CN109646430A - n-3多不饱和脂肪酸在制备预防沙门氏菌感染药物中的应用 - Google Patents
n-3多不饱和脂肪酸在制备预防沙门氏菌感染药物中的应用 Download PDFInfo
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Abstract
本发明公开了n‑3多不饱和脂肪酸在制备预防沙门氏菌感染药物中的应用，属于预防沙门氏菌感染领域。本发明通过沙门氏菌感染动物模型验证，n‑3多不饱和脂肪酸可显著降低死亡率，使得小鼠感染沙门氏菌的存活率从对照组的56％提高到了75％，提升33％。此外，n‑3多不饱和脂肪酸价格低廉，来源广泛，是常用的营养补品，安全稳定，还有重多健康益，如可预防心脑血管疾病、肥胖、代谢综合症等；可在沙门氏菌爆发期，但尚未出现感染症状时补充n‑3多不饱和脂肪酸来预防沙门氏菌感染或减缓病程，减少抗生素使用，避免抗生素带来的负面作用，且易于操作，具有很好的应用前景。
Description
技术领域
本发明属于预防沙门氏菌感染领域，具体涉及n-3多不饱和脂肪酸在制备预防沙门氏菌感染药物中的应用。
背景技术
细菌感染现有的治疗机理几乎都是通过抗生素的杀菌作用，且各种致病菌发病机理千差万别，比如：幽门螺杆菌产生的毒素和有毒性作用的酶能破坏胃黏膜屏障，使机体产生炎症和免疫反应，增加胃泌素的分泌，最终导致慢性胃炎、消化性溃疡、胃癌和黏膜相关性淋巴样组织(MALT)淋巴瘤；绿脓杆菌分泌的外毒素A(PEA)进入敏感细胞后被活化而发挥毒性作用，使得哺乳动物的蛋白合成受阻并引起组织坏死，可出现肝细胞坏死、肺出血、肾坏死以及休克。沙门氏菌是革兰氏阴性菌，是一种重要的食源性致病菌，通过被污染的水和食物传播，可感染多种动物和人，沙门氏菌感染后穿过肠道屏障，进入血液，随血液循环到达全身各个脏器，例如肝脏、脾脏等，并定植在脏器中，感染后会造成伤寒、肠胃炎、败血症甚至造成死亡。沙门氏菌每年给养殖业造成巨大经济损失，并危害公共健康和食品安全。
由于各种感染的作用机制完全不同，目前普适的方法都是利用抗生素直接杀菌，例如氯霉素、土霉素等。针对沙门氏菌，由于抗生素的滥用，其对抗生素耐药性增强，耐药谱加宽，且抗生素可能积攒在禽畜肉质中，影响肉类品质；抗生素处理还会扰乱正常肠道菌群平衡。沙门氏菌通常是无征兆地爆发，未有一定程度的病症是不能使用抗生素治疗的，抗生素有其负面影响，临床上不使用抗生素提前预防沙门氏菌的感染。因此，寻找一种更好预防或控制沙门氏菌感染且安全无副作用的方法是十分必要的。
发明内容
为了解决上述问题，本发明利用n-3多不饱和脂肪酸实现安全无副作用的沙门氏菌感染的预防或控制。n-3多不饱和脂肪酸，包括二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)，对动脉粥样硬化、心血管疾病、恶性肿瘤、神经退行性疾病、关节炎等慢性炎症有减轻作用。n-3多不饱和脂肪酸的健康益处被广泛报道，其也被作为均衡膳食中一部分，被国内外权威机构推荐摄入，其中世界卫生组织(WHO)推荐每天n-3多不饱和脂肪酸摄入量1％～2％，中国营养学会推荐18岁以上人群每天摄入EPA+DHA250～2000mg(宏量营养素可接受范围AMDR)。n-3多不饱和脂肪酸可以在沙门氏菌爆发期作为无副作用预防方式，感染后也可以减缓病程减轻疾病。
本发明的第一个目的是提供n-3多不饱和脂肪酸在制备预防或控制沙门氏菌感染药物中的应用。
本发明的第二个目的是提供一种预防或控制沙门氏菌感染的药物组合物，所述药物组合物包含n-3多不饱和脂肪酸。
在本发明的一种实施方式中，所述的药物组合物还包括药物载体和/或药用辅料。
