Enterobacter cloacae Z0206多糖的制备及其缓解高脂饲喂小鼠脂代谢紊乱的作用及免疫学机制研究
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摘要
本课题组从自然界分离得到一株高产多糖菌株,经鉴定命名为Enterobacter cloacaeZ0206。前期在实验室环境条件下,初步建立了20206多糖的发酵条件参数,并初步揭示Z0206多糖不仅具有免疫调节、抗氧化功能,而且具有降血糖、特别是降血脂功能。为了建立一套适用于工业化生产的Z0206多糖发酵工艺,并进一步阐明Z0206多糖对高脂日粮诱导下机体脂代谢紊乱的缓解作用及机制,本研究以玉米淀粉、豆粕粉、玉米浆干粉等为发酵原料,采用单因素试验、正交试验及响应面设计对Z0206多糖的工业化发酵条件及培养基组成进行了优化；结合离子交换色谱、凝胶渗透色谱等现代分离技术获得Z0206多糖的主要组分,并通过红外光谱、高效液相色谱、气相色谱、核磁共振、原子力显微镜等现代仪器分析手段初步解析了Z0206多糖主要组分的化学组成及结构；再以高脂诱导的C57BL/6肥胖小鼠和TNF-a刺激的3T3-L1小鼠脂肪细胞为模型,研究了Z0206多糖对高脂诱导肥胖小鼠脂代谢紊乱的缓解作用及初步分子机制。主要结果如下：
试验一.Z0206多糖产业化发酵条件建立及培养基组成优化
本试验选择能够进行产业化生产的玉米淀粉、豆粕粉、玉米浆干粉等为主要发酵原料对Z0206多糖的发酵条件和发酵培养基组成进行了筛选和优化。
在多糖的发酵条件优化方面,采用单因素试验优化了Z0206多糖的发酵温度、发酵转速和初始pH值,结果表明：Z0206多糖发酵的最佳温度为30℃、转速为250rpm、初始pH值为7.0。
在发酵培养基组成优化方面,首先采用单因素试验对发酵培养基成分进行了筛选,结果表明：以玉米淀粉为Z0206多糖工业化生产的碳源,以豆粕粉、玉米浆干粉和KN03为复合氮源,以CaCl2、K2HPO43H2O及KH2PO4为无机盐组成；采用正交试验设计优化了培养基中无机盐浓度,结果表明：当CaCl2,1g/L; K2HPO43H2O,3g/L; KH2PO4,3g/L时多糖产量最高；根据Box-Benhnken中心组合设计原理,以Z0206多糖产量为响应值,设计三因素三水平的响应面试验,优化了Z0206多糖发酵的最佳碳氮、源浓度为：玉米淀粉,240.95g/L；豆粕粉,22.19g/L；玉米浆干粉,6.61g/L。在以上优化条件下Z0206多糖的产量可达27.75g/L,是前期多糖产量的2倍以上。
试验二.Z0206多糖的分离纯化、化学组成及结构的初步分析
在优化了Z0206多糖发酵条件和培养基组成的基础上,进一步对发酵获得的Z0206多糖进行了分离纯化、化学组成及结构分析。在Z0206多糖的分离纯化方面,本试验结合Sevage和酶法脱蛋白,20%H2O2脱色,透析和冷冻干燥获得Z0206脱蛋白多糖(EPS)；并采用DEAE-52离子交换柱层析和Superose12凝胶色谱层析对EPS进行分离纯化,获得EPS-1和EPS-3两个主要多糖组分,得率分别为40.8%和26.7%。
在此基础上,采用凝胶渗透色谱、气相色谱、液相色谱及化学方法对以上两个组分的化学组成进行了分析,结果显示：EPS-1的相对分子质量为2527Da,是仅由葡萄糖组成的中性糖；EPS-3的相对分子质量为1.23x106Da,是由岩澡糖、半乳糖、葡萄糖、丙酮酸和糖醛酸组成的酸性糖,摩尔质量比为1.65：1.83：1：1.62：1.20。采用红外光谱仪、核磁共振仪、原子力显微镜和激光粒度仪对两个组分的结构进行了初步分析,结果表明：EPS-1和EPS-3糖链中均含有-CH2-基团,并存在α和β两种糖苷键构型。除此之外,EPS-3糖链中还存在糖醛酸、丙酮酸和岩澡糖单元；EPS-1的平均粒径为50.75nm,而EPS-3的平均粒径为210.3nm；在空间形貌上,EPS-1和EPS-3糖分子间均相互缠绕,聚集紧密成团,形成无规则排列的球状。
以上结果综合表明,Z0206多糖由中性糖和酸性糖组分构成,化学组成包括葡萄糖、半乳糖、岩澡糖,以及丙酮酸和糖醛酸单元；Z0206多糖链存在α和β两种糖苷键构型,在空间上呈现无规则排列的球状结构。
试验三.Z0206多糖缓解高脂诱导肥胖小鼠脂代谢紊乱的作用研究
在优化了Z0206多糖的发酵条件及培养基组成,并初步分析了Z0206多糖化学组成及结构的基础上,本试验通过建立高脂日粮诱导形成的C57BL/6肥胖小鼠模型,从表型变化、血液生化指标、组织形态等多方面研究了Z0206粗多糖(CEPS)及其脱蛋白多糖(EPS)对高脂诱导肥胖小鼠脂代谢紊乱的缓解作用。试验选取6周龄的雄性C57BL/6小鼠,分为普通日粮组(ND)和高脂日粮组(HFD),分别给与普通饲料(10%脂肪含量,Kca1%)和高脂饲料(45%脂肪含量,Kcal%),连续饲喂12周直至两组的平均体重差异显著。再将饲喂高脂日粮的小鼠随机分为高脂组(HFD)、Z0206粗多糖组(HFD+CEPS)和Z0206脱蛋白多糖组(HFD+EPS),多糖组每天分别灌胃200mg/kg.BW两种多糖溶液(10mg/mL), ND组和HFD组每天灌胃等体积的生理盐水,连续灌胃42d。