Helicobacter pylori Infection: A 40-Year Journey through Shifting the Paradigm to Transforming the Management

The first publication of Helicobacter pylori (H. pylori) 1983 coincided with the first edition of this Journal, Digestive Diseases, and set the scene for a fundamental revision of understanding gastric pathophysiology and for re-visiting the clinical chapters on gastroduodenal diseases [1]. The long-held dogma of the stomach being a sterile organ, protected by its acidity from bacterial colonization invalidated by the discovery of H. pylori infection.

H. pylori was rapidly identified as a cause of gastritis and soon recognized to be the principal cause of peptic ulcer disease (PUD). This epoch-making milestone in Medicine revolutionized the management of PUD and anti-infective drugs became an essential part of treatment regimens. Eradication of H. pylori resulted in the permanent cure of PUD with prevention of further relapses. In recognition of the discovery of H. pylori and their pioneering work in PUD, the Nobel Prize 2005 in Medicine and Physiology was awarded to Barry Marshall and Robin Warren, from Perth in Western Australia.

As research progressed, H. pylori became recognised as the main risk factor in the multifactorial pathogenesis of gastric cancer [2‒4]. And this opened the doors to explore realistic options for gastric cancer prevention strategies [5].

The discovery of Campylobacter pyloridis was a stroke of brilliance. It required an inspired mind to see what generations of pathologists and investigators had not seen or had misinterpreted when they applied conventional methods for the histological assessment of gastric biopsies.

Robin Warren identified spiral microorganisms on the gastric epithelial surface and observed the constant association with an inflammatory cell infiltrate, predominantly polymorphonuclear cells, within the gastric mucosa [1, 2]. This inflammatory pattern with polymorphonuclear- and lympho- plasma cellular infiltration, typically found in conjunction with bacterial infections, prompted him to suggest a causal role for these microbes in the pathogenesis of chronic active gastritis. The discovery became confirmed by isolation and culture of the spiral bacteria from biopsies of patients with chronic active gastritis [1]. The high density of the bacteria reported at the antrum-prepyloric biopsy site and the morphological similarity with intestinal Campylobacters led to the initial name Campylobacter pylori. After further study, it was clear that the spiral-shaped bacterium was distinct from the Campylobacter genus and the bacterium was reclassified in 1989 according to distinct taxonomic criteria and assigned to a new genus, and the species named H. pylori [6].

The discovery of H. pylori opened new directions and imperatives for basic and clinical research in gastroduodenal pathologies, particularly gastric cancer and attracted scientists and clinicians across medical, biological, and technical disciplines. The aim of this paper was to provide a short illustration of the H. pylori journey, with inevitable personal bias, and a selection of clinical highlights which contributed to advancing clinical management along these past 4 decades (Fig. 1).

The initial period following the discovery of H. pylori was the most exciting but troubled time with a decade which became a truly scientific battlefield. There were on one side enthusiasts were embarking on research to understand the pathogenetic role of this new bacterium and on the other sceptical opponents who rejected any causal role of the organism in gastroduodenal disease. Initially, research focused on the pathogenicity of H. pylori as a cause of chronic gastritis and PUD. The proof of H. pylori causality of chronic gastritis came from the fulfilment of Koch’s postulates by the individual self-experiments of Barry Marshall and Arthur Morris, both of whom ingested a broth containing live H. pylori organisms and both became infected and subsequently developed gastritis. Gastric inflammation was associated with an impairment in the gastric acid secretory function and a complete morphological, as well as functional recovery took place after elimination of the microorganisms [7, 8].

Already in those early years, specific bacterial virulence factors related to colonization, survival and cytotoxicity of H. pylori were detected and paved the way for ongoing intense research on the bacterial pathogenicity [9‒11]. In the increasing list of key virulence factors, the discovery of the cag pathogenicity island accelerated our understanding of the H. pylori pathogenicity in the interaction with the host defences and immunological response [12‒15].