在本发明的一种实施方式中，所述的药物组合物的剂型为医学上认可的任意一种剂型。
本发明的第二个目的是提供一种预防或控制沙门氏菌感染的药物制剂，所述药物制剂包含n-3多不饱和脂肪酸。
在本发明的一种实施方式中，所述制剂包括粉剂、注射液、胶囊、片剂、口服液。
本发明的第三个目的是提供一种在预防或控制沙门氏菌感染的食品或饲料，所述食品或饲料的配方包含n-3多不饱和脂肪酸。
本发明的第四个目的是提供一种预防或控制沙门氏菌感染的膳食补充剂，所述膳食补充剂的配方包含n-3多不饱和脂肪酸。
本发明的第五个目的是提供一种预防或控制沙门氏菌感染的中保健品，所述保健品的配方包含n-3多不饱和脂肪酸。
在本发明的一种实施方式中，所述的n-3多不饱和脂肪酸包括二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)。
本发明的n-3多不饱和脂肪酸在制备预防或控制沙门氏菌感染药物中的应用通过喂食-感染模型实验验证，所述模型实验包括：
(1)利用N-3组饲料、普通饲料分别喂食小鼠；
(2)将步骤(1)喂食的各小鼠进行感染实验，观察感染后的病变情况。
本发明的n-3多不饱和脂肪酸在制备预防或控制沙门氏菌感染药物中的应用通过以下实验所证实，实验方法如下：
1、建立小鼠沙门氏菌感染模型：沙门氏菌感染引起的肝脏组织病变，通过肝脏切片染色试验和小鼠感染沙门氏菌的存活率试验来验证预防、控制效果；沙门氏菌经口感染，会穿过肠道屏障，进入血液，随血液定植在各器官，例如肝脏，引起组织病变；感染沙门氏菌后，会引起小鼠体重下降、甚至死亡。
2、n-3多不饱和脂肪酸预防或控制沙门氏菌感染效果实验：
(1)将辐照小鼠基础维持饲料破碎、称量；N-3组饲料：在普通饲料中添加1％W/WEPA和1％W/W DHA，后加水捏合成团；N-6组添加2％W/W红花籽油，加水捏合成团；模型组(model)仅加水捏合成团；
(2)7周龄雌性C57BL/6小鼠经过适应性喂养一周后，随机分组，分别喂养不同饲料，食用实验饲料7天后，在感染之前4小时禁食禁水，灌胃鼠伤寒沙门氏菌SL1344(1x106/只)，感染后2小时恢复提供水和饲料。
本发明的有益效果：
1、本发明发现n-3多不饱和脂肪酸可有效提高沙门氏菌感染后存活率。利用喂食-感染实验模型验证了n-3多不饱和脂肪酸在预防沙门氏菌感染的效果，n-3多不饱和脂肪酸组小鼠感染沙门氏菌的存活率从模型组的56％提高到了75％，提高了33％；而富含n-6多不饱和脂肪酸的n-6组，死亡率最高；n-3多不饱和脂肪酸有效减轻沙门氏菌感染造成的小鼠脾脏肿大情况，防止出现体重骤减；此外，还能够明显降低沙门氏菌引起的IL-1β、IL-6、TNF-α、IFN-γ的升高，缓解肝脏组织损伤。
2、可在沙门氏菌爆发期，但尚未出现感染症状或症状较轻时补充n-3多不饱和脂肪酸，以预防沙门氏菌感染或减缓病程，减少抗生素使用。n-3多不饱和脂肪酸价格低廉，来源广泛，比如鱼油等物质。膳食补充n-3多不饱和脂肪酸的健康益处被广泛承认，且安全性稳定，已被多种临床实验证实。并且相对抗生素的无差别杀菌，n-3多不饱和脂肪酸不会扰乱正常肠道菌群，也不会导致细菌耐药性，且易于操作，应用前景广阔。
附图说明
图1为不同饲料喂养小鼠感染沙门氏菌存活率(n＝16)；
图2为不同饲料喂养小鼠感染沙门氏菌肝脏切片HE染色结果；
图3为不同饲料喂养小鼠感染沙门氏菌体重变化(n＝16)(第0天感染沙门氏菌)；
图4为感染前和感染后五天小鼠脾脏指数；
图5为感染前和感染后五天后小鼠肝脏炎症因子表达情况。
具体实施方式
实施例1：
