2022, Vol. 62
益生菌抑制幽门螺杆菌的作用机制及研究进展
http://dx.doi.org/10.13343/j.cnki.wsxb.20220170
中国科学院微生物研究所，中国微生物学会
中国科学院微生物研究所，中国微生物学会
文章信息
- 商燕燕, 李滢, 谢新强, 张菊梅, 吴清平. 2022
- SHANG Yanyan, LI Ying, XIE Xinqiang, ZHANG Jumei, WU Qingping.
- 益生菌抑制幽门螺杆菌的作用机制及研究进展
- Research progress in the mechanism of probiotics inhibiting Helicobacter pylori
- 微生物学报, 62(11): 4336-4352
- Acta Microbiologica Sinica, 62(11): 4336-4352
-
文章历史
- 收稿日期：2022-03-16
- 修回日期：2022-05-26
- 网络出版日期：2022-06-13
引用本文 |
商燕燕, 李滢, 谢新强, 张菊梅, 吴清平. 益生菌抑制幽门螺杆菌的作用机制及研究进展[J]. 微生物学报, 2022, 62(11): 4336-4352.
Shang Yanyan, Li Ying, Xie Xinqiang, Zhang Jumei, Wu Qingping. Research progress in the mechanism of probiotics inhibiting Helicobacter pylori[J]. Acta Microbiologica Sinica, 2022, 62(11): 4336-4352.
益生菌抑制幽门螺杆菌的作用机制及研究进展
1. 广东省科学院微生物研究所(广东省微生物分析检测中心), 广东 广州 510070;
2. 广东环凯生物科技有限公司, 广东 广州 510663
2. 广东环凯生物科技有限公司, 广东 广州 510663
摘要：幽门螺杆菌在胃部疾病的发病过程中起着重要作用，是导致胃炎、胃溃疡，甚至胃癌的关键因素之一。随着胃部疾病患者幽门螺杆菌阳性检出率的不断升高，人们对于胃病和幽门螺杆菌的相关性研究也有了一定进展。如今，对于幽门螺杆菌阳性患者根除治疗的必要性，以及抗生素治疗耐药性等问题已引起广泛关注。在这种情况下，益生菌作为相对安全的天然微生物，在抑制幽门螺杆菌并促进胃部健康的益生功能方面具有重要的研究潜力。本综述对幽门螺杆菌的致病机理、不同基因分型的致病程度等方面进行了总结，并对益生菌抑制幽门螺杆菌的机制进行了探讨。建议在治疗幽门螺杆菌感染时，应与常规的治疗手段结合应用，不仅会增加幽门螺杆菌的根除率，还能减少治疗相关的副作用。
关键词：幽门螺杆菌 致病机制 益生菌 抑菌
Research progress in the mechanism of probiotics inhibiting Helicobacter pylori
1. Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, Guangdong, China;
2. Guangdong Huankai Biotechnology Co., Ltd., Guangzhou 510663, Guangdong, China
2. Guangdong Huankai Biotechnology Co., Ltd., Guangzhou 510663, Guangdong, China
Abstract: Helicobacter pylori (Hp) plays a role in the pathogenesis of gastric diseases and is one of the key factors leading to gastritis, gastric ulcer, and even gastric cancer. With the continuous increase in the positive detection rate of Hp in patients with gastric diseases, scientists have achieved certain progress in the research on the association between gastric diseases and Hp. The eradication therapy for Hp-positive patients and the antibiotic resistance of Hp have attracted increasing attention. Probiotics, as relatively safe natural microorganisms, have great research potential and significance for their functions of inhibiting Hp and improving gastric health. This review summarizes the pathogenic mechanism of Hp and the pathogenicity of different genotypes, and then elaborates the mechanism of probiotics inhibiting Hp. It is recommended that the treatment of Hp infection should combine probiotics with conventional therapies, which will not only increase the eradication rate of Hp but also reduce the side effects associated with treatment.
Keywords:
Helicobacter pylori pathogenic mechanism probiotics antibacterial mechanism
1 幽门螺杆菌及其研究现状
幽门螺杆菌(Helicobacter pylori，Hp)是一种革兰氏阴性、微需氧细菌，其属于螺杆菌属，一般定殖于胃黏液层和胃窦黏膜上皮细胞之间，因其生存于胃部及十二指肠而获名[1]。1982年，澳大利亚科学家鲁宾·华伦和巴利·马歇尔首次分离获得Hp，并验证了其与胃部疾病的关系[2]。1994年，幽门螺旋杆菌被世界卫生组织(WHO)确定为第Ⅰ类致癌因子[3]，自此彻底改变了人们对胃部疾病的防控措施。2021年，美国食品药品监督管理局(Food and Drug Administration，FDA)再次确定Hp为第Ⅰ类致癌物。
通过Hp抗原、抗体以及尿素酶代谢产物等检测方法[4‒5]，流行病学家曾在全球开展过Hp感染的流行病学调查，研究发现，世界超过50%人口罹患Hp感染。目前普遍认为，Hp主要通过口-口、粪-口或胃-口传播[6]，这种特殊的传播模式解释了Hp流行感染的特征：卫生条件稍逊的发展中国家以及有共餐习惯的民族Hp感染率更高，而发达国家Hp感染率较低。据统计，Hp感染人数最高的地区是非洲(70.1%)，南美洲(69.4%)和西亚(66.6%)，超过一半的人口患有Hp感染，Hp患病率最低的地区是大洋洲(24.4%)，西欧(34.3%)和北美(37.1%)，近三分之一的人口感染了Hp[7]。相关数据表明，在日本，50年代之前出生的人群幽门螺杆菌感染率高达90%，之后感染程度呈现下降趋势，直到2000年后出生的人感染率已经不到2%[8]。这种广泛分布的感染可能与生活方式和环境因素有关，而且具有较高社会地位和教育水平的人群显示更低的幽门螺杆菌感染致病率，饮食条件也是不容忽视的因素之一。
对于全球现存Hp分离株的全基因组序列分析发现，不同地区人群感染的Hp基因分型具有特殊的地域特征[9]，微生物学家发现，Hp的分型还具有评估其致病风险的作用。根据其进化特征，Hp可被分为东亚型、亚洲型、欧洲型、非洲型、新非洲型以及美洲Ⅱ型[10]。目前在全球不同地方，上述亚型不单以全球各大洲大洋命名，亦是对应区域主要的Hp流行株，不同流行株的致病能力不同，其中东亚型的致病性最强。本文作者针对广州地区胃黏膜样本进行分离，结果显示，几乎全部幽门螺杆菌分离株的亚型都是东亚型，也就是说广州地区，甚至全中国感染的都是致病性最强的一种Hp[11]。
幽门螺杆菌作为在全球范围内流行程度最高的致病菌之一，其感染会引起很多胃肠疾病，如慢性活动性胃炎、胃十二指肠溃疡、胃黏膜相关淋巴组织淋巴瘤、胃癌等消化系统疾病[12‒15]。相关数据显示，10%‒20%的Hp感染者在感染后会发展为消化性溃疡，1%‒2%将发展为胃癌。多项临床前瞻性队列研究证实，根除Hp是防治消化系统疾病的重要措施，也可以降低人群胃癌的发生率，对促进胃部健康具有重要意义。
目前根除Hp标准的一线治疗是一个为期一周的“三联疗法”，即组成为质子泵抑制剂联合抗生素克拉霉素和阿莫西林[16‒17]。临床上联合铋剂或PPI的抗生素治疗不仅会导致患者肠胃不适、恶心呕吐等副作用，还存在耐药性增强的风险，研究发现，抗菌药物对于Hp的根除率正在逐年下降[18]。不仅如此，我们的研究表明，有的Hp分离株甚至对多种抗生素同时耐药，针对这种高毒力多药耐药株，普通的临床治疗手段已经不能够达到明显的治疗效果[11, 19]。近年来，益生菌作为相对安全的微生物，在调节人体健康状况方面显现出了较大的优势，也因此引起了人们的广泛关注。益生菌能够抑制Hp的研究报道增多，由于其不会出现耐药性增强等生物安全隐患，在体内、体外和临床中的探索逐渐成为研究的重点，具有极大的开发潜能。
益生菌(probiotics)是一类促进宿主健康、改善体内微生态平衡的有益活性微生物的总称[20]。它源于宿主并促进宿主健康，通过产生细菌素等抗菌代谢物，对微生物区系的组成和微生态的平衡起调节作用，在一定程度上抑制致病微生物的生长和定殖[21]。用口服益生菌的方法代替或者减少抗生素治疗，不仅能够减少幽门螺杆菌在胃部的定殖量，缓解胃部炎症[22]，还能提高患者依从性，减少副作用，在治疗感染的老人和儿童方面具有更加突出的优势。
2 幽门螺杆菌的致病机制研究幽门螺杆菌能够分泌尿素酶[23]，上调周围环境的pH值，从而在胃部酸性环境中存活。它运动能力和黏附能力很强，研究发现，Hp能够穿透胃黏膜的上皮细胞并与之紧密结合。目前认为，Hp的致病性除了其本身的毒力相关因素如鞭毛、分泌毒素外，亦与其引起胃部微生态紊乱密切相关。