研究结果显示：与高脂日粮组相比,CEPS和EPS均可减缓小鼠增重,降低空腹血糖浓度和血清胰岛素水平,提高胰岛素敏感指数(ISI)及小鼠口服葡萄糖耐量(P<0.05),并降低肥胖小鼠肝脏指数,皮下脂肪、腹部脂肪及附睾周脂指数,表明CEPS和EPS能抑制高脂诱导的脂肪过度沉积,并提高小鼠的胰岛素敏感性；血清生化指标结果表明：CEPS和EPS能通过降低血清游离脂肪酸(FFA)含量(P<0.05)以及总胆固醇(TC)、甘油三酯(TG)和低密度脂蛋白(LDL-c)的水平(P<0.05),并一定程度提高血清高密度脂蛋白(HDL-c)的水平,从而缓解高脂诱导的脂代谢紊乱现象；组织形态观察结果表明：CEPS和EPS均能通过缓解肥胖小鼠肝脏细胞的变形、肿胀、抑制脂滴形成,从而维护肝脏组织的结构完整性,缓解高脂诱导的肝脏脂肪变性；CEPS和EPS也能通过抑制肥胖小鼠附睾脂肪细胞过度增大,从而缓解高脂日粮导致的脂肪细胞肥大的现象；基因和蛋白检测结果显示：CEPS和EPS均能通过促进肥胖小鼠脂肪组织脂联素(Adiponectin)、内脏脂肪特异性丝氨酸蛋白酶抑制剂(Vaspin)、Visftin等胰岛素敏感性因子的mRNA表达,降低瘦素(Leptin)、抵抗素(Resistin)等胰岛素抵抗因子的mRNA表达,同时激活过氧化物酶体增生物激活受体γ (PPARγ)表达,并提高胰岛素作用通路中Aktl的磷酸化水平、胰岛素受体底物1(IRS-1)和葡萄糖转运蛋白4(Glut4)的基因表达,从而增强肥胖小鼠脂肪组织的胰岛素敏感性,调节机体能量代谢水平。
以上结果综合表明Z0206多糖能通过增强高脂诱导肥胖小鼠的葡萄糖摄取能力,缓解肝脏组织脂肪变性和脂肪组织过度肥大,从而缓解胰岛素抵抗；并通过调控脂肪因子表达和血脂平衡,维护机体脂代谢平衡,从而起到改善脂代谢紊乱的作用。
试验四.Z0206多糖缓解脂代谢紊乱的免疫学机制研究
在研究了Z0206多糖缓解高脂诱导的肥胖小鼠脂代谢紊乱作用的基础上,进一步从脂肪炎症的角度,采用免疫组化、流式细胞仪、荧光定量、Western blotting等技术探究了Z0206多糖缓解脂代谢紊乱的免疫学机制。脂肪组织巨噬细胞研究结果表明：CEPS和EPS均能通过减少附睾前脂肪组织中F4/80阳性细胞数量,降低CDllc+阳性细胞比例,同时减少巨噬细胞形成的"Crown like structure"数量,从而减少高脂诱导的脂肪组织巨噬细胞浸润；同时,CEPS和EPS均能通过上调M2型巨噬细胞标记基因CD209、CD163和Mg12的表达和下调M1型巨噬细胞标记基因F4/80、CD11c和单核细胞趋化蛋白-1(MCP-1)的表达,从而促进脂肪组织巨噬细胞由M1型向M2型分化；脂肪炎症因子表达方面,体内试验结果显示：CEPS和EPS均能提高附睾脂肪组织中抑炎细胞因子IL-10的表达,降低促炎细胞因子TNF-α、IL-6的表达；体外试验结果显示：Z0206多糖组分EPS-3同样能降低TNF-α刺激下3T3-L1小鼠脂肪细胞NO产生和促炎细胞因子TNF-α、IL-6、IL-1β的基因表达,并提高抑炎细胞因子IL-10的基因表达,由此表明Z0206多糖通过调控炎症因子的表达缓解了高脂诱导的脂肪炎症反应；基因及蛋白检测结果揭示：Z0206多糖可能通过下调脂肪细胞TLR4表达,降低IKBα磷酸化,抑制NF-κB活性,同时降低c-Jun氨基端激酶的磷酸化水平,从而缓解肥胖小鼠脂肪组织慢性低度炎症。
以上结果综合表明Z0206多糖一方面可以通过减少高脂诱导肥胖小鼠脂肪组织巨噬细胞浸润,并促进巨噬细胞由M1型向M2型分化；另一方面,Z0206多糖可能通过抑制脂肪细胞TLR4/IκBαa/NF-κB途径和c-Jun途径,降低促炎细胞因子生成,从而缓解高脂诱导下的脂肪组织炎症,有效防止脂代谢紊乱的发生。
In our previous study, Enterobacter cloacae Z0206, a bacterial strain, can produce large amounts of exopolysaccharides (EPS), was isolated from nature. The culture medium was optimized under laboratory conditions and EPS was found to have antioxidant, immunomodulatory, antiviral, hypoglycemic and especially hypolipidemic bioactivities. In order to establish a set of fermentation process for industrialized production and further clarify the effect of Z0206polysaccharide on lipid metabolism disorder induced by high fat diet. In the present study, we firstly optimized the industrial fermentation conditions and medium composition of EPS produce by Enterobacter cloacae Z0206with corn starch, soybean meal and corn steep power as substrates. The exopolysaccharide was purified with iron exchange chromatography and gel column chromatography, after that the chemical composition and structure of the main components were analyzed by a combination of Infrared Spectroscopy (IR), high Performance Liquid Chromatography (HPLC) and gas chromatography (GC) as well as nuclear magnetic resonance (NMR) and atomic force microscope (AFM). On the base of this, the effects of EPS produced by Enterobacter cloacae Z0206on lipid metabolism disorder in high fat diet induced C57BL/6mice and TNF-a induced3T3-L1were studied. The main results are as bellows:
