Helicobacter pylori 幽门螺杆菌

Helicobacter pylori 幽门螺杆菌
Electron micrograph of H. pylori possessing multiple flagella (negative staining) 幽门螺杆菌多鞭毛（阴性染色）电子显微照片
Scientific classification 科学分类
Domain:	Bacteria
Phylum:	Campylobacterota
Class:	"Campylobacteria" "弯曲杆菌"
Order:	Campylobacterales
Family:	Helicobacteraceae
Genus:	Helicobacter
Species:	H. pylori
Binomial name 双名
Helicobacter pylori 幽门螺杆菌 (Marshall et al. 1985) Goodwin et al., 1989 (Marshall 等人，1985 年）Goodwin 等人，1989 年
Synonyms
Campylobacter pylori Marshall et al. 1985 幽门弯曲杆菌 Marshall 等人，1985 年

Helicobacter pylori, previously known as Campylobacter pylori, is a gram-negative, flagellated, helical bacterium. Mutants can have a rod or curved rod shape, and these are less effective.^[1][2] Its helical body (from which the genus name, Helicobacter, derives) is thought to have evolved in order to penetrate the mucous lining of the stomach, helped by its flagella, and thereby establish infection.^[3][2] The bacterium was first identified as the causal agent of gastric ulcers in 1983 by the Australian doctors Barry Marshall and Robin Warren.^[4][5]
幽门螺旋杆菌以前被称为幽门弯曲杆菌，是一种革兰氏阴性、有鞭毛的螺旋状细菌。突变体可呈杆状或弯曲杆状，但效果较差。 ^{[1] [2]} 它的螺旋体（螺旋杆菌属名由此而来）被认为是为了在鞭毛的帮助下穿透胃粘膜从而建立感染而进化而来的。 ^{[3] [2]} 1983 年，澳大利亚医生巴里-马歇尔和罗宾-沃伦首次确认这种细菌是胃溃疡的病原体。 ^{[4] [5]}

Infection of the stomach with H. pylori is not the cause of illness itself; over half of the global population is infected but most are asymptomatic.^[6][7] Persistent colonization with more virulent strains can induce a number of gastric and extragastric disorders.^[8] Gastric disorders due to infection begin with gastritis, inflammation of the stomach lining.^[9] When infection is persistent the prolonged inflammation will become chronic gastritis. Initially this will be non-atrophic gastritis, but damage caused to the stomach lining can bring about the change to atrophic gastritis, and the development of ulcers both within the stomach itself or in the duodenum, the nearest part of the intestine.^[9] At this stage the risk of developing gastric cancer is high.^[10] However, the development of a duodenal ulcer has a lower risk of cancer.^[11]Helicobacter pylori is a class 1 carcinogen, and potential cancers include gastric mucosa-associated lymphoid tissue (MALT) lymphomas and gastric cancer.^[9][10] Infection with H. pylori is responsible for around 89 per cent of all gastric cancers, and is linked to the development of 5.5 per cent of all cases of cancer worldwide.^[12][13] H. pylori is the only bacterium known to cause cancer.^[14]
幽门螺杆菌感染胃本身并不是疾病的原因；全球有一半以上的人受到感染，但大多数人没有症状。 ^{[6] [7]} 毒力较强的菌株持续定植可诱发多种胃病和胃外疾病。 ^[8] 感染引起的胃病首先是胃炎，即胃黏膜发炎。 ^[9] 当感染持续存在时，长期的炎症将转变为慢性胃炎。起初是非萎缩性胃炎，但胃黏膜受损后会转变为萎缩性胃炎，并在胃内或十二指肠（肠道的最近部分）发生溃疡。 ^[9] 在这个阶段，患胃癌的风险很高。 ^[10] 然而，十二指肠溃疡发生癌变的风险较低。 ^[11] 幽门螺杆菌是1类致癌物，潜在的癌症包括胃黏膜相关淋巴组织（MALT）淋巴瘤和胃癌。 ^{[9] [10]} 幽门螺杆菌感染是约89%胃癌的罪魁祸首，全球5.5%的癌症病例与幽门螺杆菌感染有关。 ^{[12] [13]} 幽门螺杆菌是唯一已知的致癌细菌。 ^[14]

Extragastric complications that have been linked to H. pylori include anemia due either to iron-deficiency or vitamin B12 deficiency, diabetes mellitus, cardiovascular, and certain neurological disorders.^[15] An inverse link has also been claimed with H. pylori having a positive protective effect on many disorders including asthma, esophageal cancer, IBD (including GERD and Crohn's disease) and other disorders.^[15]
与幽门螺杆菌有关的胃肠外并发症包括缺铁性贫血或维生素B12缺乏症、糖尿病、心血管疾病和某些神经系统疾病。 ^[15] 也有人声称幽门螺杆菌与许多疾病有反向联系，对哮喘、食道癌、肠道疾病（包括胃食管反流病和克罗恩病）和其他疾病有积极的保护作用。 ^[15]

Some studies suggest that H. pylori plays an important role in the natural stomach ecology by influencing the type of bacteria that colonize the gastrointestinal tract.^[16][17] Other studies suggest that non-pathogenic strains of H. pylori may beneficially normalize stomach acid secretion, and regulate appetite.^[18]
一些研究表明，幽门螺杆菌通过影响胃肠道定植细菌的类型，在胃的自然生态中发挥着重要作用。 ^{[16] [17]} 其他研究表明，非致病性幽门螺杆菌菌株可能有益于正常胃酸分泌和调节食欲。 ^[18]

In 2023, it was estimated that about two-thirds of the world's population were infected with H. pylori, being more common in developing countries.^[19] The prevalence has declined in many countries due to eradication treatments with antibiotics and proton-pump inhibitors, and with increased standards of living.^[20][21]
据估计，到2023年，全球约有三分之二的人口感染幽门螺杆菌，发展中国家的感染率更高。 ^[19] 由于抗生素和质子泵抑制剂的根除治疗，以及生活水平的提高，许多国家的发病率已经下降。 ^{[20] [21]}

Microbiology 微生物学[edit]

Helicobacter pylori is a species of gram-negative bacteria in the Helicobacter genus.^[22] About half the world's population is infected with H. pylori but only a few strains are pathogenic. H pylori is a helical bacterium having a predominantly helical shape, also often described as having a spiral or S shape.^[23][24] Its helical shape is better suited for progressing through the viscous mucosa lining of the stomach, and is maintained by a number of enzymes in the cell wall's peptidoglycan.^[1] The bacteria reach the less acidic mucosa by use of their flagella.^[25] Three strains studied showed a variation in length from 2.8–3.3 μm but a fairly constant diameter of 0.55–0.58 μm.^[23] H. pylori can convert from a helical to an inactive coccoid form, that may possibly become viable, known as viable but nonculturable (VBNC).^[26]
幽门螺杆菌是一种革兰氏阴性菌，属于幽门螺杆菌属。 ^[22] 全球约有一半人口感染幽门螺杆菌，但只有少数菌株具有致病性。幽门螺杆菌是一种主要呈螺旋形的细菌，也常被描述为螺旋形或 S 形。 ^{[23] [24]} 它的螺旋形状更适合在粘稠的胃粘膜内壁中穿行，并通过细胞壁肽聚糖中的多种酶来维持。 ^[1] 细菌通过鞭毛到达酸性较低的粘膜。 ^[25] 所研究的三个菌株的长度变化范围为 2.8-3.3 μm，但直径相当稳定，为 0.55-0.58 μm。 ^[23] 幽门螺杆菌可以从螺旋状转化为非活性茧状，这种茧状有可能成为有活力的，即有活力但不可培养（VBNC）。 ^[26]

Helicobacter pylori is microaerophilic – that is, it requires oxygen, but at lower concentration than in the atmosphere. It contains a hydrogenase that can produce energy by oxidizing molecular hydrogen (H₂) made by intestinal bacteria.^[27]
幽门螺旋杆菌具有嗜微气的特性，也就是说，它需要氧气，但氧气的浓度低于大气中的浓度。它含有一种氢化酶，可以通过氧化肠道细菌产生的分子氢（H ₂ ）产生能量。 ^[27]

H. pylori can be demonstrated in tissue by Gram stain, Giemsa stain, H&E stain, Warthin-Starry silver stain, acridine orange stain, and phase-contrast microscopy. It is capable of forming biofilms. Biofilms help to hinder the action of antibiotics and can contribute to treatment failure.^[28][29]
组织中的幽门螺杆菌可通过革兰氏染色法、Giemsa 染色法、H&E 染色法、Warthin-Starry 银染色法、吖啶橙染色法和相位对比显微镜来显示。它能够形成生物膜。生物膜有助于阻碍抗生素的作用，并可能导致治疗失败。 ^{[28] [29]} 。

To successfully colonize H. pylori uses many different virulence factors including oxidase, catalase, and urease.^[30] Urease is the most abundant protein, its expression representing about 10% of the total protein weight.^[31]
幽门螺杆菌为了成功定植，会使用许多不同的毒力因子，包括氧化酶、过氧化氢酶和尿素酶。 ^[30] 尿素酶是最丰富的蛋白质，其表达量约占蛋白质总重量的10%。 ^[31]

H. pylori possesses five major outer membrane protein families.^[30] The largest family includes known and putative adhesins. The other four families are porins, iron transporters, flagellum-associated proteins, and proteins of unknown function. Like other typical gram-negative bacteria, the outer membrane of H. pylori consists of phospholipids and lipopolysaccharide (LPS). The O-antigen of LPS may be fucosylated and mimic Lewis blood group antigens found on the gastric epithelium.^[30]
幽门螺杆菌拥有五大外膜蛋白家族。 ^[30] 最大的家族包括已知的和推测的粘附蛋白。其他四个家族包括孔蛋白、铁转运体、鞭毛相关蛋白和功能不明的蛋白。与其他典型的革兰氏阴性细菌一样，幽门螺杆菌的外膜由磷脂和脂多糖（LPS）组成。LPS的O抗原可能是岩藻糖基化的，与胃上皮细胞上的路易斯血型抗原相似。 ^[30]

Genome 基因组[edit]

Helicobacter pylori consists of a large diversity of strains, and hundreds of genomes have been completely sequenced.^[32][33][34] The genome of the strain 26695 consists of about 1.7 million base pairs, with some 1,576 genes.^[35][36] The pan-genome, that is the combined set of 30 sequenced strains, encodes 2,239 protein families (orthologous groups OGs).^[37] Among them, 1,248 OGs are conserved in all the 30 strains, and represent the universal core. The remaining 991 OGs correspond to the accessory genome in which 277 OGs are unique to one strain.^[38]
幽门螺杆菌由多种多样的菌株组成，目前已对数百个菌株的基因组进行了完整测序。 ^{[32] [33] [34]} 26695菌株的基因组由大约170万个碱基对组成，其中有大约1576个基因。 ^{[35] [36]} 泛基因组，即 30 个测序菌株的组合，编码 2 239 个蛋白质家族（同源组 OGs）。 ^[37] 其中，1 248 个 OGs 在所有 30 个菌株中都是保守的，代表了通用核心。其余的 991 个 OG 与附属基因组相对应，其中 277 个 OG 为一个菌株所独有。 ^[38]

There is an unusually high number of restriction modification systems in the genome of H. pylori.^[39] These provide a defence against bacteriophages.^[39]
幽门螺杆菌的基因组中存在异常多的限制性修饰系统。 ^[39] 这些系统提供了抵御噬菌体的能力。 ^[39]

Transcriptome 转录组[edit]

