两株乳酸杆菌对高脂饮食大鼠胆固醇影响及相关机制研究
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摘要
第一章降胆固醇益生菌株的体外筛选及菌株鉴定
目的：
从体检正常人群的粪便中分离出细菌菌株,从中体外筛选出有较好降胆固醇能力的菌株并予以鉴定,以利于进一步的研究。
方法：
以加入胆固醇的MRS培养基为载体,进行降胆固醇菌株的筛选,并对两株分解胆固醇效果好的细菌菌株进行耐酸耐胆汁及16sDNA部分序列测定的鉴定。
结果：
筛选出2株降胆固醇能力在30%以上的菌株,降解率是9-41-A36.8%, M1-1631.5%。两株菌均表现出较好的耐酸耐胆汁能力。对9-41-A和M1-16进行鉴定,初步鉴定9-41-A为植物乳杆菌,M1-16为发酵乳杆菌。
结论：
菌株9-41-A和M1-16在体外培养基中都有较强的降胆固醇能力和耐酸耐胆盐能力,经初步鉴定分别为植物乳杆菌及发酵乳杆菌。
第二章两株乳酸杆菌对饮食诱导的高脂血症SD大鼠模型胆固醇代谢影响的研究
目的：
观察乳酸杆菌9-41-=A和M1-16对高脂饮食喂养的SD大鼠体内胆固醇代谢的影响,评价其对高脂血症SD大鼠模型降胆固醇作用的有效性,从而为筛选到有利于人体的具备降胆固醇功能的菌株,为进一步了解其在体内的作用机制提供依据。
方法：
随机将40只SD大鼠分为初始体重无差异的4组,正常饮食组喂养普通饲料,高脂模型组、L.9-41-A组和L.M1-16组喂养高脂饮食,另外分别给L.9-41-A组和L.M1-16组的大鼠添加植物乳杆菌L.9-41-A或发酵乳杆菌L.M1-16。6周末处死大鼠,检测大鼠血脂指标,血清谷丙转氨酶,肝脂质、粪脂质,体重增加量,Lee指数,肝指数、体脂指数,肝组织病理学检查,小肠内容物菌群分析及粪便水分等指标。
结果：
1、高脂模型组的血清TCH,TG,LDL-C水平较之正常对照组均有明显升高(P<0.05),L.9-41-A组和L.M1-16组的血清TCH,TG,LDL-C水平较之高脂模型组明显下降,以L.9-41-A组效果较好。各组大鼠间的HDL-C没有明显差异(P>0.05)。
2、高脂模型组肝脏胆固醇和甘油三酯均比正常对照组升高,其差异有统计学意义。与高脂模型组比较,益生菌L.9-41-A组和L.M1-16组均可降低肝组织中胆固醇和甘油三酯的含量(P<0.05)。
3、高脂饮食的各组大鼠粪便胆固醇和胆汁酸排出量均高于正常饮食组,差异有统计学意义(P<0.05)。两组益生菌组大鼠粪便胆固醇和胆汁酸排出量又高于高脂模型组,差异有统计学意义(P<0.05)。
4、肝脏病理检查,高脂模型组脂肪浸润程度明显高于正常饮食组。两组益生菌可以显著改善肝脂肪浸润。
5、至第6周末各高脂饲料组体重均比正常饲料组增加明显(P<0.05),差异有统计学意义,以高脂模型组和L.M1-16组增加量最多,L.9-41-A组次之。
6、第6周末四组SD大鼠中正常组和L.9-41-A组的Lee’s指数最低,相较于模型组具有统计学意义(P<0.05)。正常组、L.9-41-A组和L.M1-16组的肝指数均出现明显下降(P<0.05)。正常组的体脂指数较其他高脂饮食组均小(P<0.05),模型组的体脂指数最高,益生菌组较模型组稍低,但组间比较无统计学意义(P>0.05)。
7、相较于高脂模型组,两组益生菌组的大肠杆菌菌落计数明显下降(P<0.05)。四组SD大鼠小肠内容物的肠球菌计数无明显差异(P>0.05)。高脂模型组的乳酸杆菌与双歧杆菌的数量要明显低于其他各组,而两组益生菌组可以明显增加小肠乳酸菌与双歧杆菌的数量(P<0.05)。
8、第6周末,两株乳酸杆菌可增加大鼠粪便水分含量(P<0.05)
9、四组大鼠间血清谷丙转氨酶无明显差异(P)0.05)。
结论：
1、以改良高脂饮食配方连续喂养SD大鼠6周后,可以成功造出大鼠高胆固醇血症模型。
2、植物乳杆菌L.9-41-A和发酵乳杆菌L.M1-16对SD大鼠高脂血症模型均有降低胆固醇和甘油三酯的作用,以L.9-41-A菌株较好。L.9-41-A菌可能还具有减轻体重的作用。
3、植物乳杆菌L.9-41-A和发酵乳杆菌L.M1-16增加了高脂饲料大鼠粪便中的胆固醇和胆汁酸排出量。
4、两株乳酸杆菌能够改善调节SD大鼠肠道内菌群,表现为增加乳酸杆菌和双歧杆菌的菌落数。
第三章两株乳酸杆菌对高胆固醇血症大鼠胆固醇代谢相关基因表达的影响
目的：
探讨植物乳杆菌L.9-41-A和发酵乳杆菌L.M1-16对高脂血症SD大鼠模型胆固醇及胆汁酸代谢途径中部分相关基因mRNA表达的影响,以进一步了解乳酸菌发挥降胆固醇作用的体内可能机制。
方法：
第6周末处死大鼠,低温保存各组肝脏及回肠粘膜上皮标本,用实时荧光定量PCR技术检测大鼠肝脏3-羟基-3-甲基戊二酸单酰辅酶A还原酶HMGCR,低密度脂蛋白受体LDL-R,胆固醇7α-羟化酶CYP7A1及回肠法尼酯受体FXR mRNA的相对表达。
结果：
1、与正常饲料组的大鼠比较,各高脂饲料组的大鼠肝脏HMGCR表达量都明显降低,各高脂饲料组中以L.9-41-A组最低,而高脂模型组与L.M1-16组之间无显著差异(P>0.05)
2、较之正常饲料组的大鼠,高脂模型组的大鼠肝脏LDL-R的表达量要明显降低,而两株益生菌组对大鼠肝脏LDL-R mRNA的表达有着极为明显的上调作用(P<0.05)。
3、较之正常饲料组的大鼠,高脂模型组和两株益生菌组的大鼠肝脏CYP7A1的表达量均明显上升,以益生菌L.9-41-A组上升幅度最大(P<0.05)。