1. Medium composition Optimization of EPS produced by E. cloacae Z0206
The industrial fermentation conditions and medium composition of EPS produce by Enterobacter cloacae Z0206were optimized with corn starch, soybean meal and corn steep power as substrates.
The optimization of fermentation conditions and the culture medium for the production of EPS from Enterobacter cloacae Z0206was studied using one-factor-at-a-time method, orthogonal matrix method and response surface methodology (RSM) with agroindustrial by-products as the main fermentation substrate. The results of one-factor-at-a-time test showed that the best conditions for title bacterial growth and EPS production were: fermentation temperature30℃, speed250rpm and initial pH7.0. The suitable carbon and complex nitrogen sources were corn starch and soy bean meal, corn steep powder and KNO3respectively. The concentration of inorganic salts and complex nitrogen sources were optimized by orthogonal matrix design. At last a three level, three factor Box-Behnken factorial design was used to optimize the level of three factors significantly affecting the yield of EPS. The optimal medium composition was determined as follows:240.95g/L cornstarch,22.19g/L soybean meal,6.61g/L corn steep powder,3g/L K2HPO43H2O,3g/L KH2PO4and1g/L CaCl2, with a corresponding yield of27.75g/L, which was approximately two times higher than that in the basal medium.
2. Purification, chemical composition and structure analysis of EPS
On the basis of optimization of fermentation conditions and culture medium, Z0206polysaccharide was further purified and its chemical composition and structure was analyzed. Crude exopolysaccharides (CEPS) were obtained from the fermentation broth by ethanol precipitation, EPS was obtained through deproteinization, decolorization and dialysis. The deproteinized exopolysaccharides were further purified through a DEAE-52iron exchange chromatography column and a Suprose12gel column. Two main components (EPS-1and EPS-3) were isolated by eluting with distilled water and a gradient of0-0.5mol/L NaCl solution, their yield was40.8%and26.7%respectively.
