헬리코박터 파일로리 감염 2023년 nature

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의문 1. 헬리코박터 파일로리 감염율 선진국 50%, 기타국가 80%

            감염되어있으나 무증상 80%

        2. 제산제+항생제로 균제거 가능.. 항생제 내성률 10%에서 30%로 증가..

과연 헬리코박터 파일로리 제거치료가 유일한 치료법일까?

썩을 고기를 먹고사는 독수리, 하이에나는 왜 건강하게 살 수있는 것일까?

위산보충제가 더 나은 치료일 것으로 추정 new medicine

https://www.youtube.com/watch?v=aYDD4-VPxO8 

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Helicobacter pylori infection

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• Primer
• Published: 20 April 2023

Helicobacter pylori infection

• Peter Malfertheiner, 
• M. Constanza Camargo, 
• Emad El-Omar, 
• Jyh-Ming Liou, 
• Richard Peek, 
• Christian Schulz, 
• Stella I. Smith & 
• Sebastian Suerbaum 

Nature Reviews Disease Primers volume 9, Article number: 19 (2023) Cite this article

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Abstract

Helicobacter pylori infection causes chronic gastritis, which can progress to severe gastroduodenal pathologies, including peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori is usually transmitted in childhood and persists for life if untreated. The infection affects around half of the population in the world but preval‎ence varies according to location and sanitation standards. H. pylori has unique properties to colonize gastric epithelium in an acidic environment. The pathophysiology of H. pylori infection is dependent on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors, resulting in distinct gastritis phenotypes that determine possible progression to different gastroduodenal pathologies. The causative role of H. pylori infection in gastric cancer development presents the opportunity for preventive screen-and-treat strategies. Invasive, endoscopy-based and non-invasive methods, including breath, stool and serological tests, are used in the diagnosis of H. pylori infection. Their use depends on the specific individual patient history and local availability. H. pylori treatment consists of a strong acid suppressant in various combinations with antibiotics and/or bismuth. The dramatic increase in resistance to key antibiotics used in H. pylori eradication demands antibiotic susceptibility testing, surveillance of resistance and antibiotic stewardship.

요약

헬리코박터 파일로리 감염은

만성 위염을 유발하여

소화성 궤양, 위암 및 위 점막 관련 림프 조직 림프종을 포함한

심각한 위 십이지장 병리로 진행될 수 있습니다.

H. 파일로리균은

보통 어린 시절에 전염되며

치료하지 않으면 평생 지속됩니다.

전 세계 인구의 약 절반이 감염되지만

지역과 위생 기준에 따라 유병률이 달라집니다.

H. 파일로리는

산성 환경에서 위 상피에 식민지를 형성하는 독특한 특성을 가지고 있습니다.

H. 파일로리 감염의 병태생리는

복잡한 박테리아 독성 메커니즘과 숙주 면역 체계 및 환경 요인과의 상호 작용에 따라 달라지며,

그 결과 다양한 위염 표현형이 나타나며,

이는 다양한 위십이지장 병리로 진행될 수 있는 가능성을 결정합니다.

위암 발생에 있어

H. 파일로리 감염의 원인적 역할은

예방적 검사 및 치료 전략의 기회를 제공합니다.

호흡, 대변 및 혈청학적 검사를 포함한

침습적, 내시경 기반 및 비침습적 방법이 H. 파일로리 감염의 진단에 사용됩니다.

이러한 방법은

환자 개개인의 병력 및 지역적 가용성에 따라 다릅니다.

H. 파일로리 치료는

항생제 및/또는 비스무트와 다양한 조합의

강력한 위산 억제제로 구성됩니다.

H. 파일로리 박멸에 사용되는

주요 항생제에 대한 내성이 급격히 증가함에 따라

항생제 감수성 검사, 내성 감시 및 항생제 관리가 필요합니다.

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Introduction

Helicobacter pylori is the most frequent cause of chronic gastritis and variably leads to severe gastroduodenal pathologies in some patients, including gastric and duodenal peptic ulcer disease (PUD), gastric cancer, and gastric mucosa-associated lymphoid tissue (MALT) lymphoma1,2,3. The diverse pathologies attributed to H. pylori infection are caused by complex interactions of bacterial virulence, host genetics and environmental factors4,5, which result in different phenotypes of chronic gastritis (Table 1). These phenotypes are defined as antral-predominant, corpus-predominant gastritis or pangastritis according to the highest gastritis severity within gastric anatomical compartments.

소개

헬리코박터 파일로리는

만성 위염의 가장 흔한 원인이며

일부 환자에서 위 및 십이지장 소화성 궤양 질환(PUD),

위암,

위 점막 관련 림프 조직(MALT) 림프종1,2,3 을 포함한

심각한 위 십이지장 병리를 다양하게 유발합니다.

H. 파일로리 감염으로 인한 다양한 병리는

박테리아 독성, 숙주 유전학 및 환경 요인의 복잡한 상호작용으로 인해 발생하며4,5,

이로 인해 만성 위염의 다양한 표현형이 나타납니다(표 1).

이러한 표현형은 위 해부학적 구획 내에서 가장 높은 위염 중증도에 따라

전위 우세성 위염,

체부 우세성 위염 또는

팽만성 위염으로 정의됩니다.

Table 1 Disease phenotypes of H. pylori infection

Full size table

The milestone discovery of H. pylori invalidated the dogmatic assumption of the acidic stomach as a sterile organ. This finding required a fundamental revision of gastric pathophysiology and gastroduodenal pathologies. Although spiral microorganisms in the stomach had been reported6, it was not until 1982 that Warren and Marshall identified a bacterial infection as the cause of chronic gastritis and succeeded in isolating the responsible microorganism7 (Fig. 1). The proof of concept that H. pylori infection causes gastritis was obtained by voluntary self-experiments with ingestion of a bacterial broth and cure of gastritis following H. pylori eradication (that is, fulfilment of the Koch’s postulates)8,9. The Koch’s postulates requires proof of causality for a pathogen to induce disease and cure of disease when the causal agent is removed — this finding was eventually confirmed in clinical trials10. The bacterium originally referred to as Campylobacter pylori (C. pyloridis) became reclassified as H. pylori in 1989 (ref. 11). Peptic ulcer, considered an acid-driven disease in the traditional pathophysiological concept, became an infection-driven disease12,13,14. The standard therapy with long-term acid suppression became short-term H. pylori eradication therapy14. For the discovery that eventually led to the permanent cure of peptic ulcers by H. pylori eradication, Marshall and Warren were awarded the Nobel prize in Physiology or Medicine in 2005 (ref. 15). To this day, continuous scientific progress and new clinical developments have led to frequent modifications and updates to the clinical management of H. pylori10.

H. 파일로리의 획기적인 발견은

산성 위가 무균 기관이라는 독단적인 가정을 무효화했습니다.

이 발견은 위 병리 생리와 위 십이지장 병리에 대한 근본적인 수정이 필요했습니다.

위장에 나선형 미생물이 있다는 보고는 있었지만6,

1982년에야 Warren과 Marshall이 만성 위염의 원인으로

박테리아 감염을 확인하고

원인 미생물을 분리하는 데 성공했습니다7 (그림 1).

헬리코박터 파일로리 감염이 위염을 유발한다는 개념 증명은

박테리아 국물을 섭취하고

헬리코박터 파일로리 제균 후 위염이 완치되는

자발적 자가 실험(즉, 코흐의 가설의 충족)8,9 을 통해 얻어졌습니다.

코흐의 가설은

병원체가 질병을 유발하고

원인균을 제거하면 질병이 완치된다는 인과관계를 증명해야 하며,

이 결과는 결국 임상시험에서 확인되었습니다10.

원래 캄필로박터 파일로리 (C. 파일로리디스)로 불렸던 이 세균은

1989년에 H. 파일로리로 재분류되었습니다(참조 11).

전통적인 병태생리학적 개념에서

산에 의한 질환으로 간주되던 소화성 궤양은

감염에 의한 질환이 되었습니다12,13,14.

장기간의 위산 억제를 통한 표준 치료법은

단기간의 헬리코박터 파일로리 제균 치료가 되었습니다14.

결국

소화성 궤양을 영구적으로 치료할 수 있게 된

H. 파일로리 제균의 발견으로 마샬과 워렌은

2005년에 노벨 생리의학상을 수상했습니다(참고 15).

오늘날까지

지속적인 과학적 진보와 새로운 임상 개발로 인해

H. pylori의 임상 관리가

자주 수정되고 업데이트되었습니다10.

Fig. 1: Key developments in H. pylori clinical research and management.

Helicobacter pylori was discovered and reported at a conference in 1982 but the finding was not further disseminated before the first publication in 1983 (ref. 7). The timeline highlights key developments in clinical research of H. pylori infection and its therapeutic management since 1982 (refs. 1,10,11,12,14,15,17,21,70,184,224,241,311,336,377,378,379,380,381,382,383). OLGA, Operative Link on Gastritis Assessment; OLGIM, Operative Link on Gastritis/Intestinal Metaplasia Assessment; PPI, proton pump inhibitor.

헬리코박터 파일로리는 1982년 학회에서 발견되어 보고되었지만 1983년 처음 발표되기 전까지는 더 이상 널리 알려지지 않았습니다(참조 7). 이 타임라인은 1982년 이후 헬리코박터 파일로리 감염에 대한 임상 연구 및 치료 관리의 주요 발전을 보여줍니다(참조. 1,10,11,12,14,15,17,21,70,184,224,241,311,336,377,378,379,380,381,382,383). OLGA, 위염 평가에 대한 수술적 연계; OLGIM, 위염/장상피화생 평가에 대한 수술적 연계; PPI, 프로톤 펌프 억제제.

H. pylori infects nearly half of the population in the world, with strong differences between geographical areas but with consistent trends towards a decreasing incidence16. Around 80% of individuals with H. pylori infection remain asymptomatic, but gastritis develops in all individuals with the infection, with unpredictable and potentially severe individual outcomes as well as high morbidity and mortality17,18.

This Primer provides an update on current epidemiological trends of H. pylori infection, key aspects of its pathogenicity and its role in gastroduodenal pathologies. An important focus is also on gastric cancer prevention by H. pylori eradication. The diagnostic and therapeutic management of H. pylori infection is discussed according to current international guidelines. The dramatic increase in antibiotic resistance requires special measures, including the incorporation of new molecular methods for antibiotic susceptibility testing, the adaptation of individual treatment regimens and the implementation of antibiotic stewardship.

H. 파일로리균은

전 세계 인구의 거의 절반이 감염되어 있으며,

지역마다 큰 차이가 있지만 발병률이 감소하는 추세입니다16.

H. 파일로리균 감염자의 약 80%는 무증상 상태이지만,

감염된 모든 사람에게서 위염이 발생하며,

예측할 수 없고 잠재적으로 심각한 결과를 초래할 수 있으며

이환율과 사망률이 높습니다17,18.

이 입문서에서는 헬리코박터 파일로리 감염의 최신 역학 동향, 병원성의 주요 측면 및 위십이지장 병리에서의 역할에 대한 최신 정보를 제공합니다. 또한 H. 파일로리 제균을 통한 위암 예방에 중점을 두고 있습니다.

현재 국제 가이드라인에 따라

H. 파일로리 감염의 진단 및 치료 관리에 대해 논의합니다.

항생제 내성의 급격한 증가는

항생제 감수성 검사를 위한 새로운 분자 방법의 통합,

개별 치료 요법의 적응 및 항생제 관리의 실행을 포함한

특별한 조치를 필요로 합니다.

Epidemiology

H. pylori infection

Once individuals acquire H. pylori infection, the pathogen usually persists throughout their lifetime2. However, spontaneous clearance was reported in 9 of 58 (15.5%) children during the 20 years of follow-up of a retrospective cohort study from 2002 (ref. 19). Clearance of H. pylori does often occur in patients with advanced atrophic gastritis20. The global preval‎ence of H. pylori infection in adults has declined from 50–55% to 43% during 2014–2020 (refs. 16,17), mostly attributed to improvement of socioeconomic status, living standards and hygiene conditions16,21,22,23. The increased use of antibiotics, including eradication therapies, in individuals with the infection might be a further contributor.

Preval‎ence varies substantially with age, ethnicity, associated diseases, geographic regions, socioeconomic status and hygiene conditions16,21. For young age groups, the 2002 study showed that most newly acquired H. pylori infections occurred before the age of 10 years19. The overall crude incidence rate was 1.4% per year, ranging from 2.1% at 4–5 years, 1.5% at age 7–9 years, to 0.3% at 21–23 years of age19. During 2014–2020, the preval‎ence of infection in children and adults was higher in low-income and middle-income countries, including in Africa, the Eastern Mediterranean, Russia, and Middle America and South America, than in high-income countries but was reduced in Western Pacific regions17 (Fig. 2). The preval‎ence of infection is higher in adults than in children. It is also higher in rural developing areas than in urban developed regions2. Preval‎ence of H. pylori infection in children has been decreasing owing to improvements in socioeconomic status and hygiene conditions; however, the global preval‎ence in children remained as high as 34% during 2014–2020 (refs. 17,24). The higher preval‎ence in older individuals compared with children is explained by most (90%) of H. pylori infections being acquired in childhood and persisting throughout life rather than by a higher risk of infection at older age.

역학

H. 파일로리 감염

일단 H. 파일로리균에 감염되면,

이 병원체는 보통 평생 동안 지속됩니다2.

그러나

2002년부터 20년간 후향적 코호트 연구를 추적 관찰한 결과

58명 중 9명(15.5%)에서 자연 제균이 보고되었습니다(참조 19).

진행성 위축성 위염 환자에서

H. 파일로리 제균이 종종 발생합니다20.

전 세계 성인 H. 파일로리균 감염 유병률은 2014-2020년 사이에

50-55%에서 43%로 감소했으며(참고 16,17),

이는 대부분 사회경제적 지위, 생활 수준 및 위생 상태의 개선에 기인합니다16,21,22,23.

감염자에서 박멸 요법을 포함한 항생제 사용이 증가한 것도 또 다른 원인일 수 있습니다.

유병률은

연령, 인종, 관련 질환, 지역, 사회경제적 지위 및 위생 상태에 따라

크게 달라집니다16,21.

젊은 연령대의 경우,

2002 년 연구에 따르면 새로 획득 한 대부분의 H. 파일로리 감염은

10 세 이전에 발생했습니다19.

