Robin Warren (b. 1937) 罗宾·沃伦 在50%活检病人的胃窦观察到弯曲的细菌 重要的是胃粘膜炎症总是靠近能见细菌的地方。 a pathologist from Perth, Australia, observed small curved bacteria colonizing the lower part of the stomach (antrum) in about 50% of patients from which biopsies had been taken. 在50%活检病人的胃窦观察到弯曲的细菌 He made the crucial observation that signs of inflammation were always present in the gastric mucosa close to where the bacteria were seen. 重要的是胃粘膜炎症总是靠近能见细菌的地方。

Barry Marshall (b. 1951) 他们发现该菌见于几乎所有患胃炎、十二指肠和胃肠溃疡的病人 A young clinical fellow, became interested in Warren's findings and together they initiated a study of biopsies from 100 patients. After several attempts, Marshall succeeded in cultivating a hitherto unknown bacterial species (later denoted Helicobacter pylori) from several of these biopsies. 马歇尔从活检组织中培养出了当时未知的细菌-幽门螺杆菌 They found that the organism was present in almost all patients with gastric inflammation, duodenal ulcer or gastric ulcer. 他们发现该菌见于几乎所有患胃炎、十二指肠和胃肠溃疡的病人 Based on these results, they proposed that Helicobacter pylori is involved in the aetiology of these diseases. 因此，推测幽门螺杆菌与该病的病因有关。

Was Hp a pathogen? Testing the hypothesis 1. Do patients have antibodies? 2. Do antibacterials heal gastritis? 3. Have Koch’s postulates been fulfilled? 4. What is the disease process? How does it infect? How does it survive in the acid stomach?

铋

A lot data would be needed before the new bacterium could be accepted as a pathogen Q1. Do patients with bacteria have antibodies? Q2. Do antibacterial agents heal gastritis? Q3. Had Koch’s postulates been fulfilled for the new bacteria? Q4. What is the natural history of the disease process? Q5. Was this disease confined to people with ulcers? Q6. How does Helicobacter survive in the stomach? Q7. Do ulcer treatments affect the bacteria? 柯霍法则：建立疾病和微生物间因果关系的研究思维标准

Koch’s postulates for the new bacteria： 柯霍氏法则 1.病原菌存在于每个病例，能解释病理学上的改变 2.病原菌可从宿主分离，并能在培养基中培养。 3. 培养的病原菌接种到健康易感宿主，能产生相同疾病。 4. 细菌应在实验性感染的宿主重现，其特征与由原菌病相同。

临床试验：抗菌药是否有效？ 铋 替硝唑 2>1: tinidazole 有效 3>1或4>2 :抗菌药效强 1 cimetidine 8w + placebo 2w 2 cimetidine 8w + tinidazole 2w 3 bismuth 8w + placebo 2w 4 bismuth 8w + tinidazole 2w

An attempt to fulfil Koch’s postulates: the experiment Cultured a patient with gastritis Underwent baseline endoscopy Treated the patient successfully Drank bacteria 109 c.f.u. –d3-5 vague illness, halitosis口臭 –d5-8 vomiting, no acid present! – d8 – endoscopy and biopsy Histological gastritis –Hp is a pathogen Med J. Aust1984

Even though peptic ulcers could be healed by inhibiting gastric acid production, they frequently relapsed, since bacteria and inflammation of the stomach remained. 抗酸药虽能治愈溃疡，但易复发，因细菌和炎症尚存 In treatment studies, Marshall and Warren showed that patients could be cured from their peptic ulcer disease only when the bacteria were eradicated from the stomach. 治疗中显示：只有胃内细菌清除，溃疡才能治愈 Thanks to the discovery, peptic ulcer disease is no longer a chronic, frequently disabling condition, but a disease that can be cured by a short regimen of antibiotics and acid secretion inhibitors. 该发现使得原本慢性的、无药可治的胃溃疡变成了只 需抗生素等药物短期就可治愈的疾病

Peptic ulcer – an infectious disease! 消化性溃疡是一种感染性疾病 Barry Marshall and Robin Warren, who with tenacity and a prepared mind challenged prevailing dogmas. By using technologies generally available (fibre endoscopy, histological silver staining and bacteria culture), they made an irrefutable case that the HP is causing disease. 马歇尔和沃伦凭着坚忍不拔的毅力和有准备的头脑挑战传统， 用常规技术作出了不可反驳的结论：细菌是溃疡病的祸首。 In 1982, stress and lifestyle were considered the major causes of peptic ulcers. 1982年前认为生活压力和生活方式是胃溃疡的主要原因 It is now firmly established that Helicobacter pylori (HP) causes more than 90% of duodenal ulcers and up to 80% of gastric ulcers. 现已证明，90％以上 的十二指肠溃疡和80％以上的胃溃疡由幽门螺杆菌引起。 The link between HP infection and subsequent gastritis and peptic ulcer disease has been established through studies of human volunteers, antibiotic treatment studies and epidemiological studies. 幽门螺杆菌与胃炎、消化性溃疡之间的关系已通过志愿者的研 究、抗生素治疗和流行病学调查确定。

HP causes life-long infection HP is a spiral-shaped Gram-negative bacterium that colonizes the stomach in about 50% of all humans. In countries with high socio-economic standards infection is considerably less common than in developing countries where virtually everyone may be infected. 幽门螺杆菌寄生于50% 人的胃中，发达国家的感染率远低于发展中国家，其实发展中国家人人都可能被感染 Infection is typically contracted in early childhood, frequently by transmission from mother to child, and the bacteria may remain in the stomach for the rest of the person's life. 感染是在童年，常由母-儿传播，此后细菌在胃中保留终生 This infection is initiated in the lower part of the stomach. As first reported by Robin Warren, the presence of HP is always associated with an inflammation of the underlying gastric mucosa as evidenced by an infiltration of inflammatory cells. 感染始于胃窦，细菌的存在伴随着以炎细胞浸染为迹象的胃粘膜下层炎症

