Division of Geographic Medicine and Infectious Diseases and Department of Medicine, Tufts-New England Medical Center, and Tufts University School of Medicine, Boston, Massachusetts 马萨诸塞州波士顿塔夫茨新英格兰医学中心和塔夫茨大学医学院地理医学和传染病科和医学系
Probiotics are generally defined as microorganisms that, when consumed, generally confer a health benefit on humans. There is considerable interest in probiotics for a variety of medical conditions, and millions of people around the world consume probiotics daily for perceived health benefits. Lactobacilli, bifidobacteria, and lactococci have generally been regarded as safe. There are 3 theoretical concerns regarding the safety of probiotics: (1) the occurrence of disease, such as bacteremia or endocarditis; (2) toxic or metabolic effects on the gastrointestinal tract; and (3) the transfer of antibiotic resistance in the gastrointestinal flora. In this review, the evidence for safety of the use of or the study of probiotics is examined. Although there are rare cases of bacteremia or fungemia related to the use of probiotics, epidemiologic evidence suggests no population increase in risk on the basis of usage data. There have been many controlled clinical trials on the use of probiotics that demonstrate safe use. The use of probiotics in clinical trials should be accompanied by the use of a data-safety monitoring board and by knowledge of the antimicrobial susceptibilities of the organism used. 益生菌通常被定义为食用后通常对人类健康有益的微生物。人们对益生菌治疗各种医疗状况非常感兴趣，世界各地有数百万人每天食用益生菌以获得健康益处。乳杆菌、双歧杆菌和乳球菌通常被认为是安全的。关于益生菌的安全性，理论上存在3个担忧：（1）疾病的发生，如菌血症或心内膜炎； (2)对胃肠道的毒性或代谢作用； (3)胃肠道菌群中抗生素耐药性的转移。在本次综述中，对益生菌的使用或研究的安全性证据进行了审查。尽管存在与使用益生菌相关的菌血症或真菌血症的罕见病例，但流行病学证据表明，根据使用数据，人群的风险并未增加。许多关于益生菌使用的对照临床试验证明了其安全使用。在临床试验中使用益生菌应同时使用数据安全监测委员会并了解所用生物体的抗菌敏感性。
Lactobacilli have a long history of safe use in foods and dairy products [1]. There is a natural association of lactobacilli with human flora, and lactobacilli are found in animals as well as plants [2]. Lactic acid bacteria have traditionally been used in fermented milks and by different societies around the world for the treatment of intestinal disturbances, especially in children [3]. Rarely, lactic acid bacilli will cause infection in humans, which has manifested as either bacteremia or endocarditis, particularly in immunocompromised hosts [4-9]. 乳酸杆菌在食品和乳制品中的安全使用有着悠久的历史[1]。乳酸菌与人类菌群存在天然关联，并且在动物和植物中都发现了乳酸菌[2]。乳酸菌传统上被用于发酵乳中，并被世界各地不同的社会用于治疗肠道紊乱，特别是儿童的肠道紊乱[3]。乳酸杆菌很少会引起人类感染，表现为菌血症或心内膜炎，特别是在免疫功能低下的宿主中[4-9]。
Lactobacilli fall into the category of organisms classified as "generally regarded as safe" [10]. Organisms that are generally regarded as safe include lactobacilli, lactococci, Bifidobacterium, and yeast. There are other probiotic organisms, such as Enterococcus, Bacillus, and other spore-forming bacteria, as well as streptococci, that are not generally regarded as safe but have been used as probiotics. In this review, I will focus on the 乳酸杆菌属于“普遍认为安全”的生物体类别[10]。通常被认为安全的生物体包括乳杆菌、乳球菌、双歧杆菌和酵母。还有其他益生菌，如肠球菌、芽孢杆菌和其他孢子形成细菌，以及链球菌，通常不被认为是安全的，但已被用作益生菌。在这篇评论中，我将重点关注
data regarding the safety of probiotics. In addition, I will pay particular attention to the safety of Lactobacillus rhamnosis (Lactobacillus ), given that this is the organism for which the most extensive number of human studies have been published [11-15]. It is also the organism that our group is currently pursuing in a series of research studies [16]. 有关益生菌安全性的数据。此外，我会特别关注鼠李糖乳杆菌 （乳杆菌 ）的安全性，因为这是已发表的人体研究最多的生物体[11-15]。这也是我们课题组目前正在进行一系列研究的有机体[16]。
Table 1 provides the list of human populations in which Lactobacillus GG has been studied and in whom there is evidence of safety . The populations studied include pregnant women, premature neonates, elderly individuals, children with rotavirus diarrhea, children and adults hospitalized with diarrhea, malnourished children from Peru, patients with rheumatoid arthritis, adults with Crohn's disease, adults with Helicobacter pylori infection, and adults with Clostridium difficile-associated diarrhea. There are also a number of studies in which the safe use of other probiotics has been studied [25-30] (table 2). One subject of these studies has been the use of Lactobacillus casei Shirota to treat critically ill children. There are a number of studies of adults with C. difficile-associated diarrhea and the use of probiotics. The organisms studied in this context include Lactobacillus plantarum, Saccharomyces boulardii, and Lactobacillus acidophilus plus 表 1 提供了已对乳杆菌 GG 进行研究且有安全性证据 的人群列表。研究人群包括孕妇、早产儿、老年人、轮状病毒腹泻儿童、因腹泻住院的儿童和成人、秘鲁营养不良儿童、类风湿关节炎患者、克罗恩病成人、幽门螺杆菌感染成人和梭菌感染成人艰难梭菌相关性腹泻。还有许多研究对其他益生菌的安全使用进行了研究[25-30]（表2）。这些研究的主题之一是使用干酪乳杆菌代田来治疗危重儿童。有许多关于成人艰难梭菌相关腹泻和益生菌使用的研究。在此背景下研究的生物体包括植物乳杆菌、布拉酵母菌和嗜酸乳杆菌