Single-cell transcriptomics using single-cell RNA-Seq gave the complete transcriptome of H. pylori which was published in 2010. This analysis of its transcription confirmed the known acid induction of major virulence loci, including the urease (ure) operon and the Cag pathogenicity island.^[40] A total of 1,907 transcription start sites 337 primary operons, and 126 additional suboperons, and 66 monocistrons were identified. Until 2010, only about 55 transcription start sites (TSSs) were known in this species. 27% of the primary TSSs are also antisense TSSs, indicating that – similar to E. coli – antisense transcription occurs across the entire H. pylori genome. At least one antisense TSS is associated with about 46% of all open reading frames, including many housekeeping genes.^[40] About 50% of the 5′ UTRs (leader sequences) are 20–40 nucleotides (nt) in length and support the AAGGag motif located about 6 nt (median distance) upstream of start codons as the consensus Shine–Dalgarno sequence in H. pylori.^[40]
利用单细胞 RNA-Seq 进行的单细胞转录组学研究获得了幽门螺杆菌的完整转录组，并于 2010 年发表。对幽门螺杆菌转录的分析证实了已知的酸诱导主要毒力基因座，包括尿素酶（ure）操作子和Cag致病性岛。 ^[40] 共确定了 1,907 个转录起始位点、337 个主操作子、126 个附加子操作子和 66 个单密码子。直到 2010 年，该物种中只有约 55 个转录起始位点（TSSs）为人所知。27%的主转录起始位点也是反义转录起始位点，这表明与大肠杆菌类似，整个幽门螺杆菌基因组都存在反义转录。至少有一个反义TSS与大约46%的开放阅读框相关，其中包括许多看家基因。 ^[40] 约50%的5 ′ UTR（领导序列）长度为20-40个核苷酸（nt），支持位于起始密码子上游约6 nt（中位距离）的AAGGag图案，这是幽门螺杆菌中的共识Shine-Dalgarno序列。 ^[40]

Proteome 蛋白质组[edit]

The proteome of H. pylori has been systematically analyzed and more than 70% of its proteins have been detected by mass spectrometry, and other methods. About 50% of the proteome has been quantified, informing of the number of protein copies in a typical cell.^[41]
我们对幽门螺杆菌的蛋白质组进行了系统分析，并通过质谱法和其他方法检测到其 70% 以上的蛋白质。约50%的蛋白质组已被定量，从而了解了典型细胞中蛋白质的拷贝数。 ^[41]

Studies of the interactome have identified more than 3000 protein-protein interactions. This has provided information of how proteins interact with each other, either in stable protein complexes or in more dynamic, transient interactions, which can help to identify the functions of the protein. This in turn helps researchers to find out what the function of uncharacterized proteins is, e.g. when an uncharacterized protein interacts with several proteins of the ribosome (that is, it is likely also involved in ribosome function). About a third of all ~1,500 proteins in H. pylori remain uncharacterized and their function is largely unknown.^[42]
对相互作用组的研究已经确定了 3000 多种蛋白质之间的相互作用。这提供了蛋白质之间如何相互作用的信息，无论是稳定的蛋白质复合物还是更动态的瞬时相互作用，都有助于确定蛋白质的功能。这反过来又有助于研究人员发现未表征蛋白质的功能，例如，当一个未表征蛋白质与核糖体的多个蛋白质相互作用时（即它也可能参与核糖体的功能）。在幽门螺杆菌所有约 1,500 种蛋白质中，约有三分之一仍未定性，其功能在很大程度上也是未知的。 ^[42]

Infection 感染[edit]

An infection with Helicobacter pylori can either have no symptoms even when lasting a lifetime, or can harm the stomach and duodenal linings by inflammatory responses induced by several mechanisms associated with a number of virulence factors. Colonization can initially cause H. pylori induced gastritis, an inflammation of the stomach lining that became a listed disease in ICD11.^[43][44][45] This will progress to chronic gastritis if left untreated. Chronic gastritis may lead to atrophy of the stomach lining, and the development of peptic ulcers (gastric or duodenal). These changes may be seen as stages in the development of gastric cancer, known as Correa's cascade.^[46][47] Extragastric complications that have been linked to H. pylori include anemia due either to iron-deficiency or vitamin B12 deficiency, diabetes mellitus, cardiovascular, and certain neurological disorders.^[15]
感染幽门螺旋杆菌后，既可能终生无症状，也可能通过与多种致病因子相关的几种机制诱发的炎症反应损害胃和十二指肠黏膜。幽门螺杆菌的定植最初会引起胃炎，这是一种胃黏膜炎症，已被列入国际疾病分类（ICD11）。 ^{[43] [44] [45]} 如果不及时治疗，会发展为慢性胃炎。慢性胃炎可能会导致胃黏膜萎缩，出现消化性溃疡（胃溃疡或十二指肠溃疡）。这些变化可被视为胃癌发展的阶段，即科雷亚级联。 ^{[46] [47]} 与幽门螺杆菌有关的胃外并发症包括缺铁性贫血或维生素B12缺乏症、糖尿病、心血管疾病和某些神经系统疾病。 ^[15]

Peptic ulcers are a consequence of inflammation that allows stomach acid and the digestive enzyme pepsin to overwhelm the protective mechanisms of the mucous membranes. The location of colonization of H. pylori, which affects the location of the ulcer, depends on the acidity of the stomach.^[48] In people producing large amounts of acid, H. pylori colonizes near the pyloric antrum (exit to the duodenum) to avoid the acid-secreting parietal cells at the fundus (near the entrance to the stomach).^[30] G cells express relatively high levels of PD-L1 that protects these cells from H. pylori-induced immune destruction.^[49] In people producing normal or reduced amounts of acid, H. pylori can also colonize the rest of the stomach.
消化性溃疡是胃酸和消化酶胃蛋白酶压倒粘膜保护机制的炎症后果。幽门螺杆菌的定植位置会影响溃疡的位置，这取决于胃的酸度。 ^[48] 在胃酸分泌旺盛的人群中，幽门螺杆菌会在幽门窦（十二指肠的出口）附近定植，以避开胃底（胃的入口附近）分泌胃酸的顶细胞。 ^[30] G细胞表达相对较高水平的PD-L1，可保护这些细胞免受幽门螺杆菌诱导的免疫破坏。 ^[49] 在胃酸分泌正常或减少的人群中，幽门螺杆菌也可以在胃的其他部位定植。

The inflammatory response caused by bacteria colonizing near the pyloric antrum induces G cells in the antrum to secrete the hormone gastrin, which travels through the bloodstream to parietal cells in the fundus.^[50] Gastrin stimulates the parietal cells to secrete more acid into the stomach lumen, and over time increases the number of parietal cells, as well.^[51] The increased acid load damages the duodenum, which may eventually lead to the formation of ulcers.
幽门窦附近的细菌定植引起的炎症反应会诱导窦内的G细胞分泌荷尔蒙胃泌素，胃泌素会通过血液到达胃底的顶细胞。 ^[50] 胃泌素刺激顶细胞向胃腔分泌更多的胃酸，随着时间的推移，顶细胞的数量也会增加。 ^[51] 酸负荷的增加会损害十二指肠，最终可能导致溃疡的形成。

Helicobacter pylori is a class I carcinogen, and potential cancers include gastric mucosa-associated lymphoid tissue (MALT) lymphomas and gastric cancer.^[9][10][52] Less commonly diffuse large B-cell lymphoma of the stomach is a risk.^[53] Infection with H. pylori is responsible for around 89 per cent of all gastric cancers, and is linked to the development of 5.5 per cent of all cases of cancer worldwide.^[12][13] Although the data varies between different countries, overall about 1% to 3% of people infected with Helicobacter pylori develop gastric cancer in their lifetime compared to 0.13% of individuals who have had no H. pylori infection.^[54][30] H. pylori-induced gastric cancer is the third highest cause of worldwide cancer mortality as of 2018.^[55] Because of the usual lack of symptoms, when gastric cancer is finally diagnosed it is often fairly advanced. More than half of gastric cancer patients have lymph node metastasis when they are initially diagnosed.^[56]
幽门螺杆菌是一类致癌物质，潜在的癌症包括胃黏膜相关淋巴组织（MALT）淋巴瘤和胃癌。 ^{[9] [10] [52]} 较少见的胃弥漫性大B细胞淋巴瘤是一种危险。 ^[53] 幽门螺杆菌感染是约89%胃癌的罪魁祸首，全球5.5%的癌症病例与幽门螺杆菌感染有关。 ^{[12] [13]} 虽然不同国家的数据有所不同，但总体而言，约有1%至3%的幽门螺杆菌感染者在一生中会患上胃癌，而未感染幽门螺杆菌的人患胃癌的比例仅为0.13%。 ^{[54] [30]} 截至2018年，幽门螺杆菌诱发的胃癌是全球癌症死亡的第三大原因。 ^[55] 由于通常没有症状，当胃癌最终确诊时，往往已是相当晚期。一半以上的胃癌患者在最初确诊时已出现淋巴结转移。 ^[56]

Chronic inflammation that is a feature of cancer development is characterized by infiltration of neutrophils and macrophages to the gastric epithelium, which favors the accumulation of pro-inflammatory cytokines, reactive oxygen species (ROS) and reactive nitrogen species (RNS) that cause DNA damage.^[57] The oxidative DNA damage and levels of oxidative stress can be indicated by a biomarker, 8-oxo-dG.^[57][58] Other damage to DNA includes double-strand breaks.^[59]
慢性炎症是癌症发展的一个特征，其特点是中性粒细胞和巨噬细胞浸润胃上皮，这有利于促炎细胞因子、活性氧（ROS）和活性氮（RNS）的积累，从而导致DNA损伤。 ^[57] DNA氧化损伤和氧化应激水平可以通过生物标记物8-oxo-dG来表示。 ^{[57] [58]} DNA的其他损伤包括双链断裂。 ^[59]

Small gastric and colorectal polyps are adenomas that are more commonly found in association with the mucosal damage induced by H. pylori gastritis.^[60][61] Larger polyps can in time become cancerous.^[62][60] A modest association of H. pylori has been made with the development of colorectal cancers but as of 2020 causality had yet to be proved.^[63][62]
小的胃息肉和大肠息肉是腺瘤，更常见于幽门螺杆菌胃炎引起的粘膜损伤。 ^{[60] [61]} 较大的息肉可在一段时间后发生癌变。 ^{[62] [60]} 幽门螺杆菌与结肠直肠癌的发生略有关联，但截至2020年，其因果关系尚未得到证实。 ^{[63] [62]}

Signs and symptoms 体征和症状[edit]

Most people infected with H. pylori never experience any symptoms or complications, but will have a 10% to 20% risk of developing peptic ulcers or a 0.5% to 2% risk of stomach cancer.^[7][64] H. pylori induced gastritis may present as acute gastritis with stomach ache, nausea, and ongoing dyspepsia (indigestion) that is sometimes accompanied by depression and anxiety.^[7][65] Where the gastritis develops into chronic gastritis, or an ulcer, the symptoms are the same and can include indigestion, stomach or abdominal pains, nausea, bloating, belching, feeling hunger in the morning, feeling full too soon, and sometimes vomiting, heartburn, bad breath, and weight loss.^[66][67]
大多数感染幽门螺杆菌的人从未出现过任何症状或并发症，但会有10%至20%的风险患消化性溃疡或0.5%至2%的风险患胃癌。 ^{[7] [64]} 幽门螺杆菌诱发的胃炎可能表现为急性胃炎，伴有胃痛、恶心和持续的消化不良（消化不良），有时还伴有抑郁和焦虑。 ^{[7] [65]} 当胃炎发展为慢性胃炎或溃疡时，症状也是一样的，可能包括消化不良、胃痛或腹痛、恶心、腹胀、嗳气、早晨感到饥饿、过早饱腹感，有时还会出现呕吐、烧心、口臭和体重减轻。 ^{[66] [67]}

Complications of an ulcer can cause severe signs and symptoms such as black or tarry stool indicative of bleeding into the stomach or duodenum; blood - either red or coffee-ground colored in vomit; persistent sharp or severe abdominal pain; dizziness, and a fast heartbeat.^[66][67] Bleeding is the most common complication. In cases caused by H. pylori there was a greater need for hemostasis often requiring gastric resection.^[68] Prolonged bleeding may cause anemia leading to weakness and fatigue. Inflammation of the pyloric antrum, which connects the stomach to the duodenum, is more likely to lead to duodenal ulcers, while inflammation of the corpus may lead to a gastric ulcer.
溃疡并发症可引起严重的体征和症状，如黑色或柏油样大便，表明胃或十二指肠出血；呕吐物中带有血液--红色或咖啡色；持续剧烈或严重腹痛；头晕和心跳加快。 ^{[66] [67]} 出血是最常见的并发症。幽门螺杆菌引起的病例更需要止血，往往需要进行胃切除术。 ^[68] 长期出血会引起贫血，导致虚弱和疲劳。连接胃和十二指肠的幽门窦发炎更容易导致十二指肠溃疡，而胃窦发炎则可能导致胃溃疡。