HP感染引起的胃未端的炎症增加了胃上部非感染部位胃酸的产生，从而使易患病的十二指肠发生溃疡。 The infection is usually asymptomatic 感染常无症状 but can cause peptic ulcer 但可引起溃疡 The severity of this inflammation and its location in the stomach is of crucial importance for the diseases. 炎症的程度及其在胃内的位置对该病至关重要 In most individuals HP infection is asymptomatic. 多数感染者常无症状 About 10-15% of infected individuals experience peptic ulcer disease. Such ulcers are more common in the duodenum than in the stomach. Severe complications include bleeding and perforation. The chronic inflammation in the distal part of the stomach caused by HP infection increase acid production from the non-infected upper corpus region of the stomach. This will predispose for ulcer development in the more vulnerable duodenum. 约有10-15% 的感染者会得溃疡病， 十二指肠溃疡比胃溃疡常见。 重要的并发症有出血和穿孔。 HP感染引起的胃未端的炎症增加了胃上部非感染部位胃酸的产生，从而使易患病的十二指肠发生溃疡。

Malignancies associated with HP infection 恶性变 In some individuals HP also infects the corpus region of the stomach. This results in a more widespread inflammation that predisposes not only to ulcer, but also to cancer. This cancer ranks as number two in the world in terms of cancer deaths. HP也感染胃体，导致更广泛的炎症，不仅给溃疡病，也给癌症埋下了隐患。 该癌症的死亡率居世界第二。 Inflammation in the stomach mucosa is also a risk factor for a special type of lymphatic neoplasm in the stomach, MALT (mucosa associated lymphoid tissue) lymphoma. Since such lymphomas may regress when HP is eradicated, the bacterium plays an important role in perpetuating this tumour. 胃粘膜炎症是胃粘膜相关淋巴瘤的危险因素，因为HP消除 后，该瘤退化，细菌对瘤存在有重要作用。

Disease or not – interaction between the bacterium and the human host 患病与否是细菌与宿主相互作用的结果 HP is present only in humans and has adapted to the stomach environment. Only a minority of infected individuals develop disease. After Marshall's and Warren's discovery, research has been intense. The pathogenetic mechanisms are continuously being unravelled. 人是HP的唯一宿主，并适应了胃的环境。仅少数感染者患病，病因性机制正在广泛研究。 The bacterium itself is extremely variable, and strains differ markedly in many aspects, such as adherence to the gastric mucosa and ability to provoke inflammation. 细菌本身易变异。菌株在许多方面很不相同，如对胃粘膜的粘附及引起炎症的能力。 Even in an individual all bacteria are not identical, and during the course of infection bacteria adapt to the changing conditions in the stomach with time. 即使在同一病人，细菌都各不相同。细菌可随时适应胃内环境的变化。 Likewise, genetic variations among humans may affect their susceptibility to HP. An animal model has been established, the Mongolian gerbil. The studies of disease mechanisms promise to give more detailed information. 同样，人的基因的差异可影响其对HP的易感性。蒙古沙鼠感染的动物模型已经建立，机制的研究可望获得更详细的资料。

Antibiotics cure but can lead to resistance 抗生素可治，但易抗药 HP infection can be diagnosed by antibody tests, by identifying the organism in biopsies taken during endoscopy, or by the non-invasive breath test that identifies bacterial production of an enzyme in the stomach. HP感染可用抗体试验、活检或呼气试验诊断。 胃内细菌分泌尿素酶，分解尿素，生成CO2。 An indiscriminate use of antibiotics to eradicate HP also from healthy carriers would lead to severe problems with bacterial resistance against these important drugs. Therefore, treatment against HP should be used restrictively in patients without documented gastric or duodenal ulcer disease. 滥用抗生素预防HP感染会导致细菌的抗药性，从而使其对 重要的抗生素不敏感。因此治疗要严格限制

许多病如溃疡性结肠炎、类风湿性关节炎、动脉粥样硬化等 也是慢性炎症，溃疡病病因的发现促使人们寻找其它慢性炎 症的可能病因。 Microbial origin of other chronic inflammatory conditions? 其它慢性炎症疾病病因有可能性 Many diseases in humans such as ulcerative colitis, rheumatoid arthritis and atherosclerosis are due to chronic inflammation. The discovery that one of the most common diseases, peptic ulcer, has a microbial cause, has stimulated the search for microbes as possible causes of other chronic inflammatory conditions. 许多病如溃疡性结肠炎、类风湿性关节炎、动脉粥样硬化等 也是慢性炎症，溃疡病病因的发现促使人们寻找其它慢性炎 症的可能病因。 Recent data suggest that a dysfunction in the recognition of microbial products by the human immune system can result in disease development. The discovery of HP has led to an increased understanding of the connection between chronic infection, inflammation and cancer. 人的免疫系统对微生物产物的认知缺陷可能导致疾病，HP 的发现增加了人们对慢性感染、炎症和癌症的联系。

之前，人们认为胃炎、胃溃病是胃酸分泌过多等引起，学术 界认为“无酸就无溃疡”，没有人想到这些疾病与细菌有关。 幽门螺杆菌的发现打破了这一误区，引发了一场对胃肠道疾 病研究与治疗的革命。 以前胃炎用消炎药，往往有效，但由于当时并不认为胃炎与 细菌有关，认为这属于错误用药。直到幽门螺杆菌发现之后， 这种治病方法才得以“平反”。 幽门螺杆菌的发现引发了对消化道疾病认识的革命，使得全 世界数以亿计的胃炎、胃溃疡病患者得到合理治疗。