Re: 헬리코박터 파일로리 대사산물, 위장, 장내 미생물군집에 미치는 영향 2018

[문형철]

World J Gastroenterol

. 2018 Jul 28;24(28):3071–3089. doi: 10.3748/wjg.v24.i28.3071

Helicobacter pylori in human health and disease: Mechanisms for local gastric and systemic effects

Denisse Bravo 1, Anilei Hoare 2, Cristopher Soto 3, Manuel A Valenzuela 4, Andrew FG Quest 5

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PMCID: PMC6064966  PMID: 30065554

Abstract

Helicobacter pylori (H. pylori) is present in roughly 50% of the human population worldwide and infection levels reach over 70% in developing countries. The infection has classically been associated with different gastro-intestinal diseases, but also with extra gastric diseases. Despite such associations, the bacterium frequently persists in the human host without inducing disease, and it has been suggested that H. pylori may also play a beneficial role in health. To understand how H. pylori can produce such diverse effects in the human host, several studies have focused on understanding the local and systemic effects triggered by this bacterium. One of the main mechanisms by which H. pylori is thought to damage the host is by inducing local and systemic inflammation. However, more recently, studies are beginning to focus on the effects of H. pylori and its metabolism on the gastric and intestinal microbiome. The objective of this review is to discuss how H. pylori has co-evolved with humans, how H. pylori presence is associated with positive and negative effects in human health and how inflammation and/or changes in the microbiome are associated with the observed outcomes.

초록

헬리코박터 파일로리(H. pylori)는

전 세계 인구의 약 50%에서 발견되며,

개발도상국에서는 감염률이 70% 이상에 달합니다.

이 감염은

전통적으로 다양한 위장관 질환뿐만 아니라 위 외 질환과도 연관되어 왔습니다.

이러한 연관성에도 불구하고,

이 박테리아는 질병을 유발하지 않고 인간 숙주 내에서 자주 지속되며,

H. pylori가 건강에 유익한 역할을 할 수도 있다는 제안이 있습니다.

H. pylori가

인간 숙주 내에서 어떻게 이렇게 다양한 효과를 낼 수 있는지 이해하기 위해,

여러 연구들은 이 박테리아가 유발하는 국소적 및 전신적 효과에 초점을 맞추어 왔습니다.

H. pylori가

숙주를 손상시키는 주요 메커니즘 중 하나는

국소적 및 전신적 염증을 유발하는 것으로 여겨진다.

그러나

최근 들어 연구들은

H. pylori와 그 대사가

위장 및 장내 미생물군집에 미치는 영향에 주목하기 시작했다.

본 리뷰의 목적은

헬리코박터 파일로리가 인간과 어떻게 공진화해 왔는지,

헬리코박터 파일로리의 존재가 인간 건강에 미치는 긍정적·부정적 효과와의 연관성,

그리고 관찰된 결과와 염증 및/또는 미생물군집 변화의 연관성을 논의하는 데 있다.

Keywords: Helicobacter pylori, Co-evolution, Extra-gastric diseases, Inflammation, Microbiome

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Core tip: This review focuses on discussing how Helicobacter pylori (H. pylori) has co-evolved with humans, potential mechanisms that may explain both positive and negative correlations in population-based studies between H. pylori infection and the development of several diseases, as well as how inflammation and/or changes in the microbiome might be linked to the respective outcomes. Our analysis of the literature reveals that human infection by H. pylori has a longstanding history, whereby the consequences therefore are extremely complex and not always detrimental to the human host. Thus, future research should focus on determining how potentially beneficial consequences of this interaction could be promoted all the while preventing the disease-causing effects in humans.

핵심 요약: 본 리뷰는 헬리코박터 파일로리(H. pylori)가 인간과 어떻게 공진화해 왔는지, 인구 기반 연구에서 H. pylori 감염과 여러 질환 발병 간 양적 상관관계를 설명할 수 있는 잠재적 메커니즘, 그리고 염증 및/또는 미생물군집 변화가 각각의 결과와 어떻게 연관될 수 있는지에 초점을 맞추어 논의한다.

문헌 분석 결과,

헬리코박터 파일로리(H. pylori)에 의한 인간 감염은 오랜 역사를 지니며,

그 결과는 매우 복잡하고 항상 인간 숙주에게 해롭지만은 않다는 점이 밝혀졌다.

따라서

향후 연구는 이 상호작용의 잠재적 유익한 결과를 촉진하는 동시에

인간에게 질병을 유발하는 효과를 예방하는 방법에 초점을 맞춰야 한다.

INTRODUCTION

Helicobacter pylori (H. pylori) infects approximately 50% of the human population worldwide and the infection could reach more than 70% in developing countries[1,2] The consequences of infection have been associated with the development of different gastro-intestinal diseases, such as gastric ulcers, gastric cancer, mucosa-associated lymphoid tissue (MALT) lymphoma and biliary tract cancer[3]. Moreover, H. pylori infection has also been associated with extra gastric diseases, such us ischemic heart diseases[4], type 2 diabetes mellitus[5], anemia[6], adverse metabolic traits in obese subjects[7] and insulin resistance[8], to mention but a few.

Despite the existence of such associations, these diseases occur only in a small percentage of infected people, suggesting that the bacteria frequently persists in the human host without inducing any obvious signs of disease, and it has been suggested that H. pylori may also play a beneficial role in human health[9-14]. Indeed, recent studies indicate that the decreasing incidence of H. pylori in the developing world is paralleled by an increase in the incidence of allergies and autoimmune diseases[15]. Furthermore, the absence of H. pylori has been linked to elevated incidence of diseases, such us multiple sclerosis and celiac disease, among others[16-18].

Several studies have focused on understanding the local and systemic effects triggered by this bacterium in order to understand how H. pylori can produce such diverse effects in the human host. One of the best-characterized mechanisms involved in such effects is likely to be the damage to the host induced by local and systemic inflammation[19]. However, more recently, studies are beginning to focus on the effects of H. pylori and its metabolism on the gastric and intestinal microbiome[20-23]. This emerging field of interest could explain, at least in part, the wide variety of effects that are currently attributed to the presence of H. pylori in the human body.

In this review, we discuss such gastric and extra-gastric effects of H. pylori and the possible mechanisms involved.

서론

헬리코박터 파일로리(H. pylori)는 전 세계 인구의 약 50%를 감염시키며, 개발도상국에서는 감염률이 70% 이상에 이를 수 있다[1,2]. 이 감염의 결과는 위궤양, 위암, 점막 관련 림프조직(MALT) 림프종, 담도암 등 다양한 위장관 질환의 발병과 연관되어 왔다[3]. 또한, H. pylori 감염은 허혈성 심장 질환[4], 제2형 당뇨병[5], 빈혈[6], 비만 환자의 불량한 대사 특성[7], 인슐린 저항성[8] 등 위 외 질환과도 연관성이 보고되었습니다.

이러한 연관성이 존재함에도 불구하고, 이러한 질환들은 감염된 사람들 중 소수에게서만 발생합니다. 이는 박테리아가 인간 숙주 내에서 뚜렷한 질병 증상을 유발하지 않고도 자주 지속된다는 것을 시사하며, H. pylori가 인간 건강에 유익한 역할을 할 수도 있다는 제안이 있습니다 [9-14]. 실제로 최근 연구에 따르면, 개발도상국에서 H. pylori의 발생률 감소는 알레르기 및 자가면역 질환 발생률 증가와 병행되는 것으로 나타났습니다[15]. 더욱이, H. pylori의 부재는 다발성 경화증 및 체강 질병 등 여러 질환의 발생률 증가와 연관되어 있습니다 [16-18].

여러 연구들은 H. pylori가 인간 숙주에서 어떻게 이처럼 다양한 효과를 일으키는지를 이해하기 위해 이 박테리아가 유발하는 국소적 및 전신적 영향에 초점을 맞추어 왔다. 이러한 효과에 관여하는 가장 잘 규명된 메커니즘 중 하나는 국소적 및 전신적 염증에 의해 숙주에 유발되는 손상일 가능성이 높다[19]. 그러나 최근 들어 연구들은 헬리코박터 파일로리(H. pylori)와 그 대사가 위장 및 장내 미생물군집에 미치는 영향에 주목하기 시작했습니다[20-23]. 이 새롭게 부상하는 연구 분야는 현재 헬리코박터 파일로리(H. pylori)의 인체 내 존재에 기인하는 것으로 여겨지는 다양한 효과들을 적어도 부분적으로 설명할 수 있을 것입니다.