Table 1. Populations in whom Lactobacillus GG has been studied and has shown evidence of safety. 表 1. 已对乳杆菌 GG 进行研究并显示出安全性证据的人群。
Pregnant women 孕妇
Premature neonates 早产儿
Elderly individuals 老年人
Children with rotavirus diarrhea 患有轮状病毒腹泻的儿童
Hospitalized children 住院儿童
Hospitalized adults 住院成人
Finnish and other tourists 芬兰人和其他游客
Malnourished Peruvian children 营养不良的秘鲁儿童
Patients with rheumatoid arthritis 类风湿性关节炎患者
Adults with Crohn's disease 患有克罗恩病的成年人
Adults with Helicobacter pylori infection 患有幽门螺杆菌感染的成年人
Adults with Clostridium difficile-associated diarrhea 患有艰难梭菌相关性腹泻的成人
Bifidobacterium. Studies have been performed in patients with Crohn's disease, employing a wide array of agents, including Lactobacillus johnsonii LA1 and VSL#3 (VSL Pharmaceuticals). There have been a large number of studies of the prevention and treatment of urinary tract infections in adult women, as well as of children attending day care, in whom the occurrence of both respiratory illness and diarrhea has been examined [3135]. L. plantarum 299V has been studied in liver transplant recipients, adults in the intensive care unit, and adults with liver failure or chronic liver disease [36-38]. There are a number of studies of treatment of rotavirus diarrhea, including treatment with Bifidobacterium lactis (BB-12), Lactobacillus reuteri SD 2222, and many other probiotics . S. boulardii has been studied in patients with HIV-associated diarrhea and in adults with diarrhea and antibiotic-associated diarrhea . Intervention with probiotics in the treatment of bacterial vaginosis and vaginal candidiasis has also been well studied, with no significant adverse events; probiotics studied for this purpose include Lactobacillus fermentum (RC-14), L. rhamnosis GR-1, and L. plantarum . Many agents have been studied in patients with . pylori infections, as well as in patients with irritable bowel syndrome . 双歧杆菌。已经对克罗恩病患者进行了研究，使用了多种药物，包括约氏乳杆菌 LA1 和 VSL#3（VSL Pharmaceuticals）。已经有大量关于预防和治疗成年女性以及接受日托的儿童尿路感染的研究，并检查了儿童呼吸道疾病和腹泻的发生情况[3135]。植物乳杆菌 299V 已在肝移植受者、重症监护病房的成人以及患有肝功能衰竭或慢性肝病的成人中进行了研究[36-38]。有许多治疗轮状病毒腹泻的研究，包括用乳双歧杆菌 (BB-12)、罗伊氏乳杆菌 SD 2222 和许多其他益生菌治疗 。布拉氏链球菌已在 HIV 相关性腹泻患者以及患有腹泻和抗生素相关性腹泻的成人中进行了研究 。用益生菌干预治疗细菌性阴道病和阴道念珠菌病也得到了充分研究，没有出现明显的不良事件；为此目的研究的益生菌包括发酵乳杆菌 (RC-14)、鼠李糖乳杆菌 GR-1 和植物乳杆菌 。许多药物已在 患者中进行了研究。幽门螺杆菌感染，以及肠易激综合症患者 。
THEORETICAL ADVERSE RISKS OF PROBIOTICS 益生菌的理论上的不良风险
There are some theoretical adverse risks that have been raised with respect to the use of probiotics in humans . These theoretical risks include the potential for transmigration and the fact that colonization with probiotics may have a negative impact on gastrointestinal physiology and function, including metabolic and physiologic effects . There could also be adverse immunologic effects, both localized and generalized . Finally, there is also the potential for antibioticresistance transfer within the gastrointestinal tract from com- mensal or probiotic bacteria to other bacteria or potential pathogens . 关于在人类中使用益生菌，存在一些理论上的不良风险 。这些理论上的风险包括潜在的迁移以及益生菌定植可能对胃肠道生理和功能产生负面影响的事实，包括代谢和生理影响 。还可能存在局部和全身的不良免疫学影响 。最后，胃肠道内抗生素耐药性也有可能从共生菌或益生菌转移到其他细菌或潜在病原体 。
Transmigration potential. With respect to potential toxicity due to transmigration, there is no evidence that probiotics have more adhesive properties than do clinical strains . There are a number of studies in animal models that demonstrate that there is no increase in the translocation of other bacteria when probiotics are given [55]. In addition, probiotics mitigate the transmigration of pathogens during their use [56]. There are some human studies showing that patients who are taking probiotics are actually less likely to have transmigration than are those who are not [56]. Animal evidence suggests that there is actually a reduction in the translocation of other bacteria, as opposed to the transmigration of probiotic bacteria into the bloodstream. There is no evidence, from populationbased studies, of any increased risk of bacteremia or endocarditis due to probiotics [57]. There is also no evidence of any negative impact on the permeability of gut proteins in studies performed both in animals and in humans [58]. 迁移潜力。关于因迁移引起的潜在毒性，没有证据表明益生菌比临床菌株具有更强的粘附特性 。许多动物模型研究表明，给予益生菌后，其他细菌的易位并没有增加[55]。此外，益生菌在使用过程中可以减轻病原体的迁移[56]。一些人体研究表明，服用益生菌的患者实际上比未服用益生菌的患者更不可能发生轮回[56]。动物证据表明，与益生菌进入血液的迁移相反，其他细菌的易位实际上有所减少。基于人群的研究没有证据表明益生菌会增加菌血症或心内膜炎的风险[57]。在动物和人类中进行的研究中也没有证据表明肠道蛋白的渗透性有任何负面影响[58]。
