Helicobacter pylori is a spiral-shaped gram-negative bacterium. Its persistent infection is associated with severe gastric complications (Malfertheiner et al., 2023) and plays a significant role in the development of conditions such as gastric cancer, duodenal ulcers, and gastric ulcers, particularly contributing to the onset of gastric adenocarcinoma (Sung et al., 2021). Accurate diagnosis of H. pylori infection is essential for effective treatment. diagnostic methods include non-invasive and invasive approaches (Chen Y. C. et al., 2024). Non-invasive tests comprise the ¹³C-urea breath test, fecal antigen detection, serological tests, and molecular biology tests (e.g., PCR). Invasive tests involve endoscopy with tissue biopsy, the rapid urease test, and histopathology. Patients diagnosed with H. pylori infection typically develop chronic gastritis, making H. pylori gastritis an infectious disease that warrants eradication therapy (Ranjbar et al., 2017).

Since the discovery of H. pylori in 1983, its eradication treatments have evolved from single antibiotics (e.g., metronidazole or amoxicillin) to combinations of multiple antibiotics. Standard triple therapies, which include a proton pump inhibitor such as omeprazole along with two antibiotics like clarithromycin and amoxicillin or metronidazole, have been superseded by quadruple therapies. These quadruple therapies involve a proton pump inhibitor, bismuth agents such as bismuth potassium citrate, and two antibiotics (Malfertheiner et al., 2024). Addressing H. pylori infection requires appropriate antibacterial treatment. While the incidence of H. pylori infection has declined in developed countries (Megraud et al., 2021), it remains widespread in developing nations, with increasing drug resistance. In most cases, the infection is acquired during childhood (Malaty et al., 2002; Park et al., 2021; Yuan et al., 2022). The prevalence rate may also be influenced by local economic conditions and health care infrastructure.

Eradicating H. pylori requires a suitable treatment regimen. However, treating H. pylori infection presents challenges. Standard triple therapy (STT) comprises a proton pump inhibitor and two antibiotics. Owing to increasing antimicrobial resistance, STT is no longer effective for treating H. pylori infection (Ho et al., 2022; Boyanova et al., 2023). Consequently, the search for new H. pylori treatments and strategies to reduce antimicrobial resistance has become a primary focus.

This study comprehensively reviews H. pylori infection, antimicrobial treatment approaches, drug resistance, and the development of new anti-H. pylori drugs or novel ideas to eradicate H. pylori, which introduces novel perspectives that can optimize future treatment strategies.

Helicobacter pylori gastritis (Sugano et al., 2015) is an infectious disease that has been included in the 11th revision of the International Classification of Diseases (Malfertheiner et al., 2022). H. pylori infection has been widespread worldwide (Figure 1; Table 1), with an overall infection rate as high as 43.2% (95% CI: 40.3–45.9%) in 2011–2022 (Li et al., 2023). H. pylori infection is highly prevalent in East Asia. A systematic review and meta-analysis covering 1,377,349 individuals from 412 eligible studies indicated that the H. pylori infection rate in mainland China was 40% in 2015–2019 (Ren et al., 2022). The epidemiological landscape of H. pylori in Japan is evolving, with an infection rate of 70% in less developed areas and 40% in more developed regions (Inoue, 2017). In a Korean population of 23,770 people, the detection of anti-H. pylori IgG antibodies, indicating the presence of H. pylori infection, revealed a seroprevalence rate of 41.5% (Lim et al., 2018). A recent cross-sectional study in India, using 2,998 biopsy samples, indicated an overall prevalence of H. pylori infection of approximately 64% (Venkatesan et al., 2024).

In North America, the prevalence of H. pylori infection from 1980 to 2022 was 36.2% (95% CI: 22.6–49.9%) (Li et al., 2023). A meta-analysis covering the years 1999–2018 reported a diagnosis rate of H. pylori infection of 25.8% in the USA (Shah et al., 2024). Willems et al. reported that the H. pylori infection rate in Canada was approximately 20–30% (Willems et al., 2020). Victor et al. collected dental plaque samples from 36 families in a southwestern Mexican community and reported an H. pylori infection rate of 41.7% (Urrutia-Baca et al., 2023). In a urease test report from Brazil, involving 852 individuals, the overall H. pylori infection rate was 35.4%, with a specific infection rate of 24.7% among children and adolescents (Toscano et al., 2018). The H. pylori infection rate in Argentina falls between the high incidence observed in African countries and the lower incidence observed in other countries in the Americas (Olmos et al., 2000).