본 리뷰에서는

H. pylori의 위 내 및 위 외 효과와 관련된 가능한 메커니즘을 논의한다.

H. PYLORI AND THE CO-EVOLUTION WITH HUMANS: NEGATIVE AND POSITIVE EFFECTS

H. pylori is a Gram-negative bacterium whose presence in the stomach of infected individuals is linked to the development of several gastric diseases, such as chronic gastritis. Although it is estimated that 50% of the world population is infected by H. pylori, only a small percentage of infected patients develop more severe pathologies, such as ulcers (10%-15%) and stomach adenocarcinomas (less than 1%)[1,2], the latter representing 15.4% of the cancers produced by infectious agents worldwide in 2012[24]. These values suggest that while relevant to the development of severe diseases, including gastric cancer, this pathogen could also play other roles in the human host.

It is now well established that H. pylori has been a highly preval‎ent pathogen in humans for over sixty thousand years and that infection occurs mainly in the intimate family environment or through vertical transmission[25]. These continuous infections and contact with other bacterial strains promoted the existence of a large number of mutations and genetic variability among bacteria due to horizontal transfer of information[26-28]. The emerging differences have been characterized particularly with respect to geographic distribution and such studies have revealed that the observed genomic alterations allow H. pylori to survive in different microenvironments[29,30]. Moreover, these genetic modifications are thought to have lead to the emergence of less virulent strains, which may explain the low percentage of patients affected with serious pathologies, such as adenocarcinomas[31].

The events during human evolution associated with initial acquisition H. pylori are thought to have been the development of agrarian practices, as evidenced by the presence of DNA remnants in the H. pylori genome, such as the vir genes of Agrobacterium tumifaciens[32]. Also population migration is likely to have contributed to the acquisition of genes or genomic islands important for H. pylori virulence. One of them is the cagPAI genomic island, where cagA is one of the most important virulence genes associated with an increase in the activation of pro-inflammatory pathways and the production of pro-inflammatory cytokines in the stomach mucosa[33,34]. According to genomic analyses of H. pylori, European colonization trips to South America may have contributed to the acquisition of cagA by indigenous people living in the Andes, who possessed H. pylori without a functional cagA gene[30,35]. Moreover, other studies analyzing South American populations, such as the Colombians, have determined that the mountain people with greater similarity to the native people of that region have a higher incidence of gastric cancer compared with residents of coastal towns, who were more strongly influenced by the colonization of African migrant populations. Currently, this sector of the population has a low incidence of gastric cancer associated with H. pylori infection[36,37].

However, it has been observed that although in certain populations positive CagA strains are more numerous (as in parts of Eastern Asia), there are specific characteristics that make it unlikely for them to spread to the rest of the world, such as Western countries, with fewer positive CagA strains. These observations suggest that “fitness traits” exist, which aid in the survival of the bacteria in different hosts, in addition to other well-known factors, like difference in the lifestyles, socioeconomic levels and diet of the host population[38]. Japan, for example, has the highest rate of gastric cancer worldwide, associated with the highest presence of CagA (57%); however a lower seropreval‎ence is observed compared to other populations[39]. In contrast, despite the high preval‎ence of H. pylori in India, a low rate of gastric cancer is registered (known as the “Indian Enigma”). One of the main hypotheses seeking to explain this enigma is that the higher rate of enteric infections in more poorly developed countries could boost the immune system and limit the consequences of H. pylori infection. In addition, the high diet content of peppers, which represent an important ingredient in the Indian diet, may protect against H. pylori infection[40]. In conjunction, these examples support the hypothesis that a variety of factors contribute to the fitness of H. pylori in different human host populations.

Therefore, bacterial and host fitness are very relevant in H. pylori infection. In particular, host genetics likely affect the progression of pathologies associated with H. pylori infection. Indeed, specific polymorphisms in genes coding for cytokines, such as IL-1β, IL-8, IL-10 and TNF-α, are associated with an increase in the pro-inflammatory responses, greater colonization and infection, as well as an increased risk of gastric cancer[41-45]. Also, polymorphisms in innate immunity genes, such as the toll-like receptor 4 (TLR4), are relevant because TLR4 is implicated as a receptor responsible for H. pylori induced signaling in gastric epithelial cells. Moreover, epigenetic changes due to hypermethylation in the promoter regions of tumor suppressor genes, such as LOX, HAND1 and APC, and the alteration as well as deregulation of microRNAs (miRs) are associated with a higher preval‎ence of gastric cancer following H. pylori infection[46,47].

Despite clearly representing a human pathogen, evidence is available suggesting that this bacterium could also be considered a commensal bacteria in the human host. This notion is supported by the simple observation that the bacteria is present in so many individuals, yet generates relatively few symptoms or pathologies. This raises the issue as to whether to refer to H. pylori as a commensal or pathogen, because pathologies are likely not only to be associated with specific traits of H. pylori, but also with a series of specific conditions in the human host.

H. pylori has been found as part of the normal oral microbiota and part of the microbiota of the stomach in the absence of inflammation[48,49]. In addition, it has been reported that H. pylori infection is not associated with the onset of the gastric cancer, but rather with its recurrence and chronicity[50]. Moreover, the presence of H. pylori in the stomach microbiota may result in changes in the normal microbiota[21,23].

In this context, it is worth mentioning that several studies have attributed positive effects to H. pylori infection. These include the suppression of bacteria that cause tuberculosis (Mycobacterium tuberculosis), protection against asthma, Crohn’s disease, esophageal reflux, diarrheal diseases, as well as esophageal cancer[9-14]. This controversy has led to the discussion whether eradication of H. pylori is recommendable to help restore the host’s health status, or if alternative strategies should be developed to control virulence of the bacteria, thereby avoiding the appearance of ulcers and adenocarcinomas without eliminating the positive effects that this bacterium may have [51]. With this in mind, it is not surprising that H. pylori is so widely studied and considered a relevant target in many therapies.

H. PYLORI와 인간과의 공진화: 부정적 및 긍정적 효과

H. pylori는 그람 음성균으로, 감염된 개인의 위 내 존재는 만성 위염과 같은 여러 위 질환의 발병과 연관되어 있다. 전 세계 인구의 약 50%가 H. pylori에 감염된 것으로 추정되지만, 감염된 환자 중 극히 일부(궤양 10~15%, 위 선암 1% 미만[1,2])만이 위궤양이나 위 선암과 같은 중증 질환을 발병한다. 후자의 경우 2012년 전 세계 감염성 인자에 의한 암 발생의 15.4%를 차지했다[24].

이러한

수치는 위암을 포함한 중증 질환 발병과 관련이 있으면서도,

이 병원체가 인간 숙주 내에서 다른 역할도 수행할 수 있음을 시사한다.

H. pylori가

6만 년 이상 인간에게 고도로 유행하는 병원체였으며,

감염은 주로 가족 내 밀접한 환경이나 수직 전파를 통해 발생한다는 사실은

이제 잘 알려져 있다[25].

이러한 지속적인 감염과 다른 균주와의 접촉은

정보의 수평적 전파로 인해

세균 간에 다수의 돌연변이와 유전적 변이성을 촉진시켰다[26-28].

이러한 차이는 특히 지리적 분포 측면에서 두드러지게 나타났으며,

관련 연구들은 관찰된 게놈 변이가 H. pylori가

다양한 미세환경에서 생존할 수 있게 해준다는 사실을 밝혀냈다[29,30].

또한 이러한 유전적 변이는

덜 독한 균주의 출현으로 이어졌을 것으로 추정되며,

이는 선암과 같은 중증 병리를 앓는 환자의 비율이 낮은 이유를 설명해줄 수 있다[31].