The gel permeation chromatography (GPC) analysis showed that the average molecular weights of EPS-1and EPS-3was2527Da and1.23×106Da respevtively. The neutral sugars, pyruvyl groups and glucuronic acid were analyzed using GC, reversed-phase high-performance liquid chromatography (RP-HPLC) and the carbazole-sulfuric acid method. EPS-1was found to be composed of glucose, and EPS-3was composed of fucose, galactose, glucose, pyruvic acid and glucuronic acid with the relative molar ratio of1.65:1.83:1:1.62:1.20. IR analysis showed that both EPS-1and EPS-3contained-CH2-groups. NMR analysis indicated that EPS-1and EPS-3contained a and β type glycosidic linkages and EPS-3also showed uronic acid carboxyl resonance, methyl groups of the ketal-substituted pyruvate residue and methyl groups of fucose. The average particle size distribution of EPS-1was50.57nm and EPS-3was210.3nm. The photograph of EPS-1and EPS-3fraction were obtained by atomic force microscope and showed that molecules of EPS-1and EPS-3are gathered up with each other in a tight manner.
3. Effect of Z0206polysaccharide on the lipid metabolism disorder in obese mice
On the base of structure analysis of EPS produced by Enterobacter cloacae Z0206, the effects of CEPS and EPS on the lipid metabolism disorder as well as insulin resistance in high fat induced C57BL/6mice were studied. C57BL/6mice were divided into two groups at the age of6weeks, normal diet (ND) group and high fat diet (HFD) group, feeding normal diet (10%fat kcal%) and high fat diet (45%fat kcal%) respectively for12weeks. Mice in HFD group were then allocated to HFD group, Z0206crude polysaccharide group (HFD+CEPS) and Z0206deproteinization polysaccharide group (HFD+EPS). CEPS and EPS were administered to C57BL/6mice for a period of42days, and the same volume of saline solution were administered to mice in ND and HFD groups. The results showed that administration of CEPS and EPS could significantly decrease the body weight gain, fasting glucose concentration and serum insulin levels, whereas improved the insulin sensitivity index (ISI) and OGTT compared with the HFD group. In addition, CEPS and EPS significantly decreased the liver index, adipose tissue index of subcutaneous fat, retroperitoneal fat and epididymal fat, indicating that CEPS and EPS can inhibit the excessive fat deposition and improve the insulin sensitivity. At the same time, serum free fatty acid (FFA) content, cholesterol (TC), triglyceride (TG) and low density lipoprotein (LDL-c) levels were significantly decreased in CEPS and EPS treated mice. Morphology observation shows that CEPS had significant protective effects in the integrity of the organizational structure of liver and the size of adipocyte in epididymal adipose tissue were significantly decreased in CEPS treated mice, which indicated that CEPS ameliorated adipocyte hypertrophy phenomenon in epididymal fat. The results of RT-PCR and western blotting showed that CEPS and EPS could significantly increase the gene expression of insulin-sensitizing factors like adiponectin, vaspin and visftin, while reduce the gene expression of insulin resistance factors like leptin and resistin. At the same time, the expression of PPARy and its target genes, glucose transport protein4(Glut4), insulin receptor substrate1(IRS-1) and Aktl were upregulated in the groups supplemented with CEPS and EPS, which indicated that CEPS and EPS increased the insulin sensitivity of high fat diet induced mice, sequentially regulated the energy metabolism.
The above results suggested that CEPS and EPS could enhance the capacity of glucose uptake, relieve fatty degeneration and adipocyte hypertrophy in high fat diet induced mice, thus alleviate insulin resistance. They maintained the lipid metabolism metabolic balance and improved the lipid metabolism disorder by regulating the expression of adipokines and blood lipid.
4. The immune mechanism of alleviation effect of Z0206polysaccharide on lipid metabolism disorder.
On the basis of the above experiments, the insulin-sensitizing mechanism of Z0206polysaccharide was further studied from the aspect of adipose inflammation using immunohistochemistry, flow cytometry, RT-PCR and Western blotting. The results showed that CEPS and EPS could reduce the F4/80positive macrophages and the ratio of CD11positive cells, and as well as the numbers of crown like structure (CLS) in epididymal adipose tissue compared with the high fat diet induced mice. We also found that treatment with CEPS and EPS markedly reduced the M1macrophages markers, such as F4/80, CDllc and MCP-1, whereas increased the M2macrophages markers, such as CD209, CD163and Mgl2, which suggested that CEPS and EPS induced reduction in the number of adipose tissue macrophages (ATM) as well as the shift toward M2polarity. A gene expression study showed that CEPS and EPS could improve the adipose tissue inflammation via decreasing the expression of TNF-α IL-6and increasing the expression of IL-10. In vitro, the inflammation response in TNF-a induced3T3-L1adipocytes was also attenuated by CEPS and EPS through down-regulating the production of NO and expression of TNF-α、IL-6、IL-1β, while up-regulating the expression of IL-10. CEPS and EPS probably alleviated chronic inflammation in adipose tissue through down-regulation of TLR4expression, suppression of IκBcα phosphorylation, subsequent NF-κB activation, as well as phosphorylation of c-Jun.