The overall prevalence of H. pylori infection in Europe was reported to be 47.5% (95% CI: 43.0–52.1%) (Li et al., 2023). Bordin compared H. pylori infection rates across all Russian Federation communities in 2017 and 2019. Among untreated persons, the overall H. pylori infection rates were 41.8% in 2017 and 36.4% in 2019 (Bordin et al., 2022). In a seven-year prospective cross-sectional study examining the presence of H. pylori infection among 3,241 students in Gruzice, Poland, the positivity rate was 23.6% (Szaflarska-Poplawska and Soroczynska-Wrzyszcz, 2019). The reported prevalence of H. pylori infection in Germany in 2018 ranged from 20 to 40% (Fischbach and Malfertheiner, 2018). A recent meta-analysis reported infection rates of 28.6% in France, 18.8% in Denmark and 26.3% in the United Kingdom (Chen Y. C. et al., 2024).

In the representative countries of Oceania, namely, Australia and New Zealand, H. pylori infection rates vary. As reported in a global meta-analysis from 2010 to 2022, Australia recorded a rate of 24.8%, while New Zealand had a rate of 9.2% (Chen Y. C. et al., 2024). Biopsy samples collected from 12,482 individuals in South Australia from 1998 to 2017 revealed a positive H. pylori infection rate of 11.5% (Schubert et al., 2022).

The H. pylori infection rate in Africa was reported to be 52.6% (Chen Y. C. et al., 2024). Notably, the prevalence in Africa surpasses that in other continents and exhibits significant variability, depending on the geographical location. In a comprehensive review of H. pylori infection in the Middle East and North Africa, infection rates displayed wide-ranging disparities within regions, ranging from 7 to 50% in young children and from 36.8 to 94% in adults (Alsulaimany et al., 2020). A review by Smith revealed elevated infection rates, reaching 87.8% in northern Nigeria and 70.8% in Burundi and exceeding 80% in Ethiopia (Smith et al., 2022). A 2019 report from Egypt revealed an overall H. pylori infection rate of 66.1% (Galal et al., 2019).

After H. pylori infection, various gastrointestinal and systemic diseases ensue in the human body (Figure 2). H. pylori infection always causes chronic gastritis, and approximately 10–15% of infected individuals may develop peptic ulcers. Peptic ulcer disease has a lifetime risk of approximately 17% and may lead to serious complications, such as bleeding, perforation, and gastric cancer. Chronic atrophic gastritis is currently considered to be a precancerous lesion.

An increasing focus has been directed toward clinical extragastric manifestations following H. pylori infection. Research exploring the relationship between H. pylori infection and cardiovascular-related diseases has gained substantial attention. The presence of H. pylori infection in patients increases susceptibility to coronary atherosclerotic disease (Chen et al., 2013; Wang et al., 2021), stroke (Sun et al., 2023), and myocardial infarction (Wang et al., 2023). Moreover, H. pylori infection has been linked to neurological disorders, including Alzheimer’s disease (Kandpal et al., 2024) and multiple sclerosis (Arjmandi et al., 2022). Eye-related ailments such as open-angle glaucoma (Doulberis et al., 2020) and blepharitis (Sacca et al., 2006) may also result from infection. In children and young individuals, H. pylori infection has been associated with the onset of allergic systemic conditions like Asthma (Durazzo et al., 2021). H. pylori infection can induce alterations in the metabolic system, contributing to blood sugar disorders in individuals with diabetes (Chang et al., 2023). Additionally, stomach colonization by H. pylori has been implicated in accelerating liver fibrosis (Okushin et al., 2018) and mediating tumorigenesis. Encouragingly, the eradication of H. pylori has led to improvements in hematologic disorders, including iron deficiency anemia (Elbehiry et al., 2023) and primary immune thrombocytopenia (Wang et al., 2022).