인간 진화 과정에서 H. pylori의 초기 획득과 연관된 사건은 농경 관행의 발전으로 여겨지며, H. pylori 게놈 내 Agrobacterium tumifaciens의 vir 유전자와 같은 DNA 잔존물의 존재가 이를 입증한다[32]. 또한 인구 이동 역시 H. pylori의 독성에 중요한 유전자나 게놈 섬의 획득에 기여했을 가능성이 있다. 그중 하나는 cagPAI 게놈 아일랜드로, 여기서 cagA는 위 점막에서 전염증 경로의 활성화 증가 및 전염증성 사이토카인 생산과 연관된 가장 중요한 독성 유전자 중 하나이다[33,34]. H. pylori의 게놈 분석에 따르면, 유럽인들의 남미 식민지화 과정에서 안데스 지역에 거주하던 원주민들이 기능적 cagA 유전자가 없는 H. pylori를 보유하게 된 배경에는 유럽인들의 남미 진출이 기여했을 수 있다[30,35]. . 또한 콜롬비아인 등 남미 인구를 분석한 다른 연구들은 해당 지역 원주민과 더 유사한 산악 지역 주민들이 아프리카 이주민 집단의 식민지화 영향을 더 강하게 받은 해안 도시 거주자들에 비해 위암 발생률이 더 높다는 사실을 확인했습니다. 현재 이 인구 집단은 H. pylori 감염과 관련된 위암 발생률이 낮습니다[36,37].

그러나 특정 집단(동아시아 일부 지역 등)에서는 양성 CagA 균주가 더 많음에도 불구하고, CagA 양성 균주가 적은 서구 국가 등 세계 다른 지역으로 확산되기 어려운 특이적 특성들이 존재한다는 점이 관찰되었다. 이러한 관찰 결과는 숙주 집단의 생활 방식, 사회경제적 수준, 식습관 차이 등 잘 알려진 요인 외에도, 다양한 숙주 내에서 세균의 생존을 돕는 “적응 특성”이 존재함을 시사한다 [38]. 예를 들어 일본은 전 세계에서 가장 높은 위암 발병률을 보이며, 이는 CagA 양성률(57%)과 연관되어 있습니다. 그러나 다른 집단에 비해 낮은 혈청 유병률이 관찰됩니다[39]. 반면, 인도에서는 H. pylori의 높은 유병률에도 불구하고 낮은 위암 발생률(소위 “인도 수수께끼”)이 기록됩니다. 이 수수께끼를 설명하려는 주요 가설 중 하나는 저개발국에서 더 높은 장 감염률이 면역 체계를 강화하여 H. pylori 감염의 결과를 제한할 수 있다는 것입니다. 또한 인도 식단의 주요 구성 요소인 고추의 높은 섭취량은 H. pylori 감염을 예방할 수 있다[40]. 이러한 사례들은 다양한 요인들이 서로 다른 인간 숙주 집단에서 H. pylori의 적합성에 기여한다는 가설을 뒷받침한다.

따라서 H. pylori 감염에서는 세균과 숙주의 적합성이 매우 중요하다. 특히 숙주의 유전적 요인은 H. pylori 감염과 연관된 병리학적 진행에 영향을 미칠 가능성이 높다. 실제로 IL-1β, IL-8, IL-10, TNF-α와 같은 사이토카인을 암호화하는 유전자의 특정 다형성은 염증 유발 반응 증가, 더 높은 집락화 및 감염률, 위암 발병 위험 증가와 연관되어 있다 [41-45]. 또한, 선천성 면역 유전자인 Toll-like receptor 4(TLR4)의 다형성은 H. pylori가 위 상피 세포에서 유발하는 신호 전달의 수용체로 작용하는 TLR4와 관련이 있기 때문에 중요합니다. 게다가, LOX, HAND1 및 APC와 같은 종양 억제 유전자의 프로모터 영역에서 과메틸화로 인한 후생유전학적 변화와 마이크로RNA(miRNA)의 변형 및 조절 이상은 H. pylori 감염 후 위암의 높은 유병률과 연관되어 있다[46,47] .

명백한 인간 병원체임에도 불구하고, 이 박테리아가 인간 숙주 내 공생균으로도 간주될 수 있다는 증거가 존재한다. 이 개념은 박테리아가 매우 많은 개인에게 존재함에도 불구하고 상대적으로 적은 증상이나 병리를 유발한다는 단순한 관찰로 뒷받침된다. 이는 H. pylori를 공생균으로 볼 것인지 병원체로 볼 것인지에 대한 문제를 제기한다. 왜냐하면 병리학적 상태는 H. pylori의 특정 특성과 연관될 뿐만 아니라 인간 숙주 내 일련의 특정 조건과도 연관될 가능성이 있기 때문이다.

H. pylori는 염증이 없는 상태에서 정상 구강 미생물군집의 일부이자 위 미생물군집의 일부로 확인되었다[48,49].

또한, H. pylori 감염은

위암 발병과는 관련이 없으나

재발 및 만성화와는 연관성이 있다고 보고되었다[50].

더욱이

위 미생물군집 내 H. pylori의 존재는

정상 미생물군집의 변화를 초래할 수 있다[21,23].

이러한 맥락에서,

여러 연구에서 헬리코박터 파일로리 감염에 긍정적 효과를 부여한 점을

언급할 가치가 있습니다.

여기에는

결핵을 유발하는 세균(결핵균) 억제, 천식, 크론병, 식도 역류, 설사 질환 및 식도암에 대한

보호 효과가 포함됩니다[9-14].

이러한 논란으로 인해, H. pylori 박멸이 숙주의 건강 상태 회복을 돕기 위해 권장되어야 하는지, 아니면 이 박테리아가 가질 수 있는 긍정적 효과를 제거하지 않으면서 궤양 및 선암의 발생을 방지하기 위해 박테리아의 독성을 제어하는 대체 전략을 개발해야 하는지에 대한 논의가 이루어지고 있다[51]. 이러한 점을 고려할 때, H. pylori가 광범위하게 연구되고 많은 치료법에서 중요한 표적으로 간주되는 것은 놀라운 일이 아니다.

H. PYLORI COLONIZATION: PROTECTION AND PROMOTION OF INFLAMMATORY DISEASES

Protective effect of H. pylori colonization

H. pylori infection is inversely associated with the development of some diseases, suggesting that the presence of these bacteria may also be beneficial to the host, as is the case for reducing the risk of obesity, childhood asthma, inflammatory bowel disease and celiac disease among others. In some cases the data available strongly support the notion that H. pylori presence is beneficial, while for others convincing data still remains at large (Figure 1 and Table 1).

H. PYLORI 집락화: 보호 효과와 염증성 질환 촉진

H. pylori 집락화의 보호 효과

H. pylori 감염은 일부 질환 발병과 역상관 관계를 보이며, 이는 비만, 소아 천식, 염증성 장질환, 셀리악병 등의 위험 감소 사례에서처럼 이 박테리아의 존재가 숙주에게 유익할 수 있음을 시사한다. 일부 경우, 이용 가능한 데이터는 H. pylori의 존재가 유익하다는 개념을 강력하게 뒷받침하는 반면, 다른 경우에는 아직 설득력 있는 데이터가 부족합니다(그림 1 및 표 1).

Figure 1.

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Helicobacter pylori and extra-gastric disease association. Green squares represent positive correlations between Helicobacter pylori (H. pylori) and the disease, while red squares represent inverse correlations between H. pylori and the disease. Multiple sclerosis is shown in red and green because there is information suggesting both positive and inverse correlations. NAFALD: Non-alcoholic fatty acid liver disease; T2DM: Type 2 diabetes mellitus.

헬리코박터 파일로리와 위 외 질환 연관성. 녹

색 사각형은 헬리코박터 파일로리(H. pylori)와 해당 질환 간의 양의 상관관계를,

빨간색 사각형은 H. pylori와 해당 질환 간의 음의 상관관계를 나타냅니다.

다발성 경화증은 양의 상관관계와 음의 상관관계를 모두 시사하는 정보가 존재하므로 빨간색과 녹색으로 표시됩니다. NAFALD: 비알코올성 지방간 질환; T2DM: 제2형 당뇨병.

Table 1.

