NewBioWorld A
Journal of Alumni Association of Biotechnology (2025) 7(1):1-15
REVIEW
ARTICLE
Contemporary Perspectives on Helicobacter pylori:
A Review
Shivendra Singh Dewhare1*, Shifa Swaleha1
and Sneha Agrawal1
1School of Studies in Life Science, Pt. Ravishankar
Shukla University, Raipur, 492010, Chhattisgarh, India.
*Corresponding Author Email- ssdewhare@prsu.ac.in
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ARTICLE INFORMATION
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ABSTRACT
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Article history:
Received
14 April 2025
Received in revised form
27 May 2025
Accepted
Keywords:
Helicobacter pylori; Pathogenesis;
Virulence factors; Antibiotic resistance
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Helicobacter pylori
a Gram-negative, spiral-shaped bacterium flourishes in low-oxygen conditions
and is recognized as a major contributor in gastrointestinal disorder. This
bacterium is uniquely adapted to survive in acidic conditions of stomach.
Bacterium colonization, immune evasion, and mucosal layer damage are
facilitated by key virulence factors like CagA, VacA, and BabA. Eradicating
the bacterium poses significant challenges because of its capacity to alter
its antigens thereby contributing to the emergence of antibiotic resistance.
The pathogen and host engage in complex interactions during pathogenesis,
which leads to inflammation and epithelial tissue damage. Diagnostic methods
vary from invasive techniques to non-invasive approaches, including new
technologies such as PCR, next-generation sequencing, and biosensor
platforms. Increasing resistance to antibiotics, especially clarithromycin
and metronidazole, has notably diminished the effectiveness of standard
treatments. Although vaccine development is still in the experimental stage,
triple therapy has traditionally been the standard approach. More recent
treatment regimens include bismuth compounds, vonoprazan, and therapies based
on susceptibility testing have demonstrated better results. Preventive
measures focus on improving sanitation, conducting screenings, and raising
public awareness. Future research aims to explore immunomodulatory treatments,
drug delivery systems enhanced by nanotechnology, and personalized medicine
informed by pharmacogenetic insights, which could lead to more successful
eradication, strengthened host defences, and a reduction in antimicrobial
resistance in treating H. pylori.
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Graphical
Abstract:
H. pylori: A persistent pathogen
warrants sustained scientific
investigation
Introduction
DOI: 10.52228/NBW-JAAB.2025-7-1-1
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Helicobacter pylori is a
Gram-negative, microaerophilic bacterium that has a spiral shape and is
specifically adapted to thrive in the highly acidic conditions of the human
stomach. The prefix “Helico-” comes from Greek, meaning spiral or curved, which
reflects the distinct shape of H. pylori. This shape, combined with its
ability to move and colonize, allows H. pylori to invade the gastric
mucosa and form a stable “founder colony” deep inside the gastric glands. These
deeply embedded bacteria act as a reservoir, consistently replenishing the
surface population that is typically diminished by gastric peristalsis. It is
regarded as one of the most effective human pathogens, having evolved alongside
humans for over 50,000 years. It is thought to infect over half of the world's
population, particularly in areas where sanitation and hygiene are lacking (Cheok et al., 2021).
Helicobacter pylori are classified under the Helicobacteraceae family, part of the Campylobacterales
order and the ε-subdivision of the Proteobacteria. This family
encompasses various genera, including Wolinella, Flexispira, Sulfurimonas,
Thiomicrospira, and Thiovulum. Species in this genus are broadly
categorized into two primary ecological and phylogenetic groups: gastric Helicobacter
species such as H. felis, H. mustelae, H. acinonychis, and
H. heilmannii, as well as enterohepatic Helicobacter species like
H. hepaticus (Kusters et al., 2006).
H. pylori have been recognized as a Group 1 carcinogen by the International Agency
for Research on Cancer (IARC), which is a part of World Health Organization (Ali and AlHussaini 2024; Öztekin et al., 2021). It has been associated with a wide range of gastrointestinal conditions,
such as peptic ulcer disease, chronic gastritis, gastric adenocarcinoma, and
mucosa-associated lymphoid tissue (MALT) lymphoma. Since it was first
identified in 1983, H. pylori has been widely acknowledged as a major
causal factor in chronic gastric inflammation and ulcerative diseases, as well
as in its role in gastroesophageal reflux disease (Yi et al., 2025). Morphologically, H.
pylori is approximately 0.5 µm in diameter and between 3 to 5 µm in length,
this bacterium exhibits one to three helical turns. Its corkscrew-shaped
structure, created through specific cross-linking of peptidoglycan, along with
four to six unipolar flagella, allows it to move through the dense gastric
mucus. The outer membrane proteins (OMPs) serve the dual purpose of shielding
it from the severe conditions of the stomach and facilitating its attachment to
epithelial cells (Cheok et al., 2021). Considering
its persistent global influence, increasing antibiotic resistance, and complex
relationships between host and pathogen, it is vital to acquire a comprehensive
understanding of H. pylori—including its classification, pathogenicity,
treatment options, and vaccine development—to guide future clinical approaches.
1.1. Historical
Background and Discovery
Research into gastric
microbiota traces back to the late 1800s when G. Bottcher and M. Letulle (1875)
first noted the presence of bacteria at the edges of gastric ulcers. In 1892,
Giulio Bizzozero discovered spiral-shaped bacteria in the gastric mucosa of dogs
(Mazzarello et al., 2001) which contested the prevailing notion that the stomach was devoid of life
due to its acidic nature. Additional clinical observations ensued, such as W.
Krienitz's 1906 finding of similar bacteria in patients with gastric carcinoma
and necropsy analyses in the 1930s that revealed spirochetes in almost half of
the stomach cancer cases.
However, the involvement of
bacteria in gastric disease was not fully understood until the 1980s. In 1981,
Australian pathologist Robin Warren, together with clinician Barry Marshall,
began an organized investigation of curved bacteria found in gastric biopsies
from individuals with chronic gastritis. In 1983, they successfully cultured
the bacterium—initially referred to as Campylobacter pyloridis—from
human gastric tissue. Its spiral shape and biochemical similarities led to a
temporary classification within the Campylobacter genus.
Further investigations, including DNA–DNA
hybridization, 16S and 23S rRNA sequencing, fatty acid profiling, and studies
of respiratory enzymes, established that the organism was genetically distinct
from Campylobacter. Consequently, Goodwin et al., reclassified it as H.
pylori in 1989, with the genus name highlighting its helical shape and
preference for the pyloric region of the stomach.