Stomach cancer can cause nausea, vomiting, diarrhoea, constipation, and unexplained weight loss.^[69] Gastric polyps are adenomas that are usually asymptomatic and benign, but may be the cause of dyspepsia, heartburn, bleeding from the stomach, and, rarely, gastric outlet obstruction.^[60][70] Larger polyps may have become cancerous.^[60] Colorectal polyps may be the cause of rectal bleeding, anemia, constipation, diarrhea, weight loss, and abdominal pain.^[71]
胃癌可导致恶心、呕吐、腹泻、便秘和不明原因的体重减轻。 ^[69] 胃息肉是腺瘤，通常无症状且为良性，但可能导致消化不良、胃灼热、胃出血，极少数情况下还会导致胃出口梗阻。 ^{[60] [70]} 较大的息肉可能已经癌变。 ^[60] 大肠息肉可能是直肠出血、贫血、便秘、腹泻、体重减轻和腹痛的原因。 ^[71]

Pathophysiology 病理生理学[edit]

Virulence factors help a pathogen to evade the immune response of the host, and to successfully colonize. The many virulence factors of H. pylori include its flagella, the production of urease, adhesins, serine protease HtrA (high temperature requirement A), and the major exotoxins CagA and VacA.^[28][72] The presence of VacA and CagA are associated with more advanced outcomes.^[73] CagA is an oncoprotein associated with the development of gastric cancer.^[6]
致病因子有助于病原体逃避宿主的免疫反应并成功定殖。幽门螺杆菌的许多毒力因子包括鞭毛、尿素酶的产生、粘附素、丝氨酸蛋白酶HtrA（高温要求A）以及主要的外毒素CagA和VacA。 ^{[28] [72]} VacA和CagA的存在与更严重的后果有关。 ^[73] CagA是一种与胃癌发展有关的肿瘤蛋白。 ^[6]

H. pylori infection is associated with epigenetically reduced efficiency of the DNA repair machinery, which favors the accumulation of mutations and genomic instability as well as gastric carcinogenesis.^[74] It has been shown that expression of two DNA repair proteins, ERCC1 and PMS2, was severely reduced once H. pylori infection had progressed to cause dyspepsia.^[75] Dyspepsia occurs in about 20% of infected individuals.^[76] Epigenetically reduced protein expression of DNA repair proteins MLH1, MGMT and MRE11 are also evident. Reduced DNA repair in the presence of increased DNA damage increases carcinogenic mutations and is likely a significant cause of gastric carcinogenesis.^[58][77][78] These epigenetic alterations are due to H. pylori-induced methylation of CpG sites in promoters of genes^[77] and H. pylori-induced altered expression of multiple microRNAs.^[78]
幽门螺杆菌感染与DNA修复机制的表观遗传学效率降低有关，这有利于突变和基因组不稳定性的积累以及胃癌的发生。 ^[74] 研究表明，一旦幽门螺杆菌感染发展到引起消化不良，两种DNA修复蛋白ERCC1和PMS2的表达量就会严重下降。 ^[75] 约20%的感染者会出现消化不良。 ^[76] DNA修复蛋白MLH1、MGMT和MRE11的表观遗传学蛋白表达也明显减少。在 DNA 损伤增加的情况下，DNA 修复功能降低会增加致癌突变，这可能是胃癌发生的一个重要原因。 ^{[58] [77] [78]} 这些表观遗传学改变是由于幽门螺杆菌诱导的基因启动子中的 CpG 位点甲基化 ^[77] 和幽门螺杆菌诱导的多种 microRNA 的表达改变。 ^[78]

Two related mechanisms by which H. pylori could promote cancer have been proposed. One mechanism involves the enhanced production of free radicals near H. pylori and an increased rate of host cell mutation. The other proposed mechanism has been called a "perigenetic pathway",^[79] and involves enhancement of the transformed host cell phenotype by means of alterations in cell proteins, such as adhesion proteins. H. pylori has been proposed to induce inflammation and locally high levels of tumor necrosis factor (TNF), (also known as tumor necrosis factor alpha (TNFα) and/or interleukin 6 (IL-6). According to the proposed perigenetic mechanism, inflammation-associated signaling molecules, such as TNF, can alter gastric epithelial cell adhesion and lead to the dispersion and migration of mutated epithelial cells without the need for additional mutations in tumor suppressor genes, such as genes that code for cell adhesion proteins.^[80]
人们提出了幽门螺杆菌促癌的两种相关机制。一种机制涉及幽门螺杆菌附近自由基产生的增加和宿主细胞突变率的增加。另一种机制被称为 "围遗传途径"， ^[79] 涉及通过改变细胞蛋白（如粘附蛋白）来增强转化宿主细胞的表型。有人认为幽门螺杆菌会诱发炎症和局部高水平的肿瘤坏死因子（TNF）（又称肿瘤坏死因子α（TNFα）和/或白细胞介素6（IL-6））。根据所提出的围遗传学机制，与炎症相关的信号分子（如 TNF）可改变胃上皮细胞的粘附性，并导致突变上皮细胞的分散和迁移，而无需肿瘤抑制基因（如编码细胞粘附蛋白的基因）发生额外的突变。 ^[80]

Flagellum 鞭毛[edit]

The first virulence factor of Helicobacter pylori that enables colonization is its flagellum.^[81] H. pylori has from two to seven flagella at the same polar location which gives it a high motility. The flagellar filaments are about 3 μm long, and composed of two copolymerized flagellins, FlaA and FlaB, coded by the genes flaA, and flaB.^[25][72] The minor flagellin FlaB is located in the proximal region and the major flagellin FlaA makes up the rest of the flagellum.^[82] The flagella are sheathed in a continuation of the bacterial outer membrane which gives protection against the gastric acidity. The sheath is also the location of the origin of the outer membrane vesicles that gives protection to the bacterium from bacteriophages.^[82]
幽门螺杆菌实现定植的第一个毒力因子是它的鞭毛。 ^[81] 幽门螺杆菌在同一极性位置有两到七根鞭毛，这使它具有很强的运动能力。鞭毛长约3微米，由两种共聚鞭毛蛋白FlaA和FlaB组成，分别由基因flaA和flaB编码。 ^{[25] [72]} 小鞭毛蛋白 FlaB 位于近端区域，大鞭毛蛋白 FlaA 构成鞭毛的其余部分。 ^[82] 鞭毛的外鞘是细菌外膜的延续，可以抵御胃酸。鞭毛鞘也是外膜囊泡的发源地，可保护细菌免受噬菌体的侵害。 ^[82]

H. pylori is able to sense the less acidic pH gradient in the mucus, and guided by chemotaxis uses its flagella to move towards it. Once there it can burrow through to the underlying epithelial cell layer.^[82] H. pylori travels through the mucosa to the gastric pits where they colonise and live inside the gastric glands.^[83] Occasionally the bacteria are found inside the epithelial cells themselves.^[84]
幽门螺杆菌能够感知粘液中酸度较低的 pH 梯度，并在趋化作用的引导下利用鞭毛向其移动。一旦到达那里，它就会钻入下层上皮细胞层。 ^[82] 幽门螺杆菌穿过粘膜到达胃凹陷处，在那里定植并生活在胃腺中。 ^[83] 偶尔会在上皮细胞内发现细菌。 ^[84]

Urease 尿素酶[edit]

In addition to using chemotaxis to avoid areas of low pH (high acidity), H. pylori also neutralizes the acid in its environment by producing large amounts of urease, an enzyme which breaks down the urea present in the stomach to carbonic acid and ammonia. These react with the strong acids in the environment to produce a neutralized area around H. pylori.^[85] Helicobacter pylori is one of the few known types of bacterium that has a urea cycle which is uniquely configured in the bacterium.^[86] 10% of the cell is of nitrogen a balance that needs to be maintained. Any excess is stored in urea excreted in the urea cycle.^[86]
除了利用趋化作用避开 pH 值低（酸度高）的区域外，幽门螺杆菌还通过产生大量的尿素酶来中和环境中的酸性物质，这种酶可以将胃中的尿素分解成碳酸和氨。这些物质与环境中的强酸发生反应，在幽门螺杆菌周围形成一个中和区域。 ^[85] 幽门螺旋杆菌是已知的少数几种具有尿素循环的细菌之一，该细菌的尿素循环配置独特。 ^[86] 细胞中10%的氮需要保持平衡。多余的氮储存在尿素中，通过尿素循环排出体外。 ^[86]

A final stage enzyme in the urea cycle is arginase an enzyme that is crucial to the pathogenesis of H. pylori. Arginase produces ornithine and urea that the enzyme urease breaks down into carbonic acid and ammonia. Urease is the bacterium’s most abundant protein accounting for 10–15% of the bacterium's total protein content. Its expression is not only required for establishing initial colonization in the breakdown of urea to carbonic acid and ammonia but is essential for maintaining chronic infection.^[87][64] Ammonia reduces the stomach acidity allowing the bacteria to become locally established. Arginase promotes the persistence of infection by consuming arginine; arginine is used by macrophages to produce nitric oxide which has a strong antimicrobial effect.^[86][88] The ammonia produced to regulate pH is toxic to epithelial cells. ^[89]
尿素循环的最后一个酶是精氨酸酶，这种酶对幽门螺杆菌的发病至关重要。精氨酸酶产生鸟氨酸和尿素，尿素酶将鸟氨酸和尿素分解成碳酸和氨。尿素酶是该细菌最丰富的蛋白质，占细菌总蛋白质含量的 10-15%。尿素酶的表达不仅是在尿素分解成碳酸和氨的过程中建立初始定植所必需的，而且对于维持慢性感染也是必不可少的。 ^{[87] [64]} 氨能降低胃酸度，使细菌在局部立足。精氨酸酶通过消耗精氨酸促进感染的持续；巨噬细胞利用精氨酸产生一氧化氮，一氧化氮具有很强的抗菌作用。 ^{[86] [88]} 为调节 pH 值而产生的氨对上皮细胞具有毒性。 ^[89]

Adhesins 粘合剂[edit]

H. pylori must make attachment with the epithelial cells to prevent its being swept away with the constant movement and renewal of the mucus. To give them this adhesion, bacterial outer membrane proteins as virulence factors called adhesins are produced.^[90] BabA (blood group antigen binding adhesin) is most important during initial colonization, and SabA is important in persistence. BabA attaches to glycans and mucins in the epithelium.^[90] BabA (coded for by the babA2 gene) also binds to the Lewis b antigen displayed on the surface of the epithelial cells.^[91] Adherence via BabA is acid sensitive and can be fully reversed by a decreased pH. It has been proposed that BabA's acid responsiveness enables adherence while also allowing an effective escape from an unfavorable environment such as a low pH that is harmful to the organism.^[92] SabA binds to increased levels of sialyl-Lewis ^X antigen expressed on gastric mucosa.^[93]
幽门螺杆菌必须附着在上皮细胞上，以防止被不断运动和更新的粘液冲走。为了实现这种粘附，细菌产生了作为毒力因子的外膜蛋白，即粘附素。 ^[90] BabA（血型抗原结合粘附素）在最初的定殖过程中最为重要，而 SabA 在持续定殖过程中非常重要。BabA 吸附在上皮中的糖和粘蛋白上。 ^[90] BabA（由 babA2 基因编码）还能与上皮细胞表面的 Lewis b 抗原结合。 ^[91] 通过 BabA 粘附对酸敏感，pH 值降低时可完全逆转。有人认为，BabA对酸的敏感性使其能够粘附，同时还能有效地逃离不利的环境，如对生物体有害的低pH值。 ^[92] SabA能与胃粘膜上表达的更高水平的sialyl-Lewis ^X 抗原结合。 ^[93]