The morphological form of H. pylori plays a pivotal role in disease development among H. pylori-infected patients. In human gastric biopsy specimens, H. pylori predominantly exists in a spiral form (Gladyshev et al., 2020). Under adverse conditions, such as high temperature, pH fluctuations or the use of antibacterial drugs, H. pylori can transform into a latent spherical form. The intermediate stages between the spiral and spherical forms are referred to as the C-shaped and/or U-shaped forms of H. pylori, also known as the dormant state. Dormancy is regarded as a reversible state in which bacterial cells exhibit reduced metabolic activity. When favorable culture conditions are restored, the cells regain metabolic activity and can be cultured (Ierardi et al., 2020). Various antibiotics (amoxicillin, clarithromycin, metronidazole, and tetracycline) at the minimum inhibitory concentrations (MICs) induce a spherical form. Furthermore, after exposing H. pylori to omeprazole (a proton pump inhibitor) at 0.5 MIC for 3, 6, and 9 days, the bacterium could revert to the spiral form after omeprazole removal from the culture medium (Krzyzek and Grande, 2020). Patients with H. pylori infection is susceptible to reinfection if the bacterium is not completely eradicated. Vasiliy et al. noted that after one year of anti-H. pylori treatment in patients with duodenal peptic ulcers, the identification of H. pylori suggested that the bacterium may have transitioned from the dormant state to an active state (Reshetnyak and Reshetnyak, 2017). Nikita et al. reported that the virulence of the spherical form was comparable to that of the spiral form and that the spherical form increased the risk of developing gastric cancer in patients (Gladyshev et al., 2020). In summary, when patients with H. pylori infection exhibit significant symptoms, such as peptic ulcers, eradication therapy should be initiated. However, incomplete eradication with antibiotics and proton pump inhibitors may lead to the conversion of the spherical form back to the active spiral form.

Helicobacter pylori colonizes the gastric mucosa and is highly adapted to the acidic environment through complex molecular processes. Adhesion mechanisms are crucial for its sustained colonization. Two key outer membrane proteins, blood group antigen-binding adhesion (BabA) and salivary acid-binding adhesion (SabA), play significant roles (Malfertheiner et al., 2023). BabA, one of the earliest discovered H. pylori adhesins, recognizes and binds to various antigens, particularly the ABO group, facilitating survival and colonization in the stomach (Chang et al., 2023). SabA, also known as HopP, binds to sialylated Lewis x (sLex) antigens on gastric epithelial cells, promoting adhesion and survival despite the host’s immune response (Pang et al., 2014; Doohan et al., 2021). BabA initiates adhesion by binding to antigens, while SabA maintains persistent infection in an inflammatory environment. Their synergistic action and dynamic regulation enable H. pylori to efficiently colonize the host and cause disease.

Inflammasomes play a crucial role in the development of gastric inflammation caused by H. pylori (Kandpal et al., 2024). These important cytoplasmic multiprotein complexes, when activated, promote the release of pro-inflammatory cytokines such as IL-1β and IL-18 (Zheng et al., 2024). Among the various inflammasomes, the NLRP3 inflammasome is the most commonly studied in H. pylori infection. When exposed to intracellular stimuli, such as bacterial toxins and oxidative stress, or danger signaling molecules, including the loss of intracellular potassium ions and pH alterations (Mugengana et al., 2021), NLRP3 proteins are activated. This activation accelerates the development of peptic ulcers associated with H. pylori infection.

The primary virulence factors of H. pylori include Cytotoxin-associated gene A (CagA), Vacuolating cytotoxin A (VacA), Duodenal ulcer-promoting gene A (DupA), and Urease (Malfertheiner et al., 2023). CagA is a pathogenic protein delivered into host cells via the Type IV secretion system (T4SS) (Bhattacharjee et al., 2024). It activates multiple signaling pathways, such as NF-κB, MAPK/PI3K, and Wnt/β-catenin, affecting cell proliferation, motility, polarity, apoptosis, and inflammation (Ayana et al., 2014; Hayashi et al., 2017). VacA forms an anion-selective membrane channel upon contact with host cells, causing the formation of large intracellular vacuoles (Yahiro et al., 2015; Nejati et al., 2018), disrupting mitochondrial function, inducing apoptosis and autophagy, and inhibiting T and B cell proliferation (Cover and Blanke, 2005). DupA, associated with T4SS-related proteins, is implicated in urease regulation (Asimellis et al., 2005), ATPase-associated efflux pumps, and apoptotic pathways, potentially enhancing H. pylori virulence (Chen et al., 2018). Urease, composed mainly of the ureA and ureB genes and cofactors, including nickel, and regulated by the gastric microenvironment’s pH, hydrolyzes urea into ammonia and carbon dioxide. This reaction neutralizes gastric acid, creating a protective microenvironment that promotes colonization and evades the host immune system (Ha et al., 2001; Allen et al., 2023; Malfertheiner et al., 2023).