Bacteremia and endocarditis potential. We do know that lactic acid bacteria, including bifidobacteria, have been isolated as causes of bacteremia and also as causes of endocarditis [5. The list of organisms that have been associated with endocarditis or bacteremia includes L. rhamnosis, L. plantarum, L. casei, Lactobacillus paracasei, Lactobacillus salivarius, 菌血症和心内膜炎的可能性。我们确实知道，乳酸菌（包括双歧杆菌）已被分离为菌血症和心内膜炎的原因[5 。与心内膜炎或菌血症相关的微生物包括鼠李糖乳杆菌、植物乳杆菌、干酪乳杆菌、副干酪乳杆菌、唾液乳杆菌、
Table 2. Populations in whom safe use of other probiotics has been studied. 表 2.已研究其他益生菌安全使用的人群。
Critically ill children (Lactobacillus casei Shirota) 危重儿童（干酪乳杆菌代田）
Patients with Clostridium difficile-associated diarrhea (Lactobacilus plantarum, Saccharomyces boulardii, and Lactobacillus acidophilus plus Bifidobacterium) 艰难梭菌相关性腹泻患者（植物乳杆菌、布拉氏酵母菌、嗜酸乳杆菌加双歧杆菌）
Patients with Crohn's disease (Lactobacillus johnsonii LA 1, VSL#3) 克罗恩病患者（约氏乳杆菌 LA 1、VSL#3）
Adult women with urinary tract infections 患有尿路感染的成年女性
Children attending day care 孩子们参加日托
Liver transplant recipients (L. plantarum 299V) 肝移植受者（植物乳杆菌 299V）
Adults in the intensive care unit (L. plantarum ) 重症监护病房中的成人（植物乳杆菌 ）
Patients with liver failure (L. plantarum 299 V) 肝功能衰竭患者（植物乳杆菌 299 V）
Patients with rotavirus diarrhea (Bifidobacterium lactis BB-12, Lactobacillus reuteri SD 2222, and many others) 轮状病毒腹泻患者（乳双歧杆菌 BB-12、罗伊氏乳杆菌 SD 2222 等）
Patients with necrotizing enterocolitis (L. acidophilus, Bifidobacterium infantis) 坏死性小肠结肠炎患者（嗜酸乳杆菌、婴儿双歧杆菌）
Patients with HIV infection-associated diarrhea (S. boulardii) HIV 感染相关性腹泻（布拉氏链球菌）患者
Adults with diarrhea (S. boulardii, L. casei, Streptococcus thermophilus, Bacillus bulgaricus, L. acidophilus) 成人腹泻（布拉氏链球菌、干酪乳杆菌、嗜热链球菌、保加利亚芽孢杆菌、嗜酸乳杆菌）
Adults with antibiotic-associated diarrhea (L. plantarum, S. boulardii, L. acidophilus, B. bulgaricus) 患有抗生素相关性腹泻的成人（植物乳杆菌、布拉氏链球菌、嗜酸乳杆菌、保加利亚芽孢杆菌）
Patients with bacterial vaginosis and candida vaginitis (Lactobacillus fermentum RC-14 plus Lactobacillus rhamnosus GR-1, L. plantarum) 细菌性阴道病和念珠菌性阴道炎患者（发酵乳杆菌 RC-14 加鼠李糖乳杆菌 GR-1、植物乳杆菌）
Patients with Helicobacter pylori infection (many) 幽门螺杆菌感染患者（很多）
Patients with irritable bowel syndrome (many) 肠易激综合症患者（很多）
L. acidophilus, and many other lactobacilli [5]. In addition, Lactococcus lactis and Leuconostoc species, as well as Pediococcus species have been demonstrated to cause bacteremia and endocarditis. Bifidobacterium species have also been isolated from the blood and in patients with endocarditis [61]. Enterococcus species, of course, are well known as causes of bacteremia and endocarditis . 嗜酸乳杆菌和许多其他乳酸杆菌[5]。此外，乳酸乳球菌和明串珠菌属以及片球菌属已被证明可引起菌血症和心内膜炎。双歧杆菌也已从血液和心内膜炎患者体内分离出来[61]。当然，众所周知，肠球菌是菌血症和心内膜炎的病因 。
With respect to sepsis related to probiotics, there have been 3 reports of Lactobacillus GG-associated bacteremia in children with short gut syndrome, 2 cases of bacteremia in children who have central venous catheters, 1 case of endocarditis, and 1 case of a liver abscess . In addition, there has been a case of endocarditis caused by a strain of . rhamnosis whose subspecies could not be completely specified. There have been 5 cases of bacteremia associated with Bacillus subtlis [59]. There has also been a case of . acidophilus bacteremia in a patient who had HIV infection and Hodgkin disease [9] and a case of Lactobacillus infection after a bone marrow transplant [7]. 关于与益生菌相关的败血症，已有3例短肠综合征儿童乳杆菌GG相关菌血症报告、2例中心静脉导管儿童菌血症报告、1例心内膜炎报告、1例肝脓肿报告 。此外，还出现过一例由 菌株引起的心内膜炎。鼠李糖属，其亚种无法完全确定。已有 5 例与枯草芽孢杆菌相关的菌血症[59]。还有一个 的情况。一名患有艾滋病毒感染和霍奇金病的患者出现嗜酸菌菌血症[9]，以及一例骨髓移植后乳酸杆菌感染的病例[7]。
Among the cases of Lactobacillus GG bacteremia in patients with short gut syndrome, 4 occurred in 3 separate events [6, . All of the cases were characterized by the presence of central venous catheters and intestinal feeding tubes. Two of the isolates were verified by PFGE as being Lactobacillus GG, and 1 was verified by both PFGE and PCR as being Lactobacillus GG. One of the isolates was not specifically verified as being Lactobacillus GG. Two of the 4 cases involved central venous catheter infections, and 2 had positive catheter culture results. These reports underscore the possible risk of Lactobacillus GG bacteremia related to the short gut syndrome. The source of the organisms might have been contamination of central venous catheters during manipulation, especially during feeding. 在短肠综合征患者发生乳酸杆菌GG菌血症的病例中，有4例发生在3个独立的事件中[6, 。所有病例的特征都是存在中心静脉导管和肠饲管。其中 2 个分离株经 PFGE 验证为乳杆菌 GG，1 个分离株经 PFGE 和 PCR 验证为乳杆菌 GG。其中一种分离株未被具体证实为乳杆菌 GG。 4例中有2例涉及中心静脉导管感染，2例导管培养结果呈阳性。这些报告强调了与短肠综合征相关的乳杆菌 GG 菌血症的可能风险。微生物的来源可能是操作过程中，特别是喂养过程中中心静脉导管的污染。