전체 조발생률은 연간 1.4%로 4-5세 2.1%, 7-9세 1.5%, 21-23세 0.3%로 나타났습니다19. 2014~2020년 동안 어린이와 성인의 감염 유병률은 아프리카, 동부 지중해, 러시아, 중미 및 남미를 포함한 저소득 및 중간 소득 국가에서 고소득 국가보다 높았지만 서태평양 지역에서는 감소했습니다17 (그림 2). 감염 유병률은 어린이보다 성인에서 더 높습니다. 또한 도시 선진 지역보다 농촌 개발 도상국에서 더 높습니다2. 사회경제적 지위와 위생 상태의 개선으로 인해 소아에서의 H. 파일로리 감염 유병률은 감소하고 있지만, 2014-2020년 동안 전 세계 소아 유병률은 34%로 여전히 높았습니다(참조 17,24).

어린이에 비해 노인의 유병률이 높은 것은

나이가 들수록 감염 위험이 높아지기보다는

대부분의(90%) H. 파일로리 감염이 어린 시절에 획득되어 평생 동안 지속되기 때문입니다.

Fig. 2: Preval‎ence of H. pylori infection in adults and children.

a,b, Global map of Helicobacter pylori infection preval‎ence in adults during 1970–2016 (part a) and in children and adolescents (<20 years) during 2000–2021 (part b). In adults, the preval‎ence was highest in Africa, Eastern Mediterranean regions, Russia, Middle America and South America. In children, the preval‎ence was lower than that in adults in Russia, Western Pacific regions and European regions. However, the preval‎ence of H. pylori infection was similarly high in children and adults in Africa, Eastern Mediterranean regions, and Middle America and South America16,24.

a,b, 1970-2016년 성인 헬리코박터 파일로리 감염 유병률의 세계 지도(파트 a) 및 2000-2021년 소아 및 청소년(20세 미만)의 헬리코박터 파일로리 감염 유병률(파트 b). 성인의 경우 아프리카, 동부 지중해 지역, 러시아, 중미 및 남미에서 유병률이 가장 높았습니다. 어린이의 경우 러시아, 서태평양 지역 및 유럽 지역에서 성인보다 유병률이 낮았습니다. 그러나 아프리카, 동부 지중해 지역, 중미 및 남미 지역의 어린이와 성인에서 H. 파일로리 감염 유병률은 비슷하게 높았습니다16,24.

Some studies suggest increased susceptibilities to H. pylori infection in certain populations based on genetics and ethnicity; however, food sharing and housing habits may also have a role22,23,24. For example, in the Sumatra islands of Indonesia, the preval‎ence of H. pylori infection is very low in the Malay and Java populations, but is high in Batak populations, indicating that genetic factors may contribute to differential host susceptibility25. Gene and genome-wide association studies have identified that polymorphisms in IL-1B, Toll-like receptor 1 (TLR1) locus and the FCGR2A locus are associated with H. pylori seropreval‎ence26,27. However, a 2022 study has cast doubt on a role of the TLR1/6/10 locus in H. pylori seropreval‎ence28, and further studies are needed29.

Faecal–oral and oral–oral routes are considered the most likely routes of transmission30,31. Contaminated water may be a source of infection in developing countries32. H. pylori can be cultivated from the vomitus, stool and saliva of individuals with infection, indicating the potential transmissibility via these routes33. However, future studies about transmission pathways and their relative importance are urgently needed.

Person-to-person transmission within families, especially from mothers and siblings with the infection, is common in developing countries34. Genotyping studies have shown that strain concordance was detected in 10 of 18 (56%) mother–offspring and in 0 of 17 father–offspring relations35. Concordant strains in siblings were detected in 29 of 36 (81%) families35. Nevertheless, transmission within couples or spouses remains controversial35,36,37. In two studies, the ribopatterns of H. pylori strains were similar in 8 of 18 (44%) and 5 of 23 (22%) couples with H. pylori infection35,36. However, another study showed that, although restriction fragment length polymorphism patterns were similar in 5 of 13 couples, further restriction fragment length polymorphism using restriction endonucleases revealed distinct patterns in these 5 couples, indicating that transmission between spouses is infrequent37. Due to the extremely high genetic diversity of H. pylori, even short nucleotide sequences can be highly informative about transmission pathways and the direction of transmission between two individuals. Seven-gene multilocus sequence typing38 and, more recently, whole-genome sequence analysis39 have enabled the reconstruction of the spread of H. pylori in families and have great potential to answer open questions in H. pylori epidemiology.

The annual reinfection or recrudescence rate after successful eradication is low (<2%) in adults in developed countries but is higher (5–10%) in adults in developing countries and in children17,40. Some randomized trials showed that a strategy of family-based H. pylori screening and treatment can reduce the recurrence rate more than a single-patient approach41. Further well-designed, large-scale randomized trials are warranted to validate whether family-based screening and eradication may reduce the transmission of H. pylori within families.

일부 연구에서는

유전과 인종에 따라 특정 집단에서 H. 파일로리균 감염에 대한 감수성이 증가한다고 하지만,

음식 공유 및 주거 습관도 영향을 미칠 수 있습니다22,23,24.

예를 들어,

인도네시아 수마트라 섬의 경우 말레이계와 자바계 인구에서는

H. 파일로리 감염 유병률이 매우 낮지만

바탁계 인구에서는 높은 것으로 나타나

유전적 요인이 숙주 감수성 차이에 기여할 수 있음을 시사합니다25 .

유전자 및 게놈 전체 연관성 연구에 따르면 IL-1B, 톨유사수용체 1(TLR1) 유전자좌 및 FCGR2A 유전자좌의 다형성이 H. pylori 혈청 유병률과 관련이 있는 것으로 확인되었습니다26,27. 그러나 2022 년 연구에 따르면 H. 파일로리 혈청 유병률에서 TLR1/6/10 유전자좌의 역할에 대한 의문이 제기되었으며28, 추가 연구가 필요합니다29.

분변-구강 및 구강-구강 경로는

가장 가능성이 높은 전파 경로로 간주됩니다30,31.

개발도상국에서는

오염된 물이 감염의 원인이 될 수 있습니다32.

감염된 사람의 구토물, 대변, 타액에서H. 파일로리균이 배양될 수 있으므로

이러한 경로를 통한 전염 가능성이 있습니다33.

그러나 전염 경로와 그 상대적 중요성에 대한 향후 연구가 시급히 필요합니다.

특히 감염된 어머니와 형제자매로부터의 가족 내 개인 간 전염은 개발도상국에서 흔합니다34. 유전자형 연구에 따르면 어머니-자녀 관계 18건 중 10건(56%)에서, 아버지-자녀 관계 17건 중 0건에서 균주 일치성이 발견되었습니다35. 형제자매의 일치 균주는 36개 가족 중 29개(81%) 가족에서 발견되었습니다35 . 그럼에도 불구하고 부부 또는 배우자 내 전염은 여전히 논란의 여지가 있습니다35 ,36,37. 두 연구에서 H. 파일로리 균주의 리보패턴은 18쌍 중 8쌍(44%)과 23쌍 중 5쌍(22%)의 H. 파일로리 감염 부부35,36 에서 유사하게 나타났습니다. 그러나 또 다른 연구에 따르면 13쌍 중 5쌍에서 제한 단편 길이 다형성 패턴이 유사했지만, 제한 엔도뉴클레아제를 사용한 추가 제한 단편 길이 다형성에서 이 5쌍에서 뚜렷한 패턴이 나타나 배우자 간 전염이 드물다는 것을 나타냈습니다37. 헬리코박터 파일로리균의 유전적 다양성이 매우 높기 때문에 짧은 뉴클레오티드 서열이라도 두 개인 간의 전염 경로와 전염 방향에 대해 매우 유용한 정보를 제공할 수 있습니다. 7 유전자 다중 염기서열 분석38과 최근에는 전장 유전체 염기서열 분석39을 통해 가족 내 헬리코박터 파일로리 확산을 재구성할 수 있게 되었으며 헬리코박터 파일로리 역학에서 미해결 질문에 답할 수 있는 큰 잠재력을 가지고 있습니다.

성공적인 제균 후 연간 재감염 또는 재발률은 선진국 성인에서는 낮지만(<2%), 개발도상국 성인과 소아에서는 더 높습니다(5-10%)17,40. 일부 무작위 시험에 따르면 가족을 기반으로 한 H. 파일로리 검진 및 치료 전략이 단일 환자 접근법보다 재발률을 더 줄일 수 있는 것으로 나타났습니다41 . 가족 기반 검진 및 제균이 가족 내 헬리코박터 파일로리 전파를 줄일 수 있는지 검증하기 위해서는 잘 설계된 대규모 무작위 임상시험이 더 필요합니다.

H. pylori infection-related diseases

H. pylori infection is an important causal factor of gastric cancer, duodenal ulcer and gastric ulcer42.

Peptic ulcer disease

Lifetime preval‎ence of PUD in individuals with H. pylori infection is estimated at around 10%14,43,44. After 10 years, >11% of individuals with the infection develop PUD compared with 1% of individuals without the infection45. In a prospective study, the lifetime risk of developing duodenal ulcer and gastric ulcer was respectively increased by 18.4-fold and 2.9-fold in individuals with infection with cagA-positive H. pylori strains46.

H. 파일로리 감염 관련 질환

H. 파일로리 감염은

위암, 십이지장 궤양 및 위궤양의 중요한 원인 인자입니다42.

소화성 궤양 질환

헬리코박터 파일로리 감염자의 평생 유병률은 약 10%로 추정됩니다14 ,43,44. 10년 후, 감염이 없는 사람의 1%에 비해 감염이 있는 사람의 11% 이상에서 PUD가 발생합니다45. 전향적 연구에 따르면, 십이지장 궤양과 위궤양 발병의 평생 위험은 cagA 양성 H. pylori 균주에 감염된 개인에서 각각 18.4배와 2.9배 증가했습니다46.

Since the 2000s, the global preval‎ence of PUD is declining47,48,49,50 in parallel with a decreasing preval‎ence of H. pylori infection16 for various reasons47,51,52,53,54. The epidemiological trend indicates an increasing role of NSAIDs, including acetylsalicylic acid, which independently increase the risk of gastroduodenal ulcer and ulcer bleeding44,53. Of note, the risk of PUD when using these drugs is further increased in the presence of H. pylori infection55,56.

Despite changing trends in PUD worldwide, H. pylori remains the most preval‎ent cause of PUD. A study from Denmark showed an odds ratio of 4.3 (95% CI 2.2–8.3) for the association between H. pylori infection and PUD57. In a meta-analysis including endoscopic surveys and national screening programmes in unselected population samples from Europe and China, the pooled preval‎ence of PUD was 6.8% and PUD was associated with H. pylori infection in 91% of cases58. Around 3,000,000 diagnoses of PUD per year are estimated to relate to H. pylori infections and ~90% of patients with duodenal ulcers and 70–90% of patients with gastric ulcers have H. pylori infection with variation according to geographical areas52,53,58,59,60.

2000년대 이후 전 세계적으로 PUD의 유병률은 감소하고 있으며47 ,48,49,50 다양한 이유로 H. 파일로리 감염16 의 유병률 감소와 병행하여47 ,51,52,53,54. 역학적 추세는 위 십이지장 궤양 및 궤양 출혈의 위험을 독립적으로 증가시키는 아세틸 살리실산을 포함한 NSAID의 역할이 증가하고 있음을 나타냅니다44 ,53. 특히, 이러한 약물을 사용할 때 PUD의 위험은 H. 파일로리 감염이 있는 경우 더욱 증가합니다55,56.

전 세계적으로 PUD의 추세가 변화하고 있음에도 불구하고, H. 파일로리는 여전히 가장 흔한 PUD의 원인입니다. 덴마크의 한 연구에 따르면 H. 파일로리 감염과 PUD의 연관성에 대한 오즈비는 4.3 (95% CI 2.2-8.3)입니다57. 유럽과 중국에서 선별되지 않은 인구 표본을 대상으로 내시경 조사와 국가 검진 프로그램을 포함한 메타 분석에서 PUD의 전체 유병률은 6.8%였으며, 91%의 사례에서 PUD가 H. pylori 감염과 관련이 있었습니다58. 연간 약 3,000,000건의 PUD 진단이 H. pylori 감염과 관련된 것으로 추정되며 십이지장 궤양 환자의 약 90%, 위궤양 환자의 70~90%가 지역에 따라 차이는 있지만 H. pylori 감염을 가지고 있습니다52,53,58,59,60.

Gastric cancer

Around 90% of gastric cancer cases can be attributed to H. pylori infection61. In 2018, 812,000 gastric cancers, including non-Hodgkin lymphoma of gastric location, were recorded, accounting for ~37% of all cancers driven by a chronic infection, which makes H. pylori the most frequent carcinogenic pathogen62. Gastric cancer incidence and mortality differ significantly between regions, with the highest rates in Asia and Eastern Europe. The lifetime risk of gastric cancer is 1–5% in individuals with H. pylori infection, depending on ethnicity and environmental factors2,17,63. Some populations are at an increased risk of gastric cancer following H. pylori infection, probably due to genetic factors, housing situation and dietary habits, for example, increased consumption of salted or pickled foods in East Asian populations. In addition, substantially higher gastric cancer incidence is found in indigenous populations worldwide64 and in ethnic groups in the USA, including Asian Americans65. Socioeconomic, dietary and lifestyle factors, such as smoking and extent of salt intake, are contributing factors to gastric cancer development, but they are all subordinate to the presence of H. pylori infection66,67.

위암

위암의 약 90%는

H. 파일로리 감염이 원인입니다61.

2018년에는 위 위치에 발생한 비호지킨 림프종을 포함한 812,000건의 위암이 기록되었으며, 이는 만성 감염으로 인한 전체 암의 약 37%를 차지하여 가장 흔한 발암성 병원체62 로서 H. 파일로리균은 가장 흔한 발암성 병원체입니다.