Advancements in the understanding of H. pylori infection have transformed peptic ulcer treatment from anti-acid therapies to antibacterial-based approaches (Figure 3). The eradication of H. pylori by antibacterial drugs promotes ulcer healing and reduces recurrence rates. In the late 20th century, antibacterial drugs were less effective in the acidic environment of the stomach. Therefore, treatments targeting both bacteria and stomach acid were needed. Omeprazole and amoxicillin were used to be a classical dual therapy, which was highly effective and well tolerated owing to its bactericidal and antacid effects (Labenz et al., 1994). Nevertheless, plans to eradicate H. pylori have shifted to triple therapy, mainly including bismuth +2 antibacterial drugs or proton pump inhibitors (PPIs) + 2 antibacterial drugs (consisting of amoxicillin and clarithromycin, metronidazole or levofloxacin).

Increasing antibacterial resistance leads to a further reduction in treatment efficacy. For example, a successful 14-day concomitant therapy containing 1 g of metronidazole and clarithromycin produced 14,000 kg of unnecessary antibacterial agents per 1 million successful treatments (Graham, 2020). To address this issue, alternative therapies, such as Vono-triple therapy (a vonoprazan-containing therapy) and R-hybrid therapy (a reverse hybrid therapy), have been developed and have achieved eradication rates greater than 90% those of STT. However, while R-hybrid therapy has a high cure rate, it has failed to achieve significant comparative efficacy. One promising drug is vonoprazan, a potassium-competitive acid blocker (Rokkas et al., 2021).

In areas with high clarithromycin resistance, STT has been replaced with bismuth-containing quadruple therapy (BQT). The improved bismuth-containing quadruple therapy (mBCQT) consists of a PPI, bismuth, metronidazole, and tetracycline. The results showed that mBCQT achieved an H. pylori eradication rate of 88.2% after continuous treatment of patients for two weeks (Kim et al., 2019). In Greece, where clarithromycin resistance is greater than 20% and bismuth is not available, a 10-day nonbismuth-based quadruple concomitant therapy (esomeprazole, clarithromycin, amoxicillin, and metronidazole) is currently the first-line treatment for H. pylori eradication (Apostolopoulos et al., 2020). Hybrid therapy, which combines sequential therapy and concomitant therapy, is a novel two-step therapy (Chey et al., 2018). A 14-day hybrid therapy regimen (pantoprazole plus amoxicillin for 7 days, followed by pantoprazole plus amoxicillin, clarithromycin, and metronidazole for another 7 days) had an H. pylori eradication rate of 93.9% (154/164; 95% confidence interval [CI]: 90.3 to 97.5%). The H. pylori eradication rate of bismuth quadruple therapy (pantoprazole, bismuth subcitrate, tetracycline, and metronidazole for 14 days) was 92.8% (154/166; 95% CI: 88.9 to 96.7%). The H. pylori eradication rates of the two therapies are similar, but hybrid therapy has fewer adverse effects than bismuth quadruple therapy (Tsay et al., 2017). For patients allergic to penicillin who are infected with H. pylori for the first time, the triple therapy of bismuth (using bismuth potassium citrate and esomeprazole) with minocycline, cefuroxime, and full-dose metronidazole (pairwise) has the same satisfactory efficacy in H. pylori eradication, with a good safety and compliance (Zhang Y. X. et al., 2023). Nonbismuth or bismuth quadruple therapy is characterized by poor compliance and a high cost, similar to many other drugs.

High-dose dual therapy (HDDT) consisting of a PPI and amoxicillin has been proven to have a better H. pylori eradication rate and fewer adverse reactions than traditional triple or quadruple therapy (Yang et al., 2019; Zhu et al., 2020). The HDDT group (40 mg of esomeprazole and 100 mg of amoxicillin three times daily) and the bismuth-containing quadruple therapy group, which was called the TFEB group (40 mg of esomeprazole, 220 mg of bismuth potassium citrate, and 100 mg of furazolidone twice daily, combined with 500 mg of tetracycline three times daily), were treated continuously for 14 days, and the eradication rates of H. pylori reinfection in patients who failed eradication were similar in both groups. However, the incidence of adverse events in the HDDT group was significantly lower than that in the TFEB group (11.1% vs. 26.8%, p < 0.001), and the treatment compliance was good (Bi et al., 2022). The replacement of PPIs with vonoprazan was also proven to be effective. After 10 days of continuous administration, the eradication rates were 93.4% for VHA-dual therapy (20 mg of vonoprazan twice daily +750 mg of amoxicillin four times daily) and 90.9% for B-quadruple therapy (20 mg of esomeprazole +200 mg of bismuth +1,000 mg of amoxicillin +500 mg of clarithromycin twice daily). Although compliance was similar between the two therapies, the former had a lower rate of adverse events (Qian et al., 2023). VHA-dual therapy is expected to become the first-line therapy for H. pylori eradication.