In a pivotal demonstration of its pathogenic nature,
Barry Marshall ingested H. pylori and subsequently developed gastritis,
thereby confirming Koch’s postulates and establishing a causal link to peptic
ulcer disease. This revolutionary research altered the perception of gastric
pathology and led to the establishment of the European H. pylori Study
Group in 1987. The global recognition of these findings culminated in Marshall
and Warren receiving the Nobel Prize in Physiology or Medicine in 2005. Since
the 1990s, further species of Helicobacter have been discovered,
including H. felis and H. bilis, which have broadened the genus
and enhanced our comprehension of bacterial colonization in humans and animals.
The identification of H. pylori as a crucial causal factor in gastritis,
gastroduodenal ulcers, gastric cancer, and MALT lymphoma has revolutionized
diagnostic and treatment methodologies in gastroenterology (Charitos et al., 2021).
1.2. Phylogenetic
and Genomic Diversity
Helicobacter pylori has striking phylogenetic and genomic variation, consistent with its
co-evolution with human populations over greater than 100,000 years. It
exhibits large phylogenetic diversity, which has been influenced by its
widespread co-evolution with human hosts. As part of the Helicobacter pylori
Genome Project (HpGP), there are over 1,000 high-quality genomes from 50
nations that have been sequenced and compared, revealing 17 distinct
subpopulations. These encompass worldwide occurring lineages such as hpEurope,
hpAfrica1, hpAfrica2, hpAsia2, hpEastAsia, and hpSahul. Each of these
phylogeographic clusters reflects the past migrations of humans and local
adaptations. Interestingly, northern and southern Indigenous American H.
pylori strains differ in their ancestral backgrounds, the northern isolates
resembling North Asian strains and the southern strains more closely related to
East Asian populations. A separate US subpopulation that is clonally related
and does not possess the cag pathogenicity island was also found,
suggesting localized evolution. These observations for H. pylori
population structure underlines its genomic plasticity and the influence of
human lineage on bacterial diversity (Thorell et al., 2023).
1.3. Global
Prevalence and Clinical Significance
Globally, Helicobacter pylori is one of the most widespread
chronic infections, with an estimated prevalence of 43.9% among adults and
35.1% among children and adolescents from 2015 to 2022, as detailed in a
substantial meta-analysis involving 6.2 million participants from 111
countries. Despite a 15.9% reduction observed since 1990, infection rates
remain elevated in low- and middle-income areas such as Africa (52.7%) and
Southeast Asia (46.7%). The analysis revealed a corresponding decrease in
gastric cancer rates in populations where the prevalence of H. pylori
has dropped, underscoring its significance to global health (Chen et al.,
2024).
In India, a meta-analysis conducted in 2025
across 15 states found a pooled prevalence of 58%, with 54% among individuals
suffering from gastrointestinal diseases and 61% among those without such
conditions. The highest burden of infection was noted in Rajasthan (69%) and
Telangana (68.5%), while Gujarat reported the lowest rate (9%). Among children,
the prevalence ranged from 34% in those with gastrointestinal issues to 49% in
those without. Alarmingly, rates reached 70% among ulcer patients and 63% among
individuals diagnosed with gastric cancer, pointing to H. pylori’s
significant involvement in major gastric disorders. Socioeconomic conditions,
inadequate sanitation, and unclean water sources play a critical role in its
persistence in India, highlighting the need for national monitoring and
preventive public health measures (Puzhakkal et al., 2025).
2. Epidemiology
Recent
research indicates that H. pylori continue to be widely prevalent in
developing nations, while its occurrence is decreasing in more developed areas.
In Europe, seroprevalence varies significantly, ranging from 17% among Dutch
individuals to 84% for Ghanaians. Areas like Southeast Hungary and Russia have
reported rates as high as 65.6%, whereas Armenia is experiencing an increase
with age. In Asia, prevalence remains notable—with figures of 52.3% in Hebei,
China, and 48.4% in Wenzhou—although Taiwan has observed a decline to 21.2%.
The Middle East has reported some of the highest prevalence rates, including
88.6% in Jordan and 68% in Iran. In Latin America, the rates vary from 31.7% in
Brazil to as high as 62.9% in Peru, frequently associated with socioeconomic
inequalities. In Arctic Canada, there are significant disparities between
Indigenous (66%) and non-Indigenous (22%) populations. The study concludes that
H. pylori remain a major global health issue with significant geographic,
ethnic, and socioeconomic differences, emphasizing the necessity of ongoing
surveillance to guide treatment and prevention efforts (Hooi et al., 2017;
Mezmale et al., 2020)
In spite of extensive research, the precise transmission mode
of H. pylori is still not fully understood. Nevertheless,
person-to-person transmission is generally accepted as the main route, via
oral–oral, fecal–oral, gastro-oral, and sometimes through iatrogenic means,
such as using contaminated endoscopic tools. Additionally, mother-to-child
transmission has been noted, especially during the early postnatal stage (Liu
et al., 2024; Mezmale et al., 2020)
These findings highlight the crucial role of close household
interaction in acquiring the infection early in life. The oral cavity is
increasingly recognized as a possible reservoir for the bacterium. A
well-established connection between H. pylori colonization and
periodontal disease supports the idea of oral–oral transmission. Various
meta-analyses show a substantially higher risk of chronic periodontitis among
individuals who are H. pylori positive. Environmental sources are
gaining attention as well. Studies using PCR techniques have found H. pylori
DNA in wastewater and well water, even in the absence of fecal indicators,
suggesting the possibility of waterborne transmission. Food items such as
mussels, lettuce, and unpasteurized milk have also tested positive for either
live H. pylori or its genetic markers, indicating further potential
exposure routes through contaminated food or animal products. These results
imply that H. pylori transmission involves multiple factors, shaped by
hygiene, sanitation, dietary habits, and socioeconomic conditions (Mezmale et
al., 2020).
Although reinfection rates are low (<2%) in developed
nations, they tend to be higher (5–10%) in developing countries and among
children. New evidence indicates that strategies focused on family-based
screening and treatment might reduce reinfection rates more effectively than
individual treatments, although extensive trials are necessary to validate
their impact on public health (Malfertheiner et al., 2023).