위암 발생률과 사망률은 지역별로 큰 차이를 보이며 아시아와 동유럽에서 가장 높습니다. 위암의 평생 위험은 인종과 환경적 요인에 따라 H. 파일로리 감염자의 경우 1-5%입니다2,17,63. 일부 인구는 유전적 요인, 주거 환경, 식습관(예: 동아시아 인구의 소금에 절인 음식 또는 절인 식품 섭취 증가)으로 인해 H. 파일로리 감염 후 위암 위험이 증가합니다. 또한 전 세계 원주민 인구64 와 아시아계 미국인을 포함한 미국 내 소수 민족 집단에서 위암 발병률이 상당히 높은 것으로 나타났습니다65. 흡연 및 소금 섭취량과 같은 사회경제적, 식이 및 생활습관 요인도 위암 발병의 원인이지만, 모두 H. 파일로리 감염의 존재에 종속됩니다66,67.

Extra-gastric diseases

Unexplained iron-deficiency anaemia, vitamin B12 deficiency and some cases of idiopathic thrombocytopenic purpura can be related to H. pylori infection68,69. Antigen mimicry-induced autoimmunity related to H. pylori has been suggested in idiopathic thrombocytopenic purpura70,71. Furthermore, other associations of H. pylori infection with diseases localized outside the stomach have been reported, including cardiovascular diseases, ischaemic heart disease, metabolic syndrome, diabetes mellitus, hepatobiliary diseases, non-alcohol fatty liver disease and neurodegenerative diseases, which have been attributed to persistent and low-grade systemic inflammation72,73,74. Most of these associations are based on limited and inconsistent data and remain inconclusive, and only a few, mostly observational, studies have documented a significant decrease in some of these manifestations when H. pylori is eradicated73.

In children, particularly in the USA and Europe, an inverse association between H. pylori infection and asthma and allergy has been reported75,76,77, although this link has not been unequivocally confirmed78. The often reported inverse association between H. pylori infection and the risk of gastro-oesophageal reflux disease (GERD), Barrett oesophagus and oesophageal adenocarcinoma remains highly controversial79,80, and evidence for positive and negative associations exists79,80,81,82,83,84,85. Explanations for the discrepancies might lie in differing study protocols and H. pylori testing methodologies as well as in heterogeneity in the selection of patient and control populations. At present, the controversial findings and debates about a potential benefit of H. pylori for specific clinical scenarios have no confirmation nor impact on the management of the infection86.

위 외 질환

설명할 수 없는

철분 결핍성 빈혈,

비타민 B12 결핍 및

특발성 혈소판 감소성 자반증의 일부 사례는

H. 파일로리 감염68,69 과 관련이 있을 수 있습니다.

특발성 혈소판 감소성 자반증에서는

H. 파일로리와 관련된 항원 모방에 의한

자가 면역이 제안되었습니다70,71.

또한 심혈관 질환, 허혈성 심장 질환, 대사 증후군, 당뇨병, 간 담도 질환, 비 알코올성 지방간 질환 및 신경 퇴행성 질환을 포함하여 지속적이고 낮은 등급의 전신 염증72,73,74 을 포함하여 위 외부에 국한된 질병과 H. pylori 감염의 다른 연관성이보고되었습니다.

이러한 연관성의 대부분은 제한적이고 일관되지 않은 데이터에 근거하고 있으며 아직 결정적이지 않으며, 대부분 관찰 연구인 몇몇 연구들만이 H. 파일로리를 박멸했을 때 이러한 증상 중 일부가 현저히 감소한다는 사실을 입증했습니다73.

특히 미국과 유럽에서 소아에서

H. 파일로리 감염과 천식 및 알레르기 사이의 역 연관성이 보고되었지만75,76,77,

이 연관성이 명확하게 확인되지는 않았습니다78.

위식도 역류 질환(GERD),

바렛 식도 및 식도 선암의 위험과 H. 파일로리 감염 사이의 역관계에 대해서는

여전히 논란이 많으며79,80,

양성 및 음성 연관성에 대한 증거가 존재합니다79,80,81,82,83,84,85.

이러한 불일치에 대한 설명은 서로 다른 연구 프로토콜과 H 파일로리 검사 방법론, 그리고 환자 및 대조군 선정의 이질성에서 찾을 수 있습니다. 현재 특정 임상 시나리오에 대한 헬리코박터 파일로리의 잠재적 이점에 대한 논란의 여지가 있는 연구 결과와 논쟁은 감염 관리에 대한 확인이나 영향을 미치지 않습니다86 .

Mechanisms/pathophysiology

H. pylori microbiology

H. pylori is Gram-negative, microaerophilic curved or S-shaped bacteria that are highly motile due to a unipolar bundle of sheathed flagella. The cell envelope has a characteristic Gram-negative structure, but many other components have unique features adapted to the habitat of H. pylori in the human stomach2. In comparison with many other pathogenic bacteria, H. pylori has a small ~1.6-Mbp genome consisting of a single circular chromosome that encodes ~1,600 proteins87,88. The H. pylori core genome consists of ~1,100 genes present in all H. pylori strains, whereas the remaining accessory part of the genome comprises genes variably found in strain subsets89, for example, a large number of diverse restriction–modification systems (genetic elements that provide protection against foreign DNA), providing variable DNA methylation90. Extensive variation of genome content and gene sequences between strains, and even within the bacteria present in the stomach of one individual39,91,92, is a prominent characteristic of H. pylori and results from the unusual combination of very high mutation and recombination rates93. H. pylori has a high mutation frequency due to lack of a classical mismatch repair pathway in combination with the pro-mutagenic properties of its DNA polymerase I94,95. H. pylori is naturally competent and can take up DNA by means of the unique ComB DNA uptake system with similarities to a type IV secretion system (T4SS)96,97.

DNA sequence diversity can rapidly spread through H. pylori populations due to recombination between strains98,99. After import, DNA can be integrated into the chromosome based on homology, and such chromosomal imports have a unique bimodal length distribution, enabling H. pylori to adapt its genome to new environments in an extremely efficient way100.

H. pylori strains show a characteristic population structure that reflects their coevolution with their human hosts and has led to conclusions about the history of its association with humans101,102,103. H. pylori was acquired by modern humans in Africa at least ~100,000 years ago, possibly by a host jump from an unknown animal source. The most ancestral phylogeographic population of H. pylori is hpAfrica2, mostly found in Southern Africa. Further important, widespread and more recently evolved populations include hpAfrica1, hpNEAfrica, hpEurope, hpEastAsia, hpAsia2 and hpSahul104,105. A major step in the evolution of H. pylori from the ancestral hpAfrica2 population to the populations that have spread over the globe was the acquisition of the cag pathogenicity island (cagPAI) by ancestral H. pylori from an unknown source. cagPAI encodes components of the Cag T4SS106,107, which is a protein complex that spans the bacterial cell envelope and can directly deliver diverse effector molecules into host cells following adherence. Hence, whether strains possess an active Cag T4SS has substantial effects on their interaction with hosts. cagPAI-positive strains elicit far more inflammation than cagPAI-negative strains.

Bacterial factors involved in colonization and pathogenesis

H. pylori is highly adapted to the colonization of a unique ecological niche in the deep gastric mucus layer. Several mechanisms, including motility, urease production, adhesion and others, are important in H. pylori colonization (Box 1).

메커니즘/병태생리학

H. 파일로리 미생물학

H. 파일로리는

그람 음성, 미호기성 곡선형 또는 S형 박테리아로, 편모의 단극 다발로 인해

운동성이 매우 뛰어납니다.

세포 외피는

특징적인 그람 음성 구조를 가지고 있지만,

다른 많은 구성 요소는 사람의 위장에 서식하는

H. 파일로리의 서식 환경에 적합한 독특한 특징을 가지고 있습니다2.

다른 많은 병원성 박테리아와 비교할 때,

H. 파일로리는 약 1,600개의 단백질을 암호화하는 단일 원형 염색체로 구성된

약 1.6-Mbp의 작은 게놈을 가지고 있습니다87,88.

H. 파일로리 핵심 게놈은 모든 H. 파일로리 균주에 존재하는 ~1,100개의 유전자로 구성되어 있는 반면, 게놈의 나머지 보조 부분은 균주 하위 집합에서 다양하게 발견되는 유전자로 구성되어 있습니다89, 예를 들어 다양한 제한-수정 시스템(외부 DNA로부터 보호하는 유전적 요소)으로 다양한 DNA 메틸화를 제공합니다90. 균주 간, 심지어 한 개인의 위장에 존재하는 박테리아 내에서도 게놈 함량과 유전자 서열의 광범위한 변화39,91,92 는 H. 파일로리의 두드러진 특징이며 매우 높은 돌연변이 및 재조합률93 의 특이한 조합으로 인한 결과입니다. H. 파일로리는 DNA 중합효소 I94,95 의 친 돌연변이 유발 특성과 함께 고전적인 불일치 복구 경로가 없기 때문에 돌연변이 빈도가 높습니다. H. 파일로리는 자연적으로 유능하며, 4형 분비 시스템(T4SS)96,97 과 유사한 독특한 ComB DNA 흡수 시스템을 통해 DNA를 흡수할 수 있습니다.

DNA 서열 다양성은 균주 간의 재조합으로 인해 H. 파일로리 집단에 빠르게 확산될 수 있습니다98,99. 수입 후 DNA는 상동성을 기반으로 염색체에 통합될 수 있으며, 이러한 염색체 수입은 독특한 바이모달 길이 분포를 가지므로 H. 파일로리가 매우 효율적인 방식으로 새로운 환경에 게놈을 적응시킬 수 있습니다100.

H. 파일로리 균주는 인간 숙주와의 공진화를 반영하는 특징적인 개체군 구조를 보여 인간과의 연관 역사에 대한 결론을 이끌어냈습니다101,102,103. H. 파일로리는 적어도 약 10만 년 전에 아프리카에서 현대 인류가 미지의 동물로부터 숙주 이동을 통해 획득했을 가능성이 높습니다. H. 파일로리의 가장 조상적인 계통지리학적 집단은 대부분 남아프리카에서 발견되는 hp아프리카2입니다. 더 중요하고 광범위하며 최근에 진화한 개체군으로는 hp아프리카1, hpNEAfrica, hp유럽, hp동아시아, hp아시아2 및 hp사훌104,105 이 있습니다. H. 파일로리가 조상 hpAfrica2 집단에서 전 세계로 퍼진 집단으로 진화하는 과정에서 중요한 단계는 조상 H. 파일로리가 알 수 없는 출처로부터 cag 병원성 섬(cagPAI)을 획득한 것입니다. cagPAI는 세균 세포 외피에 걸쳐 있고 부착 후 다양한 이펙터 분자를 숙주 세포로 직접 전달할 수 있는 단백질 복합체인 Cag T4SS106,107의 성분을 암호화합니다. 따라서 균주가 활성 Cag T4SS를 보유하고 있는지 여부는 숙주와의 상호 작용에 상당한 영향을 미치며, cagPAI 양성 균주는 cagPAI 음성 균주보다 훨씬 더 많은 염증을 유발합니다.

식민지화 및 발병에 관여하는 박테리아 인자

H. 파일로리는 깊은 위 점액층에 있는 독특한 생태적 틈새의 식민지화에 고도로 적응되어 있습니다. 운동성, 우레아제 생산, 접착력 등 여러 가지 메커니즘이 H. 파일로리 군집화에 중요합니다(상자 1).

Box 1 Bacterial, environmental and host factors contributing to H. pylori-induced gastric cancer pathogenesis

Bacterial virulence factors

• Cag type IV secretion system106,123,167

• vacA allelic genotypes linked to disease, for example, s1/m1/i1 alleles139,165

• Adhesins, for example, BabA, SabA and HopQ118,119,120

Environmental factors

• Smoking

• Dietary factors (low iron, high salt, and/or low fresh fruit and vegetable intake)167,383

Host genetic factors

• Single-nucleotide polymorphisms in cytokine and growth factor genes encoding proteins that have been implicated in pathogenesis (IL-1β, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A/B, IFNγ, TNF, TGFβ) and their receptors (IL-RN, TGFR), innate immune receptors shown to be activated by Helicobacter pylori (TLR2, TLR4, CD14, NOD1, NOD2), enzymes involved in signal transduction cascades (PLCE1, PKLR, PRKAA1), glycoproteins (MUC1, PSCA) and DNA repair enzymes (ERCC2, XRCC1, XRCC3)29,387

Gastric inflammatory phenotypes and associated gastric functions165,166,167

• Corpus-predominant gastritis

• Atrophic gastritis (Operative Link on Gastritis Assessment (OLGA) III–IV)

• Hypochlorhydria

• High gastrin levels

• Low pepsinogen I levels and ratio of pepsinogen I to pepsinogen II

Gastric dysbiosis of microbes other than H. pylori160,364,384

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Motility

Flagella-driven motility is essential for the entry of H. pylori into the mucus layer and for maintaining a swimming reservoir in the mucus108 (Fig. 3). H. pylori has a unipolar bundle of rotating sheathed flagella, with filaments composed of two flagellin proteins109 that evade activating the innate immune system via TLR5 due to specific adaptation of their amino acid sequences110,111. The direction of movement is controlled by chemotaxis and energy taxis, enabling bacteria orientation through pH and bicarbonate (and possibly other) gradients in the gastric mucus112. Motility can be inhibited in vitro by small molecule compounds that reduce H. pylori colonization density, which may be a future treatment approach113.

운동성

편모에 의한 운동성은 H. 파일로리가 점액층으로 진입하고 점액에 수영 저수지를 유지하는 데 필수적입니다108 (그림 3). H. 파일로리는 두 개의 편모 단백질109 로 구성된 필라멘트가 있는 회전하는 피복 편모의 단극 다발을 가지고 있으며, 아미노산 서열의 특정 적응으로 인해 TLR5 를 통한 선천 면역 체계의 활성화를 회피합니다110 ,111. 이동 방향은 케모택시 및 에너지 택시에 의해 제어되어 위 점액의 pH 및 중탄산염(및 기타) 구배를 통해 박테리아가 방향을 잡을 수 있게 합니다112. 운동성은 저분자 화합물에 의해 시험관 내에서 억제될 수 있으며, 이는 향후 치료 접근법이 될 수 있습니다113.

Fig. 3: H. pylori infection and pathogenesis.

Key aspects of bacterial colonization involve flagellar motility, urease activity, mechanisms of adhesion and damage to the gastric epithelium via vacuolization. The Helicobacter pylori pathogenicity island exerts a key role in inflammation, composes a type IV secretory system (T4SS) and promotes the intracellular injection of cytotoxin-associated gene A (CagA) antigen. The host immune response is characterized by initial mucosal invasion with polymorphonuclear cells followed by activation of the innate and adaptive immune system with complex T helper 1 (TH1), TH17 and regulatory T (Treg) cell interactions. Leb, Lewis b blood group antigen; sLex, sialyl-Lewis x antigen.