In addition to the use of modifying drugs to improve eradication rates, patient compliance is also a factor that directly affects treatment success. Patients received telephone follow-ups on the 3rd, 14th, and 30th days of treatment, and the results showed that semiautomatic intensive follow-ups improved the H. pylori eradication rate and patient compliance (Chen et al., 2021). The use of technology-enhanced communication strategies, such as telephone re-education, text messaging, social media re-education, and structured patient counseling programs, enables patients to comprehensively understand the treatment process, leading to improved eradication rates and compliance (Zhao et al., 2020; Chua et al., 2022).

Helicobacter pylori colonizes the surface of the gastric mucosa and is protected by the gastric mucus layer, making it difficult to remove H. pylori from the stomach. Resistance of H. pylori gradually develops over the course of treatment owing to limited selection of antibacterial agents and the limited frequency of treatment. Furthermore, when patients who have previously used antibacterial drugs are treated, the resistance rate increases, as does the risk of treatment failure (Guo C. G. et al., 2022). Clarithromycin is one of the most important drugs for the treatment of H. pylori worldwide, but its primary resistance rate has significantly increased, from 17.2 to 19.7% or even 27.2% (Kasahun et al., 2020). Metronidazole shows a universal drug resistance pattern worldwide, with the resistance rate > 15% on all continents (Table 1; Savoldi et al., 2018; Boyanova et al., 2020; Gisbert, 2020; Schubert et al., 2021; Chen et al., 2022; Borka Balas et al., 2023). The primary resistance rates are expected to continue increasing in the future (Savoldi et al., 2018). Resistance rates are on the rise, affecting not only clarithromycin and metronidazole but also drugs such as levofloxacin, which are often deemed alternative therapies. Currently, the rates of H. pylori resistance to clarithromycin, metronidazole, and levofloxacin are 27.2, 39.7, and 22.5%, respectively, worldwide (Kasahun et al., 2020). In the United States, the rates of resistance to clarithromycin, metronidazole, and levofloxacin are 17.6, 43.6, and 57.8%, respectively (Hulten et al., 2021). Over a 10-year period, the resistance rate to clarithromycin increased from 17.5 to 21.4% in European countries. The H. pylori resistance was assessed, and 201 strains showed double resistance, most commonly to clarithromycin and metronidazole (Megraud et al., 2021). In the Asia Pacific region, overall resistance to clarithromycin increased from 7 to 21% over the same period (Jiang et al., 2022). In a study of 125 Vietnamese patients with peptic gastric ulcers, the percentages of patients who were resistant to amoxicillin, clarithromycin, metronidazole, levofloxacin, and tetracycline were 27.5, 50.0, 67.5, 35.0, and 5.0%, respectively. Additionally, 7.5% of the patients were sensitive to all five antibacterial drugs, 27.5% were single-drug resistant, 42.5% were double-drug resistant, 17.5% were triple-drug resistant, and 5% were quadruple-drug resistant (Vu et al., 2022).

Primary resistance rates for clarithromycin, metronidazole, levofloxacin, and amoxicillin vary across different regions (Table 2). Metronidazole generally showed higher resistance rates than the other three antibiotics, with rates reaching up to 91% in Africa and the lowest at approximately 25% in Europe. Clarithromycin also exhibited substantial resistance, peaking at around 37% in Asia. Resistance rates for levofloxacin were highest in Asia at about 25%, with other regions not exceeding 20%. Amoxicillin consistently had low resistance rates, maintaining around 1% in Europe.