Cholesterol glucoside 胆固醇葡萄糖苷[edit]

The outer membrane contains cholesterol glucoside, a sterol glucoside that H. pylori glycosylates from the cholesterol in the gastric gland cells, and inserts it into its outer membrane.^[85] This cholesterol glucoside is important for membrane stability, morphology and immune evasion, and is rarely found in other bacteria.^[94][95]
幽门螺杆菌的外膜含有胆固醇葡糖苷，这是一种固醇葡糖苷，幽门螺杆菌从胃腺细胞中的胆固醇中糖基化后将其插入外膜。 ^[85] 这种胆固醇葡糖苷对膜的稳定性、形态和免疫逃避非常重要，在其他细菌中很少发现。 ^{[94] [95]}

The enzyme responsible for this is cholesteryl α-glucosyltransferase (αCgT) or (Cgt) encoded by the HP0421 gene.^[96] A major effect of the depletion of host cholesterol by Cgt is to disrupt cholesterol-rich lipid rafts in the epithelial cells. Lipid rafts are involved in cell signalling and their disruption causes a reduction in the immune inflammatory response particularly by reducing interferon gamma.^[97] Cgt is also secreted by the type IV secretion system, and is secreted in a selective way so that gastric niches where the pathogen can thrive are created.^[96] Its lack has been shown to give vulnerability from environmental stress to bacteria, and also to disrupt CagA mediated interactions.^[85]
这种酶是由 HP0421 基因编码的胆固醇α-葡萄糖基转移酶（αCgT）或（Cgt）。 ^[96] Cgt消耗宿主胆固醇的一个主要作用是破坏上皮细胞中富含胆固醇的脂质筏。脂质筏参与细胞信号的传递，破坏脂质筏会降低免疫炎症反应，特别是通过减少γ干扰素。 ^[97] Cgt也是由IV型分泌系统分泌的，并且是以选择性的方式分泌的，这样就形成了病原体可以生长的胃龛。 ^[96] 事实证明，缺乏Cgt会使细菌容易受到环境压力的影响，也会破坏CagA介导的相互作用。 ^[85]

Catalase 过氧化氢酶[edit]

Colonization induces an intense anti-inflammatory response as a first-line immune system defence. Phagocytic leukocytes and monocytes infiltrate the site of infection, and antibodies are produced.^[98] H. pylori is able to adhere to the surface of the phagocytes and impede their action. This is responded to by the phagocyte in the generation and release of oxygen metabolites into the surrounding space. H. pylori can survive this response by the activity of catalase at its attachment to the phagocytic cell surface. Catalase decomposes hydrogen peroxide into water and oxygen, protecting the bacteria from toxicity. Catalase has been shown to almost completely inhibit the phagocytic oxidative response.^[98] It is coded for by the gene katA.^[99]
定植会诱发强烈的抗炎反应，作为免疫系统的第一道防线。吞噬白细胞和单核细胞浸润感染部位，并产生抗体。 ^[98] 幽门螺杆菌能够粘附在吞噬细胞表面，阻碍它们的行动。吞噬细胞会对此做出反应，产生氧代谢物并释放到周围空间。幽门螺杆菌可以通过附着在吞噬细胞表面的过氧化氢酶的活性在这种反应中存活下来。过氧化氢酶将过氧化氢分解成水和氧气，保护细菌免受毒性侵害。事实证明，过氧化氢酶几乎可以完全抑制吞噬细胞的氧化反应。 ^[98] 它由 katA 基因编码。 ^[99]

Tipα 提示α[edit]

TNF-inducing protein alpha (Tipα) is a carcinogenic protein encoded by HP0596 unique to H. pylori that induces the expression of tumor necrosis factor.^[80][100] Tipα enters gastric cancer cells where it binds to cell surface nucleolin, and induces the expression of vimentin. Vimentin is important in the epithelial–mesenchymal transition associated with the progression of tumors.^[101]
TNF诱导蛋白α（Tipα）是幽门螺杆菌特有的一种由HP0596编码的致癌蛋白，可诱导肿瘤坏死因子的表达。 ^{[80] [100]} Tipα 进入胃癌细胞，与细胞表面的核素结合，诱导波形蛋白的表达。波形蛋白在与肿瘤进展相关的上皮-间质转化过程中起着重要作用。 ^[101]

CagA[edit]

CagA (cytotoxin-associated antigen A) is a major virulence factor for H. pylori, an oncoprotein that is encoded by the cagA gene. Bacterial strains with the cagA gene are associated with the ability to cause ulcers, MALT lymphomas, and gastric cancer.^[102][103] The cagA gene codes for a relatively long (1186-amino acid) protein. The cag pathogenicity island (PAI) has about 30 genes, part of which code for a complex type IV secretion system. The low GC-content of the cag PAI relative to the rest of the Helicobacter genome suggests the island was acquired by horizontal transfer from another bacterial species.^[36] The serine protease HtrA also plays a major role in the pathogenesis of H. pylori. The HtrA protein enables the bacterium to transmigrate across the host cells' epithelium, and is also needed for the translocation of CagA.^[104]
CagA（细胞毒素相关抗原 A）是幽门螺杆菌的主要毒力因子，是由 cagA 基因编码的肿瘤蛋白。带有 cagA 基因的菌株可导致溃疡、MALT 淋巴瘤和胃癌。 ^{[102] [103]} cagA 基因编码一种相对较长（1186 个氨基酸）的蛋白质。cag致病性岛（PAI）有大约30个基因，其中一部分编码复杂的IV型分泌系统。与螺旋杆菌基因组的其他部分相比，cag致病性岛的GC含量较低，这表明该致病性岛是通过水平转移从其他细菌物种获得的。 ^[36] 丝氨酸蛋白酶HtrA在幽门螺杆菌的发病机制中也起着重要作用。HtrA蛋白能使细菌穿过宿主细胞的上皮细胞，也是CagA转运所必需的。 ^[104] .

The virulence of H. pylori may be increased by genes of the cag pathogenicity island; about 50–70% of H. pylori strains in Western countries carry it.^[105] Western people infected with strains carrying the cag PAI have a stronger inflammatory response in the stomach and are at a greater risk of developing peptic ulcers or stomach cancer than those infected with strains lacking the island.^[30] Following attachment of H. pylori to stomach epithelial cells, the type IV secretion system expressed by the cag PAI "injects" the inflammation-inducing agent, peptidoglycan, from their own cell walls into the epithelial cells. The injected peptidoglycan is recognized by the cytoplasmic pattern recognition receptor (immune sensor) Nod1, which then stimulates expression of cytokines that promote inflammation.^[106]
幽门螺杆菌的致病力可能会因cag致病岛基因而增强；在西方国家，约有50-70%的幽门螺杆菌菌株携带cag致病岛基因。 ^[105] 西方人感染了携带cag致病岛基因的菌株后，胃部的炎症反应会更强烈，患消化性溃疡或胃癌的风险比感染了不携带致病岛基因的菌株的人更高。 ^[30] 幽门螺杆菌附着到胃上皮细胞后，由cag PAI表达的IV型分泌系统会从自身细胞壁向上皮细胞 "注射 "炎症诱导剂--肽聚糖。注入的肽聚糖会被细胞质模式识别受体（免疫传感器）Nod1识别，然后刺激细胞因子的表达，从而促进炎症。 ^[106] .

The type-IV secretion apparatus also injects the cag PAI-encoded protein CagA into the stomach's epithelial cells, where it disrupts the cytoskeleton, adherence to adjacent cells, intracellular signaling, cell polarity, and other cellular activities.^[107] Once inside the cell, the CagA protein is phosphorylated on tyrosine residues by a host cell membrane-associated tyrosine kinase (TK). CagA then allosterically activates protein tyrosine phosphatase/protooncogene Shp2.^[108] These proteins are directly toxic to cells lining the stomach and signal strongly to the immune system that an invasion is under way. As a result of the bacterial presence, neutrophils and macrophages set up residence in the tissue to fight the bacteria assault.^[109] Pathogenic strains of H. pylori have been shown to activate the epidermal growth factor receptor (EGFR), a membrane protein with a TK domain. Activation of the EGFR by H. pylori is associated with altered signal transduction and gene expression in host epithelial cells that may contribute to pathogenesis. A C-terminal region of the CagA protein (amino acids 873–1002) has also been suggested to be able to regulate host cell gene transcription, independent of protein tyrosine phosphorylation.^[103] A great deal of diversity exists between strains of H. pylori, and the strain that infects a person can predict the outcome.
IV型分泌装置还会将cag PAI编码蛋白CagA注入胃上皮细胞，从而破坏细胞骨架、与邻近细胞的粘附、细胞内信号传导、细胞极性和其他细胞活动。 ^[107] 进入细胞后，CagA 蛋白会被宿主细胞膜上的酪氨酸激酶（TK）磷酸化。然后，CagA 会异位激活蛋白酪氨酸磷酸酶/原癌基因 Shp2。 ^[108] 这些蛋白质对胃黏膜细胞具有直接毒性，并向免疫系统发出入侵正在发生的强烈信号。由于细菌的存在，中性粒细胞和巨噬细胞在组织中定居下来，以对抗细菌的攻击。 ^[109] 幽门螺杆菌的致病菌株已被证明能激活表皮生长因子受体（EGFR），这是一种具有TK结构域的膜蛋白。幽门螺杆菌对表皮生长因子受体的激活与宿主上皮细胞中信号转导和基因表达的改变有关，这可能会导致发病。CagA蛋白的C端区域（氨基酸873-1002）也被认为能够调节宿主细胞的基因转录，而不受蛋白酪氨酸磷酸化的影响。 ^[103] 幽门螺杆菌菌株之间存在着很大的差异，感染人的菌株可以预测感染结果。

VacA[edit]

VacA (vacuolating cytotoxin auto transporter) is another major virulence factor encoded by the vacA gene.^[110] All strains of H. pylori carry this gene but there is much diversity, and only 50% produce the encoded cytotoxin.^[87][31] The four main subtypes of vacA are s1/m1, s1/m2, s2/m1, and s2/m2. s1/m1 and s1/m2 are known to cause an increased risk of gastric cancer.^[111] VacA is an oligomeric protein complex that causes a progressive vacuolation in the epithelial cells leading to their death.^[112] The vacuolation has also been associated with promoting intracellular reservoirs of H. pylori by disrupting the calcium channel cell membrane TRPML1.^[113] VacA has been shown to increase the levels of COX2, an up-regulation that increases the production of a prostaglandin indicating a strong host cell inflammatory response.^[112][114]
VacA（空泡化细胞毒素自动转运体）是由 vacA 基因编码的另一个主要毒力因子。 ^[110] 幽门螺杆菌的所有菌株都携带这种基因，但其种类繁多，只有 50%的菌株能产生编码的细胞毒素。 ^{[87] [31]} vacA 的四个主要亚型是 s1/m1、s1/m2、s2/m1 和 s2/m2。 ^[111] VacA是一种寡聚蛋白复合物，会使上皮细胞逐渐空泡化，导致细胞死亡。 ^[112] 空泡化还与通过破坏钙通道细胞膜 TRPML1 促进幽门螺杆菌细胞内储存有关。 ^[113] VacA已被证明能提高COX2的水平，这种上调能增加前列腺素的产生，表明宿主细胞有强烈的炎症反应。 ^{[112] [114]}

Outer membrane proteins and vesicles
外膜蛋白和囊泡[edit]

About 4% of the genome encodes for outer membrane proteins that can be grouped into five families.^[115] The largest family includes bacterial adhesins. The other four families are porins, iron transporters, flagellum-associated proteins, and proteins of unknown function. Like other typical gram-negative bacteria, the outer membrane of H. pylori consists of phospholipids and lipopolysaccharide (LPS). The O-antigen of LPS may be fucosylated and mimic Lewis blood group antigens found on the gastric epithelium.^[30]
约 4% 的基因组编码外膜蛋白，这些蛋白可分为五个家族。 ^[115] 最大的家族包括细菌粘附蛋白。其他四个家族包括孔蛋白、铁转运体、鞭毛相关蛋白和功能未知蛋白。与其他典型的革兰氏阴性细菌一样，幽门螺杆菌的外膜由磷脂和脂多糖（LPS）组成。LPS的O抗原可能是岩藻糖基化的，与胃上皮细胞上的路易斯血型抗原相似。 ^[30]

H. pylori forms blebs from the outer membrane that pinch off as outer membrane vesicles to provide an alternative delivery system for virulence factors including CagA.^[85]
幽门螺杆菌的外膜会形成出血点，这些出血点会挤压成外膜囊泡，为包括 CagA 在内的致病因子提供另一种输送系统。 ^[85] .