박테리아 군집화의 주요 측면에는 편모 운동성, 우레아제 활성, 부착 메커니즘 및 진공화를 통한 위 상피 손상 등이 포함됩니다. 헬리코박터 파일로리 병원성 섬은 염증에서 핵심적인 역할을 하며, IV형 분비 시스템(T4SS)을 구성하고 세포독소 관련 유전자 A(CagA) 항원의 세포 내 주입을 촉진합니다. 숙주 면역 반응은 다형 핵 세포를 통한 초기 점막 침입에 이어 복잡한 T 헬퍼 1(TH1), TH17 및 조절 T(Treg) 세포 상호 작용을 통한 선천성 및 적응성 면역 체계의 활성화가 특징입니다. Leb, 루이스 b 혈액형 항원; sLex, 시알릴-루이스 x 항원.

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Urease

H. pylori produces abundant amounts of urease, aided by a unique system of accessory proteins that procure the required nickel, which is essential for urease holoenzyme activity, protects the bacterium from nickel toxicity and regulates urease activity by controlling urea influx into bacterial cells114,115. Urease is essential for colonization, most likely because the enzyme, by cleaving urea into ammonia and carbon dioxide, enables the bacteria to survive brief periods of exposure to very low pH values, which H. pylori may encounter in the gastric lumen during transmission116. Through urease activity, urea provides an always available nitrogen source for the organism.

우레아제

H. 파일로리는

우레아제 홀로효소 활동에 필수적인 니켈을 조달하는 독특한 보조 단백질 시스템의 도움으로

다량의 우레아제를 생산하며,

니켈 독성으로부터 박테리아를 보호하고

박테리아 세포로의 요소 유입을 조절하여 우레아제 활동을 조절합니다114,115.

요소 분해 효소는

요소를 암모니아와 이산화탄소로 분해하여

박테리아가 매우 낮은 pH 값에 단기간 노출되어도 생존할 수 있게 해 주는데,

이는 이 효소가 H. 파일로리가 전파되는 동안 위 내강에서 발생할 수 있는

매우 낮은 pH 값에 박테리아가 단기간 생존할 수 있게 해 주기 때문입니다116.

요소분해효소 활동을 통해 요소는

유기체가 항상 사용할 수 있는

질소 공급원을 제공합니다.

Adhesion

H. pylori can adhere to gastric epithelial cells by attaching surface molecules that are anchored on its outer membrane (adhesins) to host cell receptors. Adherence enables H. pylori to achieve high colonization despite epithelial cell shedding, mucus layer turnover and the physical force involved in gastric emptying, all of which act to reduce colonization117. The best-studied adhesins are encoded by members of the large hop superfamily of outer membrane protein-encoding genes. BabA mediates binding to Lewis b blood group antigens that are expressed on gastric epithelial cells118. The related SabA adhesin binds to host sialyl-Lewis x antigens, which are mainly expressed on epithelial cell surfaces under inflammatory conditions119. HopQ binds to multiple carcinoembryonic antigen-related cell adhesion molecules and seems to be important for Cag T4SS functionality120,121. AlpA and AlpB mediate binding to the extracellular matrix glycoprotein laminin122. Expression‎ of adhesins varies widely between strains; the contribution of individual adhesins to bacteria–cell adherence and to pathogenesis continues to be studied.

접착력

H. 파일로리는

외막에 고정된 표면 분자(아데신)를 숙주 세포 수용체에 부착하여

위 상피 세포에 달라붙을 수 있습니다.

이러한 부착은

상피 세포의 탈락,

점액층의 회전율,

위 배출에 관여하는 물리적 힘에도 불구하고

H. 파일로리가 높은 식민지화를 달성할 수 있게 하며,

이 모든 것이 식민지화를 감소시키는 역할을 합니다117.

가장 많이 연구된 접착제는 외막 단백질 인코딩 유전자의 큰 홉 수퍼패밀리의 구성원에 의해 코딩됩니다. BabA는 위 상피 세포에서 발현되는 루이스 b 혈액형 항원과의 결합을 매개합니다118. 관련 SabA 접착신은 염증 조건에서 주로 상피 세포 표면에서 발현되는 숙주 시알릴-루이스 x 항원에 결합합니다119. HopQ는 여러 암배아 항원 관련 세포 부착 분자에 결합하며, Cag T4SS 기능에 중요한 것으로 보입니다120,121. AlpA와 AlpB는 세포외 기질 당단백질 라미닌과의 결합을 매개합니다122. 아데신의 발현은 균주마다 매우 다양하며, 박테리아-세포 부착과 발병에 대한 개별 아데신의 기여는 계속 연구되고 있습니다.

cagPAI and its translocated effectors

The ~37-kb cagPAI106 comprises ~26 genes that encode the elements of T4SS107. After cagPAI-carrying H. pylori attaches to a host cell, T4SS can translocate bacterial effector molecules into the host cell cytoplasm123, including the CagA protein, which is also encoded by the cagPAI. In addition, several other molecules can be translocated via T4SS, including heptose-containing lipopolysaccharide core precursors124,125, peptidoglycan fragments126 and bacterial DNA127. These molecules can interact with intracellular target molecules and profoundly affect intracellular signalling and cell function (Fig. 3).

After translocation, CagA undergoes tyrosine phosphorylation by cellular kinases128. The phosphorylated form can interact with multiple target molecules in the host cell, including SHP2 (ref. 129), PAR1 (refs. 130,131) and ASPP2 (ref. 132), contributing to increased cell motility, reduced cellular tight junctions, genome instability, nucleotide damage and activation of the Wnt signalling pathway that is relevant in local neoplasia formation133. Translocation of heptose-containing lipopolysaccharide core intermediates may be important in inducing pro-inflammatory responses by both epithelial and immune cells through the ALPK1–TIFA signalling pathway and may also induce mutagenic and oncogenic processes134,135,136. In addition, intracellular heptose signalling in macrophages may hamper antigen-presenting properties and subsequent T cell responses136.

Vacuolating cytotoxin

Many H. pylori strains secrete vacuolating cytotoxin A (VacA), which is an oligomeric autotransporter protein toxin that can form anion-selective membrane channels137. The effects of VacA on cells include induction of large intracellular vacuoles derived from late endosomes, induction of apoptotic cell death (following mitochondrial membrane perturbation) or necrosis, induction of autophagy, and inhibition of T cell and B cell proliferation and effects on other immune cells138,139,140. Together, these effects downregulate immune responses to H. pylori infection and promote host tolerance to the organism. Expression‎ of VacA is not essential for colonization, and its contribution to illness remains controversial.

cagPAI와 그 전위 이펙터

37kb의 cagPAI106 은 T4SS107 의 요소를 암호화하는 약 26개의 유전자로 구성되어 있습니다. cagPAI를 운반하는 H. 파일로리가 숙주 세포에 부착한 후, T4SS는 박테리아 이펙터 분자를 숙주 세포질123 로 전위시킬 수 있으며, 여기에는 cagPAI로 코딩되는 CagA 단백질도 포함됩니다. 또한 헵토스 함유 지다당류 코어 전구체124,125, 펩티도글리칸 조각126 및 박테리아 DNA127 등 여러 다른 분자가 T4SS를 통해 전위될 수 있습니다. 이러한 분자들은 세포 내 표적 분자와 상호 작용하여 세포 내 신호 및 세포 기능에 큰 영향을 미칠 수 있습니다(그림 3).

전위 후 CagA는 세포 키나아제에 의해 티로신 인산화를 거칩니다128. 인산화 된 형태는 SHP2 (참조 129), PAR1 (참조 130,131) 및 ASPP2 (참조 132)를 포함하여 숙주 세포의 여러 표적 분자와 상호 작용하여 세포 운동성 증가, 세포 긴밀한 접합 감소, 게놈 불안정성, 뉴클레오티드 손상 및 국소 신 생물 형성과 관련된 Wnt 신호 경로의 활성화에 기여할 수 있습니다133. 헵토스 함유 지다당류 핵심 중간체의 전위는 ALPK1-TIFA 신호 경로를 통해 상피세포와 면역세포 모두에 의한 전 염증 반응을 유도하는 데 중요할 수 있으며 돌연변이 유발 및 발암 과정을 유도할 수도 있습니다134 ,135,136. 또한 대식세포의 세포 내 헵토스 신호는 항원 제시 특성 및 후속 T 세포 반응을 방해할 수 있습니다136 .

세포 독소 제거

많은 H. 파일로리 균주는 음이온 선택적 막 채널을 형성할 수 있는 올리고머 자가 수송체 단백질 독소인 백신화 세포독소 A(VacA)를 분비합니다137 . VacA가 세포에 미치는 영향에는 후기 엔도솜에서 유래한 대형 세포 내 액포 유도, 미토콘드리아 막 교란에 따른 세포 사멸 또는 괴사 유도, 자가포식 유도, T 세포 및 B 세포 증식 억제 및 다른 면역 세포에 대한 영향138,139,140 이 포함됩니다. 이러한 효과를 종합하면, 이러한 효과는 H. 파일로리 감염에 대한 면역 반응을 하향 조절하고 유기체에 대한 숙주 내성을 촉진합니다. VacA의 발현은 식민지화에 필수적인 것은 아니며, 질병에 대한 기여도는 여전히 논란의 여지가 있습니다.

Immune responses to H. pyloriInnate immune evasion

The flagellins and lipopolysaccharides of H. pylori have evolved substantially differently from those of other Gram-negative bacteria and are largely not recognized by the human pattern recognition receptors TLR5 and TLR4, which signal danger to the host110,111. These and other structural variations may contribute to immune evasion by H. pylori and its success as a persistent colonizer.

Innate immune activation

Contact between H. pylori and gastric epithelial and myeloid cells induces signalling through multiple innate pathways, leading to changes in cellular homeostasis and the release of cytokines and chemokines that trigger local and systemic inflammatory responses141,142,143. As canonical TLR4-dependent and TLR5-dependent signalling is evaded, most inflammatory signalling depends on the activity of an intact cagPAI144. The bacterial components transported into epithelial cells through T4SS engage multiple intracellular receptors. Many of the affected pathways converge on the activation of nuclear factor (NF)-κB, which leads to increased expression‎ and release of IL-8 and other chemokines and cytokines145,146,147. IL-8 is a powerful attractant of neutrophils, which enter the gastric mucosa and are the defining element of the active component of chronic–active gastritis, the histological hallmark of H. pylori presence in the stomach148,149. Monocytes, macrophages and dendritic cells are also attracted to the H. pylori-colonized mucosa. Activation of phagocytic monocytes and macrophages seems to strongly depend on the delivery of heptose-containing lipopolysaccharide core intermediates via T4SS and the resulting signalling to the ALPK1–TIFA axis135. Dendritic cells can be reprogrammed by contact with the bacteria, for example, to produce IL-18, which drives the conversion of T cells to regulatory T (Treg) cells, suppressing immune activation150.

H. 파일로리에대한 면역 반응 선천성 면역 회피

H. 파일로리의 편모와 지다당류는 다른 그람 음성 박테리아와는 상당히 다르게 진화했으며, 숙주에게 위험을 알리는 인간 패턴 인식 수용체인 TLR5 및 TLR4에 의해 대부분 인식되지 않습니다110,111. 이러한 구조적 변이와 다른 구조적 변이는 H. 파일로리의 면역 회피와 지속적인 식민지화 성공에 기여할 수 있습니다.

선천성 면역 활성화

H. 파일로리와 위 상피 및 골수 세포 사이의 접촉은 여러 선천적 경로를 통해 신호를 유도하여 세포 항상성의 변화와 국소 및 전신 염증 반응을 유발하는 사이토카인 및 케모카인의 방출로 이어집니다141 ,142,143. 일반적인 TLR4 의존성 및 TLR5 의존성 신호는 회피되기 때문에 대부분의 염증 신호는 온전한 cagPAI의 활성에 의존합니다144 . T4SS를 통해 상피 세포로 운반된 박테리아 성분은 여러 세포 내 수용체와 결합합니다. 영향을 받는 많은 경로가 핵 인자(NF)-κB의 활성화로 수렴되어 IL-8 및 기타 케모카인과 사이토카인의 발현과 방출이 증가합니다145,146,147. IL-8은 위 점막으로 들어가는 호중구의 강력한 유인 물질이며, 위장에 존재하는 H. pylori의 조직학적 특징인 만성 활동성 위염의 활성 성분의 결정적인 요소입니다148,149. 단핵구, 대식세포 및 수지상 세포도 H. 파일로리 군집 점막에 끌립니다. 식세포 단핵구와 대식세포의 활성화는 T4SS를 통한 헵토스 함유 지다당류 코어 중간체의 전달과 그에 따른 ALPK1-TIFA 축으로의 신호 전달에 크게 의존하는 것으로 보입니다135. 예를 들어, 수지상 세포는 박테리아와의 접촉에 의해 재프로그래밍되어 IL-18을 생성하여 T 세포를 조절 T(Treg) 세포로 전환하여 면역 활성화를 억제할 수 있습니다150 .

Adaptive immune response

H. pylori invariably elicits a combined adaptive humoral and cellular immune response that is generally incapable of eradicating the bacteria. Colonization leads to formation of antibodies to many H. pylori antigens that have little effect on bacterial numbers151. In agreement with this apparent lack of a role of antibodies in protection against H. pylori, mice lacking antibody production can be successfully immunized against H. pylori152. H. pylori also induces the recruitment of T cells to the human gastric mucosa, including T helper 1 (TH1), TH17 and Treg cells. Experimental vaccination in mouse models suggests that both TH1 cells and TH17 cells can be important in mediating protection against H. pylori infection153. Furthermore, in mouse models, a protective effect of very early (neonatal) H. pylori infection against asthma was mediated by Treg cells accumulating in the lungs150,154,155, consistent with the hypothesis that H. pylori may downregulate systemic allergic responses through its recruitment of immunosuppressive Treg cells to the gastric mucosa and, potentially, other body sites such as the lung.