3. Microbiological
and Biochemical Profile of Helicobacter pylori
3.1 Growth and
Cultural Characteristics
Helicobacter pylori boast significant motility due to
2 to 6 unipolar sheathed flagella, which facilitate its navigation through
thick gastric mucus. For optimal growth, it requires microaerophilic conditions
with an oxygen level of 2 to 5%, carbon dioxide concentration of 5 to 10%, and
high humidity. The ideal temperature for its growth is 37 °C, and it thrives
within a specific pH range of 5.5 to 8.0, even as it colonizes the acidic
environment of gastric mucosa. H. pylori are cultured on enriched media,
such as Columbia or Brucella agar with added blood or serum and specific
antibiotic combinations like Dent or Skirrow supplements. H. pylori can
be cultured in chemically defined media when essential amino acids like
methionine, arginine, isoleucine, histidine, leucine, valine, and phenylalanine
are included; additionally, certain strains may also need alanine and/or
serine. It tests positive for catalase, oxidase, and urease—characteristics
important for its identification (Kusters et al., 2006). Colonies generally appear as small (~1 mm), smooth,
and translucent after an incubation period of 1 to 3 days (Kusters et al., 2006).
Along with culture-based
identification, H. pylori can be observed in gastric tissues using
various histological stains, including Gram stain, Giemsa, hematoxylin and
eosin (H&E), Genta stain, Warthin-Starry silver, and immunohistochemistry (Lee and Kim 2015).
In response to adverse conditions
like antibiotics and temperature shifts, bacteria can change to a coccoid form
and enter a viable but non-culturable (VBNC) state. In this state, it preserves
metabolic activity and pathogenic potential, although it cannot be cultured
through conventional techniques. When environmental conditions improve, it can
revert to its spiral shape and regain its culturing capability. With extended
incubation, particularly under suboptimal conditions, coccoid transformation is
commonly noted, reflecting adaptation to environmental stress (Horemans 2014; Ierardi et al., 2020).
3.2 Biochemical
behaviour
Helicobacter pylori exhibit three important
biochemical functions—positive results for urease, catalase, and
oxidase—crucial for its survival, colonization, and ability to cause disease in
the gastric environment. The urease enzyme, encoded by the gene cluster (ureA–H),
hydrolyzes urea into ammonia and carbon dioxide, raising the pH of the stomach
and contributing to mucosal damage, modulation of the immune response, and
resistance to oxidative stress. This enzyme requires nickel ions, which are
taken up through transporters like FecA3, FrpB4, and NixA, and it operates
effectively in both intracellular (optimal pH of 2.5–6.5) and extracellular (pH
5.0–8.0) settings. Catalase, encoded by the katA gene, converts hydrogen
peroxide into water, protecting the bacterium from reactive oxygen species
generated by the host's immune system. It is located in the cytoplasm,
periplasm, and occasionally on the surface, aiding in the prevention of
inflammation and enhancing bacterial persistence (Sharndama and Mba 2022).
Moreover, H. pylori are
also oxidase-positive, utilizing cytochrome oxidase subunits that are integral
to its microaerophilic respiration processes, further demonstrating its
adaptation to the gastric environment (Doig et al., 1999).
4.
Antigenic Profile and Virulence Factors
H.
pylori display a range of antigenic elements
and virulence attributes that aid in its colonization, evasion of the host
immune response, and the onset of gastric disorders. The table 1. outlines the
important molecules that play a role in these mechanisms, detailing their
functions and significance in the context of pathogenesis (Yamaoka 2010).
Table
1. Essential Antigenic structures and Virulence Components of
Helicobacter pylori
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Sl.
No.
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Antigen/Virulence Factor
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Gene Name
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Type
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Location
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Function/Role in
Pathogenicity
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Immune Response Elicited
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Vaccine Target
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References
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1.
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CagA
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cagA
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Virulence protein
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Injected
from cytoplasm of H. pylori to host cell cytoplasm via T4SS
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Modifies
host signalling through the phosphorylation of the EPIYA motif; interferes
with polarity and promote inflammation.
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Stimulates
pro-inflammatory cytokine production, including IL-8.
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Yes
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(Baj et al., 2020;
Yi et al., 2025)
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2.
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VacA
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vacA
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Toxin
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Cytoplasm →
extracellular or inside host cel (secreted)
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Stimulates vacuole
formation; triggers apoptosis; suppresses T cell activity; affect
mitochondria and signalling mechanisms.
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Act as chemokine for
mast cells, triggering the secretion of pro-inflammatory cytokines (TNF-α,
MIP-1, IL-6, IL-10, IL-13) and prostaglandins thus promoting inflammation.
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Yes
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(Baj et al., 2020;
Yi et al., 2025)
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3.
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BabA (Blood Group
Antigen-Binding Adhesin)
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babA
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Adhesin/OMP
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Outer
membrane
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Attaches
to ABO/Lewis b (Leb) blood group antigens and MUC5AC mucin in gastric
and oral mucosa; Enhances delivery of CagA/VacA
via T4SS
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Stimulates
release of IL-8; immune cell infiltration and increased mucosal inflammation
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Yes
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(Baj et al., 2020;
Yi et al., 2025)
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4.
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SabA
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sabA
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Adhesin/OMP
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Outer membrane
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Attaches to sialyl-Lewis
X antigens; facilitates colonization in inflamed tissues.
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Promotes the recruitment
and activation of neutrophils via selectin mimicry; contributes to ongoing
inflammation and oxidative stress; immune evasion via phase variation
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Yes
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(Baj et al., 2020;
Yi et al., 2025)
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5.
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Outer inflammatory
protein A (OipA)
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oipA (hopH)
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OMP/ virulence factor
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Outer
membrane
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Facilitates
attachment, colonization, and the inflammatory response; Triggers apoptotic
mechanisms, alters the β-catenin and miR-30b/xCT pathways and affects the
expression of cagA and vacA.
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Triggers
strong inflammatory response and the release of cytokines; inhibits the
activation of dendritic cells.
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Yes
(in oral vaccine)
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(Baj et al., 2020;
Yi et al., 2025)
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6.
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Urease
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ureA, ureB
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Enzyme
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Cytoplasm or surface
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Breaks down urea to
neutralize gastric acid; alters the flexibility of gastric mucin; crucial for
colonization.
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Modified opsonization,
improved chemotaxis of neutrophils and monocytes, promoted apoptosis through
interaction with MHC class II receptors, increased secretion of
pro-inflammatory cytokines
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Yes
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(Baj et al., 2020;
Hu et al., 1992; Michetti et al., 1999; Zhang et al., 2024)
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7.