The above results suggested that Z0206polysaccharide reduced the macrophages infiltration and modulated adipose tissue macrophage polarization. On the other hand, Z0206polysaccharide improved adipose inflammation and prevented the lipid metabolism disorder by inhibiting the TLR4/IκBα/NF-κB pathway and c-Jun pathway
试验一.Z0206多糖产业化发酵条件建立及培养基组成优化
本试验选择能够进行产业化生产的玉米淀粉、豆粕粉、玉米浆干粉等为主要发酵原料对Z0206多糖的发酵条件和发酵培养基组成进行了筛选和优化。
在多糖的发酵条件优化方面,采用单因素试验优化了Z0206多糖的发酵温度、发酵转速和初始pH值,结果表明：Z0206多糖发酵的最佳温度为30℃、转速为250rpm、初始pH值为7.0。
在发酵培养基组成优化方面,首先采用单因素试验对发酵培养基成分进行了筛选,结果表明：以玉米淀粉为Z0206多糖工业化生产的碳源,以豆粕粉、玉米浆干粉和KN03为复合氮源,以CaCl2、K2HPO43H2O及KH2PO4为无机盐组成；采用正交试验设计优化了培养基中无机盐浓度,结果表明：当CaCl2,1g/L; K2HPO43H2O,3g/L; KH2PO4,3g/L时多糖产量最高；根据Box-Benhnken中心组合设计原理,以Z0206多糖产量为响应值,设计三因素三水平的响应面试验,优化了Z0206多糖发酵的最佳碳氮、源浓度为：玉米淀粉,240.95g/L；豆粕粉,22.19g/L；玉米浆干粉,6.61g/L。在以上优化条件下Z0206多糖的产量可达27.75g/L,是前期多糖产量的2倍以上。
试验二.Z0206多糖的分离纯化、化学组成及结构的初步分析
在优化了Z0206多糖发酵条件和培养基组成的基础上,进一步对发酵获得的Z0206多糖进行了分离纯化、化学组成及结构分析。在Z0206多糖的分离纯化方面,本试验结合Sevage和酶法脱蛋白,20%H2O2脱色,透析和冷冻干燥获得Z0206脱蛋白多糖(EPS)；并采用DEAE-52离子交换柱层析和Superose12凝胶色谱层析对EPS进行分离纯化,获得EPS-1和EPS-3两个主要多糖组分,得率分别为40.8%和26.7%。
在此基础上,采用凝胶渗透色谱、气相色谱、液相色谱及化学方法对以上两个组分的化学组成进行了分析,结果显示：EPS-1的相对分子质量为2527Da,是仅由葡萄糖组成的中性糖；EPS-3的相对分子质量为1.23x106Da,是由岩澡糖、半乳糖、葡萄糖、丙酮酸和糖醛酸组成的酸性糖,摩尔质量比为1.65：1.83：1：1.62：1.20。采用红外光谱仪、核磁共振仪、原子力显微镜和激光粒度仪对两个组分的结构进行了初步分析,结果表明：EPS-1和EPS-3糖链中均含有-CH2-基团,并存在α和β两种糖苷键构型。除此之外,EPS-3糖链中还存在糖醛酸、丙酮酸和岩澡糖单元；EPS-1的平均粒径为50.75nm,而EPS-3的平均粒径为210.3nm；在空间形貌上,EPS-1和EPS-3糖分子间均相互缠绕,聚集紧密成团,形成无规则排列的球状。
以上结果综合表明,Z0206多糖由中性糖和酸性糖组分构成,化学组成包括葡萄糖、半乳糖、岩澡糖,以及丙酮酸和糖醛酸单元；Z0206多糖链存在α和β两种糖苷键构型,在空间上呈现无规则排列的球状结构。
试验三.Z0206多糖缓解高脂诱导肥胖小鼠脂代谢紊乱的作用研究
在优化了Z0206多糖的发酵条件及培养基组成,并初步分析了Z0206多糖化学组成及结构的基础上,本试验通过建立高脂日粮诱导形成的C57BL/6肥胖小鼠模型,从表型变化、血液生化指标、组织形态等多方面研究了Z0206粗多糖(CEPS)及其脱蛋白多糖(EPS)对高脂诱导肥胖小鼠脂代谢紊乱的缓解作用。试验选取6周龄的雄性C57BL/6小鼠,分为普通日粮组(ND)和高脂日粮组(HFD),分别给与普通饲料(10%脂肪含量,Kca1%)和高脂饲料(45%脂肪含量,Kcal%),连续饲喂12周直至两组的平均体重差异显著。再将饲喂高脂日粮的小鼠随机分为高脂组(HFD)、Z0206粗多糖组(HFD+CEPS)和Z0206脱蛋白多糖组(HFD+EPS),多糖组每天分别灌胃200mg/kg.BW两种多糖溶液(10mg/mL), ND组和HFD组每天灌胃等体积的生理盐水,连续灌胃42d。研究结果显示：与高脂日粮组相比,CEPS和EPS均可减缓小鼠增重,降低空腹血糖浓度和血清胰岛素水平,提高胰岛素敏感指数(ISI)及小鼠口服葡萄糖耐量(P<0.05),并降低肥胖小鼠肝脏指数,皮下脂肪、腹部脂肪及附睾周脂指数,表明CEPS和EPS能抑制高脂诱导的脂肪过度沉积,并提高小鼠的胰岛素敏感性；血清生化指标结果表明：CEPS和EPS能通过降低血清游离脂肪酸(FFA)含量(P<0.05)以及总胆固醇(TC)、甘油三酯(TG)和低密度脂蛋白(LDL-c)的水平(P<0.05),并一定程度提高血清高密度脂蛋白(HDL-c)的水平,从而缓解高脂诱导的脂代谢紊乱现象；组织形态观察结果表明：CEPS和EPS均能通过缓解肥胖小鼠肝脏细胞的变形、肿胀、抑制脂滴形成,从而维护肝脏组织的结构完整性,缓解高脂诱导的肝脏脂肪变性；CEPS和EPS也能通过抑制肥胖小鼠附睾脂肪细胞过度增大,从而缓解高脂日粮导致的脂肪细胞肥大的现象；基因和蛋白检测结果显示：CEPS和EPS均能通过促进肥胖小鼠脂肪组织脂联素(Adiponectin)、内脏脂肪特异性丝氨酸蛋白酶抑制剂(Vaspin)、Visftin等胰岛素敏感性因子的mRNA表达,降低瘦素(Leptin)、抵抗素(Resistin)等胰岛素抵抗因子的mRNA表达,同时激活过氧化物酶体增生物激活受体γ (PPARγ)表达,并提高胰岛素作用通路中Aktl的磷酸化水平、胰岛素受体底物1(IRS-1)和葡萄糖转运蛋白4(Glut4)的基因表达,从而增强肥胖小鼠脂肪组织的胰岛素敏感性,调节机体能量代谢水平。
以上结果综合表明Z0206多糖能通过增强高脂诱导肥胖小鼠的葡萄糖摄取能力,缓解肝脏组织脂肪变性和脂肪组织过度肥大,从而缓解胰岛素抵抗；并通过调控脂肪因子表达和血脂平衡,维护机体脂代谢平衡,从而起到改善脂代谢紊乱的作用。