A Helicobacter cysteine-rich protein HcpA is known to trigger an immune response, causing inflammation.^[116] A Helicobacter pylori virulence factor DupA is associated with the development of duodenal ulcers.^[117]
已知幽门螺旋杆菌富含半胱氨酸的蛋白质HcpA会引发免疫反应，导致炎症。 ^[116] 幽门螺杆菌毒力因子 DupA 与十二指肠溃疡的发生有关。 ^[117]

Mechanisms of tolerance 容忍机制[edit]

In the stomach H. pylori has to not only survive the harsh gastric acidity but also the constant sweeping of mucus by continuous peristalsis, and phagocytic attack accompanied by the release of reactive oxygen species.^[118] The need for survival has led to the development of different mechanisms of tolerance that enable their persistence.^[119] Stress conditions activate bacterial response mechanisms that are regulated by proteins expressed by regulator genes.^[119] The oxidative stress can induce potentially lethal mutagenic DNA adducts in its genome. Surviving this DNA damage is supported by transformation-mediated recombinational repair, that contributes to successful colonization.^[120][121] An overall response to multiple stressors can result from an interaction of the mechanisms. The mechanisms of tolerance and persistence can also help to overcome the effects of antibiotics.^[119]
在胃中，幽门螺杆菌不仅要在刺鼻的胃酸中生存，还要通过持续的蠕动不断清除粘液，并在释放活性氧的同时受到吞噬细胞的攻击。 ^[118] 生存的需要导致了不同的耐受机制的发展，从而使它们能够持续生存。 ^[119] 压力条件激活了细菌的反应机制，这些机制由调节基因表达的蛋白质调控。 ^[119] 氧化压力可在其基因组中诱发潜在的致命诱变 DNA 加合物。通过转化介导的重组修复，DNA损伤得以存活，这有助于成功定殖。 ^{[120] [121]} 对多种压力源的整体反应可能来自各种机制的相互作用。耐受性和持久性机制也有助于克服抗生素的影响。 ^[119]

An effective sustained colonization response is the formation of a biofilm. Layers of aggregated bacteria form a biofilm. Cells in the deep layers are nutritionally deprived, and enter the coccoid dormant-like state. Some of these cells will be antibiotic resistant, and may remain in the host as persister cells. Following eradication the persister cells can cause a recurrence of the infection.^[122][123]
有效的持续定殖反应是形成生物膜。一层层聚集的细菌形成生物膜。深层细胞缺乏营养，进入茧状休眠状态。其中一些细胞会对抗生素产生抗药性，并可能作为顽固细胞留在宿主体内。根除后，宿主细胞会导致感染复发。 ^{[122] [123]}

Transformation (the transfer of DNA from one bacterial cell to another through the intervening medium) appears to be part of an adaptation for DNA repair. H. pylori is naturally competent for transformation. While many organisms are competent only under certain environmental conditions, such as starvation, H. pylori is competent throughout logarithmic growth.^[124] All organisms encode genetic programs for response to stressful conditions including those that cause DNA damage.^[124] In H. pylori, homologous recombination is required for repairing double-strand breaks (DSBs). The AddAB helicase-nuclease complex resects DSBs and loads RecA onto single-strand DNA (ssDNA), which then mediates strand exchange, leading to homologous recombination and repair. The requirement of RecA plus AddAB for efficient gastric colonization suggests, in the stomach, H. pylori is either exposed to double-strand DNA damage that must be repaired or requires some other recombination-mediated event. In particular, natural transformation is increased by DNA damage in H. pylori, and a connection exists between the DNA damage response and DNA uptake in H. pylori,^[124] suggesting natural competence contributes to persistence of H. pylori in its human host and explains the retention of competence in most clinical isolates. H. pylori has much greater rates of recombination, and mutation than other bacteria.^[3] Genetically different strains can be found in the same host, and also in different regions of the stomach.^[125]
转化（通过介质将 DNA 从一个细菌细胞转移到另一个细菌细胞）似乎是 DNA 修复适应的一部分。幽门螺杆菌天生具有转化能力。许多生物只有在饥饿等特定环境条件下才能进行转化，而幽门螺杆菌在整个对数生长过程中都能进行转化。 ^[124] 所有生物都编码了应对压力条件（包括造成 DNA 损伤的压力条件）的基因程序。 ^[124] 幽门螺杆菌需要同源重组来修复双链断裂（DSB）。AddAB螺旋酶-核酸酶复合物切除DSB，并将RecA加载到单链DNA（ssDNA）上，然后介导链交换，导致同源重组和修复。胃的有效定植需要 RecA 和 AddAB，这表明幽门螺杆菌在胃中要么暴露于必须修复的双链 DNA 损伤，要么需要其他重组介导的事件。特别是，幽门螺杆菌的自然转化会因DNA损伤而增加，而且幽门螺杆菌的DNA损伤反应与DNA吸收之间存在联系， ^[124] 这表明自然能力有助于幽门螺杆菌在人类宿主中的持续存在，并解释了为什么大多数临床分离株都能保持能力。与其他细菌相比，幽门螺杆菌的重组和变异率要高得多。 ^[3] 在同一宿主和胃的不同区域可以发现基因不同的菌株。 ^[125]

RuvC protein is essential to the process of recombinational repair, since it resolves intermediates in this process termed Holliday junctions. H. pylori mutants that are defective in RuvC have increased sensitivity to DNA-damaging agents and to oxidative stress, exhibit reduced survival within macrophages, and are unable to establish successful infection in a mouse model.^[126] Similarly, RecN protein plays an important role in DSB repair in H. pylori.^[127] An H. pylori recN mutant displays an attenuated ability to colonize mouse stomachs, highlighting the importance of recombinational DNA repair in survival of H. pylori within its host.^[127]
RuvC 蛋白对重组修复过程至关重要，因为它能解决这一过程中被称为霍利迪连接的中间产物。RuvC缺陷的幽门螺杆菌突变体对DNA损伤剂和氧化应激的敏感性增加，在巨噬细胞中的存活率降低，并且无法在小鼠模型中成功感染。 ^[126] 同样，RecN蛋白在幽门螺杆菌的DSB修复中发挥着重要作用。 ^[127] 幽门螺杆菌的RecN突变体在小鼠胃中定植的能力减弱，这凸显了DNA重组修复对幽门螺杆菌在宿主体内存活的重要性。 ^[127]

Diagnosis 诊断[edit]

Colonization with H. pylori is not a disease in itself, but a condition associated with a number of stomach diseases.^[30] Testing is recommended in cases of peptic ulcer disease or low-grade gastric MALT lymphoma; after endoscopic resection of early gastric cancer; for first-degree relatives with gastric cancer, and in certain cases of indigestion. Other indications that prompt testing for H. pylori include long term aspirin or other non-steroidal anti-inflammatory use, unexplained iron deficiency anemia, or in cases of immune thrombocytopenic purpura.^[128] Several methods of testing exist, both invasive and non-invasive.
幽门螺杆菌定植本身并不是一种疾病，而是一种与多种胃病相关的病症。 ^[30] 建议在以下情况下进行检测：消化性溃疡病或低度胃MALT淋巴瘤；早期胃癌内镜切除术后；一级亲属患有胃癌；以及某些消化不良的病例。其他提示幽门螺杆菌检测的指征包括长期服用阿司匹林或其他非甾体抗炎药、不明原因的缺铁性贫血或免疫性血小板减少性紫癜。 ^[128] 有几种检测方法，既有侵入性的，也有非侵入性的。

Non-invasive tests for H. pylori infection include serological tests for antibodies, stool tests, and urea breath tests. Carbon urea breath tests include the use of carbon-13, or a radioactive carbon-14 producing a labelled carbon dioxide that can be detected in the breath.^[129] Carbon urea breath tests have a high sensitivity and specificity for the diagnosis of H. pylori.^[129]
幽门螺杆菌感染的非侵入性检测包括抗体血清学检测、粪便检测和尿素呼气检测。碳尿素呼气试验包括使用碳-13或放射性碳-14，产生一种可在呼气中检测到的标记二氧化碳。 ^[129] 碳尿素呼气试验对幽门螺杆菌的诊断具有很高的灵敏度和特异性。 ^[129]

Proton-pump inhibitors and antibiotics should be discontinued for at least 30 days prior to testing for H. pylori infection or eradication, as both agents inhibit H. pylori growth and may lead to false negative results.^[128] Testing to confirm eradication is recommended 30 days or more after completion of treatment for H. pylori infection. H. pylori breath testing or stool antigen testing are both reasonable tests to confirm eradication.^[128] H. pylori serologic testing, including IgG antibodies, are not recommended as a test of eradication as they may remain elevated for years after successful treatment of infection.^[128]
在进行幽门螺杆菌感染或根除检测前，应停用质子泵抑制剂和抗生素至少30天，因为这两种药物都会抑制幽门螺杆菌的生长，并可能导致假阴性结果。 ^[128] 建议在完成幽门螺杆菌感染治疗30天或更长时间后进行检测，以确认根除幽门螺杆菌。幽门螺杆菌呼气检测或粪便抗原检测都是确认根除幽门螺杆菌的合理检测方法。 ^[128] 不建议将幽门螺杆菌血清学检测（包括IgG抗体）作为根除幽门螺杆菌的检测方法，因为在成功治疗感染后，IgG抗体可能会持续升高数年。 ^[128]

An endoscopic biopsy is an invasive means to test for H. pylori infection. Low-level infections can be missed by biopsy, so multiple samples are recommended. The most accurate method for detecting H. pylori infection is with a histological examination from two sites after endoscopic biopsy, combined with either a rapid urease test or microbial culture.^[130] Generally, repeating endoscopy is not recommended to confirm H. pylori eradication, unless there are specific indications to repeat the procedure.^[128]
内窥镜活检是检测幽门螺杆菌感染的一种侵入性方法。活检可能会漏检低水平的感染，因此建议多次取样。检测幽门螺杆菌感染最准确的方法是在内镜活检后对两个部位进行组织学检查，并结合快速尿素酶测试或微生物培养。 ^[130] 一般情况下，不建议重复内镜检查以确认幽门螺杆菌根除，除非有重复检查的特殊指征。 ^[128]

Transmission 变速箱[edit]

Helicobacter pylori is contagious, and transmission is through either the oral–oral route or the fecal–oral route, but is mainly associated with the oral–oral route.^[7] Consistent with these transmission routes, the bacteria have been isolated from feces, saliva, and dental plaque.^[131] H. pylori may also be transmitted orally by drinking contaminated water.^[7] Transmission occurs mainly within families in developed nations, yet can also be acquired from the community in developing countries.^[132]
幽门螺杆菌具有传染性，可通过口-口途径或粪-口途径传播，但主要与口-口途径有关。 ^[7] 与这些传播途径相一致的是，从粪便、唾液和牙菌斑中分离出了这种细菌。 ^[131] 幽门螺杆菌也可能通过饮用受污染的水经口传播。 ^[7] 在发达国家，幽门螺杆菌主要在家庭中传播，但在发展中国家，也可能从社区中感染。 ^[132]

Prevention 预防[edit]