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Neutrophil-activating
protein A (NapA)
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napA
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Virulence protein
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Cytoplasm
→ extracellular or inside host cel (secreted)
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Encourages
the adherence of neutrophils to gastric epithelial cells and enhances the
production of reactive oxygen species (ROS) and myeloperoxidase; Stimulate
migration of neutrophils, mast cells, and monocytes through; Exhibits
ferroxidase activity thereby safeguarding DNA. Accumulates Fe²⁺; contributes to ongoing
inflammation.
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Induces
the production of IL-8, IL-6, TNF-α, IL-12, IL-23, MIP-1α (CCL3), MIP-1β
(CCL4), hexosaminidase, and IFN-γ; boosts Th1 polarization; excessively
activates antigen-specific T cells; triggers dendritic cell maturation
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Yes
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(Baj et al., 2020;
Evans Jr et al., 1995; Zhang et al., 2024)
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8.
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HopQ (Helicobacter outer membrane protein Q)
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hopQ
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OMP/
virulence factor
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Outer membrane
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Promotes attachment to
gastric epithelial cells, aids in colonization, and plays a role in the
advancement of gastrointestinal diseases. Type 1 HopQ enables the
translocation of CagA through
the T4SS by interacting with CEACAM1/3/5/6; Linked to peptic ulcers and the
development of gastric cancer.
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Stimulates
pro-inflammatory signalling through NF-κB and MAP kinase pathways; suppresses
neutrophils activity through CEACAM1 interaction;
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Yes
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(Baj et al., 2020;
Sedarat and Taylor-Robinson 2024)
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5. Pathogenesis
and Host Interaction
H.
pylori inhabit human stomach had coexisted
for millennia due to its unique adaptation lives in the stomach lining and significantly contributes to conditions
like gastritis, peptic ulcers, and gastric cancer. Its mechanism
of pathogenicity is complex, involving an intricate interaction among bacterial
virulence factors, host immune responses, and environmental influences (Yi et al., 2025).
5.1 Colonization
and Survival in the Stomach
The
development of H. pylori's disease process starts with its extraordinary
capacity to endure in the extremely acidic conditions of the human stomach.
This resilience is primarily due to the production of urease, which converts
urea into ammonia and carbon dioxide, which helps to neutralize the local pH,
enabling the bacterium to escape destruction by acid (Kusters et al., 2006).
The ammonia generated also plays a role in mucosal damage by harming epithelial
cells (Baj et al., 2020).
Moreover, H. pylori employ a set of flagella for
movement, allowing it to navigate through the thick gastric mucus layer and
position itself near the epithelial surface where the pH is relatively neutral
(Yi et al., 2025). The chemotactic movements of H. pylori are essential
for directing the bacterium toward areas with optimal pH levels and nutrient
availability (Keilberg and Ottemann 2016). Outer membrane proteins (OMPs) and
lipopolysaccharides (LPS) enable H. pylori to thrive in the gastric
environment by promoting interactions with host molecules and providing
resistance against host defence systems (Chmiela et al., 2018).
The organism is capable of forming biofilms and can
transition into coccoid shapes when under stress, which aids in its ability to
persistently colonize and develop resistance to antibiotics. These approaches
highlight H. pylori's remarkable ability to adjust and endure in the
challenging conditions of the gastric environment (Yi et al., 2025).
5.2 Adhesion to
Gastric Epithelium
Adhering
to gastric epithelial cells is a crucial step in the development of H.
pylori infection, enabling the bacterium to avoid being cleared by the
mucosa and to establish a persistent infection. Important adhesins like BabA (blood group antigen-binding
adhesin) and SabA (sialic acid-binding adhesin) aid in binding to Lewis b
antigens and sialylated glycoproteins present on the gastric epithelium
(Malfertheiner et al., 2023). The expression of these adhesins varies in a
phase-dependent manner, which allows the bacterium to adjust to the fluctuating
gastric environment and the pressures exerted by the host's immune system (Baj
et al., 2020).
Other outer membrane proteins (OMPs), such as HopZ and OipA,
further support adhesion and stimulate proinflammatory responses in host cells
(Keilberg and Ottemann 2016). The adhesion process is active, initiating signalling
pathways in host cells, including MAPK and NF-κB, which result in cytokine
production and changes to the epithelial barrier's functionality. Moreover, H.
pylori outer membrane vesicles (OMVs) contribute to host interactions by
transferring virulence factors and altering immune responses. Consequently,
adhesion is an active and complex process that supports colonization, modifies
immune responses, and initiates disease (Chmiela et al., 2018).
5.3 Host Immune
Response and Inflammation
The
immune response of the host to H. pylori is marked by chronic
inflammation that paradoxically fails to eradicate the infection. The innate
immune system recognizes bacterial elements such as LPS and peptidoglycan
through pattern recognition receptors (for example, TLR2, TLR4, and NOD1),
which activates NF-κB and leads to the release of pro-inflammatory cytokines
like IL-8. This chemokine attracts neutrophils and macrophages, which contribute
to a prolonged inflammatory response.
Despite this, H. pylori use several strategies to
escape immune clearance. The bacterium stimulates regulatory T cells (Treg) and
releases factors that inhibit the maturation of dendritic cells and their
ability to present antigens, thereby promoting immune tolerance (Kusters et
al., 2006; Malfertheiner et al., 2023; Yi et al., 2025). A chronic infection
leads to an immune environment that favors both tolerance and inflammation,
facilitating ongoing colonization. Additionally, the gastric microbiota
influences the immune response, with co-existing microbes potentially
intensifying or alleviating H. pylori-induced inflammation, thereby
impacting disease outcomes. Therefore, H. pylori's capacity to
manipulate the host immune system is crucial to its pathogenic strategy,
enabling it to remain in the host for many years (Wizenty and Sigal 2025).
5.4 Virulence
Factors and Cellular Damage
The
pathogenesis of H. pylori is driven by a range of virulence factors that
cause direct harm to host tissues and influence host cellular behavior. The CagA protein, associated with the cag pathogenicity island, enters
gastric epithelial cells via a type IV secretion system. Once it enters the
cells, CagA undergoes
phosphorylation, disrupting cellular signalling pathways such as SHP-2,
β-catenin, and PI3K/Akt, which results in changes to the cytoskeleton,
increased proliferation, and a risk of oncogenic transformation.
Another important virulence factor is the vacuolating
cytotoxin A (VacA), which
triggers the formation of vacuoles, interferes with mitochondrial function, and
induces apoptosis in epithelial cells. Additionally, VacA influences immune responses by hindering T cell activation
and antigen presentation. The dual functions of CagA and VacA in
causing epithelial injury and evading immune responses underscore their
importance in the progression of the disease (Malfertheiner et al., 2023;
Yamaoka 2010; Yi et al., 2025). Moreover, outer membrane vesicles (OMVs) play a
role in pathogenesis by acting as vehicles for the delivery of VacA,
lipopolysaccharides (LPS), and other toxins, thereby amplifying the bacterium's
impact beyond direct cell interactions (Chmiela et al., 2018).