Analysis of data from China revealed that the average resistance rate to clarithromycin was 24.0%, with single-, double-, triple-, and quadruple-drug resistance rates of 54.6, 29.0, 11.7, and 0.1%, respectively (Zhang et al., 2021). In the last 20 years, primary resistance to major antibacterial drugs (clarithromycin, metronidazole, levofloxacin, and amoxicillin) has been analyzed in China (Figure 4; Tables 1–3). Clarithromycin and metronidazole, which are commonly used as first-line treatments, have shown increased resistance, with the median rates having increased from 18.1 to 40.0% and from 43.1 to 79.9%, respectively. Since 2010, levofloxacin has been increasingly used as an alternative antibiotic. A trend toward resistance has emerged, with the primary resistance at 34.8% from 2018 to 2024. Recently, high-dose amoxicillin therapy has gained popularity as a novel treatment approach. While the median resistance rate to amoxicillin remains low at 5%, the variability in the data indicates that certain regions already exhibit relatively high resistance levels. The increasing trend of amoxicillin resistance appears to be unstoppable.

In recent years, antibacterial resistance in H. pylori-infected children has become a growing concern. Although the triple combination of PPI-CA (proton pump inhibitor, clarithromycin, and amoxicillin) is the preferred regimen, the eradication rates in children are still lower than those in adults owing to differences in susceptibility to and compliance with antimicrobial agents (Lai and Lai, 2022). Among Asian children, the primary resistance rate to clarithromycin in Southeast Asia is 10%, which is the same as that in the Americas but lower than that in Europe and the Eastern Mediterranean, where the resistance rate exceeds 15%. The primary resistance rates to metronidazole are 51% in Asia, 23% in the Americas, 91% in Africa, and 32% in Europe. As an alternative salvage therapy, levofloxacin has a primary resistance rate as high as 30% in Asia (Borka Balas et al., 2023). In Spain, 67.5% of 80 pediatric patients showed resistance to more than two antibacterial drugs, and 6.3% had double-drug resistance, with resistance to clarithromycin, metronidazole, levofloxacin, and amoxicillin being the main manifestations (Botija et al., 2021). In Germany, multidrug resistance in pediatric patients reaches 16% (Helmbold et al., 2022), and the rate of amoxicillin resistance in patients is as high as 20%, which is of great concern. In general, the drug resistance of H. pylori in children cannot be ignored. Owing to the low compliance of children, the eradication rate is greatly affected, and the possibility of developing multidrug resistance is greatly increased.

The effects of H. pylori eradication in older patients should also be considered. In a study of 264 patients diagnosed with H. pylori infection, the eradication rate in patients aged 40 years and older was greater than that in patients under 40 years of age (85.7% versus 54.7%, p = 0.002), and the eradication rate in patients older than 60 years was 100% (Tang et al., 2020). The eradication rate of the PPI-clarithromycin-amoxicillin regimen in the young and middle-aged group (≤50 years) was significantly lower than that in the aged group (>50 years) (Nishizawa et al., 2017). One possible reason for this is that younger patients have earlier exposure to clarithromycin and greater resistance, which may reduce the eradication rate. The success rates of esomeprazole treatment were significantly greater in patients over 65 years of age than in those under 65 years of age. Nonetheless, there was no significant difference in the clarithromycin resistance rates between the two groups receiving the new first-line triple therapy with vonoprazan (Saito et al., 2019), possibly due to the potent gastric acid inhibition by vonoprazan. However, another study from Japan showed that the eradication effectiveness of first-line triple therapy with amoxicillin, clarithromycin, and vonoprazan decreased with age, possibly due to reduced gastric acid secretion in older patients, reducing the need for maintenance therapy with vonoprazan (Kusunoki et al., 2019). In conclusion, the impact of age on H. pylori eradication is manifested through two primary mechanisms, namely, gastric acid secretion and premature exposure to antibiotic therapy. With an increasing age, there is a reduction in gastric acid secretion (Haruma et al., 2000). However, it is noteworthy that the predominant agents employed in the current first-line H. pylori treatment regimens often include PPIs. These agents exert a bactericidal effect by elevating the pH of gastric juice and synergizing with antibiotics (Scott et al., 1998).

In the older population, a frequent occurrence is an elevated incidence of gastric mucosal atrophy, which is coupled with diminished gastric acid secretion. Consequently, potent gastric acid inhibitors aimed at suppressing acid production are urgently needed. This context potentially elucidates the lack of discernible distinction between the efficacy of the novel gastric acid blocker vonoprazan and that of established agents, such as clarithromycin, metronidazole, or esomeprazole. Furthermore, it is important to highlight that insufficient eradication outcomes in young patients extend beyond merely premature antibiotic exposure. These suboptimal results are also intertwined with their personal habits and medication adherence (Shakya Shrestha et al., 2016).