2.1 幽门螺杆菌通过黏附发挥其致病作用幽门螺杆菌有鞭毛结构，该结构能够介导Hp从胃黏膜上皮层向pH接近7的基底层运动，对于Hp在胃中的定殖至关重要，而且任何运动和趋化系统相关的基因突变都会破坏幽门螺杆菌感染胃部和建立定殖的能力(图 1)。研究表明，当感染运动性强的Hp时一般会出现细菌感染密度增加较快的现象，会触发更高的炎症反应和严重的病理反应[24]。
|
| 图 1 幽门螺杆菌的致病机制[35] Figure 1 Pathogenic mechanism of Helicobacter pylori[35]. These mechanisms are divided into two parts: Helicobacter pylori colonization and toxin production. 1: Hp uses flagella movement to adhere to the basal layer of the stomach; 2: produce urease, which increases the pH value around Hp, improves its survival rate in the stomach, and affects the normal microecological balance of the stomach; 3: CagA is produced and injected into host cells, tyrosine phosphorylated CagA has similar functions to Gab protein, can bind to SHP-2, and activate MAP kinase (MAPK) cascade in both an Ras-dependent and Ras-independent manner; SHP-2 also regulates the Rho family of small G proteins and thus regulates the activity of Arp2/3 complexes, causing cell deformation, cell proliferation and apoptosis abnormalities (4‒6 in Figure 1); 7: VacA is produced, resulting in cell vacuoles. |
在Hp感染初期，上皮细胞会释放大量尿素，和Hp的化学受体TipB能相互吸引，导致Hp产生大量的尿素酶，生成氨，中和胃酸，提高胃部pH值，使自身能够在胃中存活(图 1)。
当Hp定殖在胃上皮的黏膜层上后，细菌黏附素与细胞受体的相互作用能够保护细菌不受蠕动和胃排空等的影响而离开胃，然后Hp利用代谢底物和营养物质来生长并释放毒素损害宿主细胞。其中血液抗原结合蛋白A (BabA)和唾液酸结合黏附素(SabA)是研究较多的黏附素，但这两种黏附素并非在所有的Hp菌株中都表达[25‒26]。
2.2 幽门螺杆菌产生毒素直接危害宿主健康 2.2.1 幽门螺杆菌分泌的CagA与其致病机制细胞毒素相关蛋白(CagA)是一种高免疫原性蛋白，它是Hp能导致癌症的重要诱因。CagA蛋白能诱发慢性炎症，上调IL-8、IL-6、IL-1β和TNF-α、活性氧(reactive oxygen species，ROS)、8-oxodG的表达，同时相关DNA的高甲基化会使DNA修复机制受阻，增加胃上皮细胞的突变率[27]。经过细胞实验和动物实验的验证，我们发现，当细胞和动物感染Hp并作用一段时间后，会引起某些促炎症因子的表达量增多，这种变化有可能就是引起细胞蜂鸟形变或动物胃炎的原因之一。cagA致病岛全称为细胞毒素相关基因致病岛，其外源基因簇能发挥致病性[28‒29]，编码Hp的Ⅳ型分泌系统并作用于宿主细胞。CagA蛋白通过Ⅳ型分泌系统注入到宿主细胞，通过Src家族激酶进行酪氨酸磷酸化。SHP-2蛋白的基因突变已在多种人类恶性肿瘤中被发现，SHP-2信号的改变最终导致基因工程小鼠胃腺癌的发生[30]，表明SHP-2在胃癌中起着重要作用，而CagA能够与这种靶分子进行相互作用。酪氨酸磷酸化的CagA与SHP-2结合，以依赖性酪氨酸磷酸化的方式使SHP-2磷酸酶活性增强，刺激Ras通路，进而引起MAP激酶(MAPK)级联[31]。也有研究发现，SHP-2可以不通过Ras通路，直接激活MAP激酶(MAPK)级联，所以，这种磷酸酶可以通过依赖Ras和不依赖Ras的途径促进细胞增殖[32]。
除了对有丝分裂的作用之外，SHP-2还能调节Rho家族的小G蛋白，诱导散射表型。这是一种类似于CagA诱导的蜂鸟表型，无论是散射表型还是蜂鸟表型都需要SHP-2的参与。Rho GTPases能够调节Wiscott-Aldrich综合征蛋白-Arp2/3复合物的活性，影响肌动蛋白聚合以及基座的形成[33‒34] (肌动蛋白细胞骨架系统的动态变化对细胞的粘附、迁移和分裂起着至关重要的作用)，进而引起细胞形变。
HGF同样能够刺激Ras、MAPK和Rho通路，进而诱导上皮细胞的散射表型。在HGF的刺激下，c-Met发生自磷酸化，通过与酪氨酸磷酸化的对接蛋白Gab家族结合，激活SHP-2并与之结合形成复合物，该复合物刺激下游通路[35] (图 1)。
幽门螺旋杆菌的毒力基因cagA的差异与位于基因3′区的重复序列有关，不同地域来源的菌株其3′区的结构有所不同[35]。调查结果显示，东亚菌株和西方菌株中第二重复序列的数目差异与胃癌发病率有关，多个重复序列的菌株更容易在酸性环境中存活，而感染了这种Hp的患者，其胃癌的发病概率更高[36‒37]。不仅如此，东亚型Hp具有更强的SHP-2结合活性和诱导上皮细胞形态学改变的能力[38‒39]。
2.2.2 幽门螺杆菌分泌的空泡毒素与其致病机制细胞空泡毒素(VacA)是一种在真核细胞系中能诱导胞浆空泡的细胞毒素。除空泡作用外，VacA还可诱导多种细胞活动，包括膜通道的形成、促进线粒体释放细胞色素c导致细胞凋亡、与细胞膜受体(RPTP α或β)结合并诱导促炎反应[40‒41]、特异性地抑制T细胞的活化和增殖[42‒44]等。VacA可嵌入宿主细胞膜，向宿主细胞质中释放碳酸氢盐和有机阴离子，能够刺激第二信使的产生，进而使AGS细胞对胃蛋白酶原的分泌量增加，有利于Hp的侵染。VacA还可以通过内吞作用进入核仁，将阴离子渗透到核仁中，从而导致弱碱的积累，然后通过水的涌入形成大的液泡(图 1)[45‒46]。此外，VacA通过影响调节细胞周期的基因来破坏细胞增殖和死亡的平衡。它还可以通过诱导宿主细胞释放IL-8而引起急性炎症反应[47]。流行病学和实验证据表明VacA的产生与体内组织损伤的发生有关[48‒50]，它通过增加宿主细胞中连接蛋白-43的水平，然后结合自噬体标记物LC3启动凋亡[51]。
不同的菌株之间空泡毒素活性有很大的差异，主要是由于信号区(s1和s2)和中间区(m1和m2)的vacA基因结构的不同。vacA基因可能包含信号区和中间区类型的任何组合，但是s2/m1组合非常罕见[52]。vacA s1基因型与cagA基因相关，在s1基因型中，s1/m1对上皮细胞的毒性比s1/m2大[53]，胃癌患者通常是s1/m1型[54‒55]。vacA s2/m2菌株几乎无毒[56]，很少与疾病相关。vacA s1型可进一步分为s1a、s1b和s1c[57]，m1型可分为m1a、m1b和m1c[58]，但亚型与临床结果之间的关系尚不清楚。最新研究显示，在中间区和信号区之间还存在一个i区，并被认为是空泡活性的第3个多态性决定因素[59]。i区有两种类型：i1和i2，目前还没有发现i区基因型与临床结果之间的关联[9]。
2.3 幽门螺杆菌造成胃部微生态失调的作用及机制人体胃部微生物群落由Hp和很多其他细菌共同构成，Hp的感染会改变胃中微生态环境和微生物群落的分布[60]。有研究表明，胃部患有疾病的人群其胃部微生物的多样性随着Hp的增加而降低，还发现胃癌患者胃中具有潜在致癌活性的细菌增加[61]。不仅如此，Hp还影响人体的远端器官，由感染或饮食改变引起的微生物组的变化，可以扰乱共生关系进而引发疾病，包括癌症。胃部生理条件的改变会影响胃的生长，胃泌素紊乱，胃粘膜疏水性下降，氧自由基积累，胃局部出现黏膜炎症，导致保护屏障受损[62]。
3 益生菌拮抗幽门螺旋杆菌的机制研究 3.1 增强黏膜屏障相关研究表明，口服益生菌能够起到保护胃肠道黏膜的作用，主要是通过增厚黏液层，促进粘蛋白以及前列腺素E2的产量等机制实现的(图 2)。黏蛋白作为胃肠道屏障的重要组成，主要由上皮细胞进行分泌，这种大分子糖蛋白能够形成黏液凝胶，对胃黏膜起到保护作用。黏蛋白分泌量的减少，主要是因为感染的Hp能够降低MUC5AC、MUC1和MUC6的表达[63‒64]。有研究显示，植物乳杆菌[65]和鼠李糖乳杆菌[66]可以提高MUC2和MUC3的表达量，改善黏蛋白产量低的情况。
|
| 图 2 益生菌拮抗幽门螺杆菌的机制[93] Figure 2 Mechanism of probiotics inhibiting Helicobacter pylori[93]. These mechanisms are divided into two parts: physiological/non-specific mechanisms and immune mechanisms. A: physiological/non-specific mechanisms include: 1: production of bacteriocins, lysis of Hp cells or inhibition of Hp growth; 2: enhancement of barrier function, enhancement of the integrity of the epithelial cell barrier; 3: production of organic acids, regulation of gastric pH value, inhibition of colonization of pathogenic bacteria; 4: increase of mucin yield, increase the thickness of mucus layer; 5: competition with pathogenic bacteria for gastric adhesion sites. B: immunomodulation: 6: probiotics stimulate dendritic cells to form anti-inflammatory pathways, thereby increasing the amount of IgA produced by B cells; 7‒8: probiotics directly or indirectly affect the signaling pathways of epithelial cells and inhibit the production of inflammatory factors such as IL-8. |