Furthermore, H. pylori release enzymes such as
proteases and phospholipases that break down the mucus layer and extracellular
matrix, enabling deeper penetration into tissues and triggering inflammation.
Collectively, these virulence factors execute a complex assault on the gastric
mucosa, resulting in tissue damage and the onset of disease (Baj et al., 2020;
Yi et al., 2025)
5.5 Long-term
Consequences
Chronic
colonization by H. pylori can result in a range of gastroduodenal
disorders, from persistent gastritis to peptic ulcers and gastric cancer.
Ongoing inflammation leads to oxidative stress, DNA damage, and changes in the
epigenetics of gastric epithelial cells, fostering genomic instability and
cancer development. Strains that are
CagA-positive pose a greater risk for gastric adenocarcinoma due to
their capacity to disrupt cellular balance and stimulate oncogenic signalling
pathways. In addition, H. pylori infection can result in atrophic
gastritis and intestinal metaplasia, which are recognized as precancerous
conditions (Baj et al., 2020; Huang et al., 2024; Malfertheiner et al., 2023).
The transition from inflammation to cancer involves a series
of molecular processes. The interaction of bacterial characteristics, host
genetics, and environmental factors, including diet and smoking, further
influences the likelihood of developing cancer. Notably, recent research
highlights the impact of the gastric microbiota on cancer risk modification.
Dysbiosis caused by H. pylori infection may either facilitate or hinder
tumor formation, depending on the makeup of the microbial community. Therefore,
the long-term effects of H. pylori infection extend beyond direct tissue
harm to encompass intricate host-microbiome interactions that affect the
progression of the disease (Kontizas and Sgouras 2021; Malfertheiner et al.,
2023; Wizenty and Sigal 2025).
6. Diagnostic
Techniques
The
identification of H. pylori infection is crucial for preventing and
managing gastric conditions, such as peptic ulcers and gastric cancer. A
variety of diagnostic approaches—both invasive and non-invasive—exist and
should be chosen based on the patient's clinical conditions, age, and medical
history (Malfertheiner et al., 2023). Merging diagnostic precision with
availability is key to ensuring early identification and effective treatment
(Fontenot and Barber 2024).
Invasive
diagnostic techniques necessitate upper gastrointestinal endoscopy and the
collection of biopsy samples. These procedures are typically advisable for
patients exhibiting warning signs, like gastrointestinal bleeding, anaemia, or
unexplained weight loss (Malfertheiner et al., 2023). Histological examination
is considered the gold standard in invasive diagnostics, as it allows for
direct observation of the bacteria and evaluates gastritis and mucosal
alterations. Several staining techniques—such as Giemsa, Hp silver stain, and
immunohistochemical stains—have been utilized to improve the visualization of
bacteria. Hematoxylin and eosin (H&E) staining is effective for evaluating
inflammation and identifying bacteria, while the Genta stain, which combines
Steiner, H&E, and alcian blue, enables a concurrent assessment of inflammation
and H. pylori. Of all these options, modified Giemsa is the most widely
used because of its ease of use, sensitivity, and affordability (Fontenot and
Barber 2024; Lee and Kim 2015).
The Rapid Urease Test (RUT) is a commonly
utilized invasive diagnostic method that depends on the potent urease activity
of Helicobacter pylori, which breaks
down urea to generate ammonia and carbon dioxide, resulting in a rise in pH
that is indicated by a phenol red indicator, causing a color change from yellow
to pink (Athavale et al., 2017; Fontenot and Barber 2024). This
straightforward, quick, and cost-effective test is typically conducted during
endoscopic procedures and is among the most frequently used diagnostic
techniques for detecting H. pylori in
regular hospital settings, especially in India, due to its high accuracy and
ease of interpretation. Utilizing RUT during endoscopy allows medical
professionals to confirm infection immediately, thereby enabling prompt
treatment decisions (Bordin et al., 2021). Its clinical importance is
underscored by its high accuracy; for instance, one study noted a sensitivity
of 96.6% and a specificity of 99.2% (Goh et al., 1994).
Nonetheless,
the accuracy of the diagnosis can be affected by factors such as previous use
of proton pump inhibitors (PPIs) or the presence of bleeding ulcers at the time
of biopsy (Fontenot & Barber, 2024). To improve both test sensitivity and
specificity, it is advisable to stop PPI use at least two weeks prior to the
procedure. Despite these challenges, the RUT remains highly clinically relevant
because it can offer rapid, on-site confirmation of infection and support
immediate therapeutic choices during endoscopic assessment (Jearth et al.,
2025).
Bacterial
culture, while not frequently employed in standard diagnostics, offers the
advantage of allowing antimicrobial susceptibility testing. Culturing H.
pylori from gastric biopsies is a complex process, requiring specific
transport conditions and microaerophilic environments. Still, it is valuable in
cases of treatment failure or when antibiotic resistance is suspected (Fontenot
and Barber 2024; Malfertheiner et al., 2023).
Among
non-invasive techniques, the Urea Breath Test (UBT) is recognized as the most
precise. This test employs isotopically labeled urea such as radioactive 14C
or nonradioactive 13C, which is broken down by urease in those
infected, generating labeled CO₂ measured in
the breath. UBT shows over 95% sensitivity and specificity but can also be
influenced by recent PPI and antibiotic intake, necessitating periods without
these medications before testing (Fontenot and Barber 2024).
The
Stool Antigen Test (SAT) presents another practical non-invasive choice. SAT
identifies bacterial antigens via enzyme immunoassays or immunochromatographic
methods, with tests based on monoclonal antibodies showing the highest level of
accuracy. SAT is suggested for both initial diagnosis and follow-up monitoring
after treatment, especially for children (Malfertheiner et al., 2023).
Serological
testing identifies circulating IgG antibodies targeting H. pylori,
making it suitable in situations where other non-invasive tests are not
available. However, it does not differentiate between current and prior
infections. It is not advisable for assessing post-eradication since antibodies
can remain detectable long after successful treatment (Fontenot and Barber
2024).
