口服微囊化噬菌体的制备及其在胃肠环境中的稳定性、释放行为和抗菌活性研究
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摘要
噬菌体是一类细菌性病毒,其中裂解性噬菌体在感染宿主菌后能快速复制增殖,并最终破裂菌体细胞从而达到抗菌效果。与传统的抗生素相比,噬菌体治疗具有特异性强、自我复制增殖、安全无残留以及来源丰富等优势,因此被认为是一种理想的抗生素替代品。
噬菌体在防治动物细菌性疾病方面卓有成效,但目前存在的问题是噬菌体缺乏合适的给药剂型,尤其是在治疗动物肠道疾病时,口服噬菌体的活性易遭胃酸、消化酶和胆汁酸盐的破坏,丧失抗菌活性。因此,开发噬菌体口服给药系统便成为噬菌体治疗领域亟待解决的问题,而以pH敏感性高分子为载体材料对噬菌体进行微囊化包埋不失为一种理想的策略。
本研究首先以海藻酸钠和壳聚糖为载体材料,通过液滴法对沙门氏菌噬菌体FelixOl进行微囊化包埋。结果显示,噬菌体在整个包埋过程中能够保持完整的生物活性,且平均包埋率达到93.3%。未包埋噬菌体Felix O1对酸极其敏感,在pH<3.7的酸性溶液中,孵育5 min活性即完全丧失。微囊化噬菌体对酸耐受性显著提高,在pH 2.4的模拟胃液中孵育1 h,效价仅降低2.58 log10PFU/g;噬菌体Felix O1在胆汁酸中不稳定,未包埋噬菌体在1%和2%的胆汁酸中孵育3h后,效价分别降低1.29和1.67log10PFU/g,而微囊化噬菌体的活性则完全保留；在模拟肠液中,微囊化噬菌体孵育6h后近乎完全释放。另外,噬菌体在湿态微球中具有很好的保存稳定性,4℃保存6个星期,活性无明显损失；对干燥微球,40℃或22℃保存6个星期后,噬菌体效价分别下降了0.90和1.20log10PFU/g,故较常温条件,微囊化噬菌体在4℃条件下保存更稳定。
为增加微囊化噬菌体在酸性环境中的稳定性,并改变其释放性能,本论文向海藻酸钙微球中分别添加了CaCO3无机微粒和乳清蛋白。结果显示海藻酸钙微球中掺合CaCO3微粒后,噬菌体的包埋率不受影响,对胃酸耐受性显著提高,在pH 2.5的模拟胃液中孵育2 h后效价仅下降0.17log10PFU/g;噬菌体在模拟肠液中的释放减慢,12小时后累计释放率约为68%。以海藻酸钠和乳清蛋白共混凝胶为载体微球时,噬菌体在pH 2.5的模拟胃液中孵育2 h后效价仅下降0.53 log10PFU/g;在模拟肠液中的释放加快,孵育3 h后噬菌体基本完全释放。释药模型的拟合结果显示噬菌体为非Fickian扩散控制型释放,微球骨架溶蚀或内部凝胶网络的酶解断裂是噬菌体释放的控制因素。在对微囊化噬菌体干燥保护剂的筛选时发现蔗糖、海藻糖、麦芽糊精和脱脂奶粉均能增加噬菌体K在干燥过程中的稳定性,且干燥保护效果与浓度相关。
动物体内实验,以鸡和小鼠为实验动物模型,研究口服微囊化噬菌体在动物消化道中的释放行为及分布规律,并比较不同载体微球间噬菌体释放行为的差异。结果显示以Chitosan-Alginate微球和Alginate/CaCO3微球为包埋载体时,微囊化噬菌体在鸡肠道中难以释放,口服后1-4 h肠道各部位释放量均低于4log10PFU/g,相比较在小鼠肠道中释放量明显增加但也不完全。而经Alginate/Whey微球包埋后,噬菌体通过鸡肌胃后的存活率显著提高,而且能够在肠道内充分释放。进一步通过对鸡的沙门氏菌攻毒保护实验证实,口服Alginate/Whey微囊化噬菌体后12h和24 h,鸡盲肠中沙门氏菌浓度分别降低了1.34和1.27log10CFU/g,减菌效果显著优于未包埋噬菌体组。
采用人结肠腺癌细胞株Caco-2体外培养模型,研究了噬菌体对胞内鼠伤寒沙门氏菌的裂解活性。结果表明噬菌体Felix O1对已侵入胞内的沙门氏菌无感染能力,仅能抑制细菌对宿主细胞的侵入,提示沙门氏菌的胞内侵袭性可能是影响噬菌体抗菌效果的限制因素之一。
综上所述,本研究成功制备出口服微囊化噬菌体,并通过体外和体内实验考察了微囊化噬菌体在胃肠道环境中的稳定性、释放行为及抗菌活性；实验结果证实微囊化包埋能保护噬菌体免受胃酸和胆汁的破坏作用,并提供足量的噬菌体进入肠道中释放,充分发挥其抗菌作用,这为噬菌体在动物细菌性疾病防治中的应用奠定了基础。
Bacteriophages (or phages) are viruses that invade bacteria cells and, in the case of lytic phages, multiply rapidly till the complete lysis of bacteria. Phage therapies have unique advantages compared with common antibiotics by their host-specificity, exponential growth, low side effects and their ubiquitous and plentiful nature. Therefore, bacteriophages have been suggested as possible alternatives to chemical antibiotics.