The demonstration of the causal role of H. pylori in PUD was increasingly complex and relied on studies involving basic physiology, pathology, and clinical trials. In duodenal ulcer, a critical clue to the role of H. pylori in pathogenesis was the predilection for colonizing the gastric antrum where the inflammation disrupted gastric hormonal homeostasis resulting in hypergastrinemia and hyperchlorhydria. Subsequent to this hyperacidity in the duodenal bulb results in gastric metaplasia which becomes the exclusive target epithelium for the focal colonization by H. pylori with induction of a “locus minoris resistentiae” and the eventual possible development of duodenal ulcer [16, 17]. Unravelling the pathogenetic role of H. pylori infection had profound influence on the development of novel treatment strategies in PUD. The initial approaches to H. pylori eradication treatments were in the form of mono- and dual therapies and included drugs including bismuth salts, metronidazole, and amoxicillin, in most cases with the addition of an acid suppressant (e.g., H₂-receptor antagonists). Anti-infective drugs in such combination regimens were superior when compared to H₂-RA alone (standard of care in ulcer treatments at the time) in preventing duodenal ulcer recurrence within 1 year. The first study to demonstrate that duodenal ulcer relapse within 12 months did only exceptionally occur with a negative posttreatment Campylobacter pylori (H. pylori) status has been using bismuth monotherapy [18]. Antibacterial drugs used in mono- and dual regimens were effective in transient suppression of the infection, but most of the time they did not achieve a permanent eradication of H. pylori infection [19, 20]. With recrudescence of H. pylori infection, PUD recurrence also occurred but with some delay. A key turning point was the successful introduction of triple therapy which achieved a high eradication rate combined with a permanent cure of PUD [21].

This heralded the new era in the management of PUD, but it took a further decade before the new treatment concept of treating H. pylori infection became accepted and widely introduced into clinical practice [22]. Initial obstacles for the broad acceptance of H. pylori eradication for the cure of PUD were the high number of pills or capsules, with two or up to three antibiotics combined, considerable side effects, difficulties of adherence for patients to this prescribed this new modality of treatment as compared to an H₂-RA and last but not least, the persisting scepticism of family physicians, and still some gastroenterologists. The breakthrough in the clinical implementation of the H. pylori eradication strategy came with the introduction of proton-pump inhibitor (PPI)-based triple therapies during the second decade (vide infra).

An essential contribution for this rapid clinical development and management of H. pylori was the early introduction of endoscopy-based diagnostics (rapid urease test, histology, culture) and non-invasive testing by serology and ¹³C (¹⁴C) – urea breath testing [23‒26]. Testing for H. pylori infection has evolved to an unique model of diagnostic performance and with procedures that can be performed on almost all biological sampling probes involving gastric tissue, blood, breath, and faeces. The particular diagnostic probe either alone or in combination is selected according to the diverse clinical scenarios associated with H. pylori infection [27].

The foundation of the European Helicobacter Study Group (EHSG) in Copenhagen 1987 was the first international organization constituted to bring scientists from all disciplines together to share the scientific progress, embark in joint research programmes, and hold regular annual conferences which have continued to grow since that time [28]. The role of this group was of particular relevance when science in H. pylori was still in its infancy and facing the opposition of the sceptics and of some pharmaceutical industry as well that felt their long-term acid suppression strategy in PUD “threatened” by the H. pylori eradication.

With the increasing evidence that H. pylori infection is the most prevalent cause of chronic gastritis world-wide, previous classification systems of gastritis required substantial revision. The Sydney histological classification of gastritis was introduced in 1990 and established the clinical pathological base on which subsequently clinical science and practice were built on. The updated version of the Sydney classification a few years later added important improvements in delineating atrophic gastritis (AG) and non-AG for reproducible and clinical important diagnoses [29, 30]. The description of various topographical phenotypes of gastritis, including grading severity of inflammation and severity of atrophy have become cardinal features for understanding the key role of H. pylori in the distinct expression of gastroduodenal pathologies, especially gastric cancer [31‒33]. After the success of curing PUD, the mucosal associated lymphoid tissue lymphoma (MALT lymphoma) became next disease to be cured through successful eradication of H. pylori infection [34, 35]. It is noteworthy that MALT lymphoma is the first malignant disease known to become curable with a short-term treatment regimen based on antibiotics [34‒36]. The critical role of H. pylori in gastric cancer was convincingly informed by remarkable epidemiological studies confirming that subjects with positive H. pylori serology were strongly associated with an increased risk of gastric adenocarcinoma [37‒40].

The early epidemiological studies provided the first scientific support leading to the declaration of H. pylori as a Group 1 carcinogen by the IARC [41]. From that time, basic and clinical research on H. pylori became intensified to study mechanisms and cofactors in gastric carcinogenesis [42, 43].

