以酒精液态饲料评估副干酪乳杆菌Lactobacillus paracasei GKS68之护肝保健功效
Evaluation of Lactobacillus paracasei GKS68 on Hepatoprotection with Alcohol Liquid Diet

作者: 陈婉屏 , 蔡侑珊 , 陈炎炼 :葡萄王生技股份有限公司,台湾 桃园; 吴文歆 :上海葡萄王企业有限公司,上海; 陈劲初 :台湾大学食品科技研究所,台湾 台北;实践大学食品营养与保健生技学系,台湾 台北;中原大学生物科技学系,台湾 桃园;

关键词: 副干酪乳杆菌Lactobacillus paracasei GKS68肝脏保健酒精性肝病(ALD) Lactobacillus para-casei GKS68 Hepatoprotective Effect Alcoholic Liver Disease (ALD)

摘要:
过量饮酒易导致代谢过程产生过多自由基,造成氧化压力,影响脂质代谢造成脂肪累积于肝脏,长期会有慢性发炎、肝纤维化与肝癌等病变的风险。近年研究显示益生菌对人体健康扮演重要的角色。本研究以酒精液态饲料评估副干酪乳杆菌Lactobacillus paracasei GKS68之护肝保健功效。连续6周口服GKS68搭配酒精性饲料的C57BL/6雄性鼠动物模式中,小鼠之体重变化及摄取量与负对照组无显着差异;6周后牺牲进行血液生化分析,AST、ALT、TG、TC与负对照组均有显着下降。另外,肝脏相对重量、高剂量组之肝脏中TG、TC与负对照组亦有显着差异;肝脏酵素GSH含量、SOD活性在高剂量组与负对照组相比具有显着提升,显示GKS68可改善酒精引起的肝细胞损伤、有效降低酒精所造成的脂肪堆积,达到肝脏保健之功效。

Abstract: Excessive drinking could increase free radicals in the metabolic process, causing oxidative stress and accumulation of abnormal metabolites in the liver which higher the risk of developing chronic disease such as inflammation, liver fibrosis, and liver cancer. Recent studies have shown that probiotics are playing an important role as beneficial supplements to human health. In this study, we evaluated the effect of probiotics
Lactobacillus paracasei GKS68 (GKS68) on liver protection with alcohol-diet mouse model. Twenty C57BL/6 male mice were divided into four groups: normal diet, alcohol-diet, alcohol-diet with low-dosage of GKS68, and alcohol-diet with high-dosage of GKS68. After six weeks of treatment, there were no significant differences in body weight and food intake among the alcohol-diet group. However, the GKS68 group showed a significant decrease in serum ALT, AST, TG, TC and the relative liver weight when compared to the negative control. In addition, the levels of liver TG and TC were significantly decreased in the high-dosage of GKS68 with a comparison of alcohol-diet. A dose-dependent effect was also observed in the concentration of GSH and the SOD activity with GKS68. These results suggested that the probiotics GKS68 could reduce the liver damage caused by alcohol drinking and was a potential candidate as functional supplementary on hepatoprotection.

1. 引言

饮酒除了造成社会公共卫生问题,长期过量饮酒更影响身体健康状况,造成医疗与社会负担,近年来受到各国的重视。酒精大多都在肝脏进行代谢,产生自由基,造成氧化压力,增加胆固醇存生成,长期过量饮酒使体内脂质代谢失衡,造成过多的脂肪堆积形成脂肪肝、肝脏发炎甚至是不可逆的肝纤维化、肝癌等病变 [1] [2] [3]。脂肪肝目前没有有效治疗的药物,但是一种可逆的状态,可经过饮食与生活习惯的调整,降低肝脏发炎、肝纤维化或肝硬化的发生 [4] [5]。