试验四.Z0206多糖缓解脂代谢紊乱的免疫学机制研究
在研究了Z0206多糖缓解高脂诱导的肥胖小鼠脂代谢紊乱作用的基础上,进一步从脂肪炎症的角度,采用免疫组化、流式细胞仪、荧光定量、Western blotting等技术探究了Z0206多糖缓解脂代谢紊乱的免疫学机制。脂肪组织巨噬细胞研究结果表明：CEPS和EPS均能通过减少附睾前脂肪组织中F4/80阳性细胞数量,降低CDllc+阳性细胞比例,同时减少巨噬细胞形成的"Crown like structure"数量,从而减少高脂诱导的脂肪组织巨噬细胞浸润；同时,CEPS和EPS均能通过上调M2型巨噬细胞标记基因CD209、CD163和Mg12的表达和下调M1型巨噬细胞标记基因F4/80、CD11c和单核细胞趋化蛋白-1(MCP-1)的表达,从而促进脂肪组织巨噬细胞由M1型向M2型分化；脂肪炎症因子表达方面,体内试验结果显示：CEPS和EPS均能提高附睾脂肪组织中抑炎细胞因子IL-10的表达,降低促炎细胞因子TNF-α、IL-6的表达；体外试验结果显示：Z0206多糖组分EPS-3同样能降低TNF-α刺激下3T3-L1小鼠脂肪细胞NO产生和促炎细胞因子TNF-α、IL-6、IL-1β的基因表达,并提高抑炎细胞因子IL-10的基因表达,由此表明Z0206多糖通过调控炎症因子的表达缓解了高脂诱导的脂肪炎症反应；基因及蛋白检测结果揭示：Z0206多糖可能通过下调脂肪细胞TLR4表达,降低IKBα磷酸化,抑制NF-κB活性,同时降低c-Jun氨基端激酶的磷酸化水平,从而缓解肥胖小鼠脂肪组织慢性低度炎症。
以上结果综合表明Z0206多糖一方面可以通过减少高脂诱导肥胖小鼠脂肪组织巨噬细胞浸润,并促进巨噬细胞由M1型向M2型分化；另一方面,Z0206多糖可能通过抑制脂肪细胞TLR4/IκBαa/NF-κB途径和c-Jun途径,降低促炎细胞因子生成,从而缓解高脂诱导下的脂肪组织炎症,有效防止脂代谢紊乱的发生。
In our previous study, Enterobacter cloacae Z0206, a bacterial strain, can produce large amounts of exopolysaccharides (EPS), was isolated from nature. The culture medium was optimized under laboratory conditions and EPS was found to have antioxidant, immunomodulatory, antiviral, hypoglycemic and especially hypolipidemic bioactivities. In order to establish a set of fermentation process for industrialized production and further clarify the effect of Z0206polysaccharide on lipid metabolism disorder induced by high fat diet. In the present study, we firstly optimized the industrial fermentation conditions and medium composition of EPS produce by Enterobacter cloacae Z0206with corn starch, soybean meal and corn steep power as substrates. The exopolysaccharide was purified with iron exchange chromatography and gel column chromatography, after that the chemical composition and structure of the main components were analyzed by a combination of Infrared Spectroscopy (IR), high Performance Liquid Chromatography (HPLC) and gas chromatography (GC) as well as nuclear magnetic resonance (NMR) and atomic force microscope (AFM). On the base of this, the effects of EPS produced by Enterobacter cloacae Z0206on lipid metabolism disorder in high fat diet induced C57BL/6mice and TNF-a induced3T3-L1were studied. The main results are as bellows:
1. Medium composition Optimization of EPS produced by E. cloacae Z0206
The industrial fermentation conditions and medium composition of EPS produce by Enterobacter cloacae Z0206were optimized with corn starch, soybean meal and corn steep power as substrates.