Data from surveillance in Finland suggest that there was no increase in Lactobacillus bacteremia during the decade 19902000 [65]. Lactobacilli represented of all positive blood cultures. There was no temporal change over the decade. Another study from the National Public Health laboratory demonstrated that lactobacilli were present in of positive blood cultures referred to the laboratory [66]. Although these cultures were reported to have lactobacilli, could not be confirmed. Lactobacillus GG accounted for 11 of the . rhamnosis strains that were recovered from the blood. L. rhamnosis constituted of all the lactobacilli that were isolated. The absence of any change in the prevalence of Lactobacillus bacteremia and, specifically, the absence of a change in Lactobacillus GG bacteremia is remarkable, given that the consumption of Lactobacillus GG increased in Finland from 1 L per person per year to per person per year over the period studied . 芬兰的监测数据表明，19902000 年的十年间，乳酸杆菌菌血症没有增加[65]。乳酸杆菌代表所有阳性血培养物中的 。十年来没有任何时间上的变化。国家公共卫生实验室的另一项研究表明，送交实验室的阳性血培养 中存在乳酸菌[66]。尽管据报道这些培养物含有乳酸杆菌，但 无法得到证实。乳杆菌GG占 的11个。从血液中回收的鼠李糖菌株。鼠李糖乳杆菌构成所有分离出的乳杆菌的 。鉴于芬兰乳杆菌 GG 的消费量从每人每年 1 升增加到 。
Of the 89 cases of Lactobacillus bacteremia in Finland from 1990 to 2000, 53% had species identification [66]; 25 had L. rhamnosis confirmed, and 22 had other lactobacilli. Eleven cases were indistinguishable from Lactobacillus GG by PFGE. None of these cases was associated with endocarditis. Most of the patients had serious comorbidities. Appropriate therapy was shown to improve survival [66]. Mortality appeared to be associated with the severity of underlying illness. 1990年至2000年芬兰89例乳酸菌菌血症中，53%进行了菌种鉴定[66]； 25 例确诊为鼠李糖乳杆菌，22 例确诊为其他乳酸杆菌。通过 PFGE 无法区分 11 例与乳杆菌 GG。这些病例均与心内膜炎无关。大多数患者患有严重的合并症。适当的治疗被证明可以提高生存率[66]。死亡率似乎与潜在疾病的严重程度有关。
Lactobacillus bacteremia in Sweden was examined over a 6year period, during which time there was an introduction of 3 probiotic strains into clinical use [67]. The probiotics studied were L. paracasei paracasei, L. acidophilus NCFB 1478, and Lactobacillus GG. There was no change in the rate of lactobacillemia, and no case in which Lactobacillus was isolated from the blood stream was identified as being related to the probiotic strains. The authors of the study recognized that most cases of lactic acid bacteremia are actually polymicrobial. 瑞典对乳酸菌菌血症进行了为期 6 年的检查，在此期间将 3 种益生菌菌株引入临床使用 [67]。研究的益生菌是副干酪乳杆菌、嗜酸乳杆菌 NCFB 1478 和乳杆菌 GG。乳杆菌血症的发生率没有变化，并且没有从血流中分离出乳杆菌的病例被鉴定为与益生菌菌株相关。该研究的作者认识到，大多数乳酸菌血症病例实际上是多种微生物引起的。
There have, however, been cases of sepsis related to probiotics. The most prominent have been associated with . boulardii [68-72]. There have been 16 reports of candidemia, encompassing 23 patients. Some of these patients developed septic shock. Many of the cases had some degree of molecular identification and confirmation of the probiotic strain [73, 74]. 然而，也有一些与益生菌相关的败血症病例。最突出的与 相关。布拉氏菌[68-72]。已有 16 起念珠菌血症报告，涉及 23 名患者。其中一些患者出现感染性休克。许多病例对益生菌菌株进行了一定程度的分子鉴定和确认[73, 74]。
Gastrointestinal toxicity studies. With respect to the potential impact of the use of probiotics on gastrointestinal physiology, there is the possible production of metabolites that might be undesirable, especially in patients with short small bowel syndrome [75]. There is a theoretical risk that the probiotic bacteria might lead to malabsorption due to deconjugation of bile salts [76]. This might, therefore, increase the risk of colon cancer [77]. However, there is no epidemiologic or clinical evidence to support this hypothesis [78], and there are experimental data to demonstrate some inhibitory effect of probiotics for colon cancer in animal models . 胃肠道毒性研究。关于使用益生菌对胃肠道生理学的潜在影响，可能会产生不良的代谢物，特别是对于短小肠综合征患者[75]。理论上存在这样的风险：益生菌可能因胆汁盐解离而导致吸收不良[76]。因此，这可能会增加患结肠癌的风险[77]。然而，没有流行病学或临床证据支持这一假设[78]，并且有实验数据证明益生菌在动物模型中对结肠癌有一定的抑制作用 。
Among the additional potential toxicities, there is also a theoretical possibility that -lactate production might occur, with the development of lactic acidosis [81]. Studies have been performed in healthy humans with an ileostomy. L. acidophilus and Bifidobacterium species have been shown to transform conjugated bile acid into nontoxic secondary salts [81]. In patients with short small bowel syndrome, it is possible that the conjugated bile acid metabolites might accumulate and lead to malabsorption [82]. This might lead to the risk of the lactate accumulation and a theoretical risk of colon cancer. There is also the theoretical possibility that there may be degradation of intestinal mucus [83]. However, in studies both in vitro and in gnotobiotic rats, there is no evidence that probiotics will degrade intestinal mucus . 在其他潜在毒性中，理论上也有可能随着乳酸性酸中毒的发生而产生 -乳酸[81]。已经在接受回肠造口术的健康人身上进行了研究。嗜酸乳杆菌和双歧杆菌已被证明可以将结合胆汁酸转化为无毒的次级盐[81]。在短小肠综合征患者中，结合胆汁酸代谢物可能会积聚并导致吸收不良[82]。这可能会导致乳酸积累的风险和理论上的结肠癌风险。理论上也存在肠粘液降解的可能性[83]。然而，在体外和无菌大鼠的研究中，没有证据表明益生菌会降解肠道粘液 。