Association of different diseases with the presence or absence of Helicobacter pylori

Disease

Association

Reference

Type/model of study

Sample size

Statistical analysis

H. pylori detection

Diagnosis of the pathology

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Different studies were analyzed considering the association of Helicobacter pylori (H. pylori) presence/absence with the corresponding disease (type of association), the type of study and model, the sample size, the type of statistical analysis employed, the method used for H. pylori detection and the method used for the disease diagnosis. Positive and inverse associations are indicated.

a

P < 0.05,

b

P < 0.01. NA: Indicates no association; IBD: Inflammatory bowel disease; IR: Insulin resistance.

Asthma: Asthma is characterized by a chronic hyper-responsiveness to specific and non-specific stimuli that favor obstruction of the airways, characterized by increased serum immunoglobulin E (IgE) levels combined with infiltration of the lungs by eosinophils, mast cells and activated CD4+ T-cells, a process orchestrated by effector T-helper 2 cells, implying the participation of the cytokines IL-4, IL-13, IL-5 and IL-9 in these events[52]. Several studies have proposed an inverse association between the presence of H. pylori infection and asthma, although this association is still controversial. While Holster et al[53] showed in a cohort of 545 children that there are no significant differences in H. pylori preval‎ence between children with asthma (7.1% vs 9.4%), others have shown either positive or negative effects. Significantly higher preval‎ence of asthma was reported in H. pylori positive compared to H. pylori negative children, based on a cohort study of 3759 children[54]. In contrast, studies involving more than 7000 adults[10,55] showed that H. pylori presence and also the CagA protein were inversely correlated with the development of asthma. More recently, Miftahussurur et al[15] reviewed several studies, surveys, cohort studies and meta-analyses in different European counties and in the United States of America (USA), involving a large number of persons. They concluded that there is a significant but weak inverse correlation between H. pylori infection, allergies and asthma, suggesting that H. pylori infection may have a beneficial protective role against development of these diseases [15].

The proposed mechanism involves the bacterial induction of naïve T cells, mainly in T helper 1 (Th1) rather than helper 2 (Th2) subsets[56,57]. On the other hand, it has also been observed that T-regulatory (Treg) cells are increased in the gastric mucosa of H. pylori- infected humans[58]. Moreover, the H. pylori virulence factors γ-glutamyl transpeptidase and VacA, induced Treg cells in the mouse gastric mucosa, resulting in the development of tolerance and a reduction in allergic responses[59]. Also, in a recent study using infant and adult airway epithelial cells infected with H. pylori, IL-8 synthesis increased 4-fold in infant versus adult cultures, suggesting that the infant epithelium elicits a higher immune response than the adult tissue. This mechanism is mediated by the H. pylori type IV secretion system and stimulation of the p38 MAP kinase pathway[60], and VacA was found to potentially also contribute to this mechanism.

천식: 천식은 특정 및 비특이적 자극에 대한 만성적 과민반응으로 기도 폐쇄를 유발하는 질환으로, 혈청 면역글로불린 E(IgE) 수치 증가와 함께 호산구, 비만세포 및 활성화된 CD4+ T세포의 폐 침윤이 특징이다. 이 과정은 효과기 T헬퍼 2 세포에 의해 조절되며, 사이토카인 IL-4, IL-13, IL-5 및 IL-9의 관여를 시사한다[52]. 여러 연구에서 H. pylori 감염과 천식 사이의 역상관 관계를 제안했으나, 이 연관성은 여전히 논란의 여지가 있다. Holster 등[53]은 545명의 아동 코호트 연구에서 천식 아동(7.1% vs 9.4%)과 비천식 아동 간 H. pylori 유병률에 유의미한 차이가 없음을 보였으나, 다른 연구에서는 긍정적 또는 부정적 효과를 보고하였다. 3759명의 아동을 대상으로 한 코호트 연구에서는 H. pylori 음성 아동에 비해 양성 아동에서 천식 유병률이 유의하게 높게 보고되었다 [54]. 반면, 7000명 이상의 성인을 대상으로 한 연구[10,55]에서는 헬리코박터 파일로리 존재 및 CagA 단백질이 천식 발병과 역상관 관계에 있음을 보여주었다. 최근 미프타후수루르 등[15]은 유럽 여러 국가와 미국에서 대규모 인원을 대상으로 한 여러 연구, 설문조사, 코호트 연구 및 메타분석을 검토하였다. 그들은 H. pylori 감염과 알레르기 및 천식 사이에 유의미하지만 약한 역상관 관계가 존재한다고 결론지었으며, 이는 H. pylori 감염이 이러한 질환 발병에 대해 유익한 보호 역할을 할 수 있음을 시사한다[15].

제안된 메커니즘은 주로 T 헬퍼 2(Th2) 하위집단보다는 T 헬퍼 1(Th1) 하위집단에서 미성숙 T 세포의 세균 유도 작용을 포함한다[56,57]. 반면, H. pylori 감염자의 위 점막에서 T조절세포(Treg)가 증가하는 현상도 관찰되었다[58]. 더욱이, H. pylori의 독성 인자인 γ-글루타밀 트랜스펩티다제(γ-GT)와 VacA는 생쥐 위 점막에서 Treg 세포를 유도하여 내성 발달과 알레르기 반응 감소를 초래했다[59]. 또한 최근 연구에서 H. pylori에 감염된 영아 및 성인 기도 상피 세포를 사용했을 때, 영아 배양군에서 성인 배양군 대비 IL-8 합성이 4배 증가하여 영아 상피가 성인 조직보다 더 높은 면역 반응을 유발함을 시사한다. 이 기전은 H. pylori의 IV형 분비 시스템과 p38 MAP 키나제 경로의 자극에 의해 매개되며[60], VacA도 이 기전에 잠재적으로 기여할 수 있는 것으로 밝혀졌다.

Inflammatory bowel disease: Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disease that develops as the consequence of a deregulated immune response. Interestingly, several studies have sought to establish a relationship between H. pylori infection and IBD. Higgins et al[61] demonstrated the effect of gastric H. pylori colonization on a distant bacterial-host immune system interaction in an experimental model of colitis. Also, H. pylori was shown to suppress the Th17 response to S. Typhimurium infection, but did not alter the Th2 or Treg response. Moreover, the authors showed that the co-infection by H. pylori/S. Typhimurium decreases inflammation in both the cecum and the stomach and that H. pylori infection induces IL-10 in the mesenteric lymph nodes, suggesting an extra-gastric mechanism for immunomodulation. Also, IBD protection is suggested to be linked to the cagA-positive status of the strain[62]. More recently, a meta-analysis performed by Castaño-Rodríguez et al[63] also revealed that H. pylori may exert an immunomodulatory effect and thereby favor the development of IBD.

염증성 장 질환: 염증성 장 질환(IBD)은 조절되지 않은 면역 반응의 결과로 발생하는 만성 염증성 장 질환이다. 흥미롭게도 여러 연구에서 H. pylori 감염과 IBD 간의 연관성을 규명하고자 시도해왔다. Higgins 등[61]은 실험적 대장염 모델에서 위 내 H. pylori 집락화가 원격 부위의 세균-숙주 면역 체계 상호작용에 미치는 영향을 입증했다.

또한 H. pylori는 S. Typhimurium 감염에 대한 Th17 반응을 억제하는 것으로 나타났으나, Th2 또는 Treg 반응에는 영향을 미치지 않았다. 더욱이 저자들은 H. pylori/S. Typhimurium 동시 감염이 맹장과 위 모두에서 염증을 감소시키고, H. pylori 감염이 장간막 림프절에서 IL-10을 유도하여 위 외부의 면역조절 기전을 시사함을 보여주었다. 또한 IBD 보호 효과는 균주의 cagA 양성 상태와 연관되어 있을 것으로 제안된다 [62]. 최근 Castaño-Rodríguez 등[63]의 메타분석에서도 H. pylori가 면역조절 효과를 발휘하여 IBD 발병을 치유할 수 있음을 밝혀냈다.'

Celiac disease: Celiac disease (CD) is an autoimmune disease whose preval‎ence in the USA has increased up to 4-fold in the past 50 years[64]. A cross-sectional study of patients who underwent esophago-gastroduodendoscopy with analysis of gastric and duodenal biopsies during a 4.5-year period showed that H. pylori preval‎ence was lower in patients with CD (4.4%) than in those without CD[65], indicating an inverse association between CD and H. pylori infection.