적응성 면역 반응

H. 파일로리는 일반적으로 박테리아를 박멸할 수 없는 적응성 체액성 및 세포성 면역 반응을 항상 유도합니다. 식민지화는 박테리아 수에 거의 영향을 미치지 않는 많은 H. 파일로리 항원에 대한 항체를 형성하게 합니다151. 항체가 헬리코박터 파일로리균에 대한 보호에 중요한 역할을 하지 않는다는 사실과 일치하여 항체 생산이 부족한 생쥐는 헬리코박터 파일로리균에 대한 면역에 성공할 수있습니다152. 또한, 헬리코박터파일로리는 T 헬퍼 1(TH1), TH17 및 Treg 세포를 포함하여 인간 위 점막에 T 세포의 모집을 유도합니다. 마우스 모델에서의 실험적 백신 접종에 따르면 TH1 세포와 TH17 세포 모두 H. 파일로리 감염에 대한 보호를 매개하는 데 중요할 수 있습니다153. 또한, 마우스 모델에서 천식에 대한 매우 초기(신생아기) H. 파일로리 감염의 보호 효과는 폐에 축적된 Treg 세포에 의해 매개되었으며150,154,155 이는 H. 파일로리가 위 점막과 잠재적으로 폐와 같은 다른 신체 부위에 면역 억제 Treg 세포를 모집함으로써 전신 알레르기 반응을 하향 조절할 수 있다는 가설과 일치합니다.

From chronic H. pylori colonization to illness

H. pylori colonization of the gastric mucosa induces a pro-inflammatory response of gastric epithelial cells, which recruits diverse immune cells to the submucosa156. The resulting condition is chronic–active gastritis, which is predominantly asymptomatic for decades of colonization in most patients. The severity of inflammation varies widely between individuals, depending on bacterial, host and environmental factors157 (Box 1).

The single most important determinant of the pro-inflammatory activity of an H. pylori strain is its possession of a functional cagPAI158. Expression‎ of additional host-interaction factors, such as a portfolio of adhesins that fits the variable host receptor makeup and promotes strong binding to epithelial cells and, therefore, promotes crosstalk between the bacterium and the host cell, contributes to the response that a strain elicits in an individual host. Tolerogenic signalling contributes to the unusual accumulation and proliferation of gastric mucosa-associated lymphoid tissue. The decades-long inflammation in the gastric mucosa is thought to be an important driving force leading to gastric atrophy and, ultimately, gastric cancer as outlined by the Correa cascade159 (Fig. 4). The Correa cascade describes a multistage, multifactorial process starting with superficial gastritis, progressing to atrophic gastritis, intestinal metaplasia and dysplasia, and culminating in gastric adenocarcinoma. A key emerging concept is that chronic inflammation, gastric atrophy and consequent achlorhydria lead to an aberrant and dysbiotic gastric microbiome that drives the process towards gastric neoplasia160,161,162. Accumulating evidence suggests that, following H. pylori eradication, newly emerging components of the gastric microbiota might be involved in the oncogenic transformation of gastric epithelial cells160,163. In other individuals, peptic ulcer disease or the rare H. pylori-associated MALT lymphoma can develop4,5,14,164. The reasons why most individuals remain apparently asymptomatic throughout their lifetime, whereas others proceed to clinical sequelae of varying severity, remain to be fully elucidated. Clinically useful, early bacterial predictive markers that could inform the decision to prescribe eradication therapy have not been identified.

만성 헬리코박터 파일로리 군집화에서 질병까지

위 점막의H. 파일로리 군집화는 위 상피 세포의 전염증 반응을 유도하여 다양한 면역 세포를 점막하층으로 모집합니다156. 그 결과 만성 활동성 위염이 발생하며, 대부분의 환자에서 수십 년 동안 주로 무증상인 경우가 많습니다. 염증의 정도는 박테리아, 숙주 및 환경 요인에 따라 개인마다 매우 다양합니다157 (상자 1).

H. 파일로리 균주의 전 염증성 활성을 결정하는 가장 중요한 단일 요인은 기능성 캐그PAI의 보유 여부입니다158. 다양한 숙주 수용체 구성에 적합하고 상피 세포에 대한 강력한 결합을 촉진하여 박테리아와 숙주 세포 간의 혼선을 촉진하는 아데신 포트폴리오와 같은 추가적인 숙주 상호작용 인자의 발현은 균주가 개별 숙주에서 유발하는 반응에 기여합니다. 내관성 신호는 위 점막 관련 림프 조직의 비정상적인 축적과 증식에 기여합니다. 위 점막에 수십 년 동안 지속되는 염증은 코레아 캐스케이드159에 설명된 대로 위 위축과 궁극적으로 위암으로 이어지는 중요한 원동력으로 생각됩니다(그림 4). 코레아 캐스케이드는 표재성 위염에서 시작하여 위축성 위염, 장의 전이 및 이형성으로 진행되고 위 선암으로 절정에 이르는 다단계의 다인자 과정을 설명합니다. 새롭게 떠오르는 핵심 개념은 만성 염증, 위 위축 및 그에 따른 무염수증이 비정상적이고 불균형적인 위 미생물을 유발하여 위 신생물을 향한 과정을 촉진한다는 것입니다160 ,161,162. 축적된 증거에 따르면, 헬리코박터 파일로리 제균 후 새롭게 등장하는 위 미생물총의 성분이 위 상피 세포의 발암성 변형에 관여할 수 있습니다160,163. 다른 사람에게는 소화성 궤양 질환이나 희귀한 H. pylori 관련 MALT 림프종이 발생할 수 있습니다4,5,14,164. 대부분의 사람들이 평생 동안 증상이 없는 반면, 다른 사람들은 다양한 중증도의 임상적 후유증으로 진행되는 이유는 아직 완전히 밝혀지지 않았습니다. 박멸 요법 처방 결정에 정보를 제공할 수 있는 임상적으로 유용한 초기 박테리아 예측 마커는 아직 밝혀지지 않았습니다.

Fig. 4: Pathogenesis of gastric adenocarcinoma triggered by H. pylori.

The Correa cascade describes the dynamic progress of gastric carcinogenesis along the stepwise evolution of chronic gastritis initiated by Helicobacter pylori infection. H. pylori causes chronic gastritis that is associated with the generation of reactive oxygen species and nitric oxide metabolites and a reduction in antioxidant vitamin C levels. The risk of gastric cancer is highest in individuals who have infection by more virulent H. pylori strains, have pro-inflammatory host genetic factors, poor diet (high salt, smoked foods), low iron levels, unhealthy lifestyle and/or smoking habit. In these individuals, sustained chronic inflammation leads to damage and loss of acid-producing parietal cells, which leads to hypochlorhydria and finally achlorhydria. The loss of acidity facilitates colonization by harmful pro-inflammatory gastric microbiota, which in turn may produce more genotoxic pro-inflammatory metabolites and carcinogens that act directly on malignant epithelial cell transformation in the stomach384,385,386.

코레아 캐스케이드는 헬리코박터 파일로리 감염으로 시작된 만성 위염의 단계적 진화에 따른 위 발암의 역동적 진행을 설명합니다. 헬리코박터 파일로리는 활성 산소종 및 산화질소 대사 산물의 생성 및 항산화 비타민 C 수치의 감소와 관련된 만성 위염을 유발합니다. 위암의 위험은 더 독성이 강한 H. 파일로리 균주에 감염되었거나, 염증성 숙주의 유전적 요인, 열악한 식단(고염식, 훈제 식품), 낮은 철분 수치, 건강에 해로운 생활 습관 및/또는 흡연 습관을 가진 사람에게서 가장 높습니다. 이러한 사람의 경우 만성 염증이 지속되면 산을 생성하는 정수리 세포가 손상되고 손실되어 저염수증과 최종적으로 무염수증으로 이어집니다. 산성도의 손실은 유해한 염증성 위 미생물에 의한 식민지화를 촉진하고, 이는 다시 위장의 악성 상피 세포 변형에 직접 작용하는 유전 독성 염증성 대사산물과 발암 물질을 더 많이 생성할 수 있습니다384,385,386.

Full size image

It is now well established that the clinical outcome of H. pylori infection depends largely on the distribution and severity of H. pylori-induced gastritis165 (Table 1). Thus, peptic ulcers are more likely in individuals with an antral-predominant pattern of gastritis characterized by high acid secretion and relative sparing of gastric corpus with its high parietal cell mass. Parietal cells secrete gastric acid and patients with peptic ulcers have a higher parietal cell mass than healthy individuals without ulcers. By contrast, gastric cancer develops in the context of corpus-predominant gastritis, gastric atrophy and a profound loss of acid secretory capacity that precedes cancer by decades166. The chronically inflamed and achlorhydric environment is further exacerbated by an aberrant pro-inflammatory and genotoxic gastric microbiota that drives the neoplastic process even after loss of H. pylori infection160,161,167. Indeed, experimental work suggests that transplantation of the gastric microbiota from humans with intestinal metaplasia or gastric cancer into germ-free mice leads to the development of precancerous gastric changes168.

H. 파일로리 감염의 임상적 결과는 H. 파일로리 유발 위염의 분포와 중증도에 따라 크게 달라진다는 것은 이제 잘 알려져 있습니다165 (표 1). 따라서 소화성 궤양은 위산 분비가 많고 정수리 세포 덩어리가 많은 위 체부가 상대적으로 보존되어 있는 전위 우세형 위염 패턴을 가진 사람에게서 더 잘 발생합니다. 정수리 세포는 위산을 분비하며 소화성 궤양 환자는 궤양이 없는 건강한 사람보다 정수리 세포 질량이 더 높습니다. 대조적으로 위암은 수십 년 전에 위염, 위 위축 및 위산 분비 능력의 심각한 손실이 있는 상태에서 암이 발생합니다166. 만성 염증 및 무산성 환경은 비정상적인 전 염증성 및 유전 독성 위 미생물에 의해 더욱 악화되어 H. 파일로리 감염 손실 후에도 종양 과정을 주도합니다160 ,161,167. 실제로 실험 연구에 따르면 장상피화생이나 위암이 있는 사람의 위 미생물을 세균이 없는 생쥐에 이식하면 전암성 위 변화가 발생한다고 합니다168.

Diagnosis, screening and prevention

DiagnosisPresentation

In daily routine, acute infection with H. pylori remains mostly undiagnosed at any age. Naturally occurring acute infection in childhood is usually not captured and is supposed to frequently present with abdominal complaints with potentially diverse aetiologies169. In adults, the clinical presentation of acute infection can entail hypochlorhydria, epigastric pain and mild-to-moderate dyspeptic symptoms as described in case reports and from challenge studies in volunteers with H. pylori for vaccine development170,171,172. By contrast, most children with H. pylori infection remain asymptomatic and complications are infrequent173.

Once established, H. pylori infection is a persisting and not self-limiting condition in adults with the potential of severe complications in some individuals. PUD, gastric cancer and MALT lymphoma174, in decreasing order of incidence, are the most important complications in adults86.

Diagnostic tests

An accurate diagnosis of H. pylori infection is required before commencing treatment42,175. Diagnostic methods for H. pylori detection include invasive and non-invasive test procedures70,176,177,178,179,180,181 (Fig. 5) (Tables 2 and 3).

Fig. 5: H. pylori diagnostic procedures.

Diagnostic procedures are selected according to clinical scenarios. Non-invasive testing with the 13C-urea breath test and stool antigen test enables diagnosis of a current infection. Serological Helicobacter pylori antibody detection does not enable differentiation between current and previous H. pylori infection, necessitating confirmation by 13C-urea breath test or stool antigen test. All invasive tests are based on biopsy samples from gastroscopy. These enable histological assessment for gastritis grading and staging, direct H. pylori detection via PCR, microbial culture, rapid urease test, and molecular examinations. Antibiotic susceptibility testing (AST) can be performed from stool or biopsy samples using microbial culture, next-generation sequencing (NGS) or real-time PCR (RT-PCR) techniques. FISH, fluorescence in situ hybridization; qPCR, quantitative PCR.

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Table 2 Indications for H. pylori testing

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Table 3 Diagnostic methods for H. pylori detection

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Invasive tests require biopsy samples obtained during gastroduodenoscopy and include the rapid urease test (RUT), histological assessment, bacterial culture and direct detection of H. pylori genetic material using PCR, quantitative PCR or fluorescence in situ hybridization. Non-invasive methods include the 13C-urea breath test (UBT), serological detection for anti-H. pylori antibodies, the stool antigen test (SAT) and direct detection of H. pylori genetic material in stool via PCR179.

RUT is a low-cost test with a specificity of 95–100%. False positive results are rare and can be explained by the presence of other urease-positive organisms such as Proteus mirabilis179. Current use of a proton pump inhibitor (PPI) may lead to false negative results in RUT as well as in all other diagnostic tests except for serological assessment175. Thus, PPI therapy should be interrupted 14 days before testing42.

Histological assessment on formalin-embedded samples is made according to the updated Sydney system, which provides information on H. pylori presence via direct visualization and on the extent of active and chronic inflammation and atrophy148,149,182. The histochemical method for assessment of H. pylori gastritis relies on haematoxylin and eosin and Giemsa stains for detection of H. pylori148. Gastritis severity is defined by the degree and extension of atrophy and/or intestinal metaplasia. Severe gastric atrophy is associated with an increased risk of gastric cancer and risk is best determined by changes according to the gastritis severity staging systems Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastritis/Intestinal Metaplasia Assessment (OLGIM)183,184.

Culture of H. pylori is 100% specific but has a relatively low sensitivity (<80%) strongly dependent on transport media and logistics and laboratory proficiency owing to the required laboratory expertise with special culture media. Limitations include costs and time constraints but microbial culture also enables phenotypical antimicrobial susceptibility testing (AST)180.

Molecular testing from formalin-embedded biopsy or RUT samples with PCR methods, of which quantitative PCR is most appropriate, and fluorescence in situ hybridization is highly accurate in the detection of H. pylori185 and can also be combined with molecular resistance testing186.

Serological assessment of serum IgG levels is used as a screening test in specific clinical scenarios but it cannot distinguish active and previous infections because of the prolonged persistence of H. pylori antibodies. A positive serological test should be confirmed with a test that indicates active infection187. Serological testing is the only method not influenced by current PPI intake. Next-generation blood tests to be used for screening in the consulting room became available in 2022 (ref. 187).

UBT uses stable isotope-labelled 13C-urea ingested with citric acid, which is then hydrolysed by bacterial urease and releases carbon dioxide and ammonia. UBT has high sensitivity and specificity (95–100%)181. SAT has a similar diagnostic accuracy as UBT. SAT is an immunological method based on monoclonal antibodies with which H. pylori antigens can be detected in stool samples180. UBT, SAT and histological assessment are the commonly used tests in clinical practice for diagnosis of H. pylori as they enable the detection of active infection. However, the availability of these tests depends on the status of regional health-care services, which can directly affect treatment decisions175,179.