4、与正常饮食组的大鼠比较,高脂模型组大鼠回肠CYP7A1表达量明显上升,益生菌L.9-41-A组和益生菌L.M1-16组的表达量上升幅度更大,差异具有统计学意义(P<0.05)。
结论：
菌株9-41-A和M1-16可能是通过直接或间接抑制肝脏HMGCR,上调肝脏LDL-R和CYP7A1,以及上调回肠FXR的mRNA表达水平来发挥降胆固醇和甘油三酯的效应的。
Chapter1Screening and Identification of Bacteria strains with Cholesterol-reducing ability in vitro
Objective:
To screen bacteria strains with the ability to reduce cholesterol in vitro from bacteria isolated from fecal samples of healthy adults and to give the targeted strains an identification for further study.
Methods:
We use modified cholesterol-MRS medium as the model to screen the potential targeted bacteria strains.After screeing,we selected two strains with better ability to reduce cholesterol and identified the two strains.
Results:
We screened out two strains with the cholesterol-reducing rate above30%,the detail rate is9-41-A36.8%and M1-1631.5%respectively. By preliminary identification we identified9-41-A as Lactobacillus plantarum strain and M1-16as Lactobacillus fermentum stain.
Conclusion:
9-41-A and M1-16had strong cholesterol-reducing,acid and bile acid tolerance abilities in vitro. Results of identification showed that 9-41-A and M2-1were Lactobacillus plantarum and Lactobacillus fermentum respectively.We plan to apply them in animal models to tset their cholesterol-lowering ability in vivo.
Chapter2Effects of two Lactobacillus strains on lipid metabolism and intestinal microflora of rats fed on a high-cholesterol diet
Objective:
To evaluate the effects of Lactobacillus plantarum9-41-A and Lactobacillus fermentum M1-16on body weight gain,lipid metabolism intestinal microflora and fecal water content of rats fed on high-cholesterol diet.
Methods:
Fourty Sprague Dawley rats were randomly divided into four groups.Control group received normal diet,model group received high-cholesterol diet,and intervention groups received high-cholesterol diet added with Lactobacillus plantarum9-41-A and Lactobacillus fermentum M1-16respectively. After a six-weeks feeding period,all rats were executed.Body weight (BW), Lee's index,liver index and fat index,cholesterol and lipid levels of serum and liver,fecal cholesterol and bile acid concentrations,intestinal microflora and fecal water content were measured.Liver lipid deposition was also classified pathologically.