益生菌是非病原性微生物,具有安全的特性 [6] [7],近年研究指出益生菌如Lactobacillus属,具肠胃道保健、免疫调节、体重管理等益处,可开发作为保健之用途 [8] - [13]。副干酪乳杆菌Lactobacillus paracasei相关研究指出,在模拟消化过程的耐酸性及耐胆盐试验,仍有80%以上存活 [14];非酒精性脂肪肝动物试验中,显着透过增强了肝脏和血清中的超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)的活性,降低发炎反应 [15];在高脂饮食的动物试验中,减轻了高脂饲料诱导的肝脂肪变性,减少了血清总甘油三酸酯和胆固醇,并出现降低空腹血糖和胰岛素的现象 [16];喂食高浓度葡萄糖具有抑制血糖上升效果,以高脂饮食喂食大鼠动物试验中,显示亦可有效抑制高血糖的现象 [17];透过促进成骨细胞分化和抑制破骨细胞形成,改善小鼠的骨质流失 [18]。本篇将进行酒精液态饲料动物模式评估副干酪乳杆菌Lactobacillus paracasei GKS68之护肝保健功效。

2. 材料与方法

2.1. 试验菌株

副干酪乳杆菌Lactobacillus paracasei GKS68经37℃、16小时于MRS培养基中培养后,于25℃以5000 rpm离心10分钟取菌泥,混入20%脱脂乳粉后冷冻干燥而得。调整菌数为2.0 × 1011 CFU/g供试验喂食。

2.2. 动物分组与试验投予

本试验经实验动物照护及使用委员会同意,核准编号IACUC No. MG109023。自台湾乐斯科生物科技股份有限公司购入八周龄之C57BL/6品系雄性鼠20只,经驯化后采随机分组,每组五只,进行试验,试验前对照组逐步增加酒精饲料中酒精含量,让动物适应含酒精之液态饲料(LDE),正常组皆喂食不含酒精之液态饲料,酒精热量由麦芽糖取代(LDC)。经酒精饲料适应后,连续六周口服头与试验物质或灭菌水(如表1),投予体积为10 mL/kg。

Table 1. The experimental groups in this study

表1. 小鼠试验组别分组

LDC1:不含酒精之液态饲料酒精热量由麦芽糖取代Lieber-Decarli control liquid diet;LDE2:含酒精之液态饲料Lieber-Decarli ethanol liquid diet。

2.3. 试验动物观察及检体采集

2.3.1. 试验动物观察

试验期间定时测量试验动物体重变化及其饲料摄取量。

2.3.2. 检体采集

牺牲时采集血液、肝脏检测所有受试小鼠血清生化值指标、肝脏中三酸甘油脂及总胆固醇含量、肝脏酵素活性指标等检测。

2.4. 评估项目

肝脏重量、血清生化指标(天门冬氨酸转氨酶Aspartate aminotransferase AST、丙胺酸转氨酶Alanine aminotransferaseALT浓度、三酸甘油脂、总胆固醇浓度)、肝脏三酸甘油脂及总胆固醇含量、肝脏酵素活性 (谷胱甘肽还原酶活性glutathione reductase GRd、超氧化物歧酶活性superoxide dismutase SOD、麸胱甘肽浓度glutathione GSH、麸胱甘肽过氧化酶活性glutathione peroxidase GPx)。

2.5. 资料分析

资料以实验结果之平均值(mean) ± 标准偏差(standard deviation S.D.)表示。采用计算机统计软件包,各试验组之数据先依单因子变异数分析(one-way analysis of variance, ANOVA)进行检定,再以Duncan’s multiple range比较各组间是否具差异性。若p值小于0.05则表示两试验组之间具有统计上显着差异。

3. 结果

3.1. 体重与摄食量变化

#表示与正常组比较p < 0.05,*表示与负对照组比较p < 0.05。#a sinificant difference with normal control (p < 0.05); *a sinificant difference with negative control (p < 0.05).