The optimization of fermentation conditions and the culture medium for the production of EPS from Enterobacter cloacae Z0206was studied using one-factor-at-a-time method, orthogonal matrix method and response surface methodology (RSM) with agroindustrial by-products as the main fermentation substrate. The results of one-factor-at-a-time test showed that the best conditions for title bacterial growth and EPS production were: fermentation temperature30℃, speed250rpm and initial pH7.0. The suitable carbon and complex nitrogen sources were corn starch and soy bean meal, corn steep powder and KNO3respectively. The concentration of inorganic salts and complex nitrogen sources were optimized by orthogonal matrix design. At last a three level, three factor Box-Behnken factorial design was used to optimize the level of three factors significantly affecting the yield of EPS. The optimal medium composition was determined as follows:240.95g/L cornstarch,22.19g/L soybean meal,6.61g/L corn steep powder,3g/L K2HPO43H2O,3g/L KH2PO4and1g/L CaCl2, with a corresponding yield of27.75g/L, which was approximately two times higher than that in the basal medium.
2. Purification, chemical composition and structure analysis of EPS
On the basis of optimization of fermentation conditions and culture medium, Z0206polysaccharide was further purified and its chemical composition and structure was analyzed. Crude exopolysaccharides (CEPS) were obtained from the fermentation broth by ethanol precipitation, EPS was obtained through deproteinization, decolorization and dialysis. The deproteinized exopolysaccharides were further purified through a DEAE-52iron exchange chromatography column and a Suprose12gel column. Two main components (EPS-1and EPS-3) were isolated by eluting with distilled water and a gradient of0-0.5mol/L NaCl solution, their yield was40.8%and26.7%respectively.
The gel permeation chromatography (GPC) analysis showed that the average molecular weights of EPS-1and EPS-3was2527Da and1.23×106Da respevtively. The neutral sugars, pyruvyl groups and glucuronic acid were analyzed using GC, reversed-phase high-performance liquid chromatography (RP-HPLC) and the carbazole-sulfuric acid method. EPS-1was found to be composed of glucose, and EPS-3was composed of fucose, galactose, glucose, pyruvic acid and glucuronic acid with the relative molar ratio of1.65:1.83:1:1.62:1.20. IR analysis showed that both EPS-1and EPS-3contained-CH2-groups. NMR analysis indicated that EPS-1and EPS-3contained a and β type glycosidic linkages and EPS-3also showed uronic acid carboxyl resonance, methyl groups of the ketal-substituted pyruvate residue and methyl groups of fucose. The average particle size distribution of EPS-1was50.57nm and EPS-3was210.3nm. The photograph of EPS-1and EPS-3fraction were obtained by atomic force microscope and showed that molecules of EPS-1and EPS-3are gathered up with each other in a tight manner.
