistant starch and chronic inflammatory bowel diseases

These studies were performed to test the benefit of resistant starch on ulcerative colitis via prebiotic and butyrate effects. Butyrate, propionate, and acetate are produced in the colon of mammals as a result of microbial fermentation of resistant starch and other dietary fibers. Butyrate plays an important role in the colonic mucosal growth and epithelial proliferation. A reduction in the colonic butyrate level induces chronic mucosal atrophy. Short-chain fatty acid enemas increase mucosal generation, crypt length, and DNA content of the colonocytes. They also ameliorate symptoms of ulcerative colitis in human patients and rats injected with trinitrobenzene sulfonic acid (TNBS). Butyrate, and also to a lesser degree propionate, are substrates for the aerobic energy metabolism, and trophic factors of the colonocytes. Adverse butyrate effects occur in normal and neoplastic colonic cells. In normal cells, butyrate induces proliferation at the crypt base, while inhibiting proliferation at the crypt surface. In neoplastic cells, butyrate inhibits DNA synthesis and arrests cell growth in the G1 phase of the cell cycle. The improvement of the TNBS-induced colonic inflammation occurred earlier in the resistant starch (RS)-fed rats than in the RS-free group. This benefit coincided with activation of colonic epithelial cell proliferation and the subsequent restoration of apoptosis. The noncollagenous basement membrane protein laminin was regenerated initially in the RS-fed group, demonstrating what could be a considered lower damage to the intestinal barrier function. The calculation of intestinal short-chain fatty acid absorption confirmed this conclusion. The uptake of short-chain fatty acids in the colon is strongly inhibited in the RS-free group, but only slightly reduced in the animals fed with RS. Additionally, RS enhanced the growth of intestinal bacteria assumed to promote health. Further studies involving patients suffering from ulcerative colitis are necessary to determine the importance of RS in the therapy of a number of intestinal diseases and the maintenance of health. Accepted: 11 August 1999     

Short Chain Fatty Acids Differentially Modulate Cellular Phenotype and c-myc Protein Levels in Primary Human Nonmalignant and Malignant Colonocytes

Short chain fatty acids may protect colonic mucosa against neoplastic transformation by modulating colonocyte phenotype, DNA synthesis, and c-myc levels. To test this hypothesis, nonmalignant and malignant human colonocytes were isolated from surgical specimens and treated with 10 mM acetate, propionate, or butyrate. Markers of cellular phenotype, DNA synthesis, and c-myc protein levels were assayed by alkaline phosphatase and dipeptidyl dipeptidase IV activities, [³H]thymidine labeling, and western blotting, respectively. Butyrate, in particular, exerted discordant effects on alkaline phosphatase (P < 0.05), and c-myc levels (P < 0.05, N 6) in nonmalignant and malignant human colonocytes. DPDD was unaffected by any of the short chain fatty acids tested. [³H]Thymidine labeling was differentially stimulated by short chain fatty acids in both cell types and greater DNA synthesis rates were observed in malignant colonocytes (P < 0.005, N = 16). These data suggest that in vitro, butyrate, in particular, may differentially modulate phenotype, DNA synthesis, and c-myc in nonmalignant and malignant human colonocytes.     

Oxidation of short and medium chain C2-C8 fatty acids in Sprague-Dawley rat colonocytes.