Due to the drawbacks of traditional diagnostic techniques
for H. pylori—such as slow results, high expenses, and dependence on
laboratory facilities— emerging
technologies like biosensors and molecular diagnostics offer a revolutionary
alternative. Biosensor employ biorecognition components like antibodies or
nucleic acids paired with transducers to identify specific markers of H.
pylori, such as CagA and VacA, with high accuracy and sensitivity. Notably, biosensors
can provide immediate results, are highly mobile, and necessitate minimal
training, making them well-suited for point-of-care applications in both
healthcare settings and areas with limited resources. Recent developments
include electrochemical and optical biosensors, as well as Microfluidic
lab-on-a-chip devices that consolidate multiple diagnostic capabilities onto a
small platform. Molecular diagnostic methods like PCR and NGS are starting to
be integrated into clinical practice. PCR allows for the swift identification
of H. pylori DNA and resistance mutations, particularly for
clarithromycin resistance. The growing application of NGS facilitates extensive
resistance profiling, enhancing precision medicine strategies. While still in
the early stages of development, these technologies demonstrate significant
potential for expediting diagnosis and could become essential assets in
worldwide initiatives aimed at improving H. pylori detection and
treatment (Fontenot and Barber 2024; Malfertheiner et al., 2023; Saxena et al.,
2021).
Fig: 1 Advancements in the diagnosis of H.
pylori: transitioning from traditional methods to innovative tools. Source:
NIAID BIOART (https://bioart.niaid.nih.gov)
7. Antibiotic
Resistance in Helicobacter pylori
Antibiotic
resistance in H. pylori is an increasing global problem that compromises
the success of typical treatment methods, especially in regions with high
infection rates. Resistance rates to commonly utilized antibiotics, including
clarithromycin, metronidazole, and fluoroquinolones, have been rising over
time, prompting a change in treatment approaches and highlighting the need for
resistance monitoring and tailored therapy (Elbaiomy et al., 2025; Hasanuzzaman
et al., 2024).
Clarithromycin resistance, which has a substantial clinical
impact, results from point mutations in the 23S rRNA gene, particularly those
identified as A2142G, A2142C, and A2143G. These mutations hinder the
antibiotic's ability to bind with the bacterial ribosome, thus making the
treatment ineffective (Hasanuzzaman et al., 2024). Clarithromycin resistance
has become a major challenge in treating H. pylori, with increasing
occurrences observed globally, notably in areas where there is widespread use
of macrolides and insufficient antibiotic stewardship (Hasanuzzaman et al.,
2024; Yi et al., 2025). Consequently, international guidelines now suggest
using clarithromycin-based triple therapy only in regions where the resistance
rate is under 15% (Hasanuzzaman et al., 2024).
Metronidazole resistance, another common problem, mainly
arises from mutations in the rdxA and frxA genes, which produce
oxygen-insensitive nitroreductases necessary for drug activation. Nevertheless,
resistance has also been found in strains that do not carry these mutations,
indicating that other factors may play a role, such as mutations in fdxB
and fur, overexpression of the hefA efflux pump and enhanced DNA
repair mechanisms (Elbaiomy et al., 2025; Hasanuzzaman et al., 2024).
Interestingly, unlike clarithromycin resistance, high levels of metronidazole
resistance are not consistently linked with treatment failure. While
amoxicillin resistance is still relatively uncommon, it is starting to appear
in certain areas. Resistance is caused by mutations in penicillin-binding
proteins, particularly PBP1A, which diminish the drug’s effectiveness in
disrupting cell wall synthesis (Hasanuzzaman et al., 2024).
Resistance to fluoroquinolones, such as levofloxacin,
generally originates from mutations in the gyrA gene, especially at
positions N87 and D91, which impair the function of the DNA gyrase enzyme,
thereby reducing their antibacterial effectiveness (Elbaiomy et al., 2025;
Hasanuzzaman et al., 2024). Rarely, rifabutin resistance arises from mutations
in the rpoB gene, and tetracycline resistance is associated with
triple-base mutations in the 16S rRNA gene (Hasanuzzaman et al., 2024). In addition to these genetic factors, efflux
pumps—particularly those from the RND and MFS families—significantly contribute
to multidrug resistance by pumping various antibiotics out of the bacterial
cell (Elbaiomy et al., 2025). Moreover, H. pylori’s ability to form
biofilms increases antibiotic tolerance, as bacteria embedded in biofilms
exhibit lower metabolic activity and heightened expression of
resistance-related mechanisms (Yi et al., 2025). Biofilms also protect coccoid
forms of the bacterium, which are more resistant to both antibiotics and host
immune responses (Elbaiomy et al., 2025; Mishra et al., 2023).
Given these obstacles, the effectiveness of standard triple
therapy is waning, and bismuth-based quadruple therapy or treatment guided by
susceptibility testing is being recommended more frequently. New adjunct
therapies—such as probiotics, antimicrobial peptides, and anti-biofilm
agents—are currently under investigation to enhance eradication success
(Hasanuzzaman et al., 2024).
Besides these molecular processes, the antibiotic resistance
exhibited by Helicobacter pylori
demonstrates significant variation across different regions, greatly affecting
the effectiveness of treatments and decisions regarding therapy worldwide. This
diversity in resistance patterns presents a significant obstacle to effective
eradication efforts. Clarithromycin and metronidazole, two frequently utilized
antibiotics, show the highest rates of global resistance, surpassing 15% in
almost all WHO regions. A meta-analysis conducted in 2024 showed that
clarithromycin resistance varied from 16.0% in the Americas to 28.9% in Asia,
and it was particularly high in children at 38.2%, compared to 25.6% in adults.
Amoxicillin and tetracycline generally exhibit low resistance rates (<10%)
in most regions, with the exception of Africa, where resistance rates for
amoxicillin (70.4%) and metronidazole (84.2%) are extremely high. In India,
significant resistance is reported for clarithromycin (35.6%) and levofloxacin
(32.8%), while metronidazole resistance remains very high at 77.7%,
highlighting the limitations of standard triple therapy. In China, the levels
of resistance to metronidazole (69%) and clarithromycin (36.7%) indicate the
urgent need for bismuth-based treatment options. Conversely, countries like
Australia and Portugal are experiencing rising clarithromycin resistance rates
exceeding 20–40%, while maintaining low levels of resistance to amoxicillin and
tetracycline. In the Americas, particularly in Mexico and Brazil,
clarithromycin resistance has been gradually climbing, reaching up to 32% and
19%, respectively, while data from several Latin American and African nations
remain sparse due to insufficient surveillance systems. Overall, the uneven
distribution of antibiotic resistance illustrates variations in antibiotic
usage, local treatment guidelines, and diagnostic capabilities, highlighting
the critical need for monitoring and antibiotic stewardship programs tailored
to specific regions (Rocha et al., 2025).