Studies suggest that probiotics may modulate the immune response of individuals and boost response to vaccines or alter the natural history of the allergic response. Probiotic bacteria can modify humoral, cellular, and nonspecific immune responses and may have an impact on the local secretion of cytokines as well as the local immune response [3]. It is thought 研究表明，益生菌可以调节个体的免疫反应并增强对疫苗的反应或改变过敏反应的自然史。益生菌可以改变体液、细胞和非特异性免疫反应，并可能对细胞因子的局部分泌以及局部免疫反应产生影响[3]。是认为
that some of these responses are strain specific and host specific [3]. The role of intestinal microflora in immune development suggests that a theoretical possibility exists that manipulations caused by probiotics could have an adverse immunomodulatory effect. An additional population in which a theoretically adverse immunologic impact might be postulated is pregnancy. However, the use of probiotics during pregnancy, in neonates, and in children has not been associated with any adverse immunologic effects . 其中一些反应是菌株特异性和宿主特异性的[3]。肠道菌群在免疫发育中的作用表明，理论上存在这样的可能性：益生菌引起的操作可能会产生不利的免疫调节作用。理论上可能会产生不利免疫影响的另一个人群是怀孕。然而，在怀孕期间、新生儿和儿童中使用益生菌并未与任何不良免疫反应相关 。
Antibiotic-resistance transfer. A major area of concern has been the potential for antibiotic-resistance transfer in the gastrointestinal tract that might take place between probiotics and pathogenic bacteria . When one examines the potential for transferable antibiotic resistance in lactic acid bacteria, one can find the presence of plasmids with antibiotic-resistance genes, including genes encoding resistance to tetracycline, erythromycin, chloramphenicol, and macrolide-lincosamidestreptogramin [87]. These resistance plasmids have been found in L. reuteri, L. fermentum, L. acidophilus, and L. plantarum in raw meat, silage, and feces of animals [88]. Streptomycin resistance, tetracycline resistance, and chloramphenicol resistance, as well the plasmid mef 214, have been found in L. lactis in raw milk and soft cheese. Tetracycline resistance has been found in L. plantarum 5057 [89]. 抗生素耐药性转移。一个主要关注领域是益生菌和致病菌之间可能发生胃肠道抗生素耐药性转移 。当人们检查乳酸菌中可转移抗生素耐药性的可能性时，可以发现带有抗生素耐药性基因的质粒的存在，包括编码四环素、红霉素、氯霉素和大环内酯-林可酰胺链霉素耐药性的基因[87]。这些抗性质粒已在生肉、青贮饲料和动物粪便中的罗伊氏乳杆菌、发酵乳杆菌、嗜酸乳杆菌和植物乳杆菌中发现[88]。在原料奶和软奶酪中的乳酸乳球菌中发现了链霉素抗性、四环素抗性和氯霉素抗性以及质粒mef 214。植物乳杆菌 5057 中已发现四环素抗性[89]。
The transfer of native Lactobacillus plasmids is quite rare. Lactose fermentation plasmids have been transferred to L. casei [90]. Bacteriocin production has been transferred to . johnsonii. There is some evidence that Leuconostoc species and Pediococcus species can accept broad-host-range antibiotic-resistance plasmids from Lactococcus species [91]. Conjugation transfer from enterococci to lactobacilli and lactococci can occur in the gut of animals, as well as in vitro; however, the transfer to lactobacilli is quite rare [86, 92]. There have been some attempts to transfer antibiotic resistance with a broad-host-range plasmid pAMB. Of 14 strains of Lactobacillus delbrueckii, 44 strains of L. acidophilus, 1 strain of Lactobacillus helveticus, 1 strain of Lactobacillus brevis, 6 strains of L. casei rhamnosis, 5 strains of L. plantarum, and 1 strain of L. fermentum, only 1 strain each of L. helveticus and L. brevis accepted the plasmid with low efficiency [93]. A tetracycline-resistance determinant has been found in Lactobacillus organisms isolated from dried sausages. Seven of 14 strains were able to transfer resistance from Lactobacillus to Enterococcus at frequencies of . Two of 14 strains could transfer to L. lactis but were unable to transfer to Staphylococcus aureus . 天然乳杆菌质粒的转移相当罕见。乳糖发酵质粒已被转移到干酪乳杆菌中[90]。细菌素生产已转移至 。约翰逊。有一些证据表明明串珠菌属和片球菌属可以接受来自乳球菌属的广泛宿主范围的抗生素抗性质粒[91]。从肠球菌到乳酸杆菌和乳球菌的接合转移可以发生在动物肠道内以及体外；然而，转移至乳酸杆菌的情况相当罕见[86, 92]。已经有一些尝试用广泛宿主范围的质粒 pAMB 来转移抗生素耐药性。仅在 14 株德氏乳杆菌、44 株嗜酸乳杆菌、1 株瑞士乳杆菌、1 株短乳杆菌、6 株干酪乳杆菌、5 株植物乳杆菌和 1 株发酵乳杆菌中，仅L. helveticus 和 L. brevis 各有 1 株菌株以低效率 接受质粒[93]。从干香肠中分离出的乳杆菌生物体中发现了四环素抗性决定簇。 14 株菌株中的 7 株能够以 的频率将耐药性从乳杆菌转移到肠球菌。 14株菌株中有2株可以转移至乳酸乳球菌，但不能转移至金黄色葡萄球菌 。
There have also been attempts at molecular identification of vancomycin-resistance genes in lactobacilli. Five strains of . reuteri and 1 strain of . rhamnosis were probed for vanA, vanB, and genes. None were found [95]. Lactobacillus GG has been studied specifically, and no plasmids have been found; there is no evidence of , and vanS, by hybridization or PCR [96]. 还尝试对乳酸杆菌中的万古霉素抗性基因进行分子鉴定。 的五株。罗伊氏菌和 1 株 。检测鼠李糖的 vanA、vanB 和 基因。没有发现[95]。专门研究了乳杆菌GG，没有发现质粒；通过杂交或 PCR 没有发现 和 vanS 的证据 [96]。