BACKGROUND: The predominant colonic short chain fatty acids, acetate, propionate, and butyrate, are oxidised into CO2 in colonocytes from rat and humans in the preferred order of butyrate (C4) > propionate (C3) > acetate (C2)- hence butyrate is considered to be the principal oxidative substrate for colonocytes. AIMS: To compare colonocyte oxidation of valerate (C5), hexanoate (C6), and octanoate (C8) with that of butyrate. METHODS: Isolated rat colonocytes were incubated in the presence of a concentration range of 1-14C labelled C2-C8 fatty acids. Oxidation rates were obtained by quantifying the production of 14CO2, and Vmax (maximum velocity) and K(m) (Michaelis-Menten constant) were calculated by computer fitting of the data to a Michaelis-Menten plot. RESULTS: The K(m) value of acetate (0.56 (SEM 0.02) mmol/l) was about fourfold higher than the K(m) of butyrate (0.13 (0.01) mmol/l), whereas the K(m) values of valerate (0.19 (0.01) mmol/l), hexanoate (0.19 (0.01) mmol/l), and octanoate (0.16 (0.01) mmol/l) were of the same order of magnitude as the K(m) of butyrate. Acetate did not influence butyrate oxidation, whereas butyrate strongly inhibited the oxidation of acetate. By contrast, valerate, hexanoate, and octanoate inhibited colonocyte oxidation of butyrate equally or more than the reverse inhibitory effect of butyrate on valerate, hexanoate, and octanoate oxidation. The maximum rates of ATP production were in the order of valerate > octanoate = hexanoate > butyrate > acetate (28.47 (0.70), 21.78 (0.75), 21.33 (0.78), 16.12 (0.49), 9.09 (0.34) (mumol/min/g) respectively). CONCLUSIONS: Valerate, hexanoate, and octanoate seem to be excellent substrates for colonocyte oxidation, similar to butyrate. These results may influence the choice of fatty acid composition in enemas used for treatment of patients in whom deficient colonocyte oxidation is suspected-for example, patients with ulcerative colitis and diversion colitis.     

Urinary organic acid profiles in fatty Zucker rats: indications for impaired oxidation of butyrate and hexanoate

The urinary excretion of 45 organic acids, monitored by gas-liquid chromatography, was compared in fatty (fa/fa) and lean (Fa/?) Zucker rats maintained on a chemically simplified diet. At the age of 6, 16, and 22 weeks, fatty rats excreted more of the various organic acids than their lean counterparts. However, the greatest difference was in the excretion of ethylmalonate, even when excretion data were normalized to body weight. The next highest excretion difference was in adipate and an unknown compound, and the third highest in pyruvate. A second group of rats examined at 7 weeks also excreted an excess of these four acids, as well as glucuronate and indole-3-acetate. The excessive excretion of ethylmalonate and adipate, which is characteristic of human genetic defects in short- and medium-chain fatty acid oxidation, suggested that the oxidation of butyrate and hexanoate might be impaired in the fatty rat. Thus, as a test of their capacity to oxidize medium- and short-chain fatty acids, two groups of fatty and lean rats were transferred to diets enriched with either trioctanoylglyceride, a medium-chain triglyceride (MCT), or sodium butyrate, a short-chain fatty acid. Both lean and fatty rats on the MCT diet, but only the lean rats on the butyrate-enriched diet, increased their excretion of adipate. However, on both the MCT and butyrate diet, ethylmalonate excretion increased only in lean rats, almost reaching amounts found previously in fatty rats. These results suggest that the fatty rat has an impairment of the beta-oxidation of butyrate and hexanoate, a defect that might increase intracellular concentrations of butyryl-CoA, the optimal primer for the synthesis of long-chain fatty acids.     

The effects of enterotoxins and short-chain fatty acids on water and electrolyte fluxes in ileal and colonic loops in vivo in the rat

The effect of cholera toxin (CT) and Escherichia coli heat-stable enterotoxin (ST) on the ileum and colon was examined in vivo in the rat in an attempt to clarify the effects of enterotoxins on colonic mucosa and to determine if these effects were influenced by short-chain fatty acids (SCFA). Both CT and ST induced similar changes in water and electrolyte fluxes, and the magnitude of these changes in loops of colon was similar to that observed in loops of ileum. The addition of luminal SCFA, acetate, propionate and butyrate did not influence the effect of either toxin in loops of ileum. However, in loops of colon exposed to CT, luminal butyrate (40 mM) largely reversed the effect of CT by converting net water secretion (mean +/- SE, -363 +/- 154 nl.cm-2.min-1) to net water absorption (470 +/- 194 nl.cm-2.min-1) and by significantly reducing the net secretion of sodium ions. In loops of colon exposed to ST, similar effects were observed although net water secretion (-784 +/- 114 nl.cm-2.min-1) was only partially reversed by butyrate (-318 +/- 102 nl.cm-2.min-1). In contrast to butyrate, acetate and propionate did not influence changes in colonic fluxes of water and sodium induced by enterotoxins. Oxidation of butyrate and glucose was observed to be depressed in colonocytes pre-exposed to CT but not to ST. In this model, colonic secretion induced by enterotoxins is similar to that observed in the ileum but differs from ileal secretion in its modulation by luminal butyrate.