Recent studies indicate that phages can be used effectively to control and treat bacterial infections in animals, but one problem is that the viability of orally administered phages may be rapidly reduced under acidic conditions of the stomach and in the presence of gastric acid, enzymes, and other digestive compounds such as bile. Without protection phages might not survive gastric passage and thus not be infective in the intestine. Therefore, it is highly necessary to develop an effective delivery system to protect orally administered phages from the harsh gastrointestinal environment enroute to the infection site in the intestine. One possible way of protection of phages is by encapsulating them in microspheres of pH-dependent polymers.
Here, we reported a process for the microencapsulation of Salmonella bacteriophage Felix 01 using natural polysaccharides such as alginate and chitosan. The results showed that the phage was efficiently entrapped in the alginate gel matrix and the microsphere formation process had no detrimental effect on the viability of phage. The mean encapsulation efficiency of phage in Chitosan-Alginate microspheres was 93.3%. In vitro studies were used to determine the effects of simulated gastric fluid (SGF) and bile salts on the viability of free and encapsulated phages. Free phages Felix O1 were found extremely sensitive to acidic environment and were not detectable after 5 min incubation in SGF when the pH value was below 3.7. The viable count of microencapsulated phages decreased only 2.58 log10PFU/g during 1 h exposure to SGF with pepsin at pH 2.4. After 3 h of incubation in 1 and 2% bile salt solutions, the free phage count decreased by 1.29 and 1.67 log10PFU/g respectively, while the viability of encapsulated phages was fully maintained. Phages were completely released from microspheres upon exposure to simulated intestinal fluid (SIF, pH 6.8) within 6 hours. The encapsulated phages in wet microspheres retained full viability when stored at 4℃during the testing period (6 weeks). The microencapsulated phages in dried form had a 0.90 log10PFU/g reduction after 6 weeks storage at 4℃, whereas a 1.20 log10PFU/g reduction occurs after 6 weeks at 22℃. The results demonstrate that dried encapsulated phage stored at 4℃shows better stability than phage kept at room temperature.
In order to develop an improved microsphere delivery system with enhanced acid resistance for oral delivery of phage. CaCO3 microparticles and whey protein were co-encapsulated with phage K into alginate microspheres and tested for its efficacy in improving the viability of phage under in vitro acidic conditions. Free phage was completely destroyed when exposed to SGF of pH 2.5. By adding CaCO3 as an antacid excipient to the alginate microspheres, the stability of encapsulated phage K in SGF was largely improved, with only a 0.17 log10PFU/g reduction after 2 h exposure to SGF at pH 2.5, but the release was delayed in SIF, the cumulative release was only about 68% after 12 h. Besides, a combination of alginate and whey protein also led to a better protection for phage K in SGF, the phage titer decreased only by 0.53 log10PFU/g after 2 h exposure to SGF at pH 2.5. In additon, the Alginate/Whey microspheres showed a rapid release profile, and an almost complete release of phage was achieved after 3 h incubation in SIF. The curve fitting data indicated that the phage release mechanism followed non-fickian diffusion pattern, which controlled by erosion of the matrix or enzymatic degradation of the hydrogel network. A number of protective agents including trehalose, sucrose, skim milk, and maltodextrin were tested and found to increase the viability of encapsulated phage K when subjected to drying. The protective effects varied with the type and concentration of each incorporated additives.
