New-found link between microbiota and obesity

Due to the grave pathological role of obesity, worldwide research is being continued to find out the causative factors involved in it. Recent advances in this field reveal a possible relationship between the compositional pattern of gut microbiota and genesis of obesity. Several study results have shown that short-chain fatty acids (SCFAs, microbiota-induced fermentation products) and lipopolysaccharides (LPS, an integral component of Gram negative microorganisms) play the key role in linking the two. Though several SCFAs are produced as microbiota-fermentation products, three of them, i.e., butyrate, propionate and acetate have been found to be definitely involved in obesity; though individually they are neither purely obesogenic nor antiobesogenic. Out of these, butyrate and propionate are predominantly antiobesogenic. Butyrate, though a major energy source for colonocytes, has been found to increase mitochondrial activity, prevent metabolic endotoxemia, improve insulin sensitivity, possess anti-inflammatory potential, increase intestinal barrier function and protect against diet-induced obesity without causing hypophagia. Propionate has been found to inhibit cholesterol synthesis, thereby antagonizing the cholesterol increasing action of acetate, and to inhibit the expression of resistin in adipocytes. Moreover, both these SCFAs have been found to cause weight regulation through their stimulatory effect on anorexigenic gut hormones and to increase the synthesis of leptin. Unlike butyrate and propionate, acetate, which is substantially absorbed, shows more obesogenic potential, as it acts as a substrate for hepatic and adipocyte lipogenesis. High fat diet increases the absorption of LPS, which, in turn, has been found to be associated with metabolic endotoxemia and to induce inflammation resulting in obesity. Multiple independent and interrelated mechanisms have been found to be involved in such linking processes which are discussed in this review work along with some possible remedial measures for prevention of weight gain and obesity.     

Topical butyrate improves efficacy of 5-ASA in refractory distal ulcerative colitis: results of a multicentre trial

BACKGROUND: The treatment of distal ulcerative colitis, refractory to conventional 5-ASA/steroid treatment, is still a matter of debate. The present study aimed at confirming, with adequate statistical power, previous data indicating the usefulness of topical butyrate and 5-ASA in the treatment of this condition. DESIGN: Double-blind, placebo-controlled, multicentre study. A total of 51 patients with distal (< 65 cm) ulcerative colitis, refractory to topical 5-ASA/cortisone, were randomly allocated to receive topical 5-ASA 2 g and 80 mM L-1 sodium-butyrate bid (Group A; 24 patients) or 5-ASA 2 g and 80 mL saline bid (Group B; 27 patients) for 6 weeks. Sigmoidoscopy with biopsies, as well as clinical and laboratory evaluations, were carried out at enrollment and at the end of the trial. Primary endpoints: remission or marked improvement in endoscopic, histologic and clinical findings. RESULTS: Most parameters showed a significant improvement vs. baseline in both groups. Remission in six patients and improvement in 12 patients in Group A vs. one remission and 13 with improvement in Group B (P < 0.05). A significant difference in favour of Group A was recorded regarding the number of bowel movements (P < 0.01), urgency (P < 0.05) and the patients' self evaluation (P < 0.01). DISCUSSION: The combined treatment with topical butyrate and 5-ASA is significantly more effective than 5-ASA alone in the management of refractory distal colitis. Further improvements in the treatment of refractory distal ulcerative colitis may be feasible based on the identification of patient subgroups and the association of two or more active drugs. Butyrate may well be one of them.     

Suppressing actions of butyrate on growth hormone (GH) secretion induced by GH-releasing hormone in rat anterior pituitary cells

We assessed the inhibitory effects of butyrate on the growth hormone (GH) secretion in order to investigate the cellular mechanisms in rat somatotrophs. Isolated anterior pituitary cells were cultured in DMEM for several hours, either in the presence (1, 3, or 10mM) or absence of butyrate, and then stimulated with 10(-7)M GHRH for 30 min, in the presence of butyrate at the concentrations used for the previous culture. The increase in GHRH-induced GH release was significantly reduced in a time-dependent and concentration-dependent manner in the cells previously cultured with butyrate. GH content (the sum of GH released into the medium induced by GHRH stimulation and the GH remaining in the cells after stimulation) was reduced by the culture of cells in the presence of butyrate, which was also inversely dependent on the concentrations used for the culture. Simultaneous addition of an L-type Ca(2+) channel blocker, nifedipine (10 pM), to the medium during 10(-9)M GHRH stimulation significantly reduced the stimulated GH release, which was further significantly decreased by a simultaneous addition of 10 mM butyrate. Butyrate blunted the GHRH (10(-9)M)-induced increase in cellular cyclic AMP and calcium ion concentrations, the activity of protein kinases (A and C), and GHmRNA expression. The expression of mRNA for GPR 41 and 43, known as receptors for short-chain fatty acids, was confirmed in the anterior pituitary cells. These findings suggest that butyrate inhibits GHRH-induced GH release as well as GH production, and the cellular inhibitory actions of butyrate occur in diverse cellular signaling pathways of rat somatotrophs.     