相关研究显示，幽门螺杆菌阳性患者在服用乳杆菌发酵制品3周和16周后，其胃内Hp定殖量降低，黏液层的损耗明显减小[67]；小鼠口服鼠李糖乳杆菌后，前列腺素E2产量以及粘液层厚度增加，从而降低了酒精等对胃黏膜的物理伤害[68]。
3.2 益生菌抑制幽门螺杆菌的定殖Hp的黏附性是其定殖于胃黏膜组织以及发挥致病性的主要因素，降低Hp黏附性是保护胃、十二指肠内腔免受炎症以及预防萎缩性胃炎的一个重要机制，可降低其致病性。一些乳杆菌分泌的代谢产物可以发挥抗粘连活性[69]。研究表明，Hp通过抑制MUC5AC、MUC1基因表达，从而使Hp感染患者的胃内黏附素合成减少[63]。所以，益生菌拮抗Hp等致病菌的机制，可能是增加黏附素的产量，保护胃黏膜屏障。相关研究显示，罗伊氏乳杆菌和嗜酸乳杆菌能够在胃上皮细胞上黏附，黏附性随乳杆菌浓度升高有增强的趋势，在结合位点方面能够与Hp形成竞争[70‒71]。Sakarya等[72]的研究表明，布拉酵母菌可以产生唾液酸苷酶，通过清除唾液酸配体来减少Hp在细胞表面的黏附。我们对实验小鼠的胃组织切片进行革兰氏染色发现，单纯灌胃Hp时，其定殖很多，进行测定后发现，定殖量在1 g小鼠胃组织中可达103.3 CFU。在感染Hp之前施加益生菌进行预防发现，Hp的感染程度大大降低，益生菌的定殖量较大[73]。上述情况均说明，益生菌能够通过自身的强粘附性与Hp形成竞争，进而抑制Hp的定殖(图 2)。
3.3 益生菌代谢产物抑制幽门螺杆菌生长研究显示，益生菌可通过分泌乳酸、短链脂肪酸[74]、过氧化氢以及细菌素等代谢物质抑制Hp生长(图 2)[75]，其中乳酸菌、粪肠球菌[76]、枯草芽孢杆菌[77]、双歧杆菌等都可以产生细菌素。Kim等[78]发现，乳酸菌可以产生7种细菌素，并能够对4种幽门螺杆菌产生拮抗作用；Lorca等[79]的实验说明，嗜酸乳杆菌的自溶会伴随幽门螺杆菌对数期增殖减少直至死亡，可以推测这种情况的出现可能与乳杆菌自溶素的释放有关；Francavilla等[80]的研究表明，罗伊氏乳杆菌的抑菌效果可能与其产生的罗伊氏菌素(reuterin)有关。此外，枯草芽孢杆菌产生的抗菌物质amicoumacin A不仅能够抑制志贺氏菌和空肠弯曲杆菌等，还能够对21种幽门螺杆菌进行抑制[77]。某些益生菌产生的乳酸还能调节胃部pH值，进而起到拮抗致病菌的作用[81]。本文作者分离出一株植物乳杆菌，能够产生溶菌酶M1，研究发现，这是除了有机酸以外另一种对Hp有拮抗作用的活性物质，推测其能够裂解Hp的细菌结构[73]。
3.4 调节宿主免疫反应有研究发现，益生菌能通过调节机体对病原菌的免疫反应，提高抗Hp的功能。正常机体中，Hp的炎症反应是通过释放几种炎性介质如细胞因子和趋化因子来鉴定的。益生菌可以通过与上皮细胞相互作用来进行免疫反应调节，从而改变抗炎作用剂的释放，缓解胃炎的症状[82‒83]。
乳杆菌可降低IL-1、IL-6、IL-8以及肿瘤坏死因子-α (TNF-α)等炎性因子水平(图 2)[84]，通过抑制Smad7通路、NF-κB通路或JAK-SATA通路减轻Hp引起的炎症反应[85‒86]。
Hp感染小鼠模型口服植物乳酸菌后，可以明显抑制血浆或胃黏膜内的IL-8、TNF-α和中性粒细胞趋化因子(CINC-1)，并可以抑制NF-κB通路的激活[87]，本文作者用分离到的植物乳杆菌进行重复实验，得到同样的结论。Zhou等[88]、赵东等[89]和刘翔等[90]的研究显示，乳酸杆菌可抑制Hp激活TLR4信号通路引起的炎性因子IL-8分泌增加，降低干扰素-γ (IFN-γ)等炎性因子水平。有研究证实，嗜酸乳杆菌产生的共轭亚油酸(CLA)，可以通过分解IKK和热休克蛋白90 (Hsp90)抑制NF-κB的活化及IL-8水平，从而减轻Hp引起的炎症反应[91]。体外研究表明，约氏乳杆菌(La1)缓解因感染Hp所致的胃部炎症的主要机制是，使产生的巨噬细胞炎症蛋白(MIP-2)和角质形成细胞衍生趋化因子(KC)减少，同时减轻中性粒细胞及淋巴细胞的浸润[92]。此外，部分乳酸杆菌可以通过抑制淋巴细胞亚型(Th1和Th17)及其细胞因子的炎症功能，刺激树突状细胞形成抗炎通路，刺激B细胞产生IgA[93]，增强免疫屏障，从而稳定黏膜功能[94]。具体引起的免疫反应过程如图 2。
3.5 维持天然微生态平衡人或动物的胃部存在大量的微生物菌群，这些微生物和宿主相互作用，共同维持胃部的微生态平衡。在正常胃液中，益生菌作为在人类胃肠道中定殖的共生细菌，对酸性条件具有一定的抵抗力[95]，它通过调节微生物菌群组成，维护正常的微生态环境，在胃部起到扶优去劣的作用，具有抑制致病菌以及条件致病菌的功效[96]。
人胃部的细菌群落组成主要是厌氧菌、兼性厌氧菌和需氧菌，其中专性厌氧菌占99%，仅类杆菌和双歧杆菌就占90%以上。由于胃分泌胃酸且蠕动节奏快，所以含有的细菌种类和数量较少，主要是革兰氏阳性菌，如链球菌、葡萄球菌和乳酸杆菌等。大量研究证实，菌群与胃肠道疾病的发生发展密切相关，胃内菌群的紊乱甚至能够促进胃癌的发展，所以，在根除Hp的治疗过程中，也应该将对胃肠道菌群平衡的影响降到最低[97]。益生菌能够通过强黏附作用以及分泌抗菌物质来抑制Hp等致病菌的定殖和生长，除此之外，产生的有机酸也能够帮助胃部恢复到正常的pH值，使很多不耐酸的致病菌难以存活。有研究表明，外源摄入益生菌制品对胃部和肠道微生态平衡具有调节作用，能够改善微生态失调的状况[98‒100]。
本文作者对实验小鼠的胃组织切片进行观察，用益生菌进行预防后再感染Hp的分组，Hp定殖量显著下降，益生菌的占比增加，胃部病理情况腺体萎缩、刷状缘明显、黏膜脱落严重，转向炎症状态缓和[73]。说明益生菌能够改善胃部微环境，进而促进胃部健康。
4 讨论由于Hp的高感染率及其感染后引发多种疾病的风险，对于阳性感染患者是否应该进行根除治疗的问题受到越来越多人的关注。随着Hp耐药风险逐年增加，我们急需寻找一种抗生素的替代或辅助疗法。由于益生菌安全性高，不良反应发生率低，在根除Hp等致病菌方面表现出色，已经成为很多学者的研究热点。
研究显示，益生菌对于胃肠道炎症有明显的改善效果，如急性胃炎、过敏性肠炎以及幽门螺杆菌引起的相关胃部疾病等[101]。大量文献报道[102]，益生菌能抑制Hp定殖与生长，减轻Hp相关性胃炎炎症程度。Masstricht-5共识中相关内容表示，其可能是通过释放抗菌产物或定殖于生存部位的竞争作用来抑制Hp[103]。相关研究表明[104]，老年人的胃肠道比青壮年的胃肠道更加脆弱，感染Hp等致病菌所致的胃炎、胃溃疡症状更加明显，恶化成胃癌的风险更高。老年人机体的耐受程度差，在进行抗生素治疗时，更容易破坏原始的肠道菌群。儿童在生长发育、药物代谢和机体免疫方面都和成年人有一定区别，抗生素治疗的种类选择相对较少，副作用多、耐受性差。所以，老年人和儿童在进行根除Hp治疗时，具有一定的特殊性，将益生菌用于Hp的治疗，能够改善患者的临床病症并减少不良反应。国内临床研究发现[105]，在针对儿童及老年Hp感染的治疗方面，微生态疗法相较于传统标准根除方案疗效显著，且复发率和不良反应发生率更低，在特殊人群的Hp感染治疗中具有一定的优越性。国外相关研究显示[106‒107]，在不使用抗生素的条件下，单一的益生菌疗法治疗Hp的根除率能够超过10%。虽然采用单一的益生菌产品治疗Hp感染难以达到标准临床效果，但是将益生菌作为传统抗生素治疗的辅助用药，能够有更显著的效果。有研究表明[108]，在标准的三联治疗方案中加入益生菌作为佐剂，能够使儿童的Hp根除率增加10%，同时可以减少恶心呕吐、腹泻、腹痛等不良症状的发生。钱小棋等[109]、周垦横[110]、王蕊蕊[111]发现，在进行四联和三联疗法的过程中，分别以思连康双歧杆菌四联活菌片、双歧杆菌三联活菌胶囊和酪酸梭菌肠球菌三联活菌片等作为佐剂，除了能够提高Hp的根除率，降低不良反应率，还能保护肠道黏膜，纠正长期慢性感染所致菌群失调，调节胃肠道正常生理功能，进而促进患者溃疡的愈合和修复。虽然益生菌疗法在疗效上存在一定局限性，但是定期摄入适量益生菌，能够防止Hp的定殖量增多，使Hp的感染率维持在较低的水平。这种方法对于儿童、老年人以及存在严重胃部疾病的患者来说，是较优的治疗选择。
有研究对市面上部分益生菌制剂进行了益生菌的分离，如“思连康”中的嗜酸乳杆菌、婴儿双歧杆菌，“金双歧”中的长双歧杆菌、保加利亚乳杆菌、“常乐康”中的酪酸梭状芽孢杆菌，“整肠生”中的地衣芽孢杆菌，台湾“亚芯”的唾液乳杆菌等，以研究不同益生菌对于Hp的抑制作用[112]。结果表明，“思连康”中的嗜酸乳杆菌和“金双歧”中的保加利亚乳杆菌都能减少Hp的定殖量，后者还能通过激活TLR4-NF-κB通路，减少炎症因子IL-8的释放。同时，发现地衣芽孢杆菌的上清液能抑制Hp的生长，且与pH值无关。与此同时，我们团队对于市售商品株副干酪乳杆菌Shirota以及“卫乐舒”中的约氏乳杆菌MH-68的抗Hp效果进行研究，发现这两株益生菌的发酵上清液均能在体外抑制Hp ATCC 43504的生长，对于Hp引起的细胞IL-8表达量增加有一定下调作用，对实验小鼠的胃部炎症有所缓解[73]。