The increase of antibiotic resistance to H. pylori worldwide188,189 demands AST in the individual patient to enable effective therapy choices following failed eradication treatment and to monitor antimicrobial resistance at the regional community level42. AST can be performed using phenotypic and genotypic approaches. Culture-based phenotypic testing requires fresh biopsy samples, but PCR-based genotypic testing can be done on fresh, formalin-embedded or RUT samples as well as on stool samples186,190,191,192. Clarithromycin resistance should be excluded before its empirical use in regions with known clarithromycin resistance rates of >15% or unknown resistance rates42. Molecular genotypic testing enables the detection of resistance against frequently used antibiotics. Clarithromycin resistance conferred by mutations in the gene encoding 23S rRNA are predominantly related to A2143G, A2142G and A2142C193. Levofloxacin resistance is conferred by point mutations in the gyrase gene gyrA194,195. The accuracy of the molecular detection methods for predicting antibiotic resistance varies between antibiotics, favouring clarithromycin and quinolone resistance detection194,196. Formalin-embedded biopsy samples enable genotypical resistance testing at a later time point after endoscopy197,198,199,200.

Infections with Helicobacter species other than H. pylori are rare and those most relevant refer to Helicobacter heilmannii, Helicobacter felis and Helicobacter suis201,202,—203. Standard H. pylori diagnostic tests (UBT, SAT, serological assessment and immunohistochemistry) have low sensitivity for the detection of these species201. The clinical relevance of these often incidentally detected rare infections is low because of the low rates of complications.

Testing for eradication success after 4–6 weeks of antibiotic treatment is primarily — with some specific exceptions — performed with non-invasive diagnostic tests UBT and SAT (see Management section)42. PPI use has to be stopped 14 days before testing to exclude recrudescence of reduced bacterial density under acid suppressive therapy.

Indications for diagnostic testing

Based on the rarity of complications in childhood, a diagnostic endoscopic examination and treatment is recommended only in those with suspected peptic ulcer disease169. In general, H. pylori detection in children is only recommended when complications arise169,204. In the group of patients with dyspepsia without alarm symptoms, such as anaemia, loss of weight or family history of gastric cancer, and age <45 years (45–55 years according to age-related gastric cancer incidence variation among world regions), non-invasive testing with UBT or SAT is the strategy of choice70,205,206. In patients aged >45 years or in the presence of alarm symptoms, endoscopy-based diagnosis is recommended to exclude mucosal changes207,208. H. pylori-associated dyspepsia is an independent entity that resembles but is distinct from functional dyspepsia1,208. A test-and-treat strategy is the most cost-effective approach in patients with H. pylori infection and dyspepsia if H. pylori preval‎ence in the population is >5%. This strategy is superior to alternative therapies including PPIs70,209,210, and the therapeutic gain of H. pylori eradication for symptom relief compared with other therapeutic options is substantial. A randomized, double-blind, placebo-controlled trial for primary prevention of peptic ulcer bleeding in older patients who were prescribed aspirin in primary care lends support to an H. pylori test-and-treat strategy in patients starting aspirin treatment. Gastrointestinal bleeding episodes within a 2-year period were reduced by 65% in the H. pylori eradication group211.

Screening and preventionH. pylori eradication as a strategy for preventing gastric cancer

Gastric cancer incidence and mortality at the population level are reduced by H. pylori eradication but more epidemiological data are required. Meta-analyses of randomized controlled trials and observational studies have concluded that moderate evidence suggests that H. pylori eradication therapy reduces the incidence of gastric cancer in healthy individuals212,213, with an overall risk reduction of 46%212. In individuals with H. pylori infection and a family history of gastric cancer in first-degree relatives, H. pylori eradication treatment reduces the risk of gastric cancer, with an overall risk reduction of 55%214. A meta-analysis of randomized and observational cohorts that included five studies that considered baseline histological findings suggests that H. pylori eradication seems to be a primary preventive strategy in individuals with non-atrophic gastritis or multifocal atrophic gastritis without intestinal metaplasia, but not in those with intestinal metaplasia or dysplasia215. In another meta-analysis, H. pylori eradication was associated with improvement in the severity of atrophic gastritis with and without intestinal metaplasia compared with placebo216. Notably, eradicating H. pylori in patients treated for early-stage gastric cancer reduces rates of metachronous gastric cancer by ~50% (range 20–70%) according to two meta-analyses of randomized trials217,218. In a pivotal trial, the reduction in metachronous gastric cancer incidence following endoscopic removal of early gastric cancer in patients receiving H. pylori eradication compared to placebo219 suggests that eradication therapy may even work in the condition of severe atrophic gastritis220.

Diffuse and intestinal types of gastric cancer221 are two major histological entities that differ in epidemiology, pathogenesis and clinical course222. However, randomized and observational studies have been unable to separately calculate the risk effects for these histological types. Further data on the benefits or adverse effects of H. pylori eradication will come from ongoing trials in China223, UK (HPSS study)224, Korea (HELPER Study)224 and Latvia (GISTAR study)225.

Targeted test-and-treat strategies for H. pylori infection

H. pylori test-and-treat strategies aim to decrease morbidity and mortality related to gastroduodenal disease (Box 2) according to the 2022 Maastricht VI/Florence guidelines86. This strategy is appropriate for individuals with non-investigated dyspepsia. Testing for H. pylori infection should also be performed in persons who use NSAIDs and have a history of peptic ulcer. In addition, evidence is accumulating that supports the eradication of H. pylori in individuals with non-ulcer dyspepsia226, idiopathic thrombocytopenic purpura227, and iron and vitamin B12 deficiency anaemia228,229. Consensus exists for eradicating H. pylori in all cases of MALT lymphoma, regardless of disease stage and prognostic factors230,231. Cure of H. pylori infection results in complete histological remission in most patients with localized MALT lymphoma232.

Box 2 Test-and-treat or endoscopy-based diagnosis in clinical management of H. pylori infection

Test-and-treat

This strategy refers to non-invasive testing of patients with dyspeptic symptoms and without alarm symptoms, such as vomiting, weight loss or anaemia, at age 50 years (range 45–55 years because of increased individual risk of gastric cancer). The non-invasive 13C-urea breath test or stool antigen test are highly accurate in diagnosing current Helicobacter pylori infection376 and surrogate markers for the histological detection of H. pylori gastritis. Serious upper gastrointestinal lesions in patients with dyspepsia in this age group are very rare; thus, non-invasive testing as an initial management step is appropriate in areas of low or intermediate gastric cancer risk388,389. Test-and-treat is superior to other management options, including empirical proton pump inhibitor therapy in patients with dyspepsia, and is more cost-effective than empirical therapy and endoscopy-based management390,391.

Endoscopy-based diagnosis

This approach is required to exclude gastric preneoplastic conditions or malignant disease in patients with dyspeptic or other symptoms referred to the upper abdomen at age >50 years or at any age in the presence of alarm symptoms. A patient with symptoms related to ulcerogenic drug (NSAIDs) use should also be considered for endoscopy70,392. Endoscopy-based investigations are the most reassuring and should be considered in patients with anxiety393.

Test-and-treat for gastric cancer prevention

This strategy targets asymptomatic individuals at increased risk of gastric cancer owing to a first-degree relative with this malignancy. The non-invasive 13C-urea breath test or stool antigen test are appropriate for younger adults. Endoscopy-based investigations should be considered in individuals >45 years of age or earlier according to the age at which gastric cancer was diagnosed in the index patient394.

Population-based test-and-treat

This approach is recommended in regions with a high gastric cancer incidence. For this purpose, serological assessment combining the detection of anti-H. pylori antibodies with measurement of pepsinogen levels provides useful information on the aetiology and atrophy stage of chronic gastritis and helps direct further management of the disease17,395,396.

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Serological assessment for gastric cancer screening

A large body of research, particularly from East Asian populations at high risk, suggests that measurement of circulating pepsinogen levels is the most useful non-invasive test to define the status of the gastric mucosa (that is, whether it is atrophic)233,234. Experts from the Kyoto Global Consensus agreed that pepsinogen levels in conjunction with anti-H. pylori antibody levels are useful for identifying individuals at increased risk for gastric cancer1. Although there are still possibilities for optimization, the ABC (gastritis A, B, C and D) screening method based on this combined measurement is useful for the detection of an increased risk for both intestinal and diffuse types of gastric cancer235. The specific groups are defined as follows, where Hp indicates H. pylori infection and PG indicates pepsinogen: A [Hp–PG–], individuals without infection; B [Hp+PG–], without chronic atrophic gastritis (CAG); C [Hp+PG+], with CAG; and D [Hp–PG+], with severe CAG; the latter two groups carry the highest risk for gastric cancer236,237.

Population endoscopic screening for gastric cancer

Around 75% of all new gastric cancer cases are diagnosed in East Asian populations238. Consequently, Japan and South Korea have established successful national screening programmes in individuals aged ≥40 years using either upper gastrointestinal series or upper endoscopy, depending on participant preference or comorbidities. Endoscopy has been the primary method for gastric cancer screening in Japan since 2017, and a study published in 2022 reported the benefits of this approach in the reduction of gastric cancer mortality239. In South Korea, the use of upper endoscopy has increased as this method is more accurate than upper gastrointestinal series for gastric cancer screening240.

Endoscopic surveillance of individuals at high risk

Although H. pylori eradication can reverse multifocal gastric atrophy and, to some extent, intestinal metaplasia, some patients with these histological lesions might benefit from surveillance at regular intervals. According to the management of precancerous conditions and lesions in the stomach (MAPS II)241 European guidelines and the Maastricht VI/Florence consensus86, individuals with advanced stages of atrophic gastritis (severe atrophic changes with and without intestinal metaplasia in both antrum and corpus, OLGA/OLGIM stages III and IV) should be followed-up with a high-quality endoscopy every 3 years. Based on growing evidence, endoscopic surveillance should also be considered in individuals with intestinal metaplasia at a single location but with a family history of gastric cancer, in those with incomplete-type intestinal metaplasia and in those with persistent H. pylori gastritis. These recommendations are primarily intended for regions with low-to-moderate gastric cancer burden, where population-based screening is not practical or economically feasible but where subgroups at risk can be identified. Although the American Gastroenterological Association does not recommend routine use of endoscopic surveillance in patients with intestinal metaplasia242, a common denominator between American Gastroenterological Association and European MAPS II guidelines is that they are based on low-quality evidence, highlighting the need for well-designed, large and long-term trials.

Management

General aspects

H. pylori gastritis is an infectious disease and all adult individuals with the infection require therapy for cure if clinical symptoms and complications are present or for prevention if at risk for complications even if asymptomatic1,42,243. H. pylori test-and-treat strategies are selected according to diverse clinical scenarios17,42,206 (Box 2). In the paediatric population, H. pylori infection rarely leads to complications and requires specific management addressed in the joint ESPGHAN/NASPGHAN Guidelines that were updated in 2016 (ref. 169). All treatment discussions in this section relate to the disease in adults.

Treatment regimens for H. pylori eradication are based on the combination of a strong acid suppressant and antibiotics. First-line therapy is selected according to locoregional or individual H. pylori antibiotic resistance patterns244,245. Treatment failures induce resistance to several of the antibiotics used in first-line regimens and render further therapies more complex and costly42,206,246,247. Second-line therapy needs to consider the first-line regimen and antibiotic resistance status (Fig. 6). Confirmation of treatment success not earlier than 4 weeks after end of therapy is mandatory to guide further management and provides important information on the effectiveness of treatment regimens in defined regions42.

Fig. 6: Suggested H. pylori therapy algorithm.

Helicobacter pylori therapy algorithm with the indication of regimens that consist of triple or quadruple combinations to be used in first-line and subsequently in case of failure. Proton pump inhibitors (PPIs) or, where available, potassium-competitive acid blockers are essential components for acid suppression to render antibiotics more effective. PPI can be substituted by potassium-competitive acid blockers where available. Antibiotics are selected according to individual antibiotic susceptibility testing (AST) or according to regional antibiotic susceptibility based on surveillance as well as according to local availability. Clarithromycin-based PPI triple therapy (PPI-TT) is a first-line therapy if local clarithromycin resistance preval‎ence is <15%. If clarithromycin resistance exceeds 15% or is unknown, the recommended first-line regimen is BiQT (PPI, bismuth, tetracycline and a nitroimidazole antibiotic). Levofloxacin-based regimens are recommended as second-line treatments if a first-line regimen with BiQT fails. Levoflaxin-based regimens include amoxicillin and PPI. If levofloxacin resistance in regional surveillance exceeds 15%, it is advisable to directly select third-line or fourth-line regimens as rescue therapy. The fourth-line regimen (rescue therapy) consists of PPI, rifabutin and amoxicillin (or clarithromycin in case of penicillin allergy).

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PPI triple therapyFirst-line setting

The introduction of PPI-based triple therapies (PPI-TT) marked a turning point in the treatment of H. pylori infection owing to their superior efficacy compared with previous approaches. The three components of PPI-TT include a PPI, clarithromycin and amoxicillin or, alternatively, metronidazole as a substitute for either amoxicillin or clarithromycin. Seven-day PPI-TT obtained initial eradication rates of >90%248,249 and, between 1997 and 2005, became the most widely recommended first-line therapy globally42,206,247,250. Treatment duration has since been recommended to be extended to 14 days owing to a substantially higher efficacy compared to the 7-day duration42,244,247. Antibiotics used in first-line PPI-TT are clarithromycin, amoxicillin and metronidazole or, more restrictive, levofloxacin and, in selected cases, furazolidone. Treatment failures with PPI-TT occur with increasing frequency and are primarily related to antibiotic resistance, insufficient acid suppression and inadequate adherence to medications10,251,252,253. Acid suppression with PPI (omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole in double standard dose) is essential and aims to raise intragastric pH to 6 or higher, which optimizes the stability, bioavailability and efficacy of antibiotics254,255. A modestly higher acid-inhibiting effect is shown for second-generation PPIs (esomeprazole, rabeprazole)256. Increased intragastric pH (optimum pH >6) enables bacterial replication, which increases the susceptibility of H. pylori to antibiotics. This is particularly important for amoxicillin, which is highly acid sensitive254,255. Less effective acid suppressants, such as histamine 2 receptor antagonists, are no longer considered in H. pylori eradication regimens246,257. PPI efficacy is further increased by doubling the PPI standard dose and should always be considered if first-line therapy fails258,259,260,261.