Figure 1. Weight changein C57BL/6 mice during the trial

图1. 试验期间小鼠体重变化

试验前负对照组、GKS68低剂量组GKS68-L组与GKS68高剂量组GKS68-H组逐步增加酒精饲料中酒精含量,让动物适应含酒精之液态饲料,正常组皆喂食不含酒精之液态饲料(酒精热量由麦芽糖取代)。试验第一周至第六周期间,正常组的体重均显着高于摄食含酒精之液态饲料组别(p < 0.05);在含酒精之液态饲料组别中,不论投与GKS68剂量高低,体重变化与负对照组相比均无显着差异(图1),摄食变化量各组别间亦无显着差异(p > 0.05)。

3.2. 相对肝脏重量变化

肝脏相对重量(g) = [肝脏重(g) ÷ 体重(g)] × 100,试验结束,负对照组其肝脏相对重量(g/100 g体重)明显大于正常组(图2),GKS68-L组与GKS68-H组之肝脏相对重量与负对照组相比均有显着下降(p < 0.05)。

3.3. 血清天门冬氨酸转氨酶(Aspartate Aminotransferase, AST)与丙胺酸转氨酶(Alanine Aminotransferase, ALT)浓度

图3显示负对照组血清之AST与ALT皆明显高于正常组(p < 0.05)。GKS68-L组与GKS68-H组之AST、ALT指标均显着低于负对照组(p < 0.05)。

#表示与正常组比较p < 0.05,*表示与负对照组比较p < 0.05。#a sinificant difference with normal control (p < 0.05); *a sinificant difference with negative control (p < 0.05).

Figure 2. Effects of Lactobacillus paracasei GKS68 on relative liver weight

图2. 副干酪乳杆菌GKS68对肝脏相对重量的影响

3.4. 血清之三酸甘油酯含量与总胆固醇浓度

图4显示负对照组血清之总胆固醇浓度与三酸甘油酯含量皆明显高于正常组。GKS68-L组与GKS68-H组血清中之三酸甘油酯含量、总胆固醇浓度相对于负对照组皆显着降低(p < 0.05)。

3.5. 肝脏总胆固醇及三酸甘油酯含量

负对照组肝脏中之总胆固醇与三酸甘油酯含量皆明显高于正常组(图5)。相较于负对照组,GKS68-H组肝脏中之三酸甘油酯、总胆固醇含量皆显着降低(p < 0.05),显示可有效降低酒精所造成的脂肪堆积。

#表示与正常组比较p < 0.05,*表示与负对照组比较p < 0.05。#a sinificant difference with normal control (p < 0.05); *a sinificant difference with negative control (p < 0.05).

Figure 3. Effects of Lactobacillus paracasei GKS68 on serum AST and ALT

图3. 副干酪乳杆菌GKS68对血清中AST与ALT影响

#表示与正常组比较p < 0.05,*表示与负对照组比较p < 0.05。#a sinificant difference with normal control (p < 0.05); *a sinificant difference with negative control (p < 0.05).

Figure 4. Effects of Lactobacillus paracasei GKS68 on serum TG and TC

图4. 副干酪乳杆菌GKS68对血清中三酸甘油酯含量与总胆固醇浓度的影响

#表示与正常组比较p < 0.05,*表示与负对照组比较p < 0.05。#a sinificant difference with normal control (p < 0.05); *a sinificant difference with negative control (p < 0.05).

Figure 5. Effects of Lactobacillus paracasei GKS68 on liver TG and TC

图5. 副干酪乳杆菌GKS68对肝脏总胆固醇及三酸甘油酯含量的影响

3.6. 肝脏酵素分析

负对照组肝脏组织之抗氧化酵素(麸胱甘肽GSH含量及麸胱甘肽过氧化酶GPx、谷胱甘肽还原酶活性GRd 、超氧化物歧化酶SOD之活性)均显着低于正常组,显示酒精会消耗清除自由基的麸胱甘肽含量并降低肝脏抗氧化酵素活性。经投予GKS68-H六周后,小鼠肝脏中的麸胱甘肽含量(图6)与超氧化物歧化酶活性显着高于负对照组(图7) (p < 0.05)。

#表示与正常组比较p < 0.05,*表示与负对照组比较p < 0.05。#a sinificant difference with normal control (p < 0.05); *a sinificant difference with negative control (p < 0.05).