尽管很多研究认为，益生菌及其代谢产物能够在体外抑制或杀死幽门螺杆菌，显著提高Hp的根除率，但是仍有学者提出不同观点。Hurduc等[113]和Goldman等[114]在采用标准三联疗法添加益生菌为佐剂的情况下，对有症状的儿童进行Hp的根除治疗，结果发现益生菌组并没有显示出更高的根除率。Lionetti等[115]的研究发现，在补充罗伊氏乳杆菌ATCC 55730 (SD2112)的20名患者中，有17名患者治疗成功，而安慰剂组20名患者中有16名治疗成功，说明益生菌的添加与否，并不能造成根除率的差异。在一项双盲安慰剂对照随机临床试验中，补充鼠李糖乳杆菌LGG后，其根除率相比于安慰剂组没有显著提高[116]。另外一些临床研究也发现，添加益生菌不能提高Hp根除率[117‒118]。同样地，多项研究表明[115, 119]，益生菌可显著降低Hp根除治疗期间的不良反应，但并非所有益生菌菌株都有效[120‒121]，这表明该功能有可能是菌株特异性的，也有可能是因为使用的益生菌产品不同、浓度不同、剂量和使用时间不同以及特异性幽门螺杆菌菌株造成的[122‒123]。
5 结论与展望回顾分析发现，有些研究中的益生菌能够在根除Hp治疗中发挥积极作用，有些研究中的益生菌没有什么疗效，这种差异可能与很多因素有关。所以，在Hp根除治疗期间，益生菌作为辅助用药，在选择和服用方法上提出以下建议：(1) 益生菌的种类，尽量不选择含有肠球菌的益生菌制剂，因为肠球菌更容易产生耐药性，且容易通过质粒传递给Hp等致病菌，进而影响Hp根除治疗的效果；(2) 益生菌的作用时间，Tong等[124]的meta分析表明，2‒4周可能是较优的用药时间；(3) 益生菌与抗生素的相互作用，建议益生菌与标准抗生素治疗用药时间间隔开，以便益生菌能更好地定殖并发挥作用。益生菌的施加剂量、与宿主及不同的Hp菌株间的关系等，仍需要大量的临床及基础研究去开发。在未来的临床研究中，仍需注意Hp耐药菌株、宿主基因多态性等影响疗效的相关因素。
总的来说，益生菌在一定程度上可以通过菌体本身或其发酵液抑制幽门螺杆菌，主要是通过竞争结合位点、调节炎症因子和产生活性抗菌物质等作用实现的，但并非所有益生菌都具有减少治疗副作用和有效提高Hp根除率的作用。因此，在拮抗幽门螺杆菌方面，益生菌并不能作为单一药物用于治疗，作为一种佐剂能够增加健康效益，将益生菌用于Hp治疗具有良好的应用前景。
References
| [1] | Veiga N, Pereira C, Resende C, Amaral O, Ferreira M, Nelas P, Chaves C, Duarte J, Cirnes L, Machado JC, Ferreira P, Correia IJ. Oral and gastric Helicobacter pylori: effects and associations. PLoS One, 2015, 10(5): e0126923. DOI:10.1371/journal.pone.0126923 |
| [2] | Goodwin CS, Armstrong JA, Chilvers T, Peters M, Collins MD, Sly L, Mcconnell W, Harper WES. Transfer of Campylobacter pylori and Campylobacter mustelae to Helicobacter gen-nov. as Helicobacter pylori comb-nov. and Helicobacter mustelae comb-nov., respectively. International Journal of Systematic Bacteriology, 1989, 39(4): 397-405. DOI:10.1099/00207713-39-4-397 |
| [3] | Schistosomes, Liver Flukes and Helicobacter pylori. Lyon: LARC, 1994. |
| [4] |
Cui JH, Li YH, Zhou JY, Wu J, Guo W, Pan BS. Development and comparison of Helicobacter pylori detection. Laboratory Medicine, 2018, 33(1): 82-87.
(in Chinese) 崔俊华, 李懿皞, 周佳烨, 吴炯, 郭玮, 潘柏申. 幽门螺杆菌检测方法的发展与比较. 检验医学, 2018, 33(1): 82-87. |
| [5] |
Zhang QF, Yu XQ, Liu JT. Research progress of detection methods for Helicobacter pylori in gastric and oral cavity. International Journal of Digestive Diseases, 2016, 36(2): 111-114.
(in Chinese) 张全锋, 余细球, 刘锦涛. 胃幽门螺杆菌与口腔幽门螺杆菌检测方法的研究进展. 国际消化病杂志, 2016, 36(2): 111-114. DOI:10.3969/j.issn.1673-534X.2016.02.012 |
| [6] | Thung I, Aramin H, Vavinskaya V, Gupta S, Park JY, Crowe SE, Valasek MA. Review article: the global emergence of Helicobacter pylori antibiotic resistance. Alimentary Pharmacology & Therapeutics, 2016, 43(4): 514-533. |
| [7] | Hooi JKY, Lai WY, Ng WK, Suen MMY, Underwood FE, Tanyingoh D, Malfertheiner P, Graham DY, Wong VWS, Wu JCY, Chan FKL, Sung JJY, Kaplan GG, Ng SC. Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology, 2017, 153(2): 420-429. DOI:10.1053/j.gastro.2017.04.022 |
| [8] | Inoue M. Changing epidemiology of Helicobacter pylori in Japan. Gastric Cancer, 2017, 20(1): 3-7. |
| [9] | Yamaoka Y, Kato M, Asaka M. Geographic differences in gastric cancer incidence can be explained by differences between Helicobacter pylori strains. Internal medicine, 2008, 47(12): 1077-1083. DOI:10.2169/internalmedicine.47.0975 |
| [10] | Tay CY, Mitchell H, Dong Q, Goh KL, Dawes IW, Lan R. Population structure of Helicobacter pylori among ethnic groups in Malaysia: recent acquisition of the bacterium by the Malay population. BMC microbiology, 2009, 9(126): 1-13. |
| [11] | Li Y, Huang ZX, Shang YY, Xie XQ, Yang RS, Chen HZ, Wang Z, Xue L, Pang R, Zhang JM, Ding Y, Chen MT, Wang J, Chen JH, WU QP. Exploration of the molecular mechanisms underlying the antibiotic resistance of Helicobacter pylori: a whole-genome sequencing-based study in southern China. Helicobacter, 2022, 27(2). DOI:10.1111/hel.12879 |
| [12] | Ahmed N, Sechi LA. Helicobacter pylori and gastroduodenal pathology: new threats of the old friend. Annals of Clinical Microbiology and Antimicrobials, 2005, 4(1): 1-10. DOI:10.1186/1476-0711-4-1 |
| [13] | Ahmad A, Govil Y, Frank BB. Gastric mucosaassociated lymphoid tissue lymphoma. The American Journal of Gastroenterology, 2003, 98(5): 975-986. DOI:10.1111/j.1572-0241.2003.07424.x |
| [14] | Van Belkum A. High-throughput epidemiologic typing in clinical microbiology. Clinical Microbiology and Infection, 2003, 9(2): 86-100. DOI:10.1046/j.1469-0691.2003.00549.x |
| [15] | Amieva M, Peek RM, Jr. Pathobiology of Helicobacter pylori-induced gastric cancer. Gastroenterology, 2016, 150(1): 64-78. DOI:10.1053/j.gastro.2015.09.004 |
| [16] |
Lu CH, Zhu QW, Ge GD. Observation of clinical efficacy of integrated traditional Chinese and western medicine in the treatment of Helicobacter pylori-related peptic ulcer. Lishizhen Medicine and Materia Medica Research, 2013, 24(3): 724-725.