In 1996, under the auspices of the EHSG, the Maastricht consensus was conceived and the first of a series of regular updates on the management of H. pylori infection, with each meeting being rapidly followed by an updated Guideline publication [44]. In patients with H. pylori related gastrointestinal disease, PUD, gastric MALT lymphoma, and severe gastritis eradication therapy were recommended. Additionally – with only modest evidence available at the time – H. pylori eradication was recommended in patients with functional dyspepsia after comprehensive gastroenterological diagnostic assessment and exclusion of other causes. Furthermore, in young dyspeptic patients (<45 years) with no alarm symptoms “Test and Treat” by using a non-invasive test (¹³C -UBT or serology) has been proposed as a strategy at the primary care level. The first recommended treatment was a 7-day regimen with a PPI and two antibiotics selected from clarithromycin, and/or a nitroimidazole (metronidazole or tinidazole) and/or amoxycillin the so-called PPI-based triple therapies [45]. Controversial debate followed this first consensus paper on H. pylori management whose merit has been to serve as catalyst to initiate several clinical trials, studying new H. pylori related disease associations, indications for therapy and treatment protocols. The new data generated the necessary evidence to guide clinical management in the years to come. The first PPI triple consisting of PPI with 2 antibiotics was reported by F. Bazzoli and introduced as “Italian triple” [46].

Pivotal trials with PPI-based triple regimens given for 7 days were not concluded until late 1999 and confirmed the high performance in treatment of H. pylori and PUD (duodenal and gastric) [47, 48]. These studies marked a decision point for treatment for H. pylori eradication and led to an increasing acceptance of physicians to prescribe H. pylori eradication in PUD and subsequently extend eradication therapy to other H. pylori-associated conditions. PPI-based triple therapy for eradication of H. pylori infection became the state-of-the-art approach for H. pylori-related conditions [49]. Before the turn of the millennium concerns began to question the potential benefits of H. pylori in protecting from gastro-oesophageal reflux disease including GERD and oesophageal adenocarcinoma [50, 51]. The debates have not completely ceased and conflicting data continue to be published [52, 53]. After the millennium additional beneficial have been claimed or reported from epidemiological association studies. Among them, an increase in asthma in H. pylori-negative children and adolescents was seen when compared to H. pylori-infected controls in the Western world but confirmatory evidence has never been provided [54, 55].

Overall, no study data for H. pylori infection have confirmed a relevant protection from any disease. Thus, whenever H. pylori infection is detected and confirmed, guidelines state that eradication treatment should be prescribed [27].

New positive associations of H. pylori infection with systemic diseases, particularly autoimmune diseases, have attracted considerable research interest during this period. Idiopathic thrombocytopenic purpura is one such example which has become an indication for eradication therapy [56]. Many other associations for H. pylori infection with cardiovascular, dermatologic, neurologic diseases, and other conditions have been reported but subsequently were found to lack proof of causality [57].

This section will briefly summarize some of the key elements in the ongoing evolution in H. pylori management since the beginning of the new millennium. As the spectrum of indications requiring testing and treatment as well as the therapeutic options have been expanded over the years, they have been debated and revised at regular consensus workshops on H. pylori management. In the Maastricht II consensus 2000 first-degree relatives of patients with gastric cancer were included as an important new indication for treatment if infected. This is a good example of the pioneering role of the Maastricht serial consensus conferences. Newly introduced indications stimulated further research to strengthen the evidence and new facts were then systematically integrated in the subsequent revised guidelines. In this way, established recommendations can be revised or new indications, treatment approaches, or strategies [58]. In several further consensus reports evidence has been strengthened for recommending H. pylori treatment in patients on non-steroidal anti-inflammatory drugs (e.g., NSAIDs, Aspirin) where H. pylori infection is an additive risk for gastroduodenal lesions, and with selected extra gastric diseases [27, 59, 60].

The need for H. pylori eradication was emphasized in patients on long-term PPI since pharmacological acid suppression favours progression of gastric preneoplastic conditions in infected patients [61, 62]. Awareness of clarithromycin resistance (overall estimate 10% in Europe at that time) caused concerns and PPI triple therapies were shown to have higher efficacy when prescribed for 14 rather than 7 days [62]. Moreover, it took a further 5 years for studies to confirm that PPI-based triple therapies when given for 14 days were superior to 7-day treatments, that PPI double dose combinations were superior to standard dose, and that PPI triple combinations which include clarithromycin should be abandoned when local/regional clarithromycin resistance exceeds 15% [62].