8. Vaccine
Development Strategies
8.1
Challenges in Vaccine Design
Creating
a vaccine for Helicobacter pylori presents significant obstacles, mainly
because the bacterium can avoid immune detection by altering its LPS and
flagellin, as well as employing immune-disrupting virulence factors such as CagA and VacA. The high
genetic diversity among different strains makes it difficult to determine
suitable antigens, which limits the effectiveness of a universal vaccine.
Although live vaccines can elicit strong immune responses, they also present
safety issues, whereas subunit or DNA vaccines, while being safer, frequently
lack adequate immunogenicity. Encouraging outcomes from animal studies often do
not translate successfully to human applications, and practical
challenges—including delivery methods, stability, and production costs—further
impede advancement. Addressing these challenges necessitates the use of
cutting-edge technologies and a more comprehensive understanding of
host-pathogen interactions (Gong et al., 2025).
8.2
Current Approaches
Despite
notable obstacles in creating a vaccine for Helicobacter pylori, such as
immune evasion, genetic diversity, and the limited effectiveness of human
trials, progress in vaccine design has paved the way for various new
strategies. The current methods can be categorized into four main types:
whole-cell vaccines, subunit vaccines, live vector vaccines, and DNA vaccines.
Whole-cell and subunit vaccines focus on promoting both mucosal and systemic
immunity, with subunit vaccines typically targeting conserved antigens like CagA, VacA, and UreB. Live vector vaccines employ
attenuated bacteria or viruses to mimic natural infections, while DNA vaccines
deliver genes encoding antigens to provoke immune responses (Gong et al., 2025).
A recent development involves outer membrane vesicle
(OMV)-based vaccines, where H. pylori strains are genetically altered to
knock out genes related to immune evasion (lpxE, lpxF, futB) and deliver
antigens through the Hbp autotransporter system. This strategy restored TLR4
recognition, activated dendritic cell maturation, and produced a mixed
Th1/Th2/Th17 immune response, resulting in a lower bacterial load and increased
IgG and mucosal IgA production in mouse models (Liu,
Q. et al., 2025).
Likewise, multi-epitope vaccines using minicells derived
from Salmonella have been developed to improve targeting and immunogenicity. A
candidate vaccine, Apt-TA-2m, which combines HpaA, VacA, and UreB
fused with an OsmY secretion
signal and a dendritic cell-specific aptamer, exhibited excellent safety and
strong mucosal and T-cell responses in murine models, significantly decreasing
gastric colonization and inflammation. These innovative approaches highlight
promising avenues in the research of H. pylori vaccine (Yang et al., 2025).
8.3
Future Directions
Recent
developments in immunoinformatics, molecular biology, and vaccine delivery
methods have reignited optimism for creating an effective vaccine against Helicobacter
pylori. Mucosal delivery systems—especially through oral and nasal
administration—are being prioritized to target the gastric mucosa, which is the
main site of infection. Researchers are also looking into combination
strategies that use vaccines in conjunction with antibiotics to enhance
eradication success and reduce the likelihood of reinfection. Approaches
utilizing multi-epitope constructs and bacterial minicell-based targeting have
demonstrated potential in preclinical studies, suggesting a viable and
cost-effective option. Nonetheless, the development of vaccines continues to be
difficult due to the bacterium's ability to evade the immune system and the
variability in individual host responses. Thus, increased global funding and
collaborative research—particularly in low- and middle-income countries
(LMICs)—will be crucial for advancing clinical applications and translating
promising candidates into practical solutions (Gong
et al., 2025; Yang et al., 2025; Sutton & Boag, 2019).
9.
Treatment and Prevention
9.1
Current treatment Strategies
Over
the past decades, treatment strategies for H. pylori infection have
evolved significantly, driven largely by rising antibiotic resistance and
variable regional eradication rates. Traditionally, the most commonly
prescribed first-line treatment was clarithromycin-based triple therapy,
consisting of a proton pump inhibitor (PPI), clarithromycin, and amoxicillin
for 7–14 days. However, the effectiveness of this regimen has been compromised
by increasing clarithromycin resistance, rendering it unsuitable in many
regions where the resistance rate exceeds 15% (Shih et al., 2022). In response
to declining eradication rates of triple therapy, bismuth quadruple
therapy—comprising a PPI, bismuth, tetracycline, and metronidazole—has gained
traction as a more effective first-line regimen in areas with high clarithromycin
resistance (Rimbara et al., 2011; Shih et al., 2022). This regimen has
demonstrated relatively stable eradication rates even in the context of
antibiotic resistance due to the low resistance rates to bismuth and
tetracycline (O'Connor et al., 2020). Additionally, concomitant therapy, which
involves the simultaneous administration of a PPI, amoxicillin, clarithromycin,
and metronidazole, has also shown promising results, with eradication rates
consistently above 94% in some regions (Shih et al., 2022).
As resistance patterns shift, so does the need to optimize
treatment duration and drug combinations. Extending the treatment duration to
14 days has shown to improve eradication rates compared to shorter regimens
(O'Connor et al., 2020). Moreover, high-dose dual therapy—comprising a PPI and
amoxicillin—has emerged as a viable alternative. However, its use is often
limited by side effects and poor patient compliance due to the high dose,
frequent administration, and extended treatment duration. As a result, it is
primarily employed as a rescue or salvage therapy (Suzuki et al., 2022).
Building on the need for more tolerable and effective
regimens, alternative therapies such as vonoprazan-based Vono-triple and
R-hybrid therapies have been developed, achieving eradication rates exceeding
90%. Vonoprazan, a potassium-competitive acid blocker (P-CAB), offers superior
acid suppression compared to traditional PPIs. This potent acid inhibition
enhances antibiotic stability in the gastric environment and improves treatment
efficacy (Huang et al., 2024; Suzuki et al., 2022). Recent studies suggest that
regimens based on vonoprazan demonstrate similar, and in some cases enhanced,
success rates for eradication when compared to traditional proton pump
inhibitor (PPI)-based triple therapies. A meta-analysis conducted in China in
2024, which included 1,560 participants, revealed eradication rates of 88.7%
for ten-day vonoprazan-based treatments versus 82.9% for fourteen-day PPI-based
therapies. The per-protocol analysis indicated even greater success with
vonoprazan implying that the enhanced acid suppression offered by
potassium-competitive acid blockers (P-CABs) might improve the stability and
bioavailability of antibiotics in the stomach. In Japan, similar results have
led to the adoption of seven-day vonoprazan-based triple therapy as the
first-line treatment over standard PPI regimens, owing to its efficacy and
better tolerability. Currently, international guidelines recommend a 14-day
triple therapy as standard first-line treatment for Helicobacter pylori eradication, which includes a PPI, amoxicillin,
and clarithromycin—however, this is advised only in regions where
clarithromycin resistance is below 15%. In China and numerous other Asian
nations, the increase in antibiotic resistance has led to the preference for a
14-day bismuth-based quadruple regimen, which consists of two antibiotics in
addition to a PPI and bismuth salt as the first-line approach. While this
treatment is effective, its longer duration, increased pill burden, and common
side effects can often hinder patient adherence and overall success rates (Gao
et al., 2024).