Rapid metabolization of PPIs leads to reduced efficacy253,262,263. Rapid and ultrarapid metabolization of PPIs varies considerably among ethnic groups and occurs more frequently in white and African American populations, whereas slow metabolization is more frequent in Asian, including Japanese and Chinese, populations264,265,266,267. The efficacy of PPI metabolism depends on various genetic mutations related to CYP2C19 polymorphism and, to a minor extent, on CYP3A4 and gastric H+,K+-ATPase genotypes255,268. Apart from the use of PPI double standard dose in rapid metabolizers, better control of acidity has been reported by increasing PPI dosing frequency up to four times or by switching to a PPI less influenced by CYP2C19 genotypes268,269,270,271. No guideline is yet available recommending CYP2C19 genotyping to guide PPI prescription in clinical practice. The pharmacokinetic and pharmacodynamic properties of the second-generation PPIs esomeprazole and, in particular, rabeprazole are less influenced by variant CYP2C19 genotypes268,270,272,273.

To overcome inadequate adherence, careful patient instruction is appropriate on how to take medications and how to proceed in case of adverse events274,275. A history of penicillin allergy, availability of susceptibility testing, local preval‎ence of antibiotic resistance and history of prior eradication therapies should be considered when deciding on the initial therapy (Fig. 6).

Antibiotic resistance

Antibiotic resistance is the most important factor in PPI-TT failure244. Clarithromycin resistance and metronidazole resistance are the most relevant resistances for PPI-TT failure42,247,276. Clarithromycin resistance has increased from 3% to 11% around the turn of the century and is now up to 15–30% worldwide188,189,248,277,278,279. In 2,852 treatment-naive patients from a European registry on H. pylori management (Hp-EuReg), resistance to clarithromycin, metronidazole and levofloxacin were 25%, 30% and 20%, respectively261,278. Resistances to tetracycline and amoxicillin were <1% in the same study. A WHO global priority list qualifies clarithromycin-resistant H. pylori infection as a high threat among community-acquired infections280, and international guidelines recommend abandoning clarithromycin-based regimens if regional resistance exceeds 15%244.

Among several modifications developed to overcome clarithromycin resistance, including sequential therapy (PPI-dual followed by PPI-TT) and hybrid therapy (PPI plus three antibiotics), only concomitant therapy (PPI plus three antibiotics simultaneously administered)244,281,282,283 was found to be superior to clarithromycin-based PPI-TT281,282. Concomitant therapy as an empirical first-line option should cautiously be considered in regions of clarithromycin resistance >15% and only used if individual AST or bismuth-based quadruple therapy (BiQT) are not locally available42,247,250. Levofloxacin as a component of PPI-TT is effective in first-line and second-line regimens in regions with low levofloxacin resistance284,285,286. However, levofloxacin resistance is now up to 20% in Europe and 18% in the Asia-Pacific region188,278,287. Although levofloxacin is not recommended as a first-line option, the high resistance restricts its use even in second-line regimens42,244,247. AST before using levofloxacin in empirical second-line regimens is advised189,244,278,287. Other quinolones, such as ciprofloxacin and moxifloxacin, which have reduced efficacy and/or less consistent results, are not an alternative to levofloxacin286,288. Sitafloxacin-based triple and dual regimens that have been successfully tested in Japan289 are not used as an alternative to levofloxacin in western countries42,244,247.

Metronidazole resistance is >25% in most areas of the world189,278 but has a minor effect on eradication efficacy when used in triple or quadruple regimens because of inconsistency between in vitro AST results and clinical efficacy and the synergism with co-administered drugs, in particular bismuth224,290,291. Resistance to amoxicillin and tetracycline is low (<2%) and these antibiotics remain a key component in standard PPI-TT and in BiQT, respectively, without the need for routine AST244,291. Rifabutin resistance is <1% and the H. pylori eradication rate of rifabutin-containing regimens is 73% according to a meta-analysis from 2020 (ref. 292). A rifabutin delayed-release preparation, combined with amoxicillin and omeprazole, obtained an eradication rate of 89%293 and FDA approval for use as a first-line therapy was granted in 2019 (ref. 294). Outside of the USA, rifabutin-containing regimens are recommended as rescue therapy only owing to the need of this drug for other critical infections and the risk of myelotoxicity in rare cases42,247. Furazolidone resistance is <5% and the drug is effective in triple and quadruple combinations; its use is limited to a few countries in Asia and South America195,295 and it may serve as rescue therapy in individual cases296.

For these antibiotic classes, mechanisms of resistance are related to drug-specific target gene mutations (macrolides and quinolones) or to detoxication (nitroimidazoles)296. H. pylori colonies may carry single-drug, multidrug or hetero resistance296,297. Isolates from antrum and corpus are reported to differ by up to 15% in AST, which may account for treatment failure if biopsy samples for AST are only taken from a single site in the stomach298,299.

항생제 내성

항생제 내성은 PPI-TT 실패의 가장 중요한 요인입니다244.

클라리스로마이신 내성과 메트로니다졸 내성은

PPI-TT 실패와 가장 관련성이 높은 내성입니다42,247,276.

클라리스로마이신 내성은 세기가 바뀌면서 3%에서 11%로 증가했으며

현재 전 세계적으로 15-30%까지 증가했습니다188,189,248,277,278,279. 유

럽 헬리코박터 파일로리 관리 레지스트리(Hp-EuReg)의 치료 경험이 없는 환자 2,852명에서 클라리스로마이신, 메트로니다졸 및 레보플록사신에 대한 내성은 각각 25%, 30% 및 20%였습니다261 ,278. 테트라사이클린과 아목시실린에 대한 내성은 같은 연구에서 1% 미만이었습니다. WHO 글로벌 우선순위 목록에 따르면 클라리스로마이신 내성 H. 파일로리 감염은 지역사회 획득 감염 중 높은 위협으로 분류되며280, 국제 가이드라인에서는 지역 내성이 15%를 초과하는 경우 클라리스로마이신 기반 요법을 포기할 것을 권장합니다244.

클라리스로마이신 내성 극복을 위해 개발된 순차 요법(PPI-듀얼 후 PPI-TT) 및 혼합 요법(PPI와 세 가지 항생제)을 포함한 여러 변형 요법 중 병용 요법(PPI와 세 가지 항생제 동시 투여)244,281,282,283 만이 클라리스로마이신 기반 PPI-TT보다 우수한 것으로 밝혀졌습니다281 ,282. 경험적 1차 치료 옵션으로서 병용 요법은 클라리스로마이신 내성이 15% 이상인 지역에서 신중하게 고려해야 하며, 개별 AST 또는 비스무트 기반 4중 요법(BiQT)을 현지에서 사용할 수 없는 경우에만 사용해야 합니다42,247,250. PPI-TT의 성분인 레보플록사신은 레보플록사신 내성이 낮은 지역에서 1차 및 2차 요법에서 효과적입니다284,285,286. 그러나 레보플록사신 내성은 현재 유럽에서 최대 20%, 아시아 태평양 지역에서는 18%에 달합니다188,278,287. 레보플록사신은 1차 옵션으로 권장되지 않지만, 높은 내성으로 인해 2차 요법에서도 사용이 제한됩니다42,244,247. 경험적 2차 요법에서 레보플록사신 사용 전 AST 검사를 권장합니다189,244,278,287. 시프로플록사신 및 목시플록사신과 같은 다른 퀴놀론계 항생제는 효과가 감소하거나 결과가 일관적이지 않으므로 레보플록사신의 대안이 될 수 없습니다286,288. 일본에서 성공적으로 시험된 시타플록사신 기반 삼중 및 이중 요법289 은 서구 국가에서는 레보플록사신의 대안으로 사용되지 않습니다42,244,247.

메트로니다졸 내성은 전 세계 대부분의 지역에서 25% 이상이지만189,278 시험관 내 AST 결과와 임상 효능 사이의 불일치 및 병용 약물, 특히 비스무트와의 시너지 효과로 인해 3중 또는 4중 요법으로 사용 시 박멸 효능에 미치는 영향은 미미합니다224,290,291. 아목시실린과 테트라사이클린에 대한 내성은 낮으며(<2%), 이러한 항생제는 각각 표준 PPI-TT와 BiQT에서 일상적인 AST가 필요 없이 핵심 성분으로 남아 있습니다244,291. 2020년 메타분석에 따르면 리파부틴 내성은 1% 미만이며 리파부틴 함유 요법의 H. 파일로리 제균률은 73%입니다(참조 292). 아목시실린 및 오메프라졸과 병용한 리파부틴 서방형 제제는 89%의 박멸률을 보였으며293 2019년에 1차 치료제로 사용하도록 FDA 승인을 받았습니다(참조 294). 미국 이외 지역에서는 리파부틴 함유 요법이 다른 중증 감염에 대한 이 약의 필요성과 드문 경우의 골수 독성 위험으로 인해 구조 요법으로만 권장됩니다42,247. 후라졸리돈 내성은 5% 미만이며 이 약은 3제 및 4제 조합에서 효과적이며, 아시아와 남미의 일부 국가로 사용이 제한되어 있고195,295 개별 사례에서 구조 요법으로 사용될 수 있습니다296.

이러한 항생제 계열의 경우 내성 기전은 약물 특이적 표적 유전자 돌연변이(마크로라이드 및 퀴놀론) 또는 해독(니트로이미다졸)과 관련이있습니다296. H. 파일로리 콜로니는 단일 약물, 다약제 또는 이종 내성을 가질 수 있습니다296,297. 항문과 코퍼스에서 분리한 균은 AST에서 최대 15%까지 차이가 나는 것으로 보고되고 있으며, 이는 위장의 단일 부위에서만 AST 생검 샘플을 채취하는 경우 치료 실패의 원인이 될 수 있습니다298,299.

Bismuth-based quadruple therapy

Bismuth has multiple beneficial properties in peptic ulcer healing that include a stimulating effect on prostaglandin synthesis, inactivation of pepsin, and bile acid binding but, most relevant in H. pylori eradication, is its bactericidal effect300,301. Bismuth subcitrate upregulates the expression‎ of genes involved in H. pylori growth and metabolism and impedes proton entry, thereby preventing lowering of the bacterial cytoplasmic pH. These mechanisms are suggested to render antibiotics more effective302. Bismuth-based quadruple therapy (BiQT; PPI, bismuth, tetracycline and a nitroimidazole antibiotic), available either as individual components or as PPI plus a capsule containing all antibacterial components, has an eradication efficacy of 90%261,291,303,304.

BiQT is recommended as an empirical first-line therapy, does not require AST, is not affected by clarithromycin resistance and overcomes metronidazole resistance owing to synergism with bismuth, as documented by its consistently high therapeutic efficacy244,291,300. Bismuth added to clarithromycin-containing regimens increases eradication efficacy also in the presence of clarithromycin resistance but, in these combinations, offers no advantage over standard BiQT300,305,306. BiQT does not contain antibiotics that are essential for cure of other infections. BiQT is an effective rescue option with a success rate of >90% following previous treatment failures303,307,308.

Regimens with potassium-competitive acid blockers

Potassium-competitive acid blockers (P-CABs), a new class of acid inhibitors, have a more potent and durable effect on acid suppression than PPIs309,310. Vonoprazan-based triple therapy (V-TT) with clarithromycin and amoxicillin in first-line achieved an eradication rate of 92.6% versus 75.9% with PPI-TT, and 98% in second-line in Japan311, which was also confirmed in western countries312. In network meta-analyses, V-TT ranked best among all current first-line empirical therapies, which was also confirmed after the inclusion of a trial conducted in western countries313,314. Vonoprazan dual therapy, consisting of vonoprazan plus amoxicillin, provides an eradication rate of H. pylori similar to that of V-TT252. Increasing resistance and absence of new antibiotics set major expectations on P-CAB-based regimens, which are being investigated in several trials309 (Supplementary Table 1).

H. pylori eradication and rescue therapies

Management of refractory H. pylori needs to consider individual or local antibiotic resistance, facilities for AST, logistics, and drug availability244,246 (Fig. 6). Following PPI-TT failure, BiQT or a regimen with antibiotics selected following AST is recommended42,244,247. Empirical therapy, with careful consideration of previously taken medications, is a valid alternative to genotypic resistance-guided therapy of refractory H. pylori infection315. BiQT is currently the best empirical approach as it is not influenced by antibiotic resistance316. If BiQT fails in first-line, levofloxacin-based triple therapy is recommended. A meta-analysis including 25 trials with levofloxacin-based triple therapy in second-line treatment reports a cumulative eradication rate of 74.5% (95% CI 70.9–77.8)317. The PPI-amoxicillin, high-dose, dual therapy is another option, with a ≥81% eradication rate achieved as second-line treatment and with an efficacy comparable to other recommended therapies318,319.

P-CABs in triple therapies and in dual combination with amoxicillin already effectively used in Asian countries will become an important option once generally available and properly adapted to regional demands in first-line and second-line eradication regimens311,313. Rifabutin-based triple therapy is well documented as effective and should be kept as rescue therapy292. Surveillance programmes at the regional level, the introduction of antibiotic stewardship, regulations in the use of antimicrobials and increased public awareness are advised to control the increasing resistance of H. pylori244,320,321.

Adverse events

Overall, eradication regimens have a favourable safety profile, with usually mild and very few severe adverse events. Mostly mild-to-moderate adverse effects occur in 30–70% of patients and include taste disturbances, nausea, headache, diarrhoea and non-specific gastrointestinal symptoms with some variations according to type of eradication therapy282,291,322,323,324.

Diarrhoea varies in preval‎ence from >1% to 15% according to definitions applied, the population treated and type of therapy325. The non-recording of adverse effects as primary criteria in clinical trials accounts for the high variations. Darkening of the tongue and faeces is characteristic of bismuth salts326. Antibiotics affect gut microbiota and lead to mostly transient dysbiosis, bacterial resistance and overgrowth of opportunistic pathogens; however, rarely of Clostridioides difficile40,325,327.