(in Chinese) 鲁昌辉, 朱庆伟, 葛广德. 中西医结合治疗幽门螺杆菌相关性消化性溃疡临床疗效观察. 时珍国医国药, 2013, 24(3): 724-725. DOI:10.3969/j.issn.1008-0805.2013.03.096 |
| [17] |
Wang GF, Xu YH, Su H, Luo B, Han ZH, Zhu RJ, Zhang LZ, Zhan SF, Xu WM. Efficacy of Bifidobacterium-based quadruple therapy in treatment of Helicobacter pylori associated peptic ulcer disease. Chinese Journal of Nosocomiology, 2013, 23(9): 2074-2076.
(in Chinese) 汪官富, 徐颖鹤, 苏杭, 罗波, 韩子华, 朱汝健, 章灵芝, 詹石斐, 徐伟铭. 双歧杆菌四联活菌片联合三联疗法治疗幽门螺杆菌阳性消化性溃疡的疗效. 中华医院感染学杂志, 2013, 23(9): 2074-2076. |
| [18] | Bang CS, Baik GH. Attempts to enhance the eradication rate of Helicobacter pylori infection. World Journal of Gastroenterology, 2014, 20(18): 5252-5262. DOI:10.3748/wjg.v20.i18.5252 |
| [19] | 李滢, 吴清平, 商燕燕, 庞锐, 杨润时, 谢新强, 薛亮, 陈谋通, 王涓, 丁郁, 张菊梅. 一种多重耐药的幽门螺旋杆菌及其应用: CN113186136B[P]. 2022-06-14. |
| [20] |
Wang ZQ, Ma LJ, Zhou HJ, Yang L, Nie HB, Xue L. Research progress on antitumor effect and mechanism of probiotics. International Journal of Stomatology, 2017, 44(6): 636-641.
(in Chinese) 王志强, 马丽娟, 周海静, 杨兰, 聂红兵, 薛龙. 益生菌抗肿瘤作用及其机制的研究进展. 国际口腔医学杂志, 2017, 44(6): 636-641. |
| [21] | 李滢, 薛亮, 吴清平, 高珺珊, 商燕燕, 谢新强, 蒋同, 陈慧贞, 李龙岩, 蔡伟程, 程彤, 张菊梅. 一株具有抗病毒能力的发酵乳杆菌PV22及其应用: CN112522160B[P]. 2022-05-10. |
| [22] | Oh B, Kim BS, Kim JW, Kim JS, Koh SJ, Kim BG, Lee KL, Chun J. The effect of probiotics on gut microbiota during the Helicobacter pylori eradication: randomized controlled trial. Helicobacter, 2016, 21(3): 165-174. DOI:10.1111/hel.12270 |
| [23] | Kolopaking MS. Urease, gastric bacteria and gastritis. Acta Medica Indonesiana, 2022, 54(1): 1-2. |
| [24] | Gu HY. Role of flagella in the pathogenesis of Helicobacter pylori. Current Microbiology, 2017, 74(7): 863-869. DOI:10.1007/s00284-017-1256-4 |
| [25] | Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D, Incecik ET, Berg DE, Covacci A, Engstrand L, Borén T. Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science, 1998, 279(5349): 373-377. DOI:10.1126/science.279.5349.373 |
| [26] | Mahdavi J, Sonden B, Hurtig M, Olfat FO, Forsberg L, Roche N, Angstrom J, Larsson T, Teneberg S, Karlsson KA. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science, 2002, 297(5581): 573-578. DOI:10.1126/science.1069076 |
| [27] | Santos JC, Ribeiro ML. Epigenetic regulation of DNA repair machinery in Helicobacter pylori-induced gastric carcinogenesis. World Journal of Gastroenterology, 2015, 21(30): 9021-9037. DOI:10.3748/wjg.v21.i30.9021 |
| [28] | Muhammad JS, Eladl MA, Khoder G. Helicobacter pylori-induced DNA methylation as an epigenetic modulator of gastric cancer: recent outcomes and future direction. Pathogens, 2019, 8(23): 1-11. |
| [29] | Matsusaka K, Funata S, Fukayama M, Kaneda A. DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus pylori. World Journal of Gastroenterology, 2014, 20(14): 3916-3926. DOI:10.3748/wjg.v20.i14.3916 |
| [30] | Judd LM, Alderman BM, Howlett M, Shulkes A, Dow C, Moverley J, Grail D, Jenkins BJ, Ernst M, Giraud AS. Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. Gastroenterology, 2004, 126(1): 196-207. DOI:10.1053/j.gastro.2003.10.066 |
| [31] | Schaeper U, Gehring NH, Fuchs KP, Sachs M, Kempkes B, Birchmeier W. Coupling of Gab1 to c-Met, Grb2, and Shp2 mediates biological responses. The Journal of Cell Biology, 2000, 149(7): 1419-1432. DOI:10.1083/jcb.149.7.1419 |
| [32] | Maroun CR, Naujokas MA, Holgado-Madruga M, Wong AJ, Park M. The tyrosine phosphatase SHP-2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Molecular and Cellular Biology, 2000, 20(22): 8513-8525. DOI:10.1128/MCB.20.22.8513-8525.2000 |
| [33] | Caron E. Regulation of Wiskott-Aldrich syndrome protein and related molecules. Current Opinion in Cell Biology, 2002, 14(1): 82-87. DOI:10.1016/S0955-0674(01)00298-8 |
| [34] | Higgs HN, Pollard TD. Regulation of actin filament network formation through ARP2/3 complex: activation by a diverse array of proteins. Annual Review of Biochemistry, 2001, 70: 649-676. DOI:10.1146/annurev.biochem.70.1.649 |
| [35] | Hatakeyama M. Helicobacter pylori CagA—a potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins. Microbes and Infection, 2003, 5(2): 143-150. DOI:10.1016/S1286-4579(02)00085-0 |
| [36] | Argent RH, Kidd M, Owen RJ, Thomas RJ, Limb MC, Atherton JC. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. Gastroenterology, 2004, 127(2): 514-523. DOI:10.1053/j.gastro.2004.06.006 |
| [37] | Azuma T, Yamakawa A, Yamazaki S, Fukuta K, Ohtani M, Ito Y, Dojo M, Yamazaki Y, Kuriyama M. Correlation between variation of the 3′ region of the cagA gene in Helicobacter pylori and disease outcome in Japan. The Journal of Infectious Diseases, 2002, 186(11): 1621-1630. DOI:10.1086/345374 |
| [38] | Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, Azuma T, Hatakeyama M. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. PNAS, 2002, 99(22): 14428-14433. DOI:10.1073/pnas.222375399 |
| [39] | Naito M, Yamazaki T, Tsutsumi R, Higashi H, Onoe K, Yamazaki S, Azuma T, Hatakeyama M. Influence of EPIYA-repeat polymorphism on the phosphorylationdependent biological activity of Helicobacter pylori CagA. Gastroenterology, 2006, 130(4): 1181-1190. DOI:10.1053/j.gastro.2005.12.038 |
| [40] | Cover TL, Blanke SR. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nature Reviews Microbiology, 2005, 3(4): 320-332. DOI:10.1038/nrmicro1095 |
| [41] | Kusters JG, Van Vliet AHM, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clinical Microbiology Reviews, 2006, 19(3): 449-490. DOI:10.1128/CMR.00054-05 |
| [42] | Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, Amedei A, DʾElios MM, Telford JL, Baldari CT. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. Journal of Experimental Medicine, 2003, 198(12): 1887-1897. DOI:10.1084/jem.20030621 |
| [43] | Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science, 2003, 301(5636): 1099-1102. DOI:10.1126/science.1086871 |
| [44] | Sundrud MS, Torres VJ, Unutmaz D, Cover TL. Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. PNAS, 2004, 101(20): 7727-7732. DOI:10.1073/pnas.0401528101 |
| [45] | Terebiznik MR, Vazquez CL, Torbicki K, Banks D, Wang T, Hong W, Blanke SR, Colombo MI, Jones NL. Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells. Infection and Immunity, 2006, 74(12): 6599-6614. DOI:10.1128/IAI.01085-06 |
| [46] | Palframan SL, Kwok T, Gabriel K. Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis. Frontiers in Cellular and Infection Microbiology, 2012, 2: 92. |