To prevent the development of H. pylori-related diseases when infection is suspected, antibiotic-based therapy regimens are recommended to eradicate the bacteria.^[45] When successful the disease progression is halted. First line therapy is recommended if low-grade gastric MALT lymphoma is diagnosed, regardless of evidence of H. pylori. However, if a severe condition of atrophic gastritis with gastric lesions is reached antibiotic-based treatment regimens are not advised since such lesions are often not reversible and will progress to gastric cancer.^[45] If the cancer is managed to be treated it is advised that an eradication program be followed to prevent a recurrence of infection, or reduce a recurrence of the cancer, known as metachronous.^{[45][133][134]}
在怀疑感染幽门螺杆菌时，为防止幽门螺杆菌相关疾病的发生，建议采用抗生素治疗方案来根除病菌。 ^[45] 如果治疗成功，疾病的发展就会停止。如果确诊为低度胃 MALT 淋巴瘤，无论是否有幽门螺杆菌感染的证据，都建议采用一线治疗。但是，如果出现严重的萎缩性胃炎并伴有胃部病变，则不建议采用抗生素治疗方案，因为这种病变往往是不可逆的，而且会发展为胃癌。 ^[45] 如果癌症能够得到治疗，建议遵循根除方案，以防止感染复发，或减少癌症复发，即所谓的转移性胃癌。 ^{[45] [133] [134]}

Due to H. pylori's role as a major cause of certain diseases (particularly cancers) and its consistently increasing resistance to antibiotic therapy, there is an obvious need for alternative treatments.^[135] A vaccine targeted towards the development of gastric cancer including MALT lymphoma, would also prevent the development of gastric ulcers.^[5] A vaccine that would be prophylactic for use in children, and one that would be therapeutic later are the main goals. Challenges to this are the extreme genomic diversity shown by H. pylori and complex host-immune responses.^[135][136]
由于幽门螺杆菌 's 是某些疾病（尤其是癌症）的主要致病菌，而且它对抗生素治疗的耐药性不断增强，因此显然需要替代疗法。 ^[135] 针对胃癌（包括 MALT 淋巴瘤）的疫苗也能预防胃溃疡的发生。 ^[5] 我们的主要目标是为儿童提供预防性疫苗，并在以后提供治疗性疫苗。幽门螺杆菌基因组的极端多样性和复杂的宿主免疫反应是其面临的挑战。 ^{[135] [136]}

Previous studies in the Netherlands, and in the US have shown that such a prophylactic vaccine programme would be ultimately cost-effective.^[137][138] However, as of late 2019 there have been no advanced vaccine candidates and only one vaccine in a Phase I clinical trial. Furthermore, development of a vaccine against H. pylori has not been a priority of major pharmaceutical companies.^[139] A key target for potential therapy is the proton-gated urea channel, since the secretion of urease enables the survival of the bacterium.^[140]
此前在荷兰和美国进行的研究表明，这种预防性疫苗计划最终将具有成本效益。 ^{[137] [138]} 然而，截至 2019 年底，还没有先进的候选疫苗，只有一种疫苗处于 I 期临床试验阶段。此外，开发幽门螺杆菌疫苗并不是各大制药公司的优先事项。 ^[139] 潜在治疗的一个关键靶点是质子门控尿素通道，因为尿素酶的分泌使细菌得以存活。 ^[140]

Treatment 治疗[edit]

Gastritis 胃炎[edit]

Following Maastricht Consensus Reports, H. pylori gastritis, has been included in ICD11, and listed as Helicobacter pylori induced gastritis.^[43][44][45] Initially the infection tends to be superficial, localised to the upper mucosal layers of the stomach.^[141] The intensity of chronic inflammation is related to the cytotoxicity of the H. pylori strain. A greater cytotoxicity will result in the change from a non-atrophic gastritis to an atrophic gastritis with the loss of mucous glands. This condition is a prequel to the development of peptic ulcers and gastric adenocarcinoma.^[141]
根据《马斯特里赫特共识报告》，幽门螺杆菌胃炎已被纳入ICD11，并被列为幽门螺杆菌诱发的胃炎。 ^{[43] [44] [45]} 最初的感染往往是浅表的，局限于胃粘膜上层。 ^[141] 慢性炎症的强度与幽门螺杆菌菌株的细胞毒性有关。细胞毒性越强，非萎缩性胃炎就会转变为萎缩性胃炎，并伴有粘液腺的脱落。这种情况是发生消化性溃疡和胃腺癌的前奏。 ^[141]

Various antibiotic plus proton-pump inhibitor drug regimens are used to eradicate the infection and thereby successfully treat the disorder^[142] with triple-drug therapy consisting of clarithromycin, amoxicillin, and a proton-pump inhibitor given for 14–21 days often being considered first line treatment.^[141]
[142] 抗生素加质子泵抑制剂的治疗方案有很多种，其中克拉霉素、阿莫西林和质子泵抑制剂三联疗法通常被认为是一线治疗方案，疗程为 14-21 天。 ^[141]

Peptic ulcers 消化性溃疡[edit]

Once H. pylori is detected in a person with a peptic ulcer, the normal procedure is to eradicate it and allow the ulcer to heal. The standard first-line therapy is a 14-day "triple therapy" consisting of acid-suppressive therapy, most commonly proton-pump inhibitors, such as omeprazole, or less commonly potassium-competitive acid blockers, such as vonoprazan, combined with the antibiotics clarithromycin and amoxicillin.^[143][144] (The actions of proton pump inhibitors against H. pylori may reflect their direct bacteriostatic effect due to inhibition of the bacterium's P-type ATPase or urease.^[145]) Variations of the triple therapy have been developed over the years, such as using a different proton pump inhibitor, as with pantoprazole or rabeprazole, or replacing amoxicillin with metronidazole for people who are allergic to penicillin.^[146] In areas with higher rates of clarithromycin resistance, other options are recommended.^[147] Such a therapy has revolutionized the treatment of peptic ulcers and has made a cure to the disease possible. Previously, the only option was symptom control using antacids, H₂-antagonists or proton pump inhibitors alone.^[148][149] Eradication of H. pylori is associated with a subsequent decreased risk of duodenal or gastric ulcer recurrence.^[128]
一旦在消化性溃疡患者体内检测出幽门螺杆菌，通常的做法是根除幽门螺杆菌，让溃疡愈合。标准的一线疗法是为期14天的 "三联疗法"，包括抑酸疗法，最常见的是质子泵抑制剂（如奥美拉唑），或较少见的钾竞争性酸阻滞剂（如沃诺普赞），以及抗生素克拉霉素和阿莫西林。 ^{[143] [144]} （质子泵抑制剂对幽门螺杆菌的作用可能是由于抑制了该细菌的P型ATP酶或尿素酶，从而直接产生抑菌作用。 ^[145] ）。多年来，三联疗法不断发展变化，如使用不同的质子泵抑制剂（如泮托拉唑或雷贝拉唑），或对青霉素过敏者用甲硝唑代替阿莫西林。 ^[146] 在克拉霉素耐药率较高的地区，建议采用其他方案。 ^[147] 这种疗法彻底改变了消化性溃疡的治疗方法，使治愈这种疾病成为可能。以前，唯一的选择是仅使用抗酸剂、H ₂ - 拮抗剂或质子泵抑制剂来控制症状。 ^{[148] [149]} 幽门螺杆菌的根除与随后十二指肠或胃溃疡复发风险的降低有关。 ^[128]

Antibiotic resistance 抗生素耐药性[edit]

Increasing antibiotic resistance is the main cause of initial treatment failure. Factors linked to resistance include mutations, efflux pumps, and the formation of biofilms.^[150][151] One of the main antibiotics used in eradication therapies is clarithromycin, but clarithromycin-resistant strains have become well-established and the use of alternative antibiotics need to be considered. Multidrug resistance has also increased.^[151] Next generation sequencing is looked to for identifying initial specific antibiotic resistances that will help in targeting more effective treatment.^[152]
抗生素耐药性的增加是初期治疗失败的主要原因。与耐药性有关的因素包括突变、外排泵和生物膜的形成。 ^{[150] [151]} 根除疗法中使用的主要抗生素之一是克拉霉素，但克拉霉素耐药菌株已十分普遍，因此需要考虑使用替代抗生素。对多种药物的耐药性也有所增加。 ^[151] 下一代测序技术可用于确定最初的特异性抗生素耐药性，这将有助于确定更有效的治疗方法。 ^[152]

In 2018 the WHO listed H. pylori as a high priority pathogen for the research and discovery of new drugs and treatments.^[153] The increasing antibiotic resistance encountered has spurred interest in developing alternative therapies using a number of plant compounds.^[154][155] Plant compounds have fewer side effects than synthetic drugs. Most plant extracts contain a complex mix of components that may not act on their own as antimicrobials but can work together with antibiotics to enhance treatment and work towards overcoming resistance.^[154] Plant compounds have a different mechanism of action that has proved useful in fighting antimicrobial resistance. Various compounds can act for example by inhibiting enzymes such as urease, and adhesions to the mucous membrane.^[156] Sulfur-containing compounds from plants with high concentrations of polysulfides, coumarins, and terpenes have all been shown to be effective against H. pylori.^[154]
2018 年，世界卫生组织将幽门螺杆菌列为研究和发现新药及治疗方法的高度优先病原体。 ^[153] 遇到的抗生素耐药性越来越强，激发了人们利用一些植物化合物开发替代疗法的兴趣。 ^{[154] [155]} 与合成药物相比，植物化合物的副作用较小。大多数植物提取物都含有复杂的混合成分，这些成分本身可能无法作为抗菌剂发挥作用，但可以与抗生素共同发挥作用，从而增强治疗效果并克服抗药性。 ^[154] 植物化合物具有不同的作用机制，这已被证明有助于对抗抗药性。例如，各种化合物可以通过抑制尿素酶等酶和粘膜附着物发挥作用。 ^[156] 植物中含有高浓度多硫化物的含硫化合物、香豆素和萜类化合物都被证明对幽门螺杆菌有效。 ^[154]

Additional rounds of antibiotics may be used or other therapies.^{[157][158][159]} In patients with any previous macrolide exposure or who are allergic to penicillin, a quadruple therapy that consisting of a proton pump inhibitor, bismuth, tetracycline, and a nitroimidazole for 10–14 days is a recommended first-line treatment option.^[160] For the treatment of clarithromycin-resistant strains of H. pylori, the use of levofloxacin as part of the therapy has been suggested.^[161][162]
可使用额外的抗生素或其他疗法。 ^{[157] [158] [159]} 对于曾接触过大环内酯类药物或对青霉素过敏的患者，推荐一线治疗方案为四联疗法，包括质子泵抑制剂、铋剂、四环素和硝基咪唑，疗程为10-14天。 ^[160] 对于治疗克拉霉素耐药的幽门螺杆菌菌株，建议使用左氧氟沙星作为治疗的一部分。 ^{[161] [162]}

Probiotic yogurts containing lactic acid bacteria, Bifidobacteria and Lactobacillus exert a suppressive effect on H. pylori infection, and their use has been shown to improve the rates of eradication.^[13] Some commensal intestinal bacteria as part of the gut microbiota produce butyrate that acts as a prebiotic and enhances the mucosal immune barrier. Their use as probiotics may help balance the gut dysbiosis that accompanies antibiotic use.^[163] Some probiotic strains have been shown to have bactericidal and bacteriostatic activity against H. pylori, and also help to balance the gut dysbiosis.^[164]
含有乳酸菌、双歧杆菌和乳酸杆菌的益生菌酸奶对幽门螺杆菌感染有抑制作用，使用这种酸奶可提高幽门螺杆菌的根除率。 ^[13] 作为肠道微生物群的一部分，一些肠道共生细菌会产生丁酸盐，作为一种益生元并增强粘膜免疫屏障。将它们用作益生菌可能有助于平衡因使用抗生素而导致的肠道菌群失调。 ^[163] 一些益生菌株对幽门螺杆菌具有杀菌和抑菌活性，也有助于平衡肠道菌群失调。 ^[164]