Results:
In lactic acid bacteria (LAB) treated groups:(1)serum total cholesterol,low-density lipoprotein and triglycerides greatly reduced than rats in model group, while high-density lipoprotein appeared almost the same. Atherogenic indexes were improved.(2) hepatic cholesterol and triglycerides were also reduced obviously and liver lipid deposition was ameliorated after a high-cholesterol diet.(3) the level of fecal cholesterol and bile acid were significantly higher than control groups.(4) both strains of lactobacilli were able to increase Lactobacillus colony and Bifidobacterium colony and decrease Escherichia coli populations in intestine compared to rats fed with high-cholesterol diet only.Moreover, LAB treated groups excreted feces with more water. Besides,compared with the model group, L.9-41-A induced a decrease in BW gain.
Conclusion:
Hypocholesterolemic effect of LAB may differ among strains.The two local strains may have the ability to exert hypocholesterol effect, increase lactobacillus colony and Bifidobacterium colony count and fecal water content,thus beneficially affect the host.Moreover, L.9-41-A might act in controlling body weight.
Chapter3Effects of Administration of two Lactobacillus strains on mRNA levels of cholesterol metabolism related genes in SD Rats
Objective:
In order to furtherly understand the possible mechanisms in vivo,we investigate the Effects of Administration of two Lactobacillus strains on mRNA levels of cholesterol metabolism genes involved in cholesterol homeostasis in SD Rats.
Methods:
mRNA expression of3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR),LDL-receptor (LDL-R),cytochrome P4507α-1(CYP7A1) and farnesoid receptor (FXR) of SD rats were measured by real-time PCR.
Results:
The hepatic HMGCR levels in LAB treated rats were significantly lower than in rats of control and model groups and the LDLR,CYP7A1and FXR mRNA levels were significantly elevated.
Conclusion:
The mechanisms of the hypocholesterolemic effect of our two strains in vivo may related to some key regulate factors in the metabolism of cholesterol and bile acids of SD rats. The hepatic HMGCR levels in LAB treated rats were significantly reduced and the LDLR,CYP7A1and FXR mRNA levels were significantly elevated.
目的：
从体检正常人群的粪便中分离出细菌菌株,从中体外筛选出有较好降胆固醇能力的菌株并予以鉴定,以利于进一步的研究。
方法：
以加入胆固醇的MRS培养基为载体,进行降胆固醇菌株的筛选,并对两株分解胆固醇效果好的细菌菌株进行耐酸耐胆汁及16sDNA部分序列测定的鉴定。
结果：
筛选出2株降胆固醇能力在30%以上的菌株,降解率是9-41-A36.8%, M1-1631.5%。两株菌均表现出较好的耐酸耐胆汁能力。对9-41-A和M1-16进行鉴定,初步鉴定9-41-A为植物乳杆菌,M1-16为发酵乳杆菌。