| [47] | Hisatsune J, Nakayama M, Isomoto H, Kurazono H, Mukaida N, Mukhopadhyay AK, Azuma T, Yamaoka Y, Sap J, Yamasaki E, Yahiro K, Moss J, Hirayama T. Molecular characterization of Helicobacter pylori VacA induction of IL-8 in U937 cells reveals a prominent role for p38MAPK in activating transcription factor-2, cAMP response element binding protein, and NF-kappaB activation. Journal of Immunology, 2008, 180(7): 5017-5027. DOI:10.4049/jimmunol.180.7.5017 |
| [48] | Fujikawa A, Shirasaka D, Yamamoto S, Ota H, Yahiro K, Fukada M, Shintani T, Wada A, Aoyama N, Hirayama T, Fukamachi H, Noda M. Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Nature Genetics, 2003, 33(3): 375-381. DOI:10.1038/ng1112 |
| [49] | Ogura K, Maeda S, Nakao M, Watanabe T, Tada M, Kyutoku T, Yoshida H, Shiratori Y, Omata M. Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil. Journal of Experimental Medicine, 2000, 192(11): 1601-1609. DOI:10.1084/jem.192.11.1601 |
| [50] | Wada A, Yamasaki E, Hirayama T. Helicobacter pylori vacuolating cytotoxin, VacA, is responsible for gastric ulceration. The Journal of Biochemistry, 2004, 136(6): 741-746. DOI:10.1093/jb/mvh181 |
| [51] | Yahiro K, Hirayama T, Moss J, Noda M. Helicobacter pylori VacA toxin causes cell death by inducing accumulation of cytoplasmic connexin 43. Cell Death & Disease, 2015, 6(e1971): 1-2. |
| [52] | Letley DP, Atherton JC. Natural diversity in the N terminus of the mature vacuolating cytotoxin of Helicobacter pylori determines cytotoxin activity. Journal of Bacteriology, 2000, 182(11): 3278-3280. DOI:10.1128/JB.182.11.3278-3280.2000 |
| [53] | Letley DP, Rhead JL, Twells RJ, Dove B, Atherton JC. Determinants of non-toxicity in the gastric pathogen Helicobacter pylori. The Journal of Biological Chemistry, 2003, 278(29): 26734-26741. DOI:10.1074/jbc.M304071200 |
| [54] | Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, Capelinha AF, Quint W, Caldas C, Van Doorn LJ, Carneiro F, Sobrinho-Simoes M. Helicobacter pylori and interleukin 1 genotyping. An opportunity to identify high-risk individuals for gastric carcinoma. Journal of the National Cancer Institute, 2002, 94(22): 1680-1687. DOI:10.1093/jnci/94.22.1680 |
| [55] | Miehlke S, Kirsch C, Agha-Amiri K, Günther T, Lehn N, Malfertheiner P, Stolte M, Ehninger G, Bayerdörffer E. The Helicobacter pylori VacA s1, m1 genotype and CagA is associated with gastric carcinoma in Germany. International Journal of Cancer, 2000, 87(3): 322-327. DOI:10.1002/1097-0215(20000801)87:3<322::AID-IJC3>3.0.CO;2-M |
| [56] | Atherton JC, Cao P, Peek RM, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific VacA types with cytotoxin production and peptic ulceration. The Journal of Biological Chemistry, 1995, 270(30): 17771-17777. DOI:10.1074/jbc.270.30.17771 |
| [57] | Van Doorn LJ, Figueiredo C, Sanna R, Pena S, Midolo P, Ng EK, Atherton JC, Blaser MJ, Quint WG. Expanding allelic diversity of Helicobacter pylori VacA. Journal of Clinical Microbiology, 1998, 36(9): 2597-2603. DOI:10.1128/JCM.36.9.2597-2603.1998 |
| [58] | Mukhopadhyay AK, Kersulyte D, Jeong JY, Datta S, Ito Y, Chowdhury A, Chowdhury S, Santra A, Bhattacharya SK, Azuma T, Nair GB, Berg DE. Distinctiveness of genotypes of Helicobacter pylori in Calcutta, India. Journal of Bacteriology, 2000, 182(11): 3219-3227. DOI:10.1128/JB.182.11.3219-3227.2000 |
| [59] | Rhead JL, Letley DP, Mohammadi M, Hussein N, Mohagheghi MA, Eshagh Hosseini M, Atherton JC. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology, 2007, 133(3): 926-936. DOI:10.1053/j.gastro.2007.06.056 |
| [60] | Kienesberger S, Cox LM, Livanos A, Zhang XS, Chung J, Perez-Perez GI, Gorkiewicz G, Zechner EL, Blaser MJ. Gastric Helicobacter pylori infection affects local and distant microbial populations and host responses. Cell Reports, 2016, 14(6): 1395-1407. DOI:10.1016/j.celrep.2016.01.017 |
| [61] | Wang LL, Zhou JH, Xin YN, Geng CX, Tian ZB, Yu XJ, Dong QJ. Bacterial overgrowth and diversification of microbiota in gastric cancer. European Journal of Gastroenterology & Hepatology, 2016, 28(3): 261-266. |
| [62] |
Wang B. Pathogenic factors of Helicobacter pylori in peptic ulcer and progress in treatment. Chinese Community Doctors, 2019, 35(19): 11-12.
(in Chinese) 王斌. 幽门螺旋杆菌在消化性溃疡中的致病因素以及治疗进展. 中国社区医师, 2019, 35(19): 11-12. DOI:10.3969/j.issn.1007-614x.2019.19.005 |
| [63] | Byrd JC, Yunker CK, Xu QS, Sternberg LR, Bresalier RS. Inhibition of gastric mucin synthesis by Helicobacter pylori. Gastroenterology, 2000, 118(6): 1072-1079. DOI:10.1016/S0016-5085(00)70360-X |
| [64] | Morgenstern S, Koren R, Moss SF, Fraser G, Okon E, Niv Y. Does Helicobacter pylori affect gastric mucin expression? Relationship between gastric antral mucin expression and H. pylori colonization. European Journal of Gastroenterology & Hepatology, 2001, 13(1): 19-23. |
| [65] | Mack DR, Michail S, Wei S, McDougall L, Hollingsworth MA. Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression. The American Journal of Physiology, 1999, 276(4): G941-G950. |
| [66] | Mack DR, Ahrne S, Hyde L, Wei S, Hollingsworth MA. Extracellular MUC3 mucin secretion follows adherence of Lactobacillus strains to intestinal epithelial cells in vitro. Gut, 2003, 52(6): 827-833. DOI:10.1136/gut.52.6.827 |
| [67] | Pantoflickova D, Corthesy-Theulaz I, Dorta G, Stolte M, Isler P, Rochat F, Enslen M, Blum AL. Favourable effect of regular intake of fermented milk containing Lactobacillus johnsonii on Helicobacter pylori associated gastritis. Alimentary Pharmacology & Therapeutics, 2003, 18(8): 805-813. |
| [68] | Lam EKY, Tai EKK, Koo MWL, Wong HPS, Wu WKK, Yu L, So WHL, Woo PCY, Cho CH. Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG. Life Sciences, 2007, 80(23): 2128-2136. DOI:10.1016/j.lfs.2007.03.018 |
| [69] | Van Loo J, Clune Y, Bosscher D, Franck A. Prebiotic oligofructose-enriched chicory inulin combination with probiotics in the prevention of colon cancer in experimental models and human volunteers. Agro Food Industry Hi-Tech, 2005, 16(4): 6-8. |
| [70] | Mukai TK, Asasaka T, Sato E, Mori K, Matsumoto M, Ohori H. Inhibition of binding of Helicobacter pylori to the glycolipid receptors by probiotic Lactobacillus reuteri. FEMS Immunology & Medical Microbiology, 2002, 32(2): 105-110. |
| [71] |
Zhao ZY, Wang JB, Liu DQ, Li Y. Anti-HP acidophilus adhesion to SGC-7901 cells and its inhibitory effect on HP-SGC-7901 cell adhesion. Chinese Journal of Laboratory Diagnosis, 2012, 16(6): 989-991.