Probiotics added to H. pylori therapies have a small and inconsistent effect on eradication rates but reduce adverse effects42, which has been shown in meta-analyses for individual probiotics as well as for mixtures322,328,329. In a new randomized controlled study, Saccharomyces boulardii combined with a mixture of probiotic bacteria modestly increased the eradication efficacy and reduced adverse effects330, whereas S. boulardii alone had no effect on eradication but remained effective in reducing adverse effects such as severe diarrhoea331. Defined probiotic mixtures have been shown to antagonize the harmful effects of antibiotics on the gut microbiota and their metabolic functions325.

Effects on peptic ulcer and MALT lymphoma

Successful H. pylori eradication achieves ulcer healing rates of >90% and continued acid inhibition with PPI is not required for uncomplicated duodenal ulcer42. Gastric ulcer requires prolonged acid inhibition for healing and endoscopic follow-up is needed to ensure complete ulcer healing and to exclude underlying gastric malignancy332. Management of bleeding peptic ulcers, both duodenal and gastric ulcers, requires immediate care by controlling and/or restoring cardiocirculatory and respiratory function and by performing emergency diagnostic endoscopic examination and endoscopic interventions according to standardized protocols333,334. PPI treatment is continued until complete healing is endoscopically documented44. H. pylori eradication should be initiated after the active bleeding phase is under control and oral nutrition can be resumed70,334. Patients with H. pylori infection exposed to ulcerogenic medications, in particular NSAIDs, are at an increased risk of complications56,335 and benefit from H. pylori testing and treatment42,70. Patients at high risk for rebleeding after H. pylori eradication, for example, those with continued NSAID use, require PPI maintenance therapy336.

H. pylori eradication is the standard-of-care initial therapy for MALT lymphomas in all stages and obtains 70–80% long-term remission in stage I disease337,338. Eradication therapy in patients negative for H. pylori after exclusion of the infection with routine diagnostics obtains cure in 30% of patients and should, therefore, always be considered as a first management step339.

Quality of life

Despite the vast number of H. pylori treatment studies, surprisingly few investigations have measured quality of life (QoL) outcomes. Several different questionnaires have been used to ascertain QoL metrics across the spectrum of diseases associated with H. pylori, and results have shown that eradication of H. pylori can either improve or worsen QoL, which may depend on the type of treatment used340. In a study from Japan, participants were included to survey improvement of GERD-related QoL measures following H. pylori treatment using a Japanese version of the QoL in reflux and dyspepsia score (QOLRAD-J) and Carlsson–Dent questionnaires341. GERD-related QoL scores improved following treatment and these were magnified among individuals with severe reflux symptoms. In another study, an 8-item Short-Form Health Survey and a modified Frequency Scale for GERD symptoms were used following H. pylori eradication342; QoL improved irrespective of treatment outcome. Finally, in a study from Thailand, patients with functional dyspepsia indicated that H. pylori infection, anxiety or depression were common, occurring in 23.3%, 23% and 7.3% of patients, respectively343. These findings suggest that eradication of H. pylori might not only improve functional dyspepsia but also potentially prevent the development of gastric cancer in some patients with functional dyspepsia by eliminating the chronic inflammatory process in the stomach.

In the UK, a randomized controlled study of QoL was conducted in 39,929 patients with dyspepsia following H. pylori therapy using a validated dyspepsia questionnaire and the psychological well-being index (PGWB) and reported no effect on QoL following therapy344. A further study in a smaller number of patients with functional dyspepsia similarly noted no improvement in QoL after eradication345. Other studies from Europe have reached different conclusions. In a study from Hungary, using the Functional Digestive Disorder Quality of Life system adapted from France to determine QoL in patients with functional dyspepsia, improvement of QoL was dependent on H. pylori therapy346. In a study from Croatia, the Gastrointestinal Symptom Rating Scale questionnaire was employed and improvement in QoL of patients with dyspepsia was found as early as 1 month into the year-long study347.

A group from Africa used the Short-Form Leeds Dyspepsia Questionnaire and the Short-Form Nepean Dyspepsia Index in health-care workers with dyspepsia and found reduced QoL in those with high dyspepsia preval‎ence348. In a study from Rwanda, dyspepsia was assessed within the general population using the Short-Form Nepean Dyspepsia Index questionnaire and noted improved QoL, which was dependent on H. pylori treatment349.

Finally, in a study examining potential detrimental consequences of eradication therapy, it was reported that patients with a duodenal ulcer in whom H. pylori eradication was successful were more likely to develop oesophagitis in the first year after treatment than those without H. pylori eradication350; however, in the subsequent 2 years, there was no difference between the groups. Collectively, these disparate results probably reflect differences in H. pylori treatment regimens, the QoL scoring systems used, varying genetic backgrounds of the host populations and differences in infecting H. pylori strains350.

삶의 질

수많은 헬리코박터 파일로리 치료 연구에도 불구하고 의외로 삶의 질(QoL) 결과를 측정한 조사는 거의 없습니다. 여러 가지 설문지를 사용하여 헬리코박터 파일로리균과 관련된 다양한 질병에 대한 삶의 질 지표를 확인했으며, 그 결과 헬리코박터 파일로리균 제균은 사용된 치료 유형에 따라 삶의 질을 개선하거나 악화시킬 수 있는 것으로 나타났습니다340. 일본의 한 연구에서는 참가자들을 대상으로 일본판 역류성 소화불량증 삶의 질 점수(QOLRAD-J) 및 칼슨-덴트 설문지341 를 사용하여 H. pylori 치료 후 GERD 관련 삶의 질 개선 정도를 조사했습니다. 치료 후 위식도역류질환 관련 삶의 질 점수가 개선되었으며, 역류 증상이 심한 사람에서 이러한 개선 효과가 더 크게 나타났습니다. 또 다른 연구에서는 8가지 항목으로 구성된 단문 건강 설문조사와 GERD 증상에 대한 수정된 빈도 척도를 사용한 결과342; 치료 결과와 관계없이 QoL이 개선되었습니다. 마지막으로, 태국의 한 연구에 따르면 기능성 소화불량증 환자는 H. 파일로리 감염, 불안 또는 우울증이 흔했으며, 각각 23.3%, 23% 및 7.3%의 환자에서 발생했습니다343 . 이러한 연구 결과는 H. 파일로리 제균이 기능성 소화불량을 개선할 뿐만 아니라 위장의 만성 염증 과정을 제거하여 일부 기능성 소화불량 환자의 위암 발병을 예방할 수 있음을 시사합니다.

영국에서는 소화불량 환자 39,929명을 대상으로 검증된 소화불량 설문지와 심리적 웰빙 지수(PGWB)를 사용하여 헬리코박터 파일로리 치료 후 삶의 질에 대한 무작위 대조 연구를 실시한 결과, 치료 후 삶의 질에 영향을 주지 않는 것으로 보고되었습니다344. 소수의 기능성 소화불량 환자를 대상으로 한 추가 연구에서도 마찬가지로 박멸 후 QoL이 개선되지 않았다고 보고했습니다345. 유럽의 다른 연구에서도 다른 결론에 도달했습니다. 기능성 소화불량 환자의 삶의 질을 측정하기 위해 프랑스에서 채택한 기능성 소화장애 삶의 질 시스템을 사용한 헝가리의 한 연구에서, 삶의 질 개선은 H. pylori 치료 여부에 따라 달라졌습니다346. 크로아티아의 한 연구에서는 위장관 증상 평가 척도 설문지를 사용했으며, 1년간의 연구 결과 소화불량 환자의 QoL 개선이 빠르면 1개월 만에 발견되었습니다347.

아프리카의 한 연구팀은 소화불량이 있는 의료 종사자를 대상으로 단문형 리즈 소화불량 설문지와 단문형 네피안 소화불량 지수를 사용한 결과, 소화불량 유병률이 높은 사람들의 QoL이 감소하는 것을 발견했습니다348. 르완다의 한 연구에서는 단문형 네피안 소화불량 지수 설문지를 사용하여 일반 인구의 소화불량을 평가한 결과, 헬리코박터 파일로리 치료에 따라 QoL이 개선되는 것으로 나타났습니다349.

마지막으로, 제균 치료의 잠재적인 해로운 결과를 조사한 연구에서, 십이지장 궤양 환자 중 H. 파일로리 제균에 성공한 환자는 치료 후 첫 해에 H. 파일로리 제균을 하지 않은 환자보다 식도염이 발생할 가능성이 더 높았지만350; 이후 2년 동안은 그룹 간에 차이가 없었다고 보고되었습니다. 이러한 상이한 결과를 종합해 볼 때, 아마도 이러한 차이는 H. pylori 치료 요법의 차이, 사용된 QoL 점수 시스템, 숙주 집단의 다양한 유전적 배경 및 감염된 H. pylori 균주의 차이를 반영하는 것으로 보입니다350 .

Outlook

A vision for the future is to provide a healthy stomach free from H. pylori to all individuals. The expectation that H. pylori incidence will decrease to the point that the bacterium will disappear spontaneously within a foreseeable time frame is unlikely to occur351. A population-wide test-and-treat strategy should therefore remain a consideration. This strategy could confer a health benefit with the prevention of H. pylori-related complications in a considerable number of individuals. However, logistic limitations, substantial health costs and risks related to the massive use of antibiotics with the fear of aggravating antibiotic resistance would be disadvantages. Thus, the identification of individuals and population subsets with a higher-than-average risk of gastric cancer should be, for now, the primary target in prevention strategies. This is the case for first-degree family members of patients with gastric cancer and populations in world regions with high gastric cancer incidence. This approach is supported by favourable cost-effectiveness and advised by expert consensus reports and guidelines17,86. A new concept for comprehensive intrafamilial H. pylori management has been proposed for regions of high H. pylori preval‎ence352. It advises actively proceeding with test-and-treat strategies in family members living in the same household as the index patient diagnosed with H. pylori based on the rationale of predominant intrafamilial spreading of the infection, mainly in childhood.

Antibiotic resistance, with its dramatic increase, demands new antimicrobial drugs that can specifically target H. pylori and avoid cross-resistance effects and induction of antibiotic resistance in H. pylori and other bacteria (Box 3). Colloidal bismuth subcitrate remains a candidate, with a direct bactericidal effect by inducing cellular swelling, vacuolization, structural degradation and cell wall eruption of H. pylori353. For now, bismuth has the limitation of cure rates of <20% if used as monotherapy301.

Urease is an essential factor for the survival of H. pylori in the acidic gastric environment, producing ammonia and carbonic acid to neutralize the acidic surroundings354. However, urease is a complex target composed of two subunits with 12 active sites354. The delineated structure of the proton-gated urea channel of urease355 and the development of a drug that can block the rapid influx of urea into the bacterium may offer a solution to inhibit the activity of urease.

Inhibition of motility by blocking the flagellar function of H. pylori might be worth considering as a therapeutic target. H. pylori flagella enable rapid movement through the viscous mucus, and disruption of a gene encoding cardiolipin synthase of H. pylori strain G27, shown in vitro, may abolish the biosynthesis of flagellum356. Furthermore, interference with the outer membrane proteins of H. pylori that confer adhesion to host glycans, mucins or gastric mucosa, such as BabA and SabA357, may impair H. pylori survival in the gastric mucosa. An anti-adhesion nanomedicine composed of H. pylori-mimicking outer membrane nanoparticles could compete with H. pylori and reduce its adhesion to gastric epithelial cells358.

Another approach is to increase the penetration of drugs into the gastric mucus layer, which includes the loosely adherent and firmly adherent mucus layers359. Conventional mucoadhesive particles usually attach to the loosely adherent layer only and are easily moved downstream to the lumen upon peristalsis359. Some potential mucus-penetrating polymeric nanoparticles can penetrate into the firmly adherent mucus layer359. Thus, delivery of selective antibiotics or other agents against H. pylori may be rendered more effective through the development of polymeric nanoparticles. H. pylori is a microaerobic organism and susceptible to increased oxygen levels, thus, the delivery of nanoparticles that include oxygen into the gastric mucus layer could render the bacterium vulnerable. In addition, multiple aspects of the interaction of H. pylori with the gastrointestinal microbiome are addressed by current research and will influence future research360,361,362,363,364. The exclusive property of H. pylori to colonize and infect the gastric mucosa affects the biodiversity of other gastric bacteria and their role in either enhancing or mitigating H. pylori-induced gastric inflammation; this needs to be further explored. H. pylori dominates the mucosa-associated community in the stomach but is less influential on the composition of bacterial communities in gastric juice365. In individuals with H. pylori infection, and even following eradication, the gastric microbial composition is dependent on the extent of gastric mucosal damage previously induced by H. pylori and gastric acidity366,367. In patients with atrophic gastritis, bacterial clusters comprising Peptostreptococcus, Streptococcus, Parvimonas, Prevotella, Rothia and Granulicatella with carcinogenetic potential become predominant, whereas the probiotic Faecalibacterium prausnitzii is depleted367. The development of targeted probiotics in the direction of antagonizing carcinogenic clusters in patients with atrophic gastritis following H. pylori eradication will serve an important purpose. It will be a further point of interest to understand the role of bacteria carried in the saliva and transiting the stomach and whether, in the absence of H. pylori, some of them become candidates for resilience and explain the entity of H. pylori-negative gastritis. The contributing role of bacteria in the development of severe gastritis into gastric cancer is shown in animal experiments and humans, and more insights are expected in this area161,368,369. Vaccine development should be pursued and lessons from previous failures will help in new approaches172.

Field and challenge studies should both be conducted after identification of effective vaccine candidates. A vaccine for preventive and therapeutic purposes might consider multiple epitopes to direct the immune response towards essential H. pylori functions such as epithelial cell adherence, proliferation and survival in the specific gastric niche230,370. Preliminary evidence shows that H. pylori reduces the efficacy of treatment with immune-checkpoint inhibitors in malignant diseases371,372. If these findings are confirmed in further investigations, a test-and-treat strategy for H. pylori could become a requirement before starting immune therapies in oncological diseases. Immune mechanisms involved in this phenomenon deserve further exploration.

Box 3 Potential therapeutic targets for non-antibiotic drugs against H. pylori infection

Urease

Block the proton-gated urea channel, inhibit the activity of urease and block the production of urease.

Flagella

Inhibit motility, impair structure and production of flagella.

Adhesion factors

Reduce the adhesion of Helicobacter pylori to gastric mucosa.

Drug delivery into gastric mucus

Increase the delivery of antibiotics or new drugs into the firmly adherent mucus.

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