Enhancement of NGF- and cholera toxin-induced neurite outgrowth by butyrate in PC12 cells

It has been shown that sodium butyrate (NaBu) does not elicit neurite outgrowth of PC12, one of the most widely used cell lines as a model of neuronal differentiation. In this study, the effects of NaBu on nerve growth factor (NGF)- and cholera toxin-induced neurite outgrowth in PC12 cells were examined. NaBu dose-dependently enhanced neurite formation induced by both agents. The maximum responses obtained at 0.5 mM NaBu were nearly twice those of the inducers alone. Propionate and valerate were also effective, but acetate and caproate were ineffective. Among the butyrate analogs with a moiety of three to five carbon atoms tested, isobutyrate, isovalerate, vinylacetate and 3-chloropropionate enhanced neurite outgrowth promoted by both inducers. However, neither alpha-, beta-, and gamma-aminobutyrates nor alpha-, beta-, and gamma-hydroxybutyrates were effective. All of the effective short-chain fatty acids and their analogs increased the level of histone acetylation, while ineffective ones did not. Furthermore, Helminthosporium carbonum toxin (HC toxin), a structurally dissimilar inhibitor of histone deacetylase, mimicked the effect of butyrate. These results suggest that NaBu enhances neurite outgrowth induced by NGF and cholera toxin in PC12 cells through a mechanism involving an increase in the level of histone acetylation.     

丁酸钠对大鼠小肠上皮细胞株-6细胞增殖和凋亡的影响

目的　观察丁酸钠对大鼠小肠上皮细胞株-6(intestinal epithelium cell line No.6,IEC-6)细胞增殖和凋亡的作用. 方法　不同浓度丁酸钠(低浓度2 mmol/L,中浓度8 mmol/L,高浓度14、20 mmol/L)处理IEC-6细胞,细胞计数试剂盒CCK-8法检测细胞增殖情况,分光光度法检测细胞内Caspase-3活性程度,流式细胞术检测细胞凋亡率. 结果 (1)加入丁酸钠(2、8、14、20mmol/L)共培养24 h后,2、8 mmol/L丁酸钠组细胞增殖速度比对照组快,差异有统计学意义(P<0.01);48 h后,14、20 mmol/L丁酸钠组细胞增殖较对照组明显受抑制,差异有统计学意义(P<0.01);72 h后,8、14、20 mmol/L丁酸钠组增殖亦明显受抑制,与对照组比较差异有统计学意义(P<0.01).(2)加入丁酸钠(2、8、14 mmol/L)共培养12 h后,8、14 mmol/L丁酸钠组与对照组比较Caspase-3活性明显升高,差异有统计学意义(P<0.05);24 h后,2、8、14 mmol/L丁酸钠组与对照组比较Caspase-3活性均升高,差异有统计学意义(P<0.05);48 h后,8、14 mmol/L丁酸钠组与对照组比较Caspase-3活性亦升高,差异有统计学意义(P<0.05).(3)加入丁酸钠(2、8、14 mmol/L)共培养12、24、48 h后,8、14 mmol/L丁酸钠组与对照组比较IEC-6细胞凋亡率均有升高,差异有统计学意义(P<0.05). 结论 中、高浓度丁酸钠有诱导IEC-6细胞凋亡,抑制IEC-6细胞增殖作用,而低浓度丁酸钠没有这种作用.     