结论：
菌株9-41-A和M1-16在体外培养基中都有较强的降胆固醇能力和耐酸耐胆盐能力,经初步鉴定分别为植物乳杆菌及发酵乳杆菌。
第二章两株乳酸杆菌对饮食诱导的高脂血症SD大鼠模型胆固醇代谢影响的研究
目的：
观察乳酸杆菌9-41-=A和M1-16对高脂饮食喂养的SD大鼠体内胆固醇代谢的影响,评价其对高脂血症SD大鼠模型降胆固醇作用的有效性,从而为筛选到有利于人体的具备降胆固醇功能的菌株,为进一步了解其在体内的作用机制提供依据。
方法：
随机将40只SD大鼠分为初始体重无差异的4组,正常饮食组喂养普通饲料,高脂模型组、L.9-41-A组和L.M1-16组喂养高脂饮食,另外分别给L.9-41-A组和L.M1-16组的大鼠添加植物乳杆菌L.9-41-A或发酵乳杆菌L.M1-16。6周末处死大鼠,检测大鼠血脂指标,血清谷丙转氨酶,肝脂质、粪脂质,体重增加量,Lee指数,肝指数、体脂指数,肝组织病理学检查,小肠内容物菌群分析及粪便水分等指标。
结果：
1、高脂模型组的血清TCH,TG,LDL-C水平较之正常对照组均有明显升高(P<0.05),L.9-41-A组和L.M1-16组的血清TCH,TG,LDL-C水平较之高脂模型组明显下降,以L.9-41-A组效果较好。各组大鼠间的HDL-C没有明显差异(P>0.05)。
2、高脂模型组肝脏胆固醇和甘油三酯均比正常对照组升高,其差异有统计学意义。与高脂模型组比较,益生菌L.9-41-A组和L.M1-16组均可降低肝组织中胆固醇和甘油三酯的含量(P<0.05)。
3、高脂饮食的各组大鼠粪便胆固醇和胆汁酸排出量均高于正常饮食组,差异有统计学意义(P<0.05)。两组益生菌组大鼠粪便胆固醇和胆汁酸排出量又高于高脂模型组,差异有统计学意义(P<0.05)。
4、肝脏病理检查,高脂模型组脂肪浸润程度明显高于正常饮食组。两组益生菌可以显著改善肝脂肪浸润。
5、至第6周末各高脂饲料组体重均比正常饲料组增加明显(P<0.05),差异有统计学意义,以高脂模型组和L.M1-16组增加量最多,L.9-41-A组次之。
6、第6周末四组SD大鼠中正常组和L.9-41-A组的Lee’s指数最低,相较于模型组具有统计学意义(P<0.05)。正常组、L.9-41-A组和L.M1-16组的肝指数均出现明显下降(P<0.05)。正常组的体脂指数较其他高脂饮食组均小(P<0.05),模型组的体脂指数最高,益生菌组较模型组稍低,但组间比较无统计学意义(P>0.05)。
7、相较于高脂模型组,两组益生菌组的大肠杆菌菌落计数明显下降(P<0.05)。四组SD大鼠小肠内容物的肠球菌计数无明显差异(P>0.05)。高脂模型组的乳酸杆菌与双歧杆菌的数量要明显低于其他各组,而两组益生菌组可以明显增加小肠乳酸菌与双歧杆菌的数量(P<0.05)。
8、第6周末,两株乳酸杆菌可增加大鼠粪便水分含量(P<0.05)
9、四组大鼠间血清谷丙转氨酶无明显差异(P)0.05)。
结论：
1、以改良高脂饮食配方连续喂养SD大鼠6周后,可以成功造出大鼠高胆固醇血症模型。
2、植物乳杆菌L.9-41-A和发酵乳杆菌L.M1-16对SD大鼠高脂血症模型均有降低胆固醇和甘油三酯的作用,以L.9-41-A菌株较好。L.9-41-A菌可能还具有减轻体重的作用。
3、植物乳杆菌L.9-41-A和发酵乳杆菌L.M1-16增加了高脂饲料大鼠粪便中的胆固醇和胆汁酸排出量。
4、两株乳酸杆菌能够改善调节SD大鼠肠道内菌群,表现为增加乳酸杆菌和双歧杆菌的菌落数。
第三章两株乳酸杆菌对高胆固醇血症大鼠胆固醇代谢相关基因表达的影响
目的：
探讨植物乳杆菌L.9-41-A和发酵乳杆菌L.M1-16对高脂血症SD大鼠模型胆固醇及胆汁酸代谢途径中部分相关基因mRNA表达的影响,以进一步了解乳酸菌发挥降胆固醇作用的体内可能机制。
方法：
第6周末处死大鼠,低温保存各组肝脏及回肠粘膜上皮标本,用实时荧光定量PCR技术检测大鼠肝脏3-羟基-3-甲基戊二酸单酰辅酶A还原酶HMGCR,低密度脂蛋白受体LDL-R,胆固醇7α-羟化酶CYP7A1及回肠法尼酯受体FXR mRNA的相对表达。
结果：
1、与正常饲料组的大鼠比较,各高脂饲料组的大鼠肝脏HMGCR表达量都明显降低,各高脂饲料组中以L.9-41-A组最低,而高脂模型组与L.M1-16组之间无显著差异(P>0.05)
2、较之正常饲料组的大鼠,高脂模型组的大鼠肝脏LDL-R的表达量要明显降低,而两株益生菌组对大鼠肝脏LDL-R mRNA的表达有着极为明显的上调作用(P<0.05)。
3、较之正常饲料组的大鼠,高脂模型组和两株益生菌组的大鼠肝脏CYP7A1的表达量均明显上升,以益生菌L.9-41-A组上升幅度最大(P<0.05)。
4、与正常饮食组的大鼠比较,高脂模型组大鼠回肠CYP7A1表达量明显上升,益生菌L.9-41-A组和益生菌L.M1-16组的表达量上升幅度更大,差异具有统计学意义(P<0.05)。
结论：
菌株9-41-A和M1-16可能是通过直接或间接抑制肝脏HMGCR,上调肝脏LDL-R和CYP7A1,以及上调回肠FXR的mRNA表达水平来发挥降胆固醇和甘油三酯的效应的。
Chapter1Screening and Identification of Bacteria strains with Cholesterol-reducing ability in vitro
Objective:
To screen bacteria strains with the ability to reduce cholesterol in vitro from bacteria isolated from fecal samples of healthy adults and to give the targeted strains an identification for further study.