(in Chinese) 赵忠岩, 王江滨, 刘冬琦, 李岩. 抗HP嗜酸乳杆菌与SGC-7901细胞的黏附及其对HP与SGC-7901细胞黏附的抑制效应. 中国实验诊断学, 2012, 16(6): 989-991. DOI:10.3969/j.issn.1007-4287.2012.06.013 |
| [72] | Sakarya S, Gunay N. Saccharomyces boulardii expresses neuraminidase activity selective for α2, 3-linked sialic acid that decreases Helicobacter pylori adhesion to host cells. APMIS, 2014, 122(10): 941-950. DOI:10.1111/apm.12237 |
| [73] | 吴清平, 商燕燕, 李滢, 谢新强, 丁郁, 王涓, 薛亮, 陈谋通, 张菊梅, 叶青华, 吴诗, 陈惠元, 吴军林. 一株产溶菌酶并高效拮抗多药耐药幽门螺杆菌的植物乳杆菌LP1Z及其应用: CN114350578B[P]. 2022-05-27. |
| [74] | Ashaolu TJ. Immune boosting functional foods and their mechanisms: a critical evaluation of probiotics and prebiotics. Biomedicine & Pharmacotherapy, 2020, 130: 110625. |
| [75] | Midolo PD, Lambert JR, Hull R, Luo F, Grayson ML. In vitro inhibition of Helicobacter pylori NCTC 11637 by organic acids and lactic acid bacteria. The Journal of Applied Bacteriology, 1995, 79(4): 475-479. DOI:10.1111/j.1365-2672.1995.tb03164.x |
| [76] | Tsai CC, Huang LF, Lin CC, Tsen HY. Antagonistic activity against Helicobacter pylori infection in vitro by a strain of Enterococcus faecium TM39. International Journal of Food Microbiology, 2004, 96(1): 1-12. DOI:10.1016/j.ijfoodmicro.2003.10.019 |
| [77] | Pinchuk IV, Bressollier P, Verneuil B, Fenet B, Sorokulova IB, Mégraud F, Urdaci MC. In vitro anti-Helicobacter pylori activity of the probiotic strain Bacillus subtilis 3 is due to secretion of antibiotics. Antimicrobial Agents and Chemotherapy, 2001, 45(11): 3156-3161. DOI:10.1128/AAC.45.11.3156-3161.2001 |
| [78] | Kim TS, Hur JW, Yu MA, Cheigh CI, Kim KN, Hwang JK, Pyun YR. Antagonism of Helicobacter pylori by bacteriocins of lactic acid bacteria. Journal of Food Protection, 2003, 66(1): 3-12. DOI:10.4315/0362-028X-66.1.3 |
| [79] | Lorca GL, Wadström T, Font De Valdez G, Ljungh Å. Lactobacillus acidophilus autolysins inhibit Helicobacter pylori in vitro. Current Microbiology, 2001, 42(1): 39-44. DOI:10.1007/s002840010175 |
| [80] | Francavilla R, Lionetti E, Castellaneta SP, Magistà AM, Maurogiovanni G, Bucci N, De Canio A, Indrio F, Cavallo L, Ierardi E, Miniello VL. Inhibition of Helicobacter pylori infection in humans by Lactobacillus reuteri ATCC 55730 and effect on eradication therapy: a pilot study. Helicobacter, 2008, 13(2): 127-134. DOI:10.1111/j.1523-5378.2008.00593.x |
| [81] | Lesbros-Pantoflickova D, Corthesy-Theulaz I, Blum AL. Helicobacter pylori and probiotics. Journal of Nutrition, 2007, 137(3): 812s-818s. DOI:10.1093/jn/137.3.812S |
| [82] | Song HY, Zhou L, Liu DY, Yao XJ, Li Y. What roles do probiotics play in the eradication of Helicobacter pylori? Current knowledge and ongoing research. Gastroenterology Research and Practice, 2018, 2018(9379480): 1-10. |
| [83] | Chakravarty K, Gaur S. Role of probiotics in prophylaxis of Helicobacter pylori infection. Current Pharmaceutical Biotechnology, 2019, 20(2): 137-145. DOI:10.2174/1389201020666190227203107 |
| [84] |
Chen YH, Wang CL, Xie Y. Progress of research into the pathogenic mechanism of Helicobacter pylori and the preventive role of probiotics in H. pylori infection. World Chinese Journal of Digestology, 2007, 15(25): 2690-2697.
(in Chinese) 陈云华, 汪春莲, 谢云. 幽门螺杆菌致病机制及益生菌防治作用的研究进展. 世界华人消化杂志, 2007, 15(25): 2690-2697. DOI:10.3969/j.issn.1009-3079.2007.25.006 |
| [85] | Yang YJ, Chuang CC, Yang HB, Lu CC, Sheu BS. Lactobacillus acidophilus ameliorates H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways. BMC Microbiology, 2012, 12: 38. DOI:10.1186/1471-2180-12-38 |
| [86] | Lee JS, Paek NS, Kwon OS, Hahm KB. Anti-inflammatory actions of probiotics through activating suppressor of cytokine signaling (SOCS) expression and signaling in Helicobacter pylori infection: a novel mechanism. Journal of Gastroenterology and Hepatology, 2010, 25(1): 194-202. DOI:10.1111/j.1440-1746.2009.06127.x |
| [87] | Thiraworawong T, Spinler JK, Werawatganon D, Klaikeaw N, Venable SF, Versalovic J, Tumwasorn S. Anti-inflammatory properties of gastric-derived Lactobacillus plantarum XB7 in the context of Helicobacter pylori infection. Helicobacter, 2014, 19(2): 144-155. DOI:10.1111/hel.12105 |
| [88] | Zhou C, Ma FZ, Deng XJ, Yuan H, Ma HS. Lactobacilli inhibit interleukin-8 production induced by Helicobacter pylori lipopolysaccharide-activated toll-like receptor 4. World Journal of Gastroenterology, 2008, 14(32): 5090-5095. DOI:10.3748/wjg.14.5090 |
| [89] |
Zhao D, Xu GF, Zou XP. Modulatory effect of probiotics on gastric mucosal IL-8, IFN-γ and IL-4, IL-10 levels in Helicobacter pylori-infected C57BL/6 mice. Chinese Journal of Gastroenterology, 2012, 17(5): 271-275.
(in Chinese) 赵东, 徐桂芳, 邹晓平. 益生菌对感染幽门螺杆菌的C57BL/6小鼠胃黏膜IL-8、IFN-γ以及IL-4、IL-10的调节效应. 胃肠病学, 2012, 17(5): 271-275. DOI:10.3969/j.issn.1008-7125.2012.05.004 |
| [90] |
Liu X, Lin MP, Ding YW, Yang T, Lin H. Role of toll-like receptor 4 in probiotic treatment of Hp infected mice. China Journal of Modern Medicine, 2011, 21(1): 32-35.
(in Chinese) 刘翔, 林漫鹏, 丁元伟, 杨涛, 林虹. TLR4在益生菌治疗小鼠Hp感染中的作用. 中国现代医学杂志, 2011, 21(1): 32-35. DOI:10.3969/j.issn.1005-8982.2011.01.008 |
| [91] | Kim JM, Kim JS, Kim YJ, Oh YK, Kim IY, Chee YJ, Han JS, Jung HC. Conjugated linoleic acids produced by Lactobacillus dissociates IKK-gamma and Hsp90 complex in Helicobacter pylori-infected gastric epithelial cells. Laboratory Investigation; a Journal of Technical Methods and Pathology, 2008, 88(5): 541-552. DOI:10.1038/labinvest.2008.16 |
| [92] | Sgouras DN, Panayotopoulou EG, Martinez-Gonzalez B, Petraki K, Michopoulos S, Mentis A. Lactobacillus johnsonii La1 attenuates Helicobacter pylori-associated gastritis and reduces levels of proinflammatory chemokines in C57BL/6 mice. Clinical and Diagnostic Laboratory Immunology, 2005, 12(12): 1378-1386. |
| [93] | Eslami M, Yousefi B, Kokhaei P, Jazayeri Moghadas A, Sadighi Moghadam B, Arabkari V, Niazi Z. Are probiotics useful for therapy of Helicobacter pylori diseases?. Comparative Immunology, Microbiology and Infectious Diseases, 2019, 64: 99-108. DOI:10.1016/j.cimid.2019.02.010 |
| [94] | Vitiñi E, Alvarez S, Medina M, Medici M, De Budeguer MV, Perdigón G. Gut mucosal immunostimulation by lactic acid bacteria. Biocell, 2000, 24(3): 223-232. |
| [95] | Gotteland M, Brunser O, Cruchet S. Systematic review: are probiotics useful in controlling gastric colonization by Helicobacter pylori?. Alimentary Pharmacology & Therapeutics, 2006, 23(8): 1077-1086. |
| [96] | Duan X, Chen P, Xu X, Han M, Li J. Role of gastric microorganisms other than Helicobacter pylori in the development and treatment of gastric diseases. Biomed Research International, 2022, 2022(6263423): 1-11. |
| [97] | 彭超. 幽门螺杆菌感染和根除对胃肠道菌群的影响及益生菌的调节作用. 南昌大学博士学位论文, 2021. |
| [98] | Dargenio C, Dargenio VN, Bizzoco F, Indrio F, Francavilla R, Cristofori F. Limosilactobacillus reuteri strains as adjuvants in the management of Helicobacter pylori infection. Medicina-Lithuania, 2021, 57(7): 1-7. |
| [99] | Sehrawat N, Yadav M, Singh M, Kumar V, Sharma VR, Sharma AK. Probiotics in microbiome ecological balance providing a therapeutic window against cancer. Seminars in Cancer Biology, 2021, 70: 24-36. DOI:10.1016/j.semcancer.2020.06.009 |
| [100] | Hu YF, Zhao MG, Lu ZX, Lv FX, Zhao HZ, Bie XM. L. johnsonii, L. plantarum, and L. rhamnosus alleviated Enterohaemorrhagic Escherichia coli-induced diarrhoea in mice by regulating gut microbiota. Microbial Pathogenesis, 2021, 154(104856): 1-7. |
| [101] | Kamiya S, Yonezawa H, Osaki T. Role of probiotics in eradication therapy for Helicobacter pylori infection. Helicobacter Pylori in Human Diseases: Advances in Microbiology, Infectious Diseases and Public Health, 2019, 11(1149): 243-255. |
| [102] | Taghizadeh S, Falsafi T, Kermanshahi RK, Ramezani R. Antagonistic and immunomodulant effects of two probiotic strains of Lactobacillus on clinical strains of Helicobacter pylori. Galen Medical Journal, 2020, 9: e1794. DOI:10.31661/gmj.v9i0.1794 |
| [103] | Malfertheiner P, Megraud F, O'Morain CA, Gisbert JP, Kuipers EJ, Axon AT, Bazzoli F, Gasbarrini A, Atherton J, Graham DY, Rokkas T, El-Omar E. M, Kuipers EJ, Ehsg. Management of Helicobacter pylori infection-the Maastricht V/florence consensus report. Gut, 2017, 66(5): 6-30. |
| [104] |
Ma XM, Liu M, Qi P, Lei MH, Wang AP. Efficacy of probiotics combined with anti-Helicobacter pylori in the treatment of elderly gastric ulcers and their effects on gastric function and intestinal flora. Chinese Journal of Gerontology, 2021, 41(17): 3665-3668.