In the same context, a recent study including 324 children with confirmed CD, the H. pylori preval‎ence was compared with a reference group of non-celiac children referred for endoscopy. The results showed that the preval‎ence of H. pylori in patients without CD was significantly higher[18], indicating that CD and gastric H. pylori infection are inversely correlated.

The mechanistic link between H. pylori infection and CD remains to be elucidated. However, recently, Lucero et al[17] demonstrated that infection by CagA positive H. pylori induced Treg markers and that this may be protective against CD progression.

 셀리악병: 셀리악 질병(CD)은 자가면역 질환으로, 미국에서의 유병률이 지난 50년간 최대 4배까지 증가했다[64]. 4.5년간 위식도-십이지장 내시경 검사를 받고 위 및 십이지장 생검을 분석한 환자를 대상으로 한 단면 연구에서, CD 환자군(4.4%)의 H. pylori 유병률이 비(非) CD 환자군보다 낮은 것으로 나타났으며[65], 이는 CD와 H. pylori 감염 사이에 역상관 관계가 있음을 시사한다.

이와 유사하게, 최근 확인된 CD 환자 324명을 대상으로 한 연구에서는 위내시경 검사를 위해 의뢰된 비셀리악 아동 대조군과 헬리코박터 파일로리 유병률을 비교하였다. 그 결과, CD가 없는 환자에서 헬리코박터 파일로리 유병률이 유의하게 높았으며[18], 이는 CD와 위 헬리코박터 파일로리 감염이 역상관 관계에 있음을 시사한다.

H. pylori 감염과 CD 사이의 기전적 연관성은 아직 명확히 밝혀지지 않았다. 그러나 최근 Lucero 등[17]은 CagA 양성 H. pylori 감염이 Treg 표지자를 유도하며, 이는 CD 진행을 억제하는 보호적 역할을 할 수 있음을 입증하였다.

Multiple sclerosis: Emerging evidence suggests that H. pylori may also be inversely associated with neurodegenerative diseases. In this context, several studies have sought to establish an association between H. pylori infection and multiple sclerosis (MS), a chronic autoimmune, inflammatory and neurodegenerative disorder of the central nervous system[66].

In a meta-analysis of nine studies involving 2806 cases (1553 patients with MS and 1253 controls), Yao et al[67] found that the preval‎ence of H. pylori infection in MS patients was lower than that in control groups. Another meta-analysis of six observational studies involving 1902 participants showed also a statistically significant lower preval‎ence of H. pylori infection in patients with MS[68].

In spite of these studies, Efthymiou et al[16] in a cohort study of 129 patients and 49 controls, showed that anti-H. pylori antibody titers were higher in 129 MS patients than in 48 healthy controls. Additionally, anti-H. pylori hsp 60 seropositivity correlated with age at disease onset, suggesting a possible role of this factor in the pathogenesis of MS[16].

In this context, it has been proposed that the inflammatory mediators induced by H. pylori infection might impact on the nervous system and induce damage[69]. Additionally, circulating pro-inflammatory cytokines, such as IL-17, and reactive oxygen species (ROS) can reach the CNS and induce damage[70]. Moreover, recent reports implicate the Galectin-3 receptor, a leptin receptor that is stimulated by H. pylori, in inducing a pro-inflammatory response via TLRs. Activation of these receptors in the CNS, triggers an inflammatory response mediated by interferon (IFN)-γ and TNF-α that is associated with neuro-pathophysiological changes [70].

다발성 경화증: 새롭게 제시된 증거에 따르면 헬리코박터 파일로리(H. pylori)는 신경퇴행성 질환과도 역상관 관계가 있을 수 있다. 이러한 맥락에서 여러 연구에서 헬리코박터 파일로리 감염과 중추신경계의 만성 자가면역성 염증성 신경퇴행성 질환인 다발성 경화증(MS) 간의 연관성을 규명하고자 시도하였다[66].

2806명의 사례(MS 환자 1553명, 대조군 1253명)를 대상으로 한 9건의 연구를 메타분석한 결과, Yao 등[67]은 MS 환자에서 H. pylori 감염 유병률이 대조군보다 낮다는 사실을 발견했습니다. 1902명의 참가자를 대상으로 한 6건의 관찰 연구에 대한 또 다른 메타 분석에서도 MS 환자에서 H. pylori 감염의 유병률이 통계적으로 유의하게 낮은 것으로 나타났습니다[68].

이러한 연구들에도 불구하고, Efthymiou 등[16]은 129명의 환자와 49명의 대조군을 대상으로 한 코호트 연구에서, 129명의 다발성 경화증 환자에서 48명의 건강한 대조군보다 H. pylori 항체 역가가 더 높다는 것을 보여주었다. 또한, H. pylori hsp 60 항체 양성률은 발병 연령과 상관관계를 보였는데, 이는 이 인자가 다발성 경화증의 병인에서 가능한 역할을 시사한다 [16].

이러한 맥락에서, 헬리코박터 파일로리 감염에 의해 유발되는 염증 매개체들이 신경계에 영향을 미쳐 손상을 유발할 수 있다는 가설이 제기되었다[69]. 또한, IL-17과 같은 순환성 전염증성 사이토카인과 활성산소종(ROS)이 중추신경계(CNS)에 도달하여 손상을 유발할 수 있다[70]. 또한 최근 보고에 따르면 헬리코박터 파일로리가 자극하는 렙틴 수용체인 갈렉틴-3 수용체가 TLR을 via로 염증성 반응을 유도하는 것으로 밝혀졌다. 중추신경계에서 이러한 수용체의 활성화는 인터페론(IFN)-γ 및 TNF-α에 의해 매개되는 염증 반응을 유발하며, 이는 신경병리생리학적 변화와 연관된다[70].

Negative effect of H. pylori colonization

Despite these observations suggesting a protective role for H. pylori against several diseases, there is a large body of literature associating H. pylori infection with the development of gastric diseases, such as peptic ulcer diseases, gastric adenocarcinoma, MALT lymphoma and biliary tract[71]. Moreover, the positive correlations between H. pylori and disease conditions have also been noted for extra-intestinal diseases, such as dermatological diseases, heart diseases, obesity, anemia, insulin resistance and non-alcoholic fatty liver disease, among others (Figure 1 and Table 1). In most of these cases, disease development is associated with the chronic inflammatory response that the infection triggers in the host.

Ischemic heart diseases: H. pylori has been suggested to contribute to the development of coronary heart diseases (CAD). In a meta-analysis of 26 studies, including more than 20000 patients, Liu et al[4] observed a significant association between H. pylori infection and the risk of myocardial infarction. In the same context, Shmuely et al[3] in a cohort study of 173 patients and 127 controls, observed that H. pylori infection was significantly higher in CAD-positive patients than in CAD-negative subjects, suggesting a positive correlation between H. pylori seropositivity and CAD. In addition, in a retrospective cohort study by Huang et al[72], involving 17332 patients with H. pylori infection and 69328 randomly selected age- and gender-matched controls, a more specific association between chronic H. pylori infection and ischemic stroke was observed since patients diagnosed with H. pylori infection exhibited a higher incidence rate of ischemic stroke. Despite such observations suggesting that the presence of H. pylori favors the development of heart disease, the mechanisms involved remain to be determined. However, because chronic inflammation is believed to be associated with an increased risk of atherosclerosis[73], this may in an indirect manner explain the augmented risk of heart disease associated with H. pylori infection.

Anemia: An association between H. pylori infection and iron deficiency was proposed based on studies showing that for individuals with idiopathic iron deficiency anemia of unknown origin and no evidence of bleeding due to lesions, iron deficiency anemia was no longer observed in any of the follow-up examinations following eradication of H. pylori[74]. In a recent retrospective cohort study, Xu et al[6] eval‎uated the relationship between anemia and H. pylori infection in 17791 subjects. They observed a higher probability for anemia in H. pylori positive populations coincident with lower hemoglobin levels.