In vivo, different phage-loaded microspheres were tested in chickens and mice to determine the release profile and gastrointestinal distribution of the encapsulated phage in the digestive tracts. The results showed that there was only a small portion of released phage was detected in chickens' intestine after 1-4 h of administration of Chitosan-Alginate and Alginate/CaCO3 microspheres (<4 Log10PFU/g), whereas the Alginate/Whey microspheres showed a complete release of phage in both chick and mouse intestine. The free and Alginate/Whey encapsulated phage Felix 01 were then administered to chickens experimentally colonized with S. Typhimurium. Treatment with encapsulated phage resulted in a 1.34 and 1.27 log10CFU/g reduction of cecal Salmonella counts at 12 h and 24 h respectively after challenge as compared with untreated controls. But no significant reduction of cecal Salmonella counts was observed in the chickens treated by free phage. The results indicated that microencapsulation of phage Felix 01 into Alginate/Whey microspheres significantly enhanced its efficacy in reducing Salmonella colonization in chickens.
The human adenocarcinoma derived Caco-2 cells were used as an in vitro model to investigate the killing activity of phage Felix 01 against intracellular Salmonella. The results showed that S. Typhimurium can invade and survive inside the Caco-2 cell monolayers. Phage Felix O1 has no lytic activity against intracellular Salmonella, but can inhibit the invasion of Caco-2 cells by the bacteria. The results indicated that the invasion and intracellular survival of Salmonella would be a limiting factor for the antimicrobial activity of bacteriophage.
In conclusion, an oral microencapsulated form of bacteriophages were successfully prepared in this study, besides, the gastrointestinal stabilities, release profiles and antimicrobial activities of the microencapsulated phages were evaluated through both in vitro and in vivo experiments. The results demonstrated that microencapsulation can protect phages against gastric juice and bile, and also facilitate oral delivery of a high enough dose of phages to the intestine. Therefore, the current encapsulation approach would lay the foundation for the therapeutic use of phages to control bacterial infections in animals.
噬菌体在防治动物细菌性疾病方面卓有成效,但目前存在的问题是噬菌体缺乏合适的给药剂型,尤其是在治疗动物肠道疾病时,口服噬菌体的活性易遭胃酸、消化酶和胆汁酸盐的破坏,丧失抗菌活性。因此,开发噬菌体口服给药系统便成为噬菌体治疗领域亟待解决的问题,而以pH敏感性高分子为载体材料对噬菌体进行微囊化包埋不失为一种理想的策略。