There is a widespread consensus that the development of antibacterial resistance in H. pylori is linked to the complex physiological process of biofilm formation (Tshibangu-Kabamba and Yamaoka, 2021). H. pylori strategically forms biofilms as a defense mechanism against external factors such as pH and oxidative stress. These biofilms predominantly consist of static cell clusters enveloped by an extracellular matrix composed of proteins and extracellular DNA (Guzman-Soto et al., 2021). Stark provided the first evidence of the ability of H. pylori to create biofilms under specific conditions, particularly in supplemented 10% Brucella broth (Stark et al., 1999). The process of H. pylori biofilm formation encompasses stages such as bacterial adhesion, biofilm assembly, maturation, and dispersion. Within mature biofilms, the majority of bacterial cells assume a spherical shape, considered the dormant state of H. pylori, contributing to its resistance and disease induction potential (Elshenawi et al., 2023). H. pylori biofilms exhibit significantly greater antibacterial tolerance than their planktonic counterparts. Notably, the amoxicillin tolerance level was shown to be up to 1,000 times greater, while that to clarithromycin, levofloxacin, and metronidazole was 31, 16, and 8 times greater, respectively, in biofilms (Fauzia et al., 2020). However, the mechanism by which biofilms enhance H. pylori tolerance remains a subject of ongoing research. This phenomenon may be associated with the upregulation of genes involved in modifying the cell wall of H. pylori within the biofilm, such as UppS (Hathroubi et al., 2020; Rahman et al., 2020) and PdgA (Zhao et al., 2023).

Efflux pumps are a type of multidrug transporters found in the bacterial cell membrane (Hou et al., 2022). These pumps actively transport antibacterial drugs out of bacterial cells, thereby reducing the drug concentration within the cells and promoting drug resistance. In the case of H. pylori, efflux pumps play a central role in the development of multidrug resistance and mediate resistance to antibacterial agents such as amoxicillin, metronidazole, clarithromycin, and tetracycline (Cai et al., 2020). In clinical multidrug-resistant H. pylori strains, the expression levels of efflux pump genes are significantly increased. These efflux pump-encoding genes are notably upregulated within biofilms, further enhancing the tolerance of H. pylori to antibiotics (Ge et al., 2018). Yonezawa et al. demonstrated that the expression of outer membrane proteins from family 5 efflux pumps, including hefa (HP0605), hefd (HP0971), and hefG (HP1327), was significantly greater in biofilm-forming cells than in planktonic cells (Yonezawa et al., 2019). These findings confirm that efflux pumps can collaborate with biofilms to amplify drug resistance and play a pivotal role in enabling H. pylori to thrive within biofilms, which are unaffected by antibiotics.

While H. pylori cells residing within biofilms may shield themselves from antibacterial drugs and the immune system, the precise impacts of H. pylori biofilms on antibiotic resistance and immune system clearance in vivo remain to be fully elucidated. Existing evidence indicates that H. pylori can indeed form biofilms, and it has been observed that genes related to efflux pumps are upregulated within biofilms. However, the mechanisms through which biofilms influence efflux pumps remain unclear. Future research aimed at enhancing the efficacy of eradication therapy should prioritize exploring the yet uncharted role of biofilms in H. pylori infections.

Drug resistance of H. pylori has a significant impact on therapeutic efficacy. Although continuous improvements of antibacterial drug combinations can make them effective in the short term, the efficacy tends to decline over time. This fact emphasizes that solving the problems of drug resistance and H. pylori eradication may be difficult if antimicrobial drugs continue to be the focus. It may be necessary to change the strategy and find a different approach to address this issue (Figure 5).

Antibacterial drugs show great therapeutic effects against H. pylori infection, but sometimes, they are not sufficient to eradicate H. pylori. In the past decade, approximately 10–30% of all first-and second-line eradication therapies recommended by global treatment guidelines have failed, which led to the development of triple therapy. Quadruple therapy, which involves adding another antimicrobial or replacing it with an acid inhibitor, was developed to overcome this problem. The wide range of antimicrobial agents extensively used for the eradication of H. pylori has led to an increase in drug resistance over time (Tshibangu-Kabamba and Yamaoka, 2021). As a result, retreatment and subsequent cure have become more difficult (Thung et al., 2016; Malfertheiner et al., 2017). To address this issue, new drugs and treatment strategies are necessary.