3. Effect of Z0206polysaccharide on the lipid metabolism disorder in obese mice
On the base of structure analysis of EPS produced by Enterobacter cloacae Z0206, the effects of CEPS and EPS on the lipid metabolism disorder as well as insulin resistance in high fat induced C57BL/6mice were studied. C57BL/6mice were divided into two groups at the age of6weeks, normal diet (ND) group and high fat diet (HFD) group, feeding normal diet (10%fat kcal%) and high fat diet (45%fat kcal%) respectively for12weeks. Mice in HFD group were then allocated to HFD group, Z0206crude polysaccharide group (HFD+CEPS) and Z0206deproteinization polysaccharide group (HFD+EPS). CEPS and EPS were administered to C57BL/6mice for a period of42days, and the same volume of saline solution were administered to mice in ND and HFD groups. The results showed that administration of CEPS and EPS could significantly decrease the body weight gain, fasting glucose concentration and serum insulin levels, whereas improved the insulin sensitivity index (ISI) and OGTT compared with the HFD group. In addition, CEPS and EPS significantly decreased the liver index, adipose tissue index of subcutaneous fat, retroperitoneal fat and epididymal fat, indicating that CEPS and EPS can inhibit the excessive fat deposition and improve the insulin sensitivity. At the same time, serum free fatty acid (FFA) content, cholesterol (TC), triglyceride (TG) and low density lipoprotein (LDL-c) levels were significantly decreased in CEPS and EPS treated mice. Morphology observation shows that CEPS had significant protective effects in the integrity of the organizational structure of liver and the size of adipocyte in epididymal adipose tissue were significantly decreased in CEPS treated mice, which indicated that CEPS ameliorated adipocyte hypertrophy phenomenon in epididymal fat. The results of RT-PCR and western blotting showed that CEPS and EPS could significantly increase the gene expression of insulin-sensitizing factors like adiponectin, vaspin and visftin, while reduce the gene expression of insulin resistance factors like leptin and resistin. At the same time, the expression of PPARy and its target genes, glucose transport protein4(Glut4), insulin receptor substrate1(IRS-1) and Aktl were upregulated in the groups supplemented with CEPS and EPS, which indicated that CEPS and EPS increased the insulin sensitivity of high fat diet induced mice, sequentially regulated the energy metabolism.
The above results suggested that CEPS and EPS could enhance the capacity of glucose uptake, relieve fatty degeneration and adipocyte hypertrophy in high fat diet induced mice, thus alleviate insulin resistance. They maintained the lipid metabolism metabolic balance and improved the lipid metabolism disorder by regulating the expression of adipokines and blood lipid.
4. The immune mechanism of alleviation effect of Z0206polysaccharide on lipid metabolism disorder.
On the basis of the above experiments, the insulin-sensitizing mechanism of Z0206polysaccharide was further studied from the aspect of adipose inflammation using immunohistochemistry, flow cytometry, RT-PCR and Western blotting. The results showed that CEPS and EPS could reduce the F4/80positive macrophages and the ratio of CD11positive cells, and as well as the numbers of crown like structure (CLS) in epididymal adipose tissue compared with the high fat diet induced mice. We also found that treatment with CEPS and EPS markedly reduced the M1macrophages markers, such as F4/80, CDllc and MCP-1, whereas increased the M2macrophages markers, such as CD209, CD163and Mgl2, which suggested that CEPS and EPS induced reduction in the number of adipose tissue macrophages (ATM) as well as the shift toward M2polarity. A gene expression study showed that CEPS and EPS could improve the adipose tissue inflammation via decreasing the expression of TNF-α IL-6and increasing the expression of IL-10. In vitro, the inflammation response in TNF-a induced3T3-L1adipocytes was also attenuated by CEPS and EPS through down-regulating the production of NO and expression of TNF-α、IL-6、IL-1β, while up-regulating the expression of IL-10. CEPS and EPS probably alleviated chronic inflammation in adipose tissue through down-regulation of TLR4expression, suppression of IκBcα phosphorylation, subsequent NF-κB activation, as well as phosphorylation of c-Jun.
The above results suggested that Z0206polysaccharide reduced the macrophages infiltration and modulated adipose tissue macrophage polarization. On the other hand, Z0206polysaccharide improved adipose inflammation and prevented the lipid metabolism disorder by inhibiting the TLR4/IκBα/NF-κB pathway and c-Jun pathway
引文
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