Recent studies suggest that the mechanism involves changes in the intracellular iron distribution associated with the uptake and trafficking of H. pylori through the cells[75], since H. pylori uptake by gastric cells is associated with an increase in total cellular iron content and its homeostasis depends on the transferrin receptor[76]. Indeed, a study by Flores et al[75] showed that H. pylori infection is associated with an increase in the total intracellular iron levels, redistribution of the transferrin receptor from the cell cytosol to the cell surface, and increased levels of ferritin. Moreover, Kato et al[77] showed that the SabA gene is highly expressed in bacterial isolates from iron deficient anemia patients, suggesting a role for this virulence factor in the development of anemia.

Non-alcoholic fatty liver disease: Non-alcoholic fatty acid disease (NAFLD) has also been suggested to be associated with H. pylori infection. In this context, a large number of reports, including cross-sectional studies, case reports and randomized-controlled studies have revealed a strong association between NAFLD and H. pylori infection[7]. In addition, it has been demonstrated in an animal model of H. pylori infection that the orally inoculated bacterium can reach the liver and cause hepatitis[78].

H. pylori infection may induce NAFLD by producing chronic systemic inflammation, increasing the levels of inflammatory cytokines, such as IL-6 and TNF-α, and activating NF-κB pathway, which induce insulin resistance (IR)[79]. The mechanisms of the pathogenesis of H. pylori-related inflammation in NAFLD involve directly reducing hepatocyte glycogen levels via a JNK signaling pathway[80], which in turn can down-regulate the expression‎ of key genes involved in glucose metabolism and accelerating lipolysis[81], thereby contributing indirectly to the development of IR. In addition, H. pylori may also induce white adipose tissue to release leptin, and then promote liver stearoyl- CoA desaturase, favoring the accumulation of fat deposits in the liver tissue[79].

Insulin resistance: Several studies have revealed a strong association between H. pylori and IR. In 2005, Aydemir et al[82] confirmed the existence of a positive correlation between chronic H. pylori infection and IR by showing that the homeostasis model assessment (HOMA-IR) of H. pylori positive subjects was significantly higher compared with H. pylori negative individuals. In another large cross-sectional study including 1,107 subjects, H. pylori seropositivity was significantly higher for patients with IR (HOMA-IR ≥ 2.5)[83]. Subsequent studies also confirmed the causal relationship between H. pylori and IR[84-86].

Mechanistically, H. pylori-induced IR may be caused indirectly by chronic inflammation or directly by activating certain signaling pathways. Several reports have confirmed that chronic inflammation is important for IR onset[87] and H. pylori-mediated chronic inflammation may increase the expression‎ of C-reactive protein, TNF-α, and IL-6[88,89]. These cytokines activate IKK/NF-κB and JNK pathways, which may trigger IR by increasing insulin receptor phosphorylation on serine[81] or by inhibition of insulin receptor substrate-1 phosphorylation on tyrosine residues[90].

Despite such evidence, a recent systematic review revealed that H. pylori eradication does not improve insulin resistance, but may increase body weight (BW) and the body mass index (BMI), suggesting that further studies are needed to clarify the effect of H. pylori eradication on metabolism [8].

Type 2 diabetes mellitus: The association between Type 2 diabetes mellitus (T2DM) and H. pylori infection is controversial. Some studies indicate that the preval‎ence of H. pylori is higher in diabetic compared with non-diabetic patients[91,92], while others indicate that there are no differences between those groups[93]. Nevertheless, more recently, He et al[94] discussed the possibility that this controversy is likely due to inconsistencies in the methods used to define H. pylori positivity, diabetic status and the reduced sample sizes, among other limitations. More recently, a meta-analysis including 57397 individuals showed that there is significantly higher preval‎ence of H. pylori infection in diabetic type 2 patients as compared with healthy individuals[5].

The possible mechanisms linking H. pylori to diabetes include alterations in IR signaling, inflammation, accumulation of ROS and oxidative DNA damage in the gastric mucosa. It has been reported that ROS levels and oxidative DNA damage increase due to neutrophil infiltration in H. pylori-infected patients[95]. Moreover, a recent study performed in 100 patients showed increased serum levels of oxidative DNA damage (8-OHdG) and oxidized low-density lipoprotein in T2DM patients positive for H. pylori infection[96].

Periodontitis: Periodontitis is characterized by the accumulation of bacterial plaque at the gingival margin, which induces an inflammatory response that leads to destruction of the connective tissue attachments to teeth, alveolar bone resorption and tooth loss[97]. The recent Global Burden of Disease Study (1990-2010) indicates that severe periodontitis is the 6th most preval‎ent disease worldwide, with an overall preval‎ence of 11.2%, although mild forms of this disease may reach over 90% of the population in developing countries[98]. Remarkably, periodontitis has also been linked to an increased risk in developing atherosclerosis, diabetes, rheumatoid arthritis and cancer[99-103]

Moreover, the oral cavity might represent a reservoir for H. pylori[104]. In a recent cross-sectional study that included 70 patients and 70 controls it was reported that the presence of H. pylori in dental plaque correlates with periodontitis and that the correlation appears to be better in severe forms of the disease [105]. Additionally, a study involving 40 patients (32 periodontitis and 8 controls) showed that periodontal disease positively correlates with gastric and oral H. pylori (P < 0.005)[106]. In this study, in spite of the small number of controls, it was shown that 70% of periodontitis patients have biopsies positive for H. pylori. Also, it is important to mention that 81% of periodontitis patients were positive for H. pylori in oral plaques.

Recently, Hu et al[107] demonstrated that H. pylori infected patients have worse periodontal parameters than non-infected individuals, suggesting that infection correlates the progression of the disease. This study also showed that the presence of periodontitis-associated bacteria was significantly higher in subjects with H. pylori infection than those without H. pylori infection. Moreover, the expression‎ of inflammatory molecules, such as IL-8, IL-6 and IFN-γ significantly increased after H. pylori infection. Interestingly, those effects were associated with the presence of CagA[107].

ROLE OF INFLAMMATION IN H. PYLORI MEDIATED DISEASES

H. pylori infection triggers several adaptative cellular mechanisms in host cells that may favor gastric cancer development and progression[108]. However, whether the disease develops or not and the final outcome are thought to depend largely on the extent of inflammation promoted by the bacteria in the host during the pre-neoplastic process[109]. Indeed, chronic inflammation is a common causative event associated with the development of several types of cancer[110,111] and, as was demonstrated in animal models, H. pylori infection is considered the major factor responsible for gastric epithelial damage and deregulation of signaling leading to irreversible epigenetic changes in the gastric mucosa, a consistent hallmark observed during the gastric carcinogenic cascade[19,109]. Initially, H. pylori-related studies focused on identifying the virulence factors implicated in these processes. Those factors epidemiologically associated with a higher risk of developing gastric cancer were tested in vitro and shown to induce signaling pathways associated with exacerbated inflammatory responses. For example, strains harboring particular vacA and cagA allele variants were found to induce elevated inflammatory responses in infected cells[112]. However, this seemingly simple scenario rapidly transited to a more complex one when epidemiological data revealed that in certain ubiquitously infected populations no correlation with elevated gastric cancer incidence was detected, as is the case for the so-called African enigma[113] where only a minor percentage of infected patients progress to develop cancer. To date, experimental studies have clarified that final disease outcome depends not only on the contribution of certain bacterial virulence factors, but also on host susceptibility, diet and environmental factors[114]. Here, it is important to mention that co-existence with the bacteria is not only to be viewed negatively (see previous and following chapters), bearing in mind that since the preval‎ence of the infection has declined in developed countries over the last decades, several disorders have emerged as a consequence of the lack of exposure to H. pylori[115]. Human beings have co-evolved with the bacterium and gastric as well as extra-gastric physiology has been conditioned to such association[116]. In order to persist in the gastric niche, H. pylori have evolved mechanisms necessary to evade and to attenuate the innate and adaptive immune systems by several mechanisms, including those implicated in evasion of recognition by pattern recognition receptors, inhibition of phagocytic killing, inhibition of killing by ROS and nitric oxide, among others[117]. Particularly, antigenic phase variation, modulation of adhesion molecules, immune inhibition by VacA protein and lipopolysaccharide (LPS) have been widely described[118]. Moreover, additional mitigating local mechanisms mediated by bacterial enzymes exist. For instance, it was recently reported that the expression‎ of a cholesterol-α-glucosyltransferase reduced cholesterol levels in gastric epithelial cells, blocking IFN-γ signaling, a classical Th1 cytokine[119]. Notably, this enzyme is present in most Helicobacter species and cholesteryl α-glucosides are also involved in resistance to antibiotics[120], interference with phagosome trafficking[121], H. pylori type IV secretion system function[122] and immune evasion by inhibiting T-cell activation[123]. On the other hand, H. pylori superoxide dismutase (SOD) has been shown to suppress the production of pro-inflammatory cytokines during in vivo infection by reducing oxidative stress. Thus, SOD from H. pylori can inhibit the production of pro-inflammatory cytokines during in vivo infection[124]