丁酸钠对杂交瘤细胞增殖及抗体分泌的影响

用含不同浓度丁酸钠完全培养液和无血清培养液培养分泌抗组织型纤溶酶原激活剂(t-PA)单克隆抗体的杂交瘤细胞。当丁酸钠浓度为0.25～0.5 mmol/L时,对杂交瘤细胞分泌抗体能力具有刺激作用,提高抗体效价2～4倍,对细胞生长无抑制作用。表明丁酸钠可作为一种添加剂用以提高杂交瘤细胞分泌抗体的能力。     

Rationale for the luminal provision of butyrate in intestinal diseases

Summary Short chain fatty acids (SCFA), especially butyrate, play central metabolic roles in maintaining the mucosal barrier in the gut. A lack of SCFA, leading to endogenous starvation of enterocytes, may be the cause of ulcerative colitis and other inflammatory conditions. The main source of SCFA is dietary fibre, but they can also be derived from structured lipids, e. g. tributyrin. Once absorbed by non-ionic diffusion or carrier-mediated anion exchanges, SCFA are either used locally as fuel for the enterocytes or enter the portal bloodstream. Butyrate has been shown to increase wound healing and to reduce inflammation in the small intestine. In the colon, butyrate is the dominant energy source for epithelial cells and affects cellular proliferation and differentiation by yet unknown mechanisms. Recent data suggest that the luminal provision of butyrate may be an appropriate means to improve wound healing in intestinal surgery and to ameliorate symptoms or inflammatory bowel diseases. Received: 16 May 2000, Accepted: 13 July 2000     

Short-chain fatty acid (SCFA) uptake into Caco-2 cells by a pH-dependent and carrier mediated transport mechanism

Summary The short-chain fatty acids, acetate, propionate, and butyrate, are the most abundant organic anions in the human colon. SCFA play a pivotal role in maintaining homeostasis in the colon. Particularly butyrate induces cell differentiation and regulates growth and proliferation of colonic mucosal epithelial cells, whereas it reduces the growth rate of colorectal cancer cell. Previous studies by several groups, including our own, using isolated membrane vesicles have demonstrated that the uptake of butyrate is at least in part mediated by a non-electrogenic SCFA⁻/HCO₃ ⁻ antiporter. The purpose of the present study was to determine (1) whether Caco-2 cells could serve as an experimental model to assess the mechanisms of SCFA transport, and (2) whether monocarboxylate transporters could play a role in SCFA transport in these cells. Caco-2 cells were found to transport ¹⁴C-butyrate in a concentration and time dependent manner. The uptake was sodium independent, but was stimulated by lowering extracellular pH. The uptake of 500μM butyrate was reduced by 49.6% ± 3.3% in the presence of propionate and by 57.2% ± 4.8% in the presence of 10 mM L-lactate. The addition of 1 mM α-cyano-4-hydroxycinnamate and phloretin, both known to be potent inhibitors of MCT1, decreased the uptake of 500 μM ¹⁴C-butyrate by 59.4% ± 4.1% and 48.9% ± 3.3%, respectively, whereas similar concentrations of DIDS did not have any effect. These data suggest that the uptake of butyrate in Caco-2 cells occurs via a carrier mediated transport system specific for monocarboxylic acids, which is in accordance with characteristics of the MCT1. Received: 28 February 2000, Accepted: 4 May 2000     

The microbiome and its pharmacological targets: therapeutic avenues in cardiometabolic diseases

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Butyrate impairs atherogenesis by reducing plaque inflammation and vulnerability and decreasing NFκB activation

Background & aimsButyrate is a four-carbon fatty acid that presents anti-inflammatory, anti-oxidative and apoptotic properties in colon and several cell lines. Because atherosclerosis has important oxidative and inflammatory components, butyrate could reduce oxidation and inflammation, impairing atherogenesis. We evaluated the effects of butyrate supplementation of butyrate on atherosclerosis and its mechanisms of action.Methods and resultsApoE knockout mice were fed on chow diet or 1% butyrate-supplemented chow diet (Butyrate) for 10 weeks to assess atherosclerosis lesions area and inflammatory status. Macrophage and endothelial cells were also pretreated with butyrate (0.5 mM) for 2 h before oxLDL stimulation to study oxLDL uptake and pro and anti-inflammatory cytokine production. Butyrate reduced atherosclerosis in the aorta by 50%. In the aortic valve, butyrate reduced CCL2, VCAM1 and MMP2 productions in the lesion site, resulting in a lower migration of macrophage and increased collagen depositions in the lesion and plaque stability. When EA.hy926 cells were pretreated with butyrate, oxLDL uptake, CD36, VCAM1, CCL2 TNF, IL1β and IL6 productions were reduced, whereas IL10 production was increased. These effects were accompanied by a lower activation of NFκB due to a lower nuclear translocation of the p65 subunit.ConclusionOral butyrate is able to slow the progression of atherosclerosis by reducing adhesion and migration of macrophages and increasing plaque stability. These actions are linked to the reduction of CD36 in macrophages and endothelial cells, decreased pro-inflammatory cytokines and lower activation of NFκB all of these data support a possible role for butyrate as an atheroprotective agent.