THE SAFETY OF LACTOBACILLUS GG 乳酸菌 GG 的安全性
Lactobacillus GG has been the given to several thousands of individuals in clinical trials . It has been administered to travelers with diarrhea in Mexico, as well as to travelers to Turkey. It has been administered to children with chronic inflammatory disease, including Crohn's disease and juvenile rheumatoid arthritis, to adults with inflammatory bowel disease, and to patients with HIV infection [97]. It has also been administered to children and pregnant women and adults with multiple food allergies. To date, no significant adverse events have been demonstrated in these and other controlled trials . 乳杆菌 GG 已在临床试验中给予数千人 。已对在墨西哥患有腹泻的旅行者以及前往土耳其的旅行者进行了注射。它已被用于患有慢性炎症性疾病（包括克罗恩病和幼年类风湿性关节炎）的儿童、患有炎症性肠病的成人以及艾滋病毒感染的患者[97]。它还用于对多种食物过敏的儿童、孕妇和成人。迄今为止，在这些和其他对照试验中尚未证实有重大不良事件 。
There are a number of intrinsic properties that are a testament to the safety of Lactobacillus GG, including the absence of any plasmids. There appear to be no plasmids that contain transferable or other antibiotic resistance. The vancomycin resistance that has been found appears to be nontransferable and chromosomal [97]. The organism has a good enzyme profile. It elaborates -glucoronidase and urease, and it also secretes an antimicrobial agent . It appears to prevent attachment or invasion of pathogens in cell culture systems in vitro [100]. It has also not been associated with platelet aggregation [101]. There is no breakdown of human intestinal glycoprotein or hog gastric mucin in vitro [102]. There has been no demonstration of mucus degradation in germ-free animals [103]. In addition, there is no invasion of Caco-2 or HeLa cell cultures, and there is evidence of prevention of pathogen invasion in cell culture systems . Lactobacillus GG 的许多内在特性证明了它的安全性，包括不含任何质粒。似乎不存在含有可转移或其他抗生素抗性的质粒。已发现的万古霉素耐药性似乎是不可转移的和染色体的[97]。该生物体具有良好的酶谱。它精心制造 -葡萄糖醛酸酶和脲酶，并且还分泌抗菌剂 。它似乎可以防止体外细胞培养系统中病原体的附着或入侵[100]。它也与血小板聚集无关[101]。人肠糖蛋白或猪胃粘蛋白在体外不会被分解[102]。目前还没有证据表明无菌动物的粘液会降解[103]。此外，不存在Caco-2或HeLa细胞培养物的入侵，并且有证据表明细胞培养系统可以防止病原体入侵 。
There is no acute toxicity in mice, and, in fact, one cannot achieve a lethal oral dose in a mouse [104]. It has been given orally to lethally irradiated mice and actually prolongs survival [104, 105]. It does not translocate to either spleen or lymph nodes. It also inhibits tumor formation and binds aflotoxin . It has been administered to well more than 3000 healthy volunteers . There is also some evidence of phenotypic differences between commercial Lactobacillus GG and L. rhamnosis isolated from blood [108]. In these studies, it appears that Lactobacillus GG has decreased in vitro adhesion and has greater resistance to serum-mediated killing. It also induces a respiratory burst [108]. 对小鼠没有急性毒性，事实上，无法在小鼠体内达到致死的口服剂量[104]。它已被口服给受到致命辐射的小鼠，实际上延长了生存期 [104, 105]。它不会转移到脾脏或淋巴结。它还抑制肿瘤形成并结合黄曲霉毒素 。已对超过 3000 名健康志愿者进行了治疗 。还有一些证据表明从血液中分离出的商业 GG 乳杆菌和鼠李糖乳杆菌之间存在表型差异 [108]。在这些研究中，乳杆菌 GG 似乎降低了体外粘附力，并且对血清介导的杀灭具有更强的抵抗力。它还会引起呼吸爆发[108]。
In conclusion, Lactobacillus GG has been proven safe both in vitro and in vivo (in animal models), as well as in a number of human studies . Although there have been rare cases of bacteremia and liver abscess in patients with short gut syndrome, overall, it is a safe probiotic. There is no other probiotic that has undergone extensive safety evaluation to a degree comparable to that undergone by Lactobacillus GG. 总之，乳酸菌 GG 已在体外和体内（动物模型）以及多项人体研究中被证明是安全的 。尽管短肠综合征患者出现菌血症和肝脓肿的情况很少见，但总体而言，它是一种安全的益生菌。没有其他益生菌经过广泛的安全评估，其程度可与乳杆菌 GG 相媲美。
GENETICALLY ENGINEERED PROBIOTICS 基因工程益生菌
Genetic modification of probiotics has been undertaken to increase certain physiologic or immunologic properties within the organism and to use the probiotic as a mucosal delivery system or a vaccine vector [109]. The use of these genetically engineered products has been quite limited to date, but the steps enumerated below should be taken for the use of any engineered strains introduced into human studies. As with any genetically engineered product, some caution must be employed when assessing safety. 人们已经对益生菌进行了基因改造，以增加生物体内的某些生理或免疫特性，并将益生菌用作粘膜递送系统或疫苗载体[109]。迄今为止，这些基因工程产品的使用相当有限，但对于引入人类研究的任何工程菌株的使用，应采取以下列举的步骤。与任何基因工程产品一样，在评估安全性时必须谨慎行事。
STEPS TO MONITOR SAFETY OF PROBIOTICS 监测益生菌安全性的步骤