本研究首先以海藻酸钠和壳聚糖为载体材料,通过液滴法对沙门氏菌噬菌体FelixOl进行微囊化包埋。结果显示,噬菌体在整个包埋过程中能够保持完整的生物活性,且平均包埋率达到93.3%。未包埋噬菌体Felix O1对酸极其敏感,在pH<3.7的酸性溶液中,孵育5 min活性即完全丧失。微囊化噬菌体对酸耐受性显著提高,在pH 2.4的模拟胃液中孵育1 h,效价仅降低2.58 log10PFU/g;噬菌体Felix O1在胆汁酸中不稳定,未包埋噬菌体在1%和2%的胆汁酸中孵育3h后,效价分别降低1.29和1.67log10PFU/g,而微囊化噬菌体的活性则完全保留；在模拟肠液中,微囊化噬菌体孵育6h后近乎完全释放。另外,噬菌体在湿态微球中具有很好的保存稳定性,4℃保存6个星期,活性无明显损失；对干燥微球,40℃或22℃保存6个星期后,噬菌体效价分别下降了0.90和1.20log10PFU/g,故较常温条件,微囊化噬菌体在4℃条件下保存更稳定。
为增加微囊化噬菌体在酸性环境中的稳定性,并改变其释放性能,本论文向海藻酸钙微球中分别添加了CaCO3无机微粒和乳清蛋白。结果显示海藻酸钙微球中掺合CaCO3微粒后,噬菌体的包埋率不受影响,对胃酸耐受性显著提高,在pH 2.5的模拟胃液中孵育2 h后效价仅下降0.17log10PFU/g;噬菌体在模拟肠液中的释放减慢,12小时后累计释放率约为68%。以海藻酸钠和乳清蛋白共混凝胶为载体微球时,噬菌体在pH 2.5的模拟胃液中孵育2 h后效价仅下降0.53 log10PFU/g;在模拟肠液中的释放加快,孵育3 h后噬菌体基本完全释放。释药模型的拟合结果显示噬菌体为非Fickian扩散控制型释放,微球骨架溶蚀或内部凝胶网络的酶解断裂是噬菌体释放的控制因素。在对微囊化噬菌体干燥保护剂的筛选时发现蔗糖、海藻糖、麦芽糊精和脱脂奶粉均能增加噬菌体K在干燥过程中的稳定性,且干燥保护效果与浓度相关。
动物体内实验,以鸡和小鼠为实验动物模型,研究口服微囊化噬菌体在动物消化道中的释放行为及分布规律,并比较不同载体微球间噬菌体释放行为的差异。结果显示以Chitosan-Alginate微球和Alginate/CaCO3微球为包埋载体时,微囊化噬菌体在鸡肠道中难以释放,口服后1-4 h肠道各部位释放量均低于4log10PFU/g,相比较在小鼠肠道中释放量明显增加但也不完全。而经Alginate/Whey微球包埋后,噬菌体通过鸡肌胃后的存活率显著提高,而且能够在肠道内充分释放。进一步通过对鸡的沙门氏菌攻毒保护实验证实,口服Alginate/Whey微囊化噬菌体后12h和24 h,鸡盲肠中沙门氏菌浓度分别降低了1.34和1.27log10CFU/g,减菌效果显著优于未包埋噬菌体组。
采用人结肠腺癌细胞株Caco-2体外培养模型,研究了噬菌体对胞内鼠伤寒沙门氏菌的裂解活性。结果表明噬菌体Felix O1对已侵入胞内的沙门氏菌无感染能力,仅能抑制细菌对宿主细胞的侵入,提示沙门氏菌的胞内侵袭性可能是影响噬菌体抗菌效果的限制因素之一。
综上所述,本研究成功制备出口服微囊化噬菌体,并通过体外和体内实验考察了微囊化噬菌体在胃肠道环境中的稳定性、释放行为及抗菌活性；实验结果证实微囊化包埋能保护噬菌体免受胃酸和胆汁的破坏作用,并提供足量的噬菌体进入肠道中释放,充分发挥其抗菌作用,这为噬菌体在动物细菌性疾病防治中的应用奠定了基础。
Bacteriophages (or phages) are viruses that invade bacteria cells and, in the case of lytic phages, multiply rapidly till the complete lysis of bacteria. Phage therapies have unique advantages compared with common antibiotics by their host-specificity, exponential growth, low side effects and their ubiquitous and plentiful nature. Therefore, bacteriophages have been suggested as possible alternatives to chemical antibiotics.
Recent studies indicate that phages can be used effectively to control and treat bacterial infections in animals, but one problem is that the viability of orally administered phages may be rapidly reduced under acidic conditions of the stomach and in the presence of gastric acid, enzymes, and other digestive compounds such as bile. Without protection phages might not survive gastric passage and thus not be infective in the intestine. Therefore, it is highly necessary to develop an effective delivery system to protect orally administered phages from the harsh gastrointestinal environment enroute to the infection site in the intestine. One possible way of protection of phages is by encapsulating them in microspheres of pH-dependent polymers.