Bismuth quadruple therapy (BQT) remained the second line option of choice at this time and levofloxacin was introduced as an alternative in case of clarithromycin-based triple therapy failure. The use of selective probiotics to improve treatment outcomes was also considered [63] but reported data remained controversial.

By 2015, antibiotic resistance rates reached alarming levels and recommendations for PPI triple therapy were firmly extended to 14 days and BQT advanced as an option for first-line treatment. The need to confirm successful eradication was also re-emphasized and the use of UBT recommended as diagnostic test of first choice [64]. The most effective approach to combat antibiotic resistance requires new therapeutic strategies and priority management revolves to H. pylori eradication for the prevention of gastric cancer and reduction of other H. pylori related disease complications (e.g., ulcer, bleeding, etc.).

During the consensus conference in Kyoto (2015), the role of H. pylori related gastritis was re-assessed and re-evaluated, which signalled a breakthrough with the definition of H. pylori gastritis as an infectious disease, independent of whether the condition is asymptomatic, associated with symptoms or with other related clinical manifestations [65].

A diagnosis of H. pylori gastritis was listed in the revised ICD 11 (2022) as a distinct entity of disease. The concept of H. pylori gastritis as an infectious disease was implemented in the management of H. pylori infection at the consensus Maastricht/Florence 2017 [64] with the recommendation that everyone infected should undergo H. pylori eradication, with few exceptions.

H. pylori antibiotic resistance continues to be a primary concern about treatment and is reported from all regions of the world, most relevant for the macrolides (clarithromycin, etc.) and the fluoroquinolones (levofloxacin, etc.) [66‒68]. Updates of international guidelines have all emphasized the need for regional monitoring of antibiotic resistance and the implementation of Antibiotic Stewardship to guarantee achieving the best H. pylori cure results and avoid the unnecessary and inappropriate use of ineffective antibiotics [69]. Antibiotics of greatest concern are clarithromycin and levofloxacin, and their use is indicated only where regular monitoring confirms low-antibiotic resistance (clarithromycin <15%) or if based on an individual patient antibiotic sensitivity test (AST) [54].

Clinical options to counteract antibiotic resistance include the Guideline choice of eradication regimens, currently BQT which shows no or minimal resistance of the constituents of this eradication regimen. Alternatively, the use of clarithromycin containing regimens should ideally be chosen after individual patient AST [64].

An important role in optimizing the management of H. pylori infection can be attributed to the Hp-EuReg (H. pylori European Registry) initiative, which collects ongoing data on H. pylori management in clinical practice across the countries of Europe [70, 71]. The initiative of the registry is instrumental in disseminating guidelines and offers an important contribution to education of clinicians. In the USA non-invasive, molecular antibiotic susceptibility testing (AST) of stool has been approved, and now provides an important new and accessible tool for management decisions. It is increasingly available and promoted [72]; however, in Europe and many other parts of the world there are still important issues of accessibility, logistics, and costs which currently prevent the widespread introduction of this important management strategy on a greater scale. The regional surveillance of antibiotic resistance and the use of eradication regimens containing antibiotics, which are not, or minimally subject to resistance, is an equally valid approach and currently is still the prioritized strategy. Much is anticipated from the availability and introduction of P-CABs in combination with amoxicillin in a dual regimen after the high efficacy which has been shown primarily in Asia and good efficacy has also been reported in Western studies [73, 74]. However, optimal dose combinations have yet to be fully explored [74]. Rescue regimens are usually selected based on consideration of previous therapies the patient has previously been prescribed but that failed [54]. An effective antibiotic choice is rifabutin, usually used for rescue treatment, in the USA a rifabutin-based regimen has now been proposed as first line in a new drug formulation [75, 76].

A selective role is reserved also for probiotics (e.g., Saccharomyces boulardii, specific strains of Lactobacilli and Bifidobacteria) as an additive treatment during H. pylori eradication to reduce adverse effects and contribute to increasing eradication efficacy [27, 59]. The inclusion of probiotics in eradication therapies may in future be considered also for reducing the development of antibiotic resistant genes (resistome) in gut microbiota [77, 78].

A prospective observational study from Japan was first to report that patients developed gastric cancer in 2.9 percent of the H. pylori infected but in none of the uninfected patients in a >7 years follow-up [79]. Successful prevention of gastric cancer by H. pylori eradication is by now well established and the current evidence is collected in authoritative systematic reviews and metaanlysis [80‒82].