H. pylori is found in saliva and dental plaque. Its transmission is known to include oral-oral suggesting that the dental plaque may act as a reservoir for the bacteria. Periodontal therapy or scaling and root planing has therefore been suggested as an additional treatment to enhance eradication rates but more research is needed.^[165]
幽门螺杆菌存在于唾液和牙菌斑中。已知幽门螺杆菌的传播途径包括口-口传播，这表明牙菌斑可能是幽门螺杆菌的贮藏库。因此，有人建议将牙周治疗或洗牙和根面平整作为一种额外的治疗方法，以提高根除率，但还需要更多的研究。 ^[165]

Cancers 癌症[edit]

Stomach cancer 胃癌[edit]

Helicobacter pylori is linked to the majority of gastric adenocarcinoma cases, and to the majority of non-cardia adenocarcinomas located at the gastroesophageal junction.^[166] The treatment for this cancer is highly aggressive with even localized disease being treated sequentially with chemotherapy and radiotherapy before surgical resection.^[167] Since this cancer, once developed, is independent of H. pylori infection, antibiotic-proton pump inhibitor regimens are not used in its treatment.^[166]
幽门螺杆菌与大多数胃腺癌病例有关，也与大多数位于胃食管交界处的非贲门腺癌有关。 ^[166] 这种癌症的治疗非常激进，即使是局部病变也要先用化疗和放疗进行连续治疗，然后再进行手术切除。 ^[167] 由于这种癌症一旦发生，就与幽门螺杆菌感染无关，因此在治疗中不使用抗生素-质子泵抑制剂方案。 ^[166]

Gastric MALT lymphoma and DLBCL
胃 MALT 淋巴瘤和 DLBCL[edit]

MALT lymphomas are malignancies of mucosa-associated lymphoid tissue. Early gastric MALTomas due to H. pylori may be successfully treated (70–95% of cases) with one or more eradication programs.^[13] Some 50–80% of patients who experience eradication of the pathogen develop within 3–28 months a remission and long-term clinical control of their lymphoma. Radiation therapy to the stomach and surrounding (i.e. peri-gastric) lymph nodes has also been used to successfully treat these localized cases. Patients with non-localized (i.e. systemic Ann Arbor stage III and IV) disease who are free of symptoms have been treated with watchful waiting or, if symptomatic, with the immunotherapy drug, rituximab, (given for 4 weeks) combined with the chemotherapy drug, chlorambucil, for 6–12 months; 58% of these patients attain a 58% progression-free survival rate at 5 years. Frail stage III/IV patients have been successfully treated with rituximab or the chemotherapy drug, cyclophosphamide, alone.^[168] Antibiotic-proton pump inhibitor eradication therapy and localized radiation therapy have been used successfully to treat H. pylori-positive MALT lymphomas of the rectum; however radiation therapy has given slightly better results and therefore been suggested to be the disease' preferred treatment.^[169] However, the generally recognized treatment of choice for patients with systemic involvement uses various chemotherapy drugs often combined with rituximab.
MALT 淋巴瘤是粘膜相关淋巴组织的恶性肿瘤。幽门螺杆菌引起的早期胃MALT淋巴瘤可通过一种或多种根除方案成功治疗（70-95%的病例）。 ^[13] 约有50%-80%的患者在根除病原体后3-28个月内病情得到缓解，淋巴瘤得到长期临床控制。胃部和周围（即胃周）淋巴结的放射治疗也被用来成功治疗这些局部病例。对无症状的非局部性（即全身性的安氏 III 期和 IV 期）患者，采用观察等待的方法进行治疗；如果有症状，则采用免疫疗法药物利妥昔单抗（用药 4 周）联合化疗药物氯霉素治疗 6-12 个月；其中 58% 的患者 5 年后无进展生存率达到 58%。单用利妥昔单抗或化疗药物环磷酰胺治疗体弱的III/IV期患者也取得了成功。 ^[168] 抗生素-质子泵抑制剂根除疗法和局部放射疗法已成功用于治疗幽门螺杆菌阳性的直肠MALT淋巴瘤；但放射疗法的疗效稍好，因此被认为是该病的首选疗法。 ^[169] 然而，对于全身受累的患者，公认的首选治疗方法是使用各种化疗药物，通常与利妥昔单抗联合使用。

A MALT lymphoma may rarely transform into a more aggressive diffuse large B-cell lymphoma (DLBCL).^[170] Where this is associated with H. pylori infection the DLBCL is less aggressive and more amenable to treatment.^{[171][172][173]} When limited to the stomach they have sometimes been successfully treated with H. pylori eradication programs.^{[53][172][174][173]} If unresponsive or showing a deterioration, a more conventional chemotherapy (CHOP), immunotherapy or local radiotherapy can be considered, and any of these or a combination have successfully treated these more advanced types. ^[172][173]
MALT淋巴瘤很少会转化为更具侵袭性的弥漫大B细胞淋巴瘤（DLBCL）。 ^[170] 如果这种淋巴瘤与幽门螺杆菌感染有关，那么DLBCL的侵袭性较小，更易于治疗。 ^{[171] [172] [173]} 当局限于胃部时，幽门螺杆菌根除计划有时能成功治疗这些疾病。 ^{[53] [172] [174] [173]} 如果没有反应或病情恶化，可以考虑采用更常规的化疗（CHOP）、免疫疗法或局部放疗，其中任何一种疗法或组合疗法都曾成功治疗过这些晚期类型。 ^{[172] [173]}

Prognosis 预后[edit]

Helicobacter pylori colonizes the stomach for decades in most people, and induces chronic gastritis, a long-lasting inflammation of the stomach. In most cases symptoms are never experienced but about 10–20% of those infected will ultimately develop gastric and duodenal ulcers, and have a possible 1–2% lifetime risk of gastric cancer.^[64]
幽门螺杆菌会在大多数人的胃中定植数十年，并诱发慢性胃炎（一种长期的胃部炎症）。在大多数情况下，患者不会出现任何症状，但约有10%-20%的感染者最终会患上胃溃疡和十二指肠溃疡，而且一生中患胃癌的风险可能高达1%-2%。 ^[64]

H. pylori thrives in a high salt diet, which is seen as an environmental risk factor for its association with gastric cancer. A diet high in salt enhances colonization, increases inflammation, increases the expression of H. pylori virulence factors, and intensifies chronic gastritis.^[175][176] Paradoxically extracts of kimchi a salted probiotic food has been found to have a preventive effect on H. pylori associated gastric carcinogenesis.^[177]
幽门螺杆菌在高盐饮食中茁壮成长，这被视为幽门螺杆菌与胃癌相关的环境风险因素。高盐饮食会促进幽门螺杆菌的定植，加重炎症，增加幽门螺杆菌毒力因子的表达，并加剧慢性胃炎。 ^{[175] [176]} 奇怪的是，人们发现泡菜提取物（一种加盐的益生菌食品）对与幽门螺杆菌相关的胃癌有预防作用。 ^[177]

In the absence of treatment, H. pylori infection, usually persists for life.^[178] Infection may disappear in the elderly as the stomach's mucosa becomes increasingly atrophic and inhospitable to colonization. Some studies in young children up to two years of age, have shown that infection can be transient in this age group.^[179][180]
在没有治疗的情况下，幽门螺杆菌感染通常会持续终身。 ^[178] 老年人的胃黏膜日益萎缩，不适合定植，因此感染可能会消失。对两岁以下幼儿的一些研究表明，该年龄组的感染可能是一过性的。 ^{[179] [180]}

It is possible for H. pylori to re-establish in a person after eradication. This recurrence can be caused by the original strain (recrudescence), or be caused by a different strain (reinfection). A 2017 meta-analysis showed that the global per-person annual rates of recurrence, reinfection, and recrudescence is 4.3%, 3.1%, and 2.2% respectively. It is unclear what the main risk factors are.^[181]
幽门螺杆菌有可能在根除后在人体内重新繁殖。这种复发可能是由原来的菌株引起的（复发），也可能是由不同的菌株引起的（再感染）。2017 年的一项荟萃分析显示，全球每人每年的复发率、再感染率和再发病率分别为 4.3%、3.1% 和 2.2%。目前尚不清楚主要的风险因素是什么。 ^[181]

Mounting evidence suggests H. pylori has an important role in protection from some diseases.^[15] The incidence of acid reflux disease, Barrett's esophagus, and esophageal cancer have been rising dramatically at the same time as H. pylori's presence decreases.^[182] In 1996, Martin J. Blaser advanced the hypothesis that H. pylori has a beneficial effect by regulating the acidity of the stomach contents.^[50][182] The hypothesis is not universally accepted as several randomized controlled trials failed to demonstrate worsening of acid reflux disease symptoms following eradication of H. pylori.^[183][184] Nevertheless, Blaser has reasserted his view that H. pylori is a member of the normal gastric microbiota.^[16] He postulates that the changes in gastric physiology caused by the loss of H. pylori account for the recent increase in incidence of several diseases, including type 2 diabetes, obesity, and asthma.^[16][185] His group has recently shown that H. pylori colonization is associated with a lower incidence of childhood asthma.^[186]
越来越多的证据表明，幽门螺杆菌在预防某些疾病方面发挥着重要作用。 ^[15] 在幽门螺杆菌 ' 存在减少的同时，胃酸倒流病、巴雷特食管和食管癌的发病率也在急剧上升。 ^[182] 1996年，Martin J. Blaser提出了幽门螺杆菌通过调节胃内容物酸度而产生有益影响的假设。 ^{[50] [182]} 这一假说并没有被普遍接受，因为几项随机对照试验未能证明根除幽门螺杆菌后胃酸倒流病症状会恶化。 ^{[183] [184]} 尽管如此，Blaser 还是重申了他的观点，即幽门螺杆菌是正常胃微生物群的一员。 ^[16] 他推测，幽门螺杆菌的消失导致胃部生理机能发生变化，这也是近来包括 2 型糖尿病、肥胖症和哮喘在内的多种疾病发病率上升的原因。 ^{[16] [185]} 他的研究小组最近发现，幽门螺杆菌定植与儿童哮喘发病率降低有关。 ^[186]

Epidemiology 流行病学[edit]

In 2023, it was estimated that about two-thirds of the world's population were infected with H. pylori infection, being more common in developing countries.^[19] H. pylori infection is more prevalent in South America, Sub-Saharan Africa, and the Middle East.^[142] The global prevalence declined markedly in the decade following 2010, with a particular reduction in Africa.^[20]
据估计，到2023年，全球约有三分之二的人口感染幽门螺杆菌，发展中国家更为常见。 ^[19] 幽门螺杆菌感染在南美洲、撒哈拉以南非洲和中东地区更为普遍。 ^[142] 在 2010 年之后的十年中，全球发病率明显下降，尤其是在非洲。 ^[20]

The age when someone acquires this bacterium seems to influence the pathologic outcome of the infection. People infected at an early age are likely to develop more intense inflammation that may be followed by atrophic gastritis with a higher subsequent risk of gastric ulcer, gastric cancer, or both. Acquisition at an older age brings different gastric changes more likely to lead to duodenal ulcer.^[178] Infections are usually acquired in early childhood in all countries.^[30] However, the infection rate of children in developing nations is higher than in industrialized nations, probably due to poor sanitary conditions, perhaps combined with lower antibiotics usage for unrelated pathologies. In developed nations, it is currently uncommon to find infected children, but the percentage of infected people increases with age. The higher prevalence among the elderly reflects higher infection rates incurred in childhood.^[30] In the United States, prevalence appears higher in African-American and Hispanic populations, most likely due to socioeconomic factors.^[187][188] The lower rate of infection in the West is largely attributed to higher hygiene standards and widespread use of antibiotics. Despite high rates of infection in certain areas of the world, the overall frequency of H. pylori infection is declining.^[189] However, antibiotic resistance is appearing in H. pylori; many metronidazole- and clarithromycin-resistant strains are found in most parts of the world.^[190]
感染这种细菌的年龄似乎会影响感染的病理结果。早年感染的人可能会出现更剧烈的炎症，随后可能会出现萎缩性胃炎，随后发生胃溃疡、胃癌或两者的风险都会更高。年长时感染会带来不同的胃部变化，更有可能导致十二指肠溃疡。 ^[178] 在所有国家，感染通常发生在幼儿期。 ^[30] 然而，发展中国家儿童的感染率要高于工业化国家，这可能是由于卫生条件差，也许再加上对无关病症的抗生素使用较少。在发达国家，受感染的儿童目前并不常见，但受感染者的比例随着年龄的增长而增加。老年人的发病率较高，反映出儿童时期的感染率较高。 ^[30] 在美国，非洲裔美国人和西班牙裔美国人的感染率似乎更高，这很可能是社会经济因素造成的。 ^{[187] [188]} 西方国家的感染率较低，这主要归因于较高的卫生标准和抗生素的广泛使用。尽管世界上某些地区的感染率较高，但幽门螺杆菌感染的总体频率正在下降。 ^[189] 然而，幽门螺杆菌出现了抗生素耐药性；在世界大部分地区发现了许多耐甲硝唑和耐克拉霉素的菌株。 ^[190]