将辐照小鼠基础维持饲料破碎、称量。N-3组饲料：在普通饲料(购于江苏协同医药生物工程有限责任公司，SPF级大小鼠维持鼠粮)中添加1％W/W EPA和1％W/W DHA，后加水捏合成团；N-6组饲料：在普通饲料中添加2％W/W红花籽油，加水捏合成团；模型组(model)仅是普通饲料加水捏合成团，作为对照；置于冰箱冷藏存放。各组分脂肪酸测量结果如表1所示。
表1各组饲料中脂肪酸含量比率(％)
注：表中比率数据由GC-MS测得；ND:not detected。
7周龄雌性C57BL/6小鼠经过适应性喂养一周后，随机分组，每天更换新饲料，防止其中脂肪酸氧化。相较于model组，n-3组每只鼠每日多摄入n-3多不饱和脂肪酸60mg(EPA30mg+DHA30mg)；n-6组每只鼠每日多摄入n-6多不饱和脂肪酸60mg。食用实验饲料7天后，在感染之前4小时禁食禁水，灌胃鼠伤寒沙门氏菌SL1344(1x106/只)，感染后2小时恢复提供水和对应脂肪酸饲料。观察动物行为和死亡只数。小鼠感染沙门氏菌存活率结果如图1所示，由小鼠存活率可以看出，膳食补充n-3多不饱和脂肪酸后，小鼠感染沙门氏菌的存活率从CTL组的56％提高到了75％，提高了33％；而模仿西方饮食富含n-6多不饱和脂肪酸的N-6组，死亡率最高。
不同饲料喂养小鼠感染沙门氏菌肝脏切片HE染色结果如图2所示，沙门氏菌感染五天后，小鼠肝脏出现炎细胞浸润(图2中的圆圈标记为发生炎细胞浸润)，N-6组最为严重，而N-3组可显著改善沙门氏菌感染引起的肝脏组织病变。
结合图3中不同饲料喂养小鼠感染前后小鼠体重变化，N-6组或者对照模型组中小鼠发生体重骤减，N-3组可显著改善小鼠身体状态，体重下降缓慢。
图4为感染前和感染五天后小鼠脾脏指数，结果表明，提前食用含n-3多不饱和脂肪酸的饲料可以有效减轻沙门氏菌感染造成的小鼠脾脏肿大。
分别取食用实验饲料七天后和感染沙门氏菌五天后小鼠，提取总肝脏mRNA进行real-time PCR，检测相关炎症因子IL-1β、IL-6、TNF-α、IFN-γ的基因表达水平，结果见图5(感染前和感染后五天小鼠肝脏炎症因子表达)。沙门氏菌感染后，引起了小鼠肝脏的炎症反应，并且食用n-3组饲料可以显著降低沙门氏菌引起的IL-1β、IL-6、TNF-α、IFN-γ的升高，与肝脏病例切片结果相符。n-3多不饱和脂肪酸可能通过降低沙门氏菌感染引起的体内炎症水平，进而缓解肝脏组织损伤。而对于正常未感染小鼠，食用不同饲料并不影响体内炎症因子的表达情况。
Claims (10)
1.n-3多不饱和脂肪酸在制备预防或控制沙门氏菌感染药物中的应用。
2.一种预防或控制沙门氏菌感染药物中的药物组合物，其特征在于，所述药物组合物包含n-3多不饱和脂肪酸。
3.根据权利要求2所述的药物组合物，其特征在于，所述的n-3多不饱和脂肪酸包括二十碳五烯酸和二十二碳六烯酸。
4.根据权利要求2或3所述的药物组合物，其特征在于，所述组合物还包括药物载体和/或药用辅料。
5.根据权利要求1-4任一所述的药物组合物，其特征在于，所述组合物的剂型为医学上认可的任意一种剂型。
6.一种预防或控制沙门氏菌感染的药物制剂，其特征在于，所述药物制剂包含n-3多不饱和脂肪酸。
7.根据权利要求6所述的药物制剂，其特征在于，所述药物制剂的剂型为医学上认可的任意一种剂型。
8.一种预防或控制沙门氏菌感染的膳食补充剂，其特征在于，所述膳食补充剂的配方包含n-3多不饱和脂肪酸。
9.一种预防或控制沙门氏菌感染的饲料，其特征在于，所述饲料的配方包含n-3多不饱和脂肪酸。
10.一种预防或控制沙门氏菌感染的食品或保健品，其特征在于，所述食品或保健品的配方包含n-3多不饱和脂肪酸。
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