To monitor the safety of probiotics as they are introduced and increasingly used around the world, it is important to conduct population-based surveillance for the isolation of probiotic bacteria from patients with infection. There should be knowledge of the susceptibility profile for any strain used in clinical trials . There should be the ability to compare the clinically isolated strain with the probiotic strain by use of molecular methods. Any trial employing a probiotic strain should have active surveillance for cases of infection associated with such use and should have active surveillance for the occurrence of other adverse effects. Although some caution may be necessary in any trial of probiotics, concern about toxicity should not preclude their study. Rather, each study should be evaluated on a case-by-case basis, examining the risk benefit and potential toxicity. There is a list of patients for whom caution might be warranted, such as those with immune compromise, premature infants, those with short bowel syndrome, those with central venous catheters, elderly patients, and those with cardiac valve disease. However, the presence of any of these factors may not necessarily preclude a clinical trial. Each study should be evaluated on a study-by-study basis, with the appropriate involvement of a human investigation review committee and a datasafety monitoring committee, as well as specific hypotheses to be tested and surveillance for bloodstream infection with the probiotic strain. Ideally, there should be population-based surveillance for Lactobacillus bacteremia, including the use of a reference laboratory and molecular confirmation. 随着益生菌在世界范围内的引入和越来越多的使用，为了监测益生菌的安全性，对从感染患者中分离益生菌进行基于人群的监测非常重要。应该了解临床试验中使用的任何菌株的敏感性概况 。应该能够利用分子方法将临床分离菌株与益生菌菌株进行比较。任何使用益生菌菌株的试验都应积极监测与此类使用相关的感染病例，并应积极监测其他不良反应的发生。尽管在任何益生菌试验中可能需要谨慎，但对毒性的担忧不应妨碍他们的研究。相反，每项研究都应根据具体情况进行评估，检查风险收益和潜在毒性。有一系列患者可能需要谨慎，例如免疫功能低下的患者、早产儿、短肠综合征患者、使用中心静脉导管的患者、老年患者和心脏瓣膜疾病患者。然而，任何这些因素的存在并不一定会妨碍临床试验。每项研究都应在逐项研究的基础上进行评估，并有人类调查审查委员会和数据安全监测委员会的适当参与，以及要测试的具体假设和监测益生菌菌株的血流感染。理想情况下，应该对乳酸菌菌血症进行基于人群的监测，包括使用参考实验室和分子确认。
Acknowledgments 致谢
Financial support. National Institutes of Health (1R21 AT001892). 经济支持。美国国立卫生研究院 (1R21 AT001892)。
Supplement sponsorship. This article was published as part of a supplement entitled "Developing Probiotics as Foods and Drugs: Scientific and Regulatory Challenges," sponsored by the Drug Information Association, the National Institutes of Health National Center for Complementary and Alternative Medicine (1R13AT003805-01 to Patricia L. Hibberd), the California Dairy Research Foundation, Chr. Hansen, the Dannon Company, General Mills, Institut Rosell, and Yakult International. 补充赞助。本文作为题为“将益生菌开发为食品和药物：科学和监管挑战”的增刊的一部分发表，该增刊由药物信息协会、美国国立卫生研究院国家补充和替代医学中心赞助（1R13AT003805-01，帕特里夏·L）希伯德），加州乳制品研究基金会，Chr。汉森、达能公司、通用磨坊、罗塞尔研究所和养乐多国际。
Potential conflicts of interest. D.R.S.: no conflicts. 潜在的利益冲突。 D.R.S.：没有冲突。
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CONFIDENCE IN DOVATO
ACROSS TREATMENT SETTINGS 对 DOVATO 各种治疗设置的信心
Treatment-
naïve
resistance
rates,
with up to
REAL-
wVRLD
EVIDENCE
RANDDMISED
CONROLLED
TRIALS
3 years of evidence 3 年证据
Treatment- 治疗-
experienced
resistance 反抗
rates, 费率，
with up to 最多
5 years 5年
of
evidence 证据
REAL- 真实的-
WORLD 世界
EVIDENCE TRIALS 证据审判
RANDOMISED CONTROLLED 随机对照
>300,000 PEOPLE LIVING WITH HIV HAVE BEEN TREATED WITH DOVATO GLOBALLY 全球超过 300,000 名艾滋病毒感染者已接受 DOVATO 治疗
DOVATO is supported 支持多瓦托
by a wealth of evidence, with the outcomes of people living with HIV captured within clinical trials and realworld evidence,
including those with:4-9,91,12 包括：4-9,91,12
NO PRIOR TREATMENT EXPERIENCE 没有既往治疗经验
NO BASELINE RESISTANCE TESTING 无基线阻力测试
HIGH BASELINE VIRAL LOAD copies nd even copies 高基线病毒载量 复制 甚至 复制
LOW CD4 + 低CD4+
COUNT cells 计数 个单元格
Patients from phase III RCTs III 期随机对照试验的患者
Patients from unique real-world cohorts 来自独特的现实世界队列的患者
DOVATO is indicated for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults and adolescents above 12 years of age weighing at least , with no known or suspected resistance to the integrase inhibitor class, or lamivudine. DOVATO 适用于治疗 12 岁以上体重至少 的成人和青少年的人类免疫缺陷病毒 1 型 (HIV-1) 感染，且对整合酶抑制剂类没有已知或疑似耐药性，或拉米夫定。
Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk/ or search for MHRA Yellowcard in the Google Play or Apple App store. Adverse events should also be reported to GSK on 0800221441 应报告不良事件。报告表格和信息可在 https://yellowcard.mhra.gov.uk/ 上找到，或在 Google Play 或 Apple App store 中搜索 MHRA Yellowcard。不良事件也应报告给GSK：0800221441
REFERENCES 参考
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Ciccullo A et al. JAIDS 2021; 88(3): 234-237. 西库洛 A 等人。艾滋病 2021 年； 88（3）：234-237。
ViiV Healthcare. Data on File. REF-223795. 2024 ViiV 医疗保健。文件上的数据。 REF-223795。 2024年
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ABBREVIATIONS 缩写