Additionally, H. pylori deregulates adaptive immune responses by interfering with antigen presentation and modulation of T-cell responses[117,118]. Eradication of H. pylori has revealed the importance of this modulation of the immune response in preventing the development of extra-gastric immune and inflammatory disorders, such as gastroesophageal reflux disease, childhood asthma and allergy, as well as metabolic disorders[15,52,54]. Although in most of the cases correlations are derived from cross-sectional studies, the most experimentally validated preventive association is the appearance of childhood asthma[115,125]. Moreover, innate immune responses are also involved, given that bronchial epithelial cells, mast cells, basophils, natural killer T cells and dendritic cells (DC) also produce inflammatory mediators[52]. This harmful effector response is modulated by CD24+CD25+ regulatory cells (Treg) present in the lung, which secrete anti-inflammatory cytokines, such as IL-10 and transforming growth factor beta (TGF-β), preventing or modulating the Th2 responses to allergens[126]. Tregs of healthy individuals shift allergen-specific immune responses toward tolerance, thereby preventing the development of asthma and other allergic disorders[52]. Also in animal models of infection, the importance of dendritic cells in H. pylori-specific adaptive immune responses was noted. Particularly tolerance induction[52,127], Treg skewing and Th17 suppression observed in mice occurred in a cagA- and vacA-independent manner[128]. Chronic exposure to H. pylori impairs dendritic cell function and inhibits Th1 development[129]. Also, H. pylori-mediated protection was linked to IL-10-secretion by peripheral blood Treg cells[130].

The importance of these immune cells has been validated in experimental animal models of infection or induced asthma. For instance, blocking CD24+CD25+ Treg cells by a CD25-neutralizing antibody abrogated Treg cell tolerance promoted by H. pylori infection and enhanced pulmonary inflammation following albumin induced asthma[131]. Also, KO animals for IL-10, TGF-β or animals depleted of Tregs, develop gastritis to an elevated extent in response to H. pylori infection. Although these animals are able to clear the infection, pre-neoplastic lesions develop since Th1 responses predominate[52]. Together, these results indicate that tolerance rather than immunity protects against H. pylori-induced gastric pre-neoplastic lesions[132]. Accordingly, decreased Treg cell function is associated with an increase in peptic ulcer development upon H. pylori infection[133].

A currently unresolved question is how H. pylori promotes tolerance in distant organs such as the lung? A recent study showed that systemic and mucosal pre-administration of recombinant neutrophil-activating protein prevented ovalbumin-induced allergic asthma in mice, indicating that secreted virulence factors may be responsible[134]. What determines the balance between tolerance or elimination of an exacerbated Th1 type chronic inflammation could be explained in part by host hyperreactivity to allergens or bacterial infection. In this respect, pro-inflammatory cytokine polymorphisms are generally thought to participate in the genesis of gastric and other types of cancer[109] and interleukin family cytokines, like IL-1β and IL-18, have emerged as central mediators of mucosal inflammation[135]. On the other hand, virulence factors can determine the type of response. For instance, blocking the TLR4 in a mouse model using a specific antibody prior to H. pylori infection, was shown to reduce the number of T-cell effectors (Th1 and Th17) and diminish the immune response[136]. In agreement with this observation, activation of TLR4 signaling was reported to be associated with gastric cancer progression by inducing mitochondrial ROS production[137]. Moreover, type I H. pylori (cag PAI+ and vacuolating toxin A+, VacA+) LPS exhibited a stimulatory effect on TLR4 signaling followed by mitogen oxidase 1 activation in cultured gastric pit cells through the lipid A portion of LPS[138]. In a similar study, LPS from some H. pylori strains were shown to act as TLR4 antagonists, which may contribute to more beneficial clinical outcomes of H. pylori infection in host individuals[139]. Additionally, H. pylori LPS from type I, but not type II strains, promotes cytotoxicity in cultured gastric mucosal cells[140]. Conversely, TLR2 mediates H. pylori-induced tolerogenic immune responses[141] and TLR9 signaling has anti-inflammatory effects during the early phase of H. pylori-induced gastritis in mice[142]. Also, additional virulence factors have been implicated in immune response suppression or tolerance, such as the suppression of dendritic cells by OipA in vitro[143], promotion of immune tolerance by VacA-mediated inhibition of T-cell proliferation and antigen-presentation[59]. Also, bacterial gamma-glutamyl transpeptidase[59] and outer membrane vesicles inhibit T-cell responses[144,145]. Furthermore, H. pylori infection has been associated inversely with IBD. Experimental immuno-regulatory properties of the H. pylori genome and particularly the immuno-regulatory sequence TTTAGGG was demonstrated to down-regulate dendritic cell-mediated production of pro-inflammatory cytokines both in an in vitro and in vivo model[146].

H. PYLORI COLONIZATION AND ITS ASSOCIATION WITH MICROBIOME SHIFTS

As discussed above, H. pylori infection has been associated both positively and negatively with the development of gastric and non-gastric diseases. Disease development is often linked to chronic inflammatory responses induced by H. pylori, as was discussed in the previous section. However, it is now becoming increasingly clear that H. pylori also induces changes in the host by altering the microbiome. This aspect will be covered in the following paragraphs.

The harsh gastric environment is thought to represent a key limitation to the complexity of the stomach microbiota[147]. This assumption, together with limitations imposed by culture-dependent strategies for bacterial identification, has historically leaded to an underestimation of the biodiversity in the stomach. In this context, the gastric microbiota was initially considered to include only a very select group of taxa, including mainly Veillonella spp., Lactobacillus spp., and Clostridium spp., besides -of course- H. pylori[148-151]. Nonetheless, with the development of more sophisticated 16S rRNA-based bacterial identification techniques, we now have gleaned deeper insight to the complexity of the gastric microbiome. Accordingly, an increasing number of publications describe greater ecosystem diversity in the stomach and, importantly, correlate the presence of H. pylori with variations in the composition of the microbiome[23,48,152-156]. Bik et al[152] identified taxa, such as Caulobacter, Actinobacillus, Corynebacterium, Rothia, Gemella, Leptotrichia, Porphyromonas, Capnocytophaga, TM7, Flexistipes, and Deinococcus in the normal microbiome. Alternatively, Li et al[155] showed that the most common genera in gastric biopsies from both normal and non-H. pylori gastritis individuals were Prevotella, Neisseria, Haemophilus, and Porphyromonas. Later, Delgado et al[153] also identified Propionibacterium, Lactobacillus and Streptococcus as dominant genera in healthy samples.

Regarding the effect of H. pylori on the gastric microbiome, there is still some controversy. No effect on either diversity and/or evenness in community members between H. pylori-positive vs H. pylori-negative samples were observed at the phylum level[152]. Likewise, in a mouse model of H. pylori infection, neither acute nor chronic H. pylori infection altered the murine gastric microbiota[157]. Similarly, others described that, although when present H. pylori dominates the microbiome, only minor differences in community structure were observed in stomach biopsies from H. pylori-positive and negative subjects[158]. However, others have shown that the presence of H. pylori dramatically reduces the diversity of the gastric microbiota[20,21,23] and modifies the microbiome by increasing the relative abundance of Proteobacteria, Spirochetes and Acidobacteria, while decreasing Actinobacteria, Bacteroidetes and Firmicutes[156]. Similar results were reported by Thorell et al[30], who performed a meta-transcriptomic analysis and reported higher levels of Firmicutes, Bacteroidetes, and Actinobacteria in subjects with low levels of H. pylori. Such discrepancies might be due to inter-subject variations, since the gastric microbiome seems to be sensitive to exogenous factors, such as diet and lifestyle, as has been shown by the analysis of monozygotic twins[159].