Methods:
We use modified cholesterol-MRS medium as the model to screen the potential targeted bacteria strains.After screeing,we selected two strains with better ability to reduce cholesterol and identified the two strains.
Results:
We screened out two strains with the cholesterol-reducing rate above30%,the detail rate is9-41-A36.8%and M1-1631.5%respectively. By preliminary identification we identified9-41-A as Lactobacillus plantarum strain and M1-16as Lactobacillus fermentum stain.
Conclusion:
9-41-A and M1-16had strong cholesterol-reducing,acid and bile acid tolerance abilities in vitro. Results of identification showed that 9-41-A and M2-1were Lactobacillus plantarum and Lactobacillus fermentum respectively.We plan to apply them in animal models to tset their cholesterol-lowering ability in vivo.
Chapter2Effects of two Lactobacillus strains on lipid metabolism and intestinal microflora of rats fed on a high-cholesterol diet
Objective:
To evaluate the effects of Lactobacillus plantarum9-41-A and Lactobacillus fermentum M1-16on body weight gain,lipid metabolism intestinal microflora and fecal water content of rats fed on high-cholesterol diet.
Methods:
Fourty Sprague Dawley rats were randomly divided into four groups.Control group received normal diet,model group received high-cholesterol diet,and intervention groups received high-cholesterol diet added with Lactobacillus plantarum9-41-A and Lactobacillus fermentum M1-16respectively. After a six-weeks feeding period,all rats were executed.Body weight (BW), Lee's index,liver index and fat index,cholesterol and lipid levels of serum and liver,fecal cholesterol and bile acid concentrations,intestinal microflora and fecal water content were measured.Liver lipid deposition was also classified pathologically.
Results:
In lactic acid bacteria (LAB) treated groups:(1)serum total cholesterol,low-density lipoprotein and triglycerides greatly reduced than rats in model group, while high-density lipoprotein appeared almost the same. Atherogenic indexes were improved.(2) hepatic cholesterol and triglycerides were also reduced obviously and liver lipid deposition was ameliorated after a high-cholesterol diet.(3) the level of fecal cholesterol and bile acid were significantly higher than control groups.(4) both strains of lactobacilli were able to increase Lactobacillus colony and Bifidobacterium colony and decrease Escherichia coli populations in intestine compared to rats fed with high-cholesterol diet only.Moreover, LAB treated groups excreted feces with more water. Besides,compared with the model group, L.9-41-A induced a decrease in BW gain.
Conclusion:
Hypocholesterolemic effect of LAB may differ among strains.The two local strains may have the ability to exert hypocholesterol effect, increase lactobacillus colony and Bifidobacterium colony count and fecal water content,thus beneficially affect the host.Moreover, L.9-41-A might act in controlling body weight.
Chapter3Effects of Administration of two Lactobacillus strains on mRNA levels of cholesterol metabolism related genes in SD Rats
Objective:
In order to furtherly understand the possible mechanisms in vivo,we investigate the Effects of Administration of two Lactobacillus strains on mRNA levels of cholesterol metabolism genes involved in cholesterol homeostasis in SD Rats.
Methods:
mRNA expression of3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR),LDL-receptor (LDL-R),cytochrome P4507α-1(CYP7A1) and farnesoid receptor (FXR) of SD rats were measured by real-time PCR.
Results:
The hepatic HMGCR levels in LAB treated rats were significantly lower than in rats of control and model groups and the LDLR,CYP7A1and FXR mRNA levels were significantly elevated.
Conclusion:
The mechanisms of the hypocholesterolemic effect of our two strains in vivo may related to some key regulate factors in the metabolism of cholesterol and bile acids of SD rats. The hepatic HMGCR levels in LAB treated rats were significantly reduced and the LDLR,CYP7A1and FXR mRNA levels were significantly elevated.
引文
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