3TC, lamivudine; CD4, cluster of differentiation 4; DTG, dolutegravir; FDA, United States Food and Drug Administration; FTC, emtricitabine; HIV, human immunodeficiency virus; ITT-E, intention-to-treat exposed; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; RCT, randomised controlled trial; RNA, ribonucleic acid; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate; XTC, emtricitabine. 3TC，拉米夫定； CD4，分化簇4； DTG，多替拉韦； FDA，美国食品和药物管理局； FTC，恩曲他滨； HIV，人类免疫缺陷病毒； ITT-E，意向治疗暴露； NRTI，核苷/核苷酸逆转录酶抑制剂； RCT，随机对照试验； RNA，核糖核酸； TAF，富马酸替诺福韦艾拉酚胺； TDF，富马酸替诺福韦二吡呋酯； XTC，恩曲他滨。
FOOTNOTES 脚注
*Data extracted from a systematic literature review of DTG+3TC real-world evidence. Overlap between cohorts cannot be fully excluded. *数据摘自 DTG+3TC 真实世界证据的系统文献综述。不能完全排除队列之间的重叠。
**The reported rate reflects the sum-total of resistance cases calculated from GEMINI I and II ( , through 144 weeks), STAT ( , through 52 weeks), and D2ARLING ( , through 24 weeks). . **报告的比率反映了根据 GEMINI I 和 II（ ，至 144 周）、STAT（ ，至 52 周）和 D2ARLING 计算出的耐药病例总数（ ，直至 24 周）。 。
TGEMINI I and II are two identical 148-week, phase III, randomised, double-blind, multicentre, parallel-group, non-inferiority, controlled clinical trials testing the efficacy of DTG/3TC in treatment-naïve patients. Participants with screening HIV-1 RNA copies/mL were randomised 1:1 to once-daily DTG/3TC ( , pooled) or DTG + TDF/FTC ( , pooled). The primary endpoint of each GEMINI study was the proportion of participants with plasma HIV-1 RNA <50 copies/mL at Week 48 (ITT-E population, snapshot algorithm). TGEMINI I 和 II 是两项相同的 148 周 III 期、随机、双盲、多中心、平行组、非劣效性对照临床试验，测试 DTG/3TC 对初治患者的疗效。筛查 HIV-1 RNA 拷贝/mL 的参与者按 1:1 随机分配至每日一次 DTG/3TC（ ，合并）或 DTG + TDF/FTC（ ，汇集）。每项 GEMINI 研究的主要终点是第 48 周时血浆 HIV-1 RNA <50 拷贝/mL 的参与者比例（ITT-E 人群，快照算法）。
FSTAT is a phase IIIb, open-label, 48-week, single-arm pilot study evaluating the feasibility, efficacy, and safety of DTG/3TC in 131 newly diagnosed HIV-1 infected adults as a first line regimen. The primary endpoint was the proportion of participants with plasma HIV-1 RNA<50 copies/mL at Week 24.6 FSTAT 是一项 IIIb 期、开放标签、为期 48 周、单组试点研究，评估 DTG/3TC 作为一线治疗方案在 131 名新诊断的 HIV-1 感染成人中的可行性、有效性和安全性。主要终点是第 24.6 周时血浆 HIV-1 RNA<50 拷贝/mL 的参与者比例
§D2ARLING is a randomised, open-label, phase IV study designed to assess the efficacy and safety of DTG/3TC in treatment-naïve people with HIV with no available baseline HIV-1 resistance testing. Participants were randomised in a ratio to receive DTG/3TC or DTG + TDF/XTC ( ). The primary endpoint was the proportion of participants with plasma HIV-1 RNA <50 copies/mL at Week 48. Results at week 24 of the study. §D2ARLING 是一项随机、开放标签的 IV 期研究，旨在评估 DTG/3TC 对于未接受过治疗且没有可用的基线 HIV-1 耐药性检测的 HIV 感染者的疗效和安全性。参与者按 比例随机分配接受 DTG/3TC 或 DTG + TDF/XTC ( )。主要终点是第 48 周血浆 HIV-1 RNA <50 拷贝/mL 的参与者比例。 研究第 24 周的结果。
| |The reported rate reflects the sum-total of resistance cases calculated from TANGO ( , through 196 weeks) and SALSA ( , through 48 weeks). | |报告的比率反映了根据 TANGO（ ，至 196 周）和 SALSA（ ，至 48 周）计算的耐药病例总数。
ITANGO is a randomised, open-label, trial testing the efficacy of DOVATO in virologically suppressed patients. Participants were randomised in a 1:1 ratio to receive DOVATO ( ) or continue with TAF-containing regimens ( ) for up to 200 weeks. At Week 148, 298 of those on TAF-based regimens switched to DOVATO. The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA copies (virologic non-response) as per the FDA Snapshot category at Week 48 (adjusted for randomisation stratification factor).8.13 #SALSA is a phase III, randomised, open-label, non-inferiority clinical trial evaluating the efficacy and safety of switching to DTG/3TC compared with continuing current antiretroviral regimens in virologically suppressed adults with HIV. Eligible participants were randomised 1:1 to switch to once-daily DTG/3TC ( ) or continue current antiretroviral regimens ( . The primary endpoint was the proportion of subjects with plasma HIV-1 RNA copies at Week 48 (ITT-E population, snapshot algorithm). 9 ITANGO 是一项随机、开放标签试验，测试 DOVATO 对病毒学抑制患者的疗效。参与者以 1:1 的比例随机接受 DOVATO ( ) 或继续接受含 TAF 的治疗方案 ( ) 长达 200 周。第 148 周时，298 名接受基于 TAF 治疗方案的患者转为使用 DOVATO。主要疗效终点是第 48 周时根据 FDA 快照类别（根据随机分层进行调整）血浆 HIV-1 RNA 拷贝 （病毒学无反应）的受试者比例8.13 #SALSA 是一项 III 期、随机、开放标签、非劣效性临床试验，旨在评估在病毒学受到抑制的成年 HIV 感染者中转用 DTG/3TC 与继续当前抗逆转录病毒治疗方案的有效性和安全性。符合条件的参与者以 1:1 的比例随机转为每日一次 DTG/3TC ( ) 或继续当前的抗逆转录病毒治疗方案 ( )。主要终点是血浆 HIV 感染受试者的比例-1 RNA 在第 48 周复制 （ITT-E 群体，快照算法 9）。
Reprints or correspondence: Dr. David R. Snydman, Box 238, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111 (DSnydman@tuftsnemc.org). 转载或通信：David R. Snydman 博士，Box 238, Tufts-New England Medical Center, 750 Washington St., Boston, MA 02111 (DSnydman@tuftsnemc.org)。