Here, we reported a process for the microencapsulation of Salmonella bacteriophage Felix 01 using natural polysaccharides such as alginate and chitosan. The results showed that the phage was efficiently entrapped in the alginate gel matrix and the microsphere formation process had no detrimental effect on the viability of phage. The mean encapsulation efficiency of phage in Chitosan-Alginate microspheres was 93.3%. In vitro studies were used to determine the effects of simulated gastric fluid (SGF) and bile salts on the viability of free and encapsulated phages. Free phages Felix O1 were found extremely sensitive to acidic environment and were not detectable after 5 min incubation in SGF when the pH value was below 3.7. The viable count of microencapsulated phages decreased only 2.58 log10PFU/g during 1 h exposure to SGF with pepsin at pH 2.4. After 3 h of incubation in 1 and 2% bile salt solutions, the free phage count decreased by 1.29 and 1.67 log10PFU/g respectively, while the viability of encapsulated phages was fully maintained. Phages were completely released from microspheres upon exposure to simulated intestinal fluid (SIF, pH 6.8) within 6 hours. The encapsulated phages in wet microspheres retained full viability when stored at 4℃during the testing period (6 weeks). The microencapsulated phages in dried form had a 0.90 log10PFU/g reduction after 6 weeks storage at 4℃, whereas a 1.20 log10PFU/g reduction occurs after 6 weeks at 22℃. The results demonstrate that dried encapsulated phage stored at 4℃shows better stability than phage kept at room temperature.
In order to develop an improved microsphere delivery system with enhanced acid resistance for oral delivery of phage. CaCO3 microparticles and whey protein were co-encapsulated with phage K into alginate microspheres and tested for its efficacy in improving the viability of phage under in vitro acidic conditions. Free phage was completely destroyed when exposed to SGF of pH 2.5. By adding CaCO3 as an antacid excipient to the alginate microspheres, the stability of encapsulated phage K in SGF was largely improved, with only a 0.17 log10PFU/g reduction after 2 h exposure to SGF at pH 2.5, but the release was delayed in SIF, the cumulative release was only about 68% after 12 h. Besides, a combination of alginate and whey protein also led to a better protection for phage K in SGF, the phage titer decreased only by 0.53 log10PFU/g after 2 h exposure to SGF at pH 2.5. In additon, the Alginate/Whey microspheres showed a rapid release profile, and an almost complete release of phage was achieved after 3 h incubation in SIF. The curve fitting data indicated that the phage release mechanism followed non-fickian diffusion pattern, which controlled by erosion of the matrix or enzymatic degradation of the hydrogel network. A number of protective agents including trehalose, sucrose, skim milk, and maltodextrin were tested and found to increase the viability of encapsulated phage K when subjected to drying. The protective effects varied with the type and concentration of each incorporated additives.
In vivo, different phage-loaded microspheres were tested in chickens and mice to determine the release profile and gastrointestinal distribution of the encapsulated phage in the digestive tracts. The results showed that there was only a small portion of released phage was detected in chickens' intestine after 1-4 h of administration of Chitosan-Alginate and Alginate/CaCO3 microspheres (<4 Log10PFU/g), whereas the Alginate/Whey microspheres showed a complete release of phage in both chick and mouse intestine. The free and Alginate/Whey encapsulated phage Felix 01 were then administered to chickens experimentally colonized with S. Typhimurium. Treatment with encapsulated phage resulted in a 1.34 and 1.27 log10CFU/g reduction of cecal Salmonella counts at 12 h and 24 h respectively after challenge as compared with untreated controls. But no significant reduction of cecal Salmonella counts was observed in the chickens treated by free phage. The results indicated that microencapsulation of phage Felix 01 into Alginate/Whey microspheres significantly enhanced its efficacy in reducing Salmonella colonization in chickens.
The human adenocarcinoma derived Caco-2 cells were used as an in vitro model to investigate the killing activity of phage Felix 01 against intracellular Salmonella. The results showed that S. Typhimurium can invade and survive inside the Caco-2 cell monolayers. Phage Felix O1 has no lytic activity against intracellular Salmonella, but can inhibit the invasion of Caco-2 cells by the bacteria. The results indicated that the invasion and intracellular survival of Salmonella would be a limiting factor for the antimicrobial activity of bacteriophage.
In conclusion, an oral microencapsulated form of bacteriophages were successfully prepared in this study, besides, the gastrointestinal stabilities, release profiles and antimicrobial activities of the microencapsulated phages were evaluated through both in vitro and in vivo experiments. The results demonstrated that microencapsulation can protect phages against gastric juice and bile, and also facilitate oral delivery of a high enough dose of phages to the intestine. Therefore, the current encapsulation approach would lay the foundation for the therapeutic use of phages to control bacterial infections in animals.
引文
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