History 历史[edit]

Helicobacter pylori migrated out of Africa along with its human host around 60,000 years ago.^[191] Research has shown that genetic diversity in H. pylori, like that of its host, decreases with geographic distance from East Africa. Using the genetic diversity data, researchers have created simulations that indicate the bacteria seem to have spread from East Africa around 58,000 years ago. Their results indicate modern humans were already infected by H. pylori before their migrations out of Africa, and it has remained associated with human hosts since that time.^[192]
大约 6 万年前，幽门螺杆菌随着人类宿主迁出非洲。 ^[191] 研究表明，幽门螺杆菌的遗传多样性与其宿主的遗传多样性一样，随着与东非的地理距离的增加而减少。研究人员利用遗传多样性数据进行了模拟，结果表明幽门螺杆菌似乎是在大约5.8万年前从东非传播出去的。他们的研究结果表明，现代人类在迁出非洲之前就已经感染了幽门螺杆菌，从那时起，幽门螺杆菌就一直与人类宿主有关。 ^[192]

H. pylori was first discovered in the stomachs of patients with gastritis and ulcers in 1982 by Barry Marshall and Robin Warren of Perth, Western Australia. At the time, the conventional thinking was that no bacterium could live in the acid environment of the human stomach. In recognition of their discovery, Marshall and Warren were awarded the 2005 Nobel Prize in Physiology or Medicine.^[193]
幽门螺杆菌是 1982 年由西澳大利亚珀斯的巴里-马歇尔和罗宾-沃伦在胃炎和溃疡患者的胃中首次发现的。当时的传统观点认为，没有细菌能在人类胃部的酸性环境中生存。为了表彰他们的发现，马歇尔和沃伦获得了 2005 年诺贝尔生理学或医学奖。 ^[193]

Before the research of Marshall and Warren, German scientists found spiral-shaped bacteria in the lining of the human stomach in 1875, but they were unable to culture them, and the results were eventually forgotten.^[182] The Italian researcher Giulio Bizzozero described similarly shaped bacteria living in the acidic environment of the stomach of dogs in 1893.^[194] Professor Walery Jaworski of the Jagiellonian University in Kraków investigated sediments of gastric washings obtained by lavage from humans in 1899. Among some rod-like bacteria, he also found bacteria with a characteristic spiral shape, which he called Vibrio rugula. He was the first to suggest a possible role of this organism in the pathogenesis of gastric diseases. His work was included in the Handbook of Gastric Diseases, but it had little impact, as it was published only in Polish.^[195] Several small studies conducted in the early 20th century demonstrated the presence of curved rods in the stomachs of many people with peptic ulcers and stomach cancers.^[196] Interest in the bacteria waned, however, when an American study published in 1954 failed to observe the bacteria in 1180 stomach biopsies.^[197]
在马歇尔和沃伦的研究之前，德国科学家于 1875 年在人的胃黏膜中发现了螺旋形细菌，但他们无法对其进行培养，结果最终被人们遗忘。 ^[182] 意大利研究人员朱利奥-比佐泽罗（Giulio Bizzozero）于 1893 年描述了生活在狗胃酸性环境中的类似形状的细菌。 ^[194] 1899年，克拉科夫雅盖隆大学的瓦莱里-雅沃斯基教授研究了人类洗胃后的沉淀物。在一些杆状细菌中，他还发现了具有螺旋状特征的细菌，并将其称为皱褶弧菌。他是第一个提出这种生物可能在胃病发病机制中发挥作用的人。他的研究成果被收录在《胃病手册》中，但由于仅以波兰文出版，影响甚微。 ^[195] 20世纪初进行的几项小型研究表明，许多患有消化性溃疡和胃癌的人的胃中存在弯曲杆菌。 ^[196] 然而，1954 年发表的一项美国研究未能在 1180 例胃活检中观察到这种细菌，人们对这种细菌的兴趣逐渐减弱。 ^[197]

Interest in understanding the role of bacteria in stomach diseases was rekindled in the 1970s, with the visualization of bacteria in the stomachs of people with gastric ulcers.^[198] The bacteria had also been observed in 1979, by Robin Warren, who researched it further with Barry Marshall from 1981. After unsuccessful attempts at culturing the bacteria from the stomach, they finally succeeded in visualizing colonies in 1982, when they unintentionally left their Petri dishes incubating for five days over the Easter weekend. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by bacterial infection and not by stress or spicy food, as had been assumed before.^[199]
20 世纪 70 年代，随着胃溃疡患者胃中细菌的可视化，人们重新燃起了了解细菌在胃病中作用的兴趣。 ^[198] 1979年，罗宾-沃伦（Robin Warren）也观察到了这种细菌，从1981年起，他与巴里-马歇尔（Barry Marshall）对其进行了进一步研究。在尝试从胃中培养这种细菌未果后，他们终于在 1982 年成功地观察到了这种细菌的菌落，当时他们无意中把培养皿放在复活节的周末里培养了五天。在最初的论文中，沃伦和马歇尔认为大多数胃溃疡和胃炎都是由细菌感染引起的，而不是像以前认为的那样是由压力或辛辣食物引起的。 ^[199]

Some skepticism was expressed initially, but within a few years multiple research groups had verified the association of H. pylori with gastritis and, to a lesser extent, ulcers.^[200] To demonstrate H. pylori caused gastritis and was not merely a bystander, Marshall drank a beaker of H. pylori culture. He became ill with nausea and vomiting several days later. An endoscopy 10 days after inoculation revealed signs of gastritis and the presence of H. pylori. These results suggested H. pylori was the causative agent. Marshall and Warren went on to demonstrate antibiotics are effective in the treatment of many cases of gastritis. In 1994, the National Institutes of Health stated most recurrent duodenal and gastric ulcers were caused by H. pylori, and recommended antibiotics be included in the treatment regimen.^[201]
起初有人对此表示怀疑，但在几年内，多个研究小组证实了幽门螺杆菌与胃炎的关系，其次是与溃疡的关系。 ^[200] 为了证明幽门螺杆菌会导致胃炎，而不仅仅是旁观者，马歇尔喝下了一烧杯幽门螺杆菌培养物。几天后，他开始恶心、呕吐。接种 10 天后的内窥镜检查发现了胃炎症状和幽门螺杆菌的存在。这些结果表明幽门螺杆菌是致病菌。马歇尔和沃伦继续证明抗生素对许多胃炎病例的治疗是有效的。1994年，美国国立卫生研究院指出，大多数复发性十二指肠溃疡和胃溃疡都是由幽门螺杆菌引起的，并建议将抗生素纳入治疗方案。 ^[201] .

The bacterium was initially named Campylobacter pyloridis, then renamed C. pylori in 1987 (pylori being the genitive of pylorus, the circular opening leading from the stomach into the duodenum, from the Ancient Greek word πυλωρός, which means gatekeeper^[202]).^[203] When 16S ribosomal RNA gene sequencing and other research showed in 1989 that the bacterium did not belong in the genus Campylobacter, it was placed in its own genus, Helicobacter from the Ancient Greek έλιξ (hělix) "spiral" or "coil".^[202][204]
这种细菌最初被命名为 "幽门弯曲杆菌"（Campylobacter pyloridis），1987 年更名为 "幽门螺杆菌"（C. pylori）（"幽门 "是 "幽门 "的属词，"幽门 "是从胃通向十二指肠的环形开口，源于古希腊语πυλωρός，意为守门人 ^[202] ）。 ^[203] 1989年，16S核糖体RNA基因测序和其他研究表明，该细菌不属于弯曲杆菌属，因此将其归入自己的属--螺旋杆菌属（Helicobacter），该属源自古希腊语έλιξ (hělix)，意为 "螺旋 "或 "线圈"。 ^{[202] [204]}

In October 1987, a group of experts met in Copenhagen to found the European Helicobacter Study Group (EHSG), an international multidisciplinary research group and the only institution focused on H. pylori.^[205] The Group is involved with the Annual International Workshop on Helicobacter and Related Bacteria,^[206] (renamed as the European Helicobacter and Microbiota Study Group^[207]), the Maastricht Consensus Reports (European Consensus on the management of H. pylori),^{[143][146][208][209]} and other educational and research projects, including two international long-term projects:
1987年10月，一批专家在哥本哈根举行会议，成立了欧洲幽门螺杆菌研究小组（EHSG），这是一个国际性多学科研究小组，也是唯一一个专注于幽门螺杆菌研究的机构。 ^[205] 该小组参与了年度国际幽门螺杆菌及相关细菌研讨会 ^[206] （已更名为欧洲幽门螺杆菌和微生物群研究小组 ^[207] ）、马斯特里赫特共识报告（欧洲幽门螺杆菌管理共识）、 ^{[143] [146] [208] [209]} 以及其他教育和研究项目，包括两个国际长期项目：

• European Registry on H. pylori Management (Hp-EuReg) – a database systematically registering the routine clinical practice of European gastroenterologists.^[210]
  欧洲幽门螺杆菌管理登记处（Hp-EuReg）--一个系统登记欧洲消化内科医生常规临床实践的数据库。 ^[210]
• Optimal H. pylori management in primary care (OptiCare) – a long-term educational project aiming to disseminate the evidence based recommendations of the Maastricht IV Consensus to primary care physicians in Europe, funded by an educational grant from United European Gastroenterology.^[211][212]
  初级保健中的幽门螺杆菌优化管理（OptiCare）--一个长期的教育项目，旨在向欧洲的初级保健医生传播马斯特里赫特第四共识的循证建议，由欧洲联合胃肠病学组织的教育基金资助。 ^{[211] [212]}

Research 研究[edit]

Results from in vitro studies suggest that fatty acids, mainly polyunsaturated fatty acids, have a bactericidal effect against H. pylori, but their in vivo effects have not been proven.^[213]
体外研究结果表明，脂肪酸（主要是多不饱和脂肪酸）对幽门螺杆菌有杀菌作用，但其体内作用尚未得到证实。 ^[213]

A suitable vaccine for H.pylori, either prophylactic or therapeutic, is an ongoing research aim.^[7] The Murdoch Children's Research Institute is working at developing a vaccine that instead of specifically targeting the bacteria, aims to inhibit the inflammation caused that leads to the associated diseases.^[139]
针对幽门螺杆菌的合适疫苗，无论是预防性的还是治疗性的，都是一项正在进行的研究目标。 ^[7] 默多克儿童研究所正在努力开发一种疫苗，它不是专门针对细菌，而是旨在抑制导致相关疾病的炎症。 ^[139]

Gastric organoids can be used as a model for the study of H. pylori pathogenesis.^[90]
胃有机体可用作研究幽门螺杆菌发病机制的模型。 ^[90]

See also 另见[edit]

• List of oncogenic bacteria
  致癌细菌清单
• Infectious causes of cancer
  癌症的传染病因

References 参考资料[edit]

External links[edit]

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• "Information on tests for H. pylori". National Institutes of Health. U.S. Department of Health and Human Services. Archived from the original on 13 June 2013.
• "European Helicobacter Study Group (EHSG)".
• "Type strain of Helicobacter pylori at BacDive". Bacterial Diversity Metadatabase.
• "Helicobacter pylori". Genome. KEGG. Japan. 26695.