Notwithstanding, further study of the mechanisms of drug resistance in H. pylori is essential. Whole-genome sequencing predicted resistance in H. pylori and showed that antimicrobial resistance is primarily due to point mutations in the genome. For example, clarithromycin resistance in H. pylori is strongly associated with the presence of the A2146C, A2146G, or A2147G mutations in exon V of the 23S rRNA gene (Lauener et al., 2019). Mutations G94E in the pbp1A gene, C2173T and G2212A in the 23S rRNA gene, T239M in the gyrA gene, G122R in the rdxA gene, and A70T and A138V in the frxA gene have been found only in drug-resistant strains (Domanovich-Asor et al., 2020). The pbp1A gene mutation is a major factor causing amoxicillin resistance, while levofloxacin resistance may be mainly attributed to mutations in single or dual genes encoding DNA gyrase subunits A and B (gyrA and gyrB) in the quinolone resistance-determining region (QRDR). Mutations at codons 87 (N to K, I, or T) and 91 (D to Y, G, or H) in the QRDR of gyrA were found in 91% of resistant strains (Tshibangu-Kabamba et al., 2020). Although these studies have some value, it should be noted that gene mutations in H. pylori are not fixed in patients from different regions and some patients may have dual or multiple resistance. Therefore, the whole-genome sequencing results may not provide a representative conclusion.

Furthermore, new therapeutic strategies can be developed. In addition to traditional combination therapies, such as concomitant and sequential therapies, probiotics and vaccines have currently become popular new therapies. Probiotics can inhibit H. pylori colonization and produce antibacterial substances (Song et al., 2018). The eradication rate of H. pylori by using probiotics combined with the triple regimen was lower than that of the bismuth quadruple regimen, indicating that bismuth is irreplaceable and can inhibit the growth of probiotics. The acidic environment of the stomach may also affect the effect of probiotics. The eradication effects of different probiotics vary with treatment duration. Therefore, more detailed studies are needed on the use of probiotics as adjuvant therapy. An H. pylori vaccine was shown to be effective at preventing H. pylori infection (Zeng et al., 2015). However, one of the concerns regarding the treatment of H. pylori infection is whether the antibodies produced in the body can travel smoothly into the gut and not be destroyed by gastric acid or pepsin. Further evaluation is needed to confirm the long-term effectiveness of vaccines. Research on stimuli-responsive materials has shown promising potential against H. pylori; yet this field remains in its nascent stage. Responsive biomaterials pose challenges, including their complex compositions, intricate manufacturing processes, elevated costs, and complex treatment procedures. Future investigations should prioritize comprehensive in vivo verification of H. pylori clearance and further enhancement of biomaterial properties. Phage and antimicrobial peptide therapies are emerging for H. pylori eradication but are still in the early stages of development. Their antimicrobial mechanisms and effectiveness compared to first-line drugs require further investigation through in vivo experiments and preclinical validation.

A different path may lead to better results. Because a strictly microaerophilic environment is suitable for survival of H. pylori, a completely novel way to change the oxygen concentration that is required for the growth of H. pylori to a level at which H. pylori cannot survive (Di et al., 2020). has been proposed. Under normal microaerobic conditions in the stomach, H. pylori infection prompts the bacterium to employ various survival mechanisms. Upon reaching the mucus layer, urease aids in resisting the acidic gastric environment, while flagella facilitate movement toward mucosal epithelial cells for colonization and the release of pathogenic factors (such as NapA, CagA, and VacA) (Figure 6). However, in the hypoxic stomach environment, bacterial cells outside the mucus layer struggle to respire and metabolize because of limited oxygen availability. This leads to a sharp reduction in energy levels, causing a transition from the active rod-shaped forms to globular shapes, which is indicative of the dormancy status or eventual death. With diminished flagella and urease activities, bacterial cells are unable to penetrate the mucus layer and to colonize epithelial cells (Figure 6). The proposed method can efficiently eradicate H. pylori without generating drug resistance. This kind of clearance does not require drugs to enter cells and is easy to achieve. This strategy may be a good therapeutic option for eradicating H. pylori in the future.

T-TH: Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing. Y-XC: Conceptualization, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing. LC: Conceptualization, Data curation, Formal analysis, Investigation, Project administration, Resources, Software, Supervision, Writing – original draft, Writing – review & editing.