(in Chinese) 马熙淼, 刘敏, 綦鹏, 雷鸣华, 王爱平. 益生菌联合抗幽门螺杆菌治疗老年胃溃疡疗效及对胃功能、肠道菌群的影响. 中国老年学杂志, 2021, 41(17): 3665-3668. DOI:10.3969/j.issn.1005-9202.2021.17.011 |
| [105] |
Xiao HX, Ye H, Deng X, Ye SM, Zhang XZ. Progress in application of probiotics in treatment of Helicobacter pylori infection in special populations. Medical Recapitulate, 2022, 28(6): 1150-1155.
(in Chinese) 肖惠霞, 叶晖, 邓鑫, 叶苏漫, 张学智. 益生菌在特殊人群幽门螺杆菌感染治疗中的应用进展. 医学综述, 2022, 28(6): 1150-1155. DOI:10.3969/j.issn.1006-2084.2022.06.020 |
| [106] | Losurdo G, Cubisino R, Barone M, Principi M, Leandro G, Ierardi E, Di Leo A. Probiotic monotherapy and Helicobacter pylori eradication: a systematic review with pooled-data analysis. World Journal of Gastroenterology, 2018, 24(1): 139-149. DOI:10.3748/wjg.v24.i1.139 |
| [107] | Dore MP, Bibbò S, Pes GM, Francavilla R, Graham DY. Role of probiotics in Helicobacter pylori eradication: lessons from a study of Lactobacillus reuteri strains DSM 17938 and ATCC PTA 6475 (Gastrus®) and a proton-pump inhibitor. The Canadian Journal of Infectious Diseases & Medical Microbiology, 2019, 2019: 3409820. |
| [108] | Fang HR, Zhang GQ, Cheng JY, Li ZY. Efficacy of Lactobacillus-supplemented triple therapy for Helicobacter pylori infection in children: a meta-analysis of randomized controlled trials. European Journal of Pediatrics, 2019, 178(1): 7-16. DOI:10.1007/s00431-018-3282-z |
| [109] |
Qian XQ, Chen LL, Zhong HB. Efficacy of probiotics combined with anti-Helicobacter pylori treatment in patients with peptic ulcer. Chinese Journal of Microecology, 2018, 30(2): 189-192.
(in Chinese) 钱小棋, 陈玲玲, 钟海兵. 益生菌联合抗幽门螺杆菌治疗对消化性溃疡患者的疗效. 中国微生态学杂志, 2018, 30(2): 189-192. DOI:10.13381/j.cnki.cjm.201802016 |
| [110] |
Zhou KH. Effect of probiotics combined with triple therapy in the treatment of pediatric Helicobacter pylori-related chronic gastritis and incidence of adverse reactions. Jilin Medical Journal, 2022, 43(1): 180-181.
(in Chinese) 周垦横. 益生菌联合三联疗法治疗小儿幽门螺杆菌相关性慢性胃炎的效果及不良反应发生率分析. 吉林医学, 2022, 43(1): 180-181. DOI:10.3969/j.issn.1004-0412.2022.01.069 |
| [111] |
Wang RR. Analysis of influencing factors of probiotic combined quadruple therapy for eradication of Helicobacter pylori. Modern Digestion & Intervention, 2021, 26(11): 1422-1424.
(in Chinese) 王蕊蕊. 益生菌联合四联疗法根除幽门螺杆菌疗效的影响因素分析. 现代消化及介入诊疗, 2021, 26(11): 1422-1424. DOI:10.3969/j.issn.1672-2159.2021.11.019 |
| [112] | 托娅. 益生菌Lactobacillus casei Zhang免疫调节和抗肿瘤作用及机理研究. 内蒙古农业大学博士学位论文, 2008. |
| [113] | Hurduc V, Plesca D, Dragomir D, Sajin M, Vandenplas Y. A randomized, open trial evaluating the effect of Saccharomyces boulardii on the eradication rate of Helicobacter pylori infection in children. Acta Paediatrica: Oslo, Norway, 2009, 98(1): 127-131. DOI:10.1111/j.1651-2227.2008.00977.x |
| [114] | Goldman CG, Barrado DA, Balcarce N, Rua EC, Oshiro M, Calcagno ML, Janjetic M, Fuda J, Weill R, Salgueiro MJ, Valencia ME, Zubillaga MB, Boccio JR. Effect of a probiotic food as an adjuvant to triple therapy for eradication of Helicobacter pylori infection in children. Nutrition: Burbank, Los Angeles County, Calif, 2006, 22(10): 984-988. DOI:10.1016/j.nut.2006.06.008 |
| [115] | Lionetti E, Indrio F, Pavone L, Borrelli G, Cavallo L, Francavilla R. Role of probiotics in pediatric patients with Helicobacter pylori infection: a comprehensive review of the literature. Helicobacter, 2010, 15(2): 79-87. DOI:10.1111/j.1523-5378.2009.00743.x |
| [116] | Szajewska H, Albrecht P, Topczewska-Cabanek A. Randomized, double-blind, placebo-controlled trial: effect of Lactobacillus GG supplementation on Helicobacter pylori eradication rates and side effects during treatment in children. Journal of Pediatric Gastroenterology and Nutrition, 2009, 48(4): 431-436. DOI:10.1097/MPG.0b013e318182e716 |
| [117] | Navarro-Rodriguez T, Silva FM, Barbuti RC, Mattar R, Moraes JP, De Oliveira MN, Bogsan CS, Chinzon D, Eisig JN. Association of a probiotic to a Helicobacter pylori eradication regimen does not increase efficacy or decreases the adverse effects of the treatment: a prospective, randomized, double-blind, placebo-controlled study. Bmc Gastroenterology, 2013, 13(56): 1-8. |
| [118] | Shavakhi A, Tabesh E, Yaghoutkar A, Hashemi H, Tabesh F, Khodadoostan M, Minakari M, Shavakhi S, Gholamrezaei A. The effects of multistrain probiotic compound on bismuth-containing quadruple therapy for Helicobacter pylori infection: a randomized placebo-controlled triple-blind study. Helicobacter, 2013, 18(4): 280-284. DOI:10.1111/hel.12047 |
| [119] | Hauser G, Salkic N, Vukelic K, JajacKnez A, Stimac D. Probiotics for standard triple Helicobacter pylori eradication: a randomized, double-blind, placebocontrolled trial. Medicine, 2015, 94(17): e685. DOI:10.1097/MD.0000000000000685 |
| [120] | Linsalata M, Russo F, Berloco P, Caruso ML, Matteo GDI, Cifone MG, Simone CDE, Ierardi E, Di Leo A. The influence of Lactobacillus brevis on ornithine decarboxylase activity and polyamine profiles in Helicobacter pylori-infected gastric mucosa. Helicobacter, 2004, 9(2): 165-172. DOI:10.1111/j.1083-4389.2004.00214.x |
| [121] | Kim MN, Kim N, Lee SH, Park YS, Hwang JH, Kim JW, Jeong SH, Lee DH, Kim JS, Jung HC, Song IS. The effects of probiotics on PPI-triple therapy for Helicobacter pylori eradication. Helicobacter, 2008, 13(4): 261-268. DOI:10.1111/j.1523-5378.2008.00601.x |
| [122] | Wilhelm SM, Johnson JL, Kale-Pradhan PB. Treating bugs with bugs: the role of probiotics as adjunctive therapy for Helicobacter pylori. The Annals of Pharmacotherapy, 2011, 45(7/8): 960-966. |
| [123] | Vítor JMB, Vale FF. Alternative therapies for Helicobacter pylori: probiotics and phytomedicine. FEMS Immunology and Medical Microbiology, 2011, 63(2): 153-164. DOI:10.1111/j.1574-695X.2011.00865.x |
| [124] | Tong JL, Ran ZH, Shen J, Zhang CX, Xiao SD. Meta-analysis: the effect of supplementation with probiotics on eradication rates and adverse events during Helicobacter pylori eradication therapy. Alimentary Pharmacology & Therapeutics, 2007, 25(2): 155-168. |