The first RCT to demonstrate gastric cancer prevention by H. pylori eradication was conducted in Hong Kong [83]. However, the beneficial effect was observed only in subjects who did not have preneoplastic lesions, AG, and intestinal metaplasia, at the time of H. pylori eradication [83]. The concept of the “point of no return” provoked an important debate to define the optimal timing and age at which “screen and treat” should be performed. There are arguments for implementing screen and treat strategies in early adult age in regions with high risk for gastric cancer [5]. Subsequent evidence has also shown the benefits for H. pylori eradication for the prevention of metachronous gastric cancer following endoscopic resection of early gastric cancer which was accompanied by reversal of AG in a subset of patients [84]. This implies that H. pylori eradication for gastric cancer prevention should be considered at any stage of AG, but the persisting condition of AG makes endoscopic follow-up at regular intervals mandatory [85]. The introduction of operative link for gastric atrophy and subsequently of operative link for gastric intestinal metaplasia have provided staging systems of AG and intestinal metaplasia that greatly contributed to identifying patients with more severe AG that remain at higher risk for progression to gastric cancer development following successful H. pylori eradication and thus mandated for endoscopic follow-up [86, 87]. The current recommended endoscopic follow-up strategies are provided in the management of epithelial preneoplastic conditions and lesions in the stomach (MAPS) guidelines [88]. Successful strategies at a population level have been reported from Taiwan where a 53% reduction of gastric cancer resulted from H. pylori “mass eradication” in the Matsu Islands [89]. The largest population-based, “Linqu” trial in China is next expected to report meaningful results in gastric cancer prevention by H. pylori eradication. In Europe, studies and experience in gastric cancer prevention with H. pylori eradication are lagging behind the initiatives in Asian countries. However, European regional studies “GISTAR,” “Eurohelican,” and the “TOGAS” trial, funded by the European Union, are catching up and will be instrumental for the implementation of H. pylori screen and treat for gastric cancer prevention also in Europe. Several international projects aiming at gastric cancer prevention are on the way. To mention as an example is “SAIL” for gastric cancer prevention with the eradication of H. pylori in the adult population of Bhutan which is based on a personal initiative to obtain funding. A recent attractive concept directed to gastric cancer prevention is the family-based approach in China where in case of an infected member (index subject), all family members should get tested and if infected undergo treatment (however, treatment should not be performed in childhood according to international consensus); this offers a new approach in high risk areas for gastric cancer [90]. In Western countries, we envisage a cost-effective strategy for gastric- and colon cancer prevention with a cost-effective strategy with combined screening for H. pylori infection/preneoplastic condition (non-invasive) and colon adenoma (colonoscopy/non-invasive) [59, 91].

H. pylori gastritis is an infectious disease and accepted as an indication for eradication therapy. Treatment options have been successfully revisited and adapted with several choices to manage the challenges of H. pylori resistance today. One may be the selection of most effective empirical therapies with regimen components not or little influenced by antibiotic resistance and with monitoring of their efficacy. The most promising alternative option will make use of new molecular techniques for antibiotic susceptibility testing in gastric biopsies, gastric juice and/or stool for individualized selection of the optimal treatment regimen. A new opportunity is the stronger and more consistent acid suppression guaranteed by P-CABs which will further develop into more effective dual therapies in combination with selective antibiotics that carry minimal risk for resistance. Antibiotic stewardship will assume a critical role in the most effective management of H. pylori resistance for individual and regional demands.

Rapidly expanding knowledge of the gastrointestinal microbiome and the increasing recognition of microbial strains competing with or potentially harm H. pylori bacteria, offer the possibility to develop selective bacterial strains to control or eradicate the infection. Finally, the hope for a prophylactic and/or therapeutic vaccine against H. pylori infection is not abandoned.

In the field of diagnostics, advances in gastrointestinal endoscopic “finesse” offer high definition endoscopy imaging, virtual chromoendoscopy and Artificial Intelligence. This will further improve the assessment of gastritis for early recognition of mucosal abnormalities and early detection of high-risk lesions. Endoscopic findings complemented by histological staging systems and with integration of molecular characteristics will allow to be built into algorithms for prevention strategies and contribute to scientific progress in the field.

The authors have no conflicts of interest to declare.

There was no funding with relation to this article.

Peter Malfertheiner coordinated the writing process and contributed to the main document draft and reviewing the manuscript. Christian Schulz contributed to the main document, references, and formatting. Richard H. Hunt contributed to the main document and reviewing the manuscript.