Figure 6. Effects of Lactobacillus paracasei GKS68 on GSH levels in liver

图6. 副干酪乳杆菌GKS68对肝脏组织之抗氧化酵素GSH含量影响

#表示与正常组比较p < 0.05,*表示与负对照组比较p < 0.05。#a sinificant difference with normal control (p < 0.05); *a sinificant difference with negative control (p < 0.05).

Figure 7. Effects of Lactobacillus paracasei GKS68 on SOD activity in liver

图7. 副干酪乳杆菌GKS68对肝脏组织之抗氧化酵素SOD活性影响

4. 讨论

根据调查,饮酒行为有增加的趋势 [19] [20],近两成的饮酒者属于过量饮酒 [20] [21],根据2018年WHO发布的酒精与健康全球状况报告指出,全世界因饮酒引起的死亡中,主要包含受伤(交通意外、自伤或是酒后暴力等)、消化系统疾病、心血管疾病、传染病、癌症等,2016年滥用酒精造成的死亡占所有死亡的5.3% [21]。酒精诱导的内毒素是革兰氏阴性细菌外膜不可或缺的组成部分,可激活肝脏中驻留的免疫细胞分泌产生促进炎症反应的信号分子以及称为活性氧(ROS)的分子,并最终导致肝损伤,藉由肠道菌相改变可能有助于预防或改善酒精性肝病 [22]。

1989年研究指出酒精性饲料喂食小鼠,在肝脏及血液分析显示三酸甘油酯与胆固醇上升,建立慢性酒精性脂肪肝之动物模式 [23]。本试验以酒精液态饲料搭配口服副干酪乳杆菌Lactobacillus paracasei GKS68喂食小鼠评估是否具护肝保健功效,在负对照组的体重变化、血清生化值、肝脏三酸甘油酯及总胆固醇浓度、肝组织的抗氧化四种酵素相较于正常组,皆呈现显着差异,显示本实验之酒精性饲料确实对小鼠造成伤害。肝细胞的AST、ALT上升为肝脏伤害之指标;本实验结果显示GKS68可有效降低血清中的AST及ALT浓度,改善酒精引起的肝细胞损伤。身体的脂肪-三酸甘油酯与胆固醇,蓄积在血管,血脂异有心血管疾病的风险,在肝脏,堆积形成脂肪肝,进而造成慢性肝炎及肝硬化;本实验中血清及肝脏中三酸甘油酯及总胆固醇浓度低于负对照组,显示GKS68有效改善酒精造成的脂质堆积现象;GSH及GPx、GRd、SO是四种肝脏清除自由基的酵素,酒精代谢产生自由基,本实验的高剂量组之GSH及SOD活性显着提高,显示藉由提升GSH及SOD活性减低自由基对肝脏所造成的伤害。

5. 结论

藉由以酒精液态饲料评估副干酪乳杆菌Lactobacillus paracasei GKS68是否具护肝保健功效。将雄性C57BL/6小鼠分组,包含正常组、负对照组、GKS68低剂量组、GKS68高剂量组。投与试验物质6周,除了正常组外,其余组别皆给予含5%的液态饲料;试验结束时,检测小鼠血清中天门冬氨酸转氨酶(AST)、丙胺酸转氨酶(ALT),并进一步检测血清中三酸甘油酯及总胆固醇浓度、肝脏中三酸甘油酯及总胆固醇含量、肝脏抗氧化酵素活性/含量等项目,藉此评估副干酪乳杆菌GKS68是否有护肝保健之效果。

本试验证实GKS68具有降低血清AST、ALT、三酸甘油酯及总胆固醇浓度,高剂量GKS68降低肝脏中三酸甘油酯与总胆固醇含量,增加麸胱甘肽含量及超氧化物歧化酶活性等功效,具发展为护肝保健食品之潜能。

NOTES

*通讯作者。

文章引用: 陈婉屏 , 蔡侑珊 , 吴文歆 , 陈炎炼 , 陈劲初 (2021) 以酒精液态饲料评估副干酪乳杆菌Lactobacillus paracasei GKS68之护肝保健功效。 食品与营养科学, 10, 24-32. doi: 10.12677/HJFNS.2021.101004

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