Interestingly, while the experimental inoculation of H. pylori into an established community in rhesus monkeys, did not affect the community membership or structure[160], pre-infection of mice with H. pylori did alter the microbiota structure in the stomach[22]. Therefore, the time-point in life when H. pylori is acquired is another aspect to be considered in the discrepancies reported for H. pylori-associated microbiome variations. Differences in both diversity and community composition were also observed in the stomachs of H. pylori-infected vs H. pylori-negative children and also in comparison to adults, regardless of the H. pylori status[161]. Thus, early acquisition of the bacterium is likely to shape the microbiome by inducing local modifications in the stomach environment. One of these effects is driven by the production of ammonia and bicarbonate from urea[162,163]. Such compounds may serve as substrates for other bacteria[164], in addition to altering the stomach pH[162,163], which facilitates the colonization by other species, such as nitrogen-reducing bacteria[165]. Moreover, H. pylori-induced increases in the stomach pH favor the migration to the stomach of some bacterial taxa that are usually restricted to the intestinal tract (Bacteroides and Clostridia) in mice[166]. Interestingly, the effect of H. pylori on acid secretion depends on the pattern of gastritis that is induced[167]. In predominantly antral gastritis, the production of gastric acid is increased (hyperchlorhydria)[168], while in predominantly corpus gastritis, acid production decreases (hypochlorhydria)[169]. Thus, microbiome shifts may differ in both cases. In fact, hyperchlorhydria increases microbial diversity in the stomach[170] and it has been implicated in the development and progression of cancer (reviewed by Espinoza et al 2018[171]). Additionally, the viscosity of the gastric mucus layer decreases when the pH increases[172], making it easier for other microorganisms to colonize the epithelium. Finally, H. pylori can directly alter the mucus barrier by modulating the expression‎ of stomach mucins[173].

As illustrated above, all these environmental modifications in the stomach may impact on the local microbiome, as well as induce changes in the entire gastrointestinal tract, since these are dynamic compartments between which fluids are exchanged and therefore microbes can easily migrate from one gastrointestinal segment to another[174]. Some of these H. pylori-mediated downstream effects in other compartments include impairment in the absorption of iron and vitamin B12 in the intestine[175,176], and alterations in carbohydrate and amino acid metabolism of the host[177]. Interestingly, besides the direct effect of H. pylori in the stomach/intestine, also the immune response triggered by the bacterium could affect the local microbiome, as well as bacterial populations at more distal sites in the human body.

Regarding the effect of H. pylori-mediated immune mediators in the microbiome, there are some contradictory reports. No statistically significant differences in the microbiota were found in CagA-positive (n = 10) compared to CagA-negative (n = 10) biopsies from human subjects[178]. Therefore, the increased production of pro-inflammatory cytokines mediated by CagA appears not to have an effect on the microbiome in this model. Nonetheless, as the sample cohort was small in that study, this question probably needs to be re-eval‎uated in larger groups of samples. In contrast, in a transgenic Drosophila model of CagA expression‎, CagA was sufficient to alter midgut host microbiota[179]. Additionally, a series of reports demonstrated differences in the intestinal microbiome related to the presence of H. pylori both in humans[180] and mice[22]. Moreover Schulz et al[158] correlated the presence of H. pylori in human individuals with modifications in the microbiome of the duodenum and the oral cavity. More specifically, Heimesaat et al[181] demonstrated that chronic infection of Mongolian gerbils with H. pylori resulted in changes in some specific genera, including increased abundance in the large intestine of Akkermansia, which is involved in mucus degradation. These changes were accompanied by variations in the expression‎ of immunity-related genes in both the stomach and the lung, with stronger effects in the former. The authors speculated that early community shifts could reflect changes in the niche microenvironment (e.g., altered gastric pH), while later shifts might be driven by the cumulative changes in the immune/inflammatory response triggered by H. pylori. These effects could also be observed at distant sites in the host organism and be driven by other members of the Helicobacter genus. For instance, natural colonization of the mouse digestive tract with Helicobacter hepaticus leads to a shift in gut microbiota, which generates subclinical inflammation and a drastic impairment of the control of Mycobacterium tuberculosis growth by the immune system[182].

It is likely that H. pylori might affect mucosal diseases at distant sites via its effects on immune cells that traffic through lymphatic vessels. H. pylori also induces a shift in the immune response toward an induction of Treg cells, mediated by VacA and GGT[59,161,183,184]. Treg cell responses are important in differentiating between self and foreign antigens, i.e., immunological tolerance. This effect could be involved in H. pylori persistence in the stomach, and also could contribute to suppressing gastric inflammation, which may explain reduced gastric disease severity in H. pylori-positive children compared to H. pylori-positive adults[161]. Such effects have been linked to alterations in the stomach physiology and its microbiota, as well as to progression of extra-gastric diseases, such as asthma[59], celiac disease[17], ischemic heart diseases, insulin resistance, Type 2 diabetes mellitus, periodontal diseases, among others (see previous sections and references listed in Table 1).

Interestingly, as was stated above, H. pylori is part of a complex microbiota in the stomach and its presence has been linked to modifications in the microbiome at other sites in the body. Therefore, it is reasonable to speculate that other community members could also contribute to changes observed following H. pylori infection of the host. Indeed, direct bacteria-bacteria interaction was described by Khosravi et al[185] between H. pylori and Streptococcus mitis, in which H. pylori transit from spiral to coccoid-shaped cells that are more resistant to stressing conditions. The exact effect of this conversion on disease progression remains to be elucidated. Also, antimicrobial molecules produced by Lactobacillus spp have been shown to be active against H. pylori strains[186-189]. Therefore, bidirectional communication and modulation between H. pylori and other community members occur, and the combination of all these interactions will be reflected in the host health status. The question as to how the microbiota shapes the immune system and how this affects its response to some diseases has been broadly discussed in the literature (see for instance, Hooper et al[190] 2012). Therefore, modifications in the microbiome induced by early acquisition of H. pylori[161] may also determine the host immune status and, as a consequence, the development of a number of systemic diseases. This is relevant, since Rolig et al[191] reported that when the microbiota is altered by antibiotic treatment, the H. pylori-triggered inflammation is reduced.

CONCLUSION

In summary, H. pylori has a strong effect in the stomach microenvironment and also on the host immunological status, leading to shifts in the microbiome at different sites of the body. These shifts are involved not only in the pathogenesis of gastric diseases, but also in some of the non-gastric H. pylori-related diseases that were discussed in this review. The question as to whether the bacterium is acquired early on or later in life is a key point when analyzing such effects, as H. pylori has been reported to co-evolve with its host, shaping the immune system and consequently, the microbiome. Therefore, a better understanding of the exact mechanisms involved in such effects, as well as the H. pylori-induced microbiome shifts that may be related to the development of specific diseases, will likely be useful to predict and hopefully prevent H. pylori-associated diseases. Ideally, one would aspire to achieving this goal while at the same time preserving the beneficial effects that H. pylori-host co-habitation appears also to offer.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Chile

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Conflict-of-interest statement: No potential conflicts of interest. No financial support.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Peer-review started: April 10, 2018

First decision: April 26, 2018

Article in press: June 27, 2018

P- Reviewer: Caruso R, Martini F S- Editor: Wang JL L- Editor: A E- Editor: Yin SY

Contributor Information

Denisse Bravo, Oral Microbiology Laboratory, Pathology and Oral Medicine Department, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile.

Anilei Hoare, Oral Microbiology Laboratory, Pathology and Oral Medicine Department, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile.

Cristopher Soto, Oral Microbiology Laboratory, Pathology and Oral Medicine Department, Faculty of Dentistry, Universidad de Chile, Santiago 8380492, Chile.

Manuel A Valenzuela, Advanced Center for Chronic Diseases, Institute for Health-Related Research and Innovation, Faculty of Health Sciences, Universidad Central de Chile, Santiago 8380447, Chile.

Andrew FG Quest, Advanced Center for Chronic Diseases, Center for Studies on Exercise, Metabolism and Cancer, Biomedical Science Institute, Faculty of Medicine, Universidad de Chile, Santiago 8380447, Chile.

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