In parallel, recent studies have emphasized the growing role
of personalized treatment strategies. Tailored therapies based on antibiotic
susceptibility testing, PCR-based resistance profiling, and CYP2C19 genotyping
have achieved eradication rates up to 93%, often outperforming empirical
regimens while minimizing adverse effects, marking a significant advancement in
individualized H. pylori management.
Despite these advancements, challenges remain—particularly
in cases of treatment failure—where bismuth quadruple therapy, although
increasingly recommended as a first-line regimen in high-resistance settings,
continues to serve as a reliable second-line or salvage therapy option
(O'Connor et al., 2020). Additionally, rifabutin-based triple therapy and
levofloxacin-containing regimens have been evaluated as potential third-line
options, however, their broader use is limited by factors such as availability,
and safety concerns (O'Connor et al., 2010). As antibiotic resistance continues
to rise globally, optimizing current therapies while developing novel treatment
strategies is imperative. The key to effective eradication lies in selecting
regimens based on local resistance patterns and incorporating high-dose or
extended-duration therapies. Avoiding the repeated use of ineffective regimens
is also crucial, as it further exacerbates resistance (Kim et al., 2020).
Given the increasing challenges, there is an urgent need to
investigate alternative and complementary methods for managing H. pylori that go beyond traditional
antibiotics. Natural products, especially those from medicinal plants, provide
a wealth of bioactive compounds with antimicrobial, anti-inflammatory, and
gastroprotective effects. These plant-based substances have demonstrated the
ability to inhibit bacterial growth, alleviate gastric inflammation, and
bolster host defense mechanisms, making them promising candidates for the
creation of new therapeutic strategies. (Chen et al., 2025; Soni & Gawri
2023; Jaiswal et al., 2024). Ongoing interdisciplinary research that combines
microbiology, pharmacology, and traditional medicine could aid in the
identification of safer and more sustainable options for eradicating H. pylori in the future.
9.2
Prevention Strategies
Preventing H.
pylori infection largely depends on addressing its primary transmission
routes, which include direct oral-oral contact via saliva or vomitus and
possible fecal-oral transmission. Waterborne spread, particularly in areas
lacking treated water, may also contribute significantly to infection. Poor
sanitation, overcrowded living conditions, and low socioeconomic status are key
risk factors linked to higher prevalence (Salih 2009). Public
health campaigns focused on Helicobacter pylori are increasingly
prioritizing both prevention and treatment approaches. The idea of screening
and treating asymptomatic carriers within high-risk groups is being explored,
as shown by initiatives in Japan, where eradicating the bacteria in young
people with early gastric lesions has been promoted as a measure to prevent
cancer (Suzuki et al., 2022). Preventing reinfection is also crucial; after
successful eradication, maintaining good hygiene and limiting antibiotic use
are vital, especially in areas with elevated reinfection rates stemming from
inadequate living conditions (O’Connor et al., 2020). An innovative,
antibiotic-free preventive method involving yogurt-inspired hybrid membrane
vesicles (hMVs)—developed by merging bacterial outer membrane vesicles (OMVs)
with milk-derived membrane vesicles (MMVs)—has shown a notable decrease in H.
pylori colonization and inflammation in mouse studies, providing a safe
preventive measure (Liu, L. et al., 2025). Further research indicates that
early interventions during childhood, enhanced hygiene practices, and targeted
eradication efforts in individuals who are genetically or virulently
predisposed can significantly help in preventing the advancement to gastric
cancer (Duan et al., 2025). Furthermore,
bioactive substances obtained from medicinal plants have shown both anti-H. pylori and anti-inflammatory
properties in experimental studies, indicating their potential as additional
preventive measures. Collectively, these efforts reflect a shift in perspective
from merely addressing the infection to embracing comprehensive strategies that
merge therapeutic, preventive, and public health methodologies in order to
reduce the worldwide impact of H. pylori-related
illnesses (Guerra-vale et al., 2022; Gupta et al., 2021; Singh et al., 2021).
Together,
these initiatives demonstrate a transition from merely treating the disease to
employing comprehensive strategies that integrate treatment, prevention, and
public health measures aimed at minimizing disease impact and addressing
antimicrobial resistance.
10.
Conclusion and Future Perspectives
Helicobacter
pylori is still a worldwide important
pathogen linked with chronic gastritis, peptic ulcer disease, and significantly
gastric cancer. Even after its discovery, three decades of scientific progress
have not eliminated H. pylori as a public health threat, particularly in
those areas of high infection prevalence and thus increasing resistance to
antibiotics. Whereas traditional triple and quadruple antibiotic regimens have
been the standard, their long-term effectiveness is undermined by escalating
antimicrobial resistance, patient compliance issues, and the possibility of gut
microbiota disruption.
Nanomedicine developments provide encouraging alternatives.
Lipid, polymeric, and metallic nanoparticles have exhibited greater drug
delivery, enhanced gastric mucosal targeting, and ability to bypass
biofilm-mediated resistance mechanisms. These nano formulations are not only
promising in eliminating the pathogen but also in countering the oncogenic and
inflammatory cascades induced by H. pylori. While most of these
approaches are yet to move beyond the preclinical and early clinical stages and
need to undergo strict human trials to establish their safety, bioavailability,
and long-term efficacy.
In the future, it is possible that combinations of
nanotechnology and immunomodulatory approaches—vaccine delivery, immune
checkpoint inhibitors, or cytokine carriers—could change the way in which H.
pylori infections are treated. In addition, region-specific stewardship of
antibiotics and customized therapy according to local resistance patterns is
critical for control. The achievement of effective elimination of Helicobacter
pylori will hinge on concerted strategies that unite scientific advance,
evidence-based clinical practice, and activated public health action. Progress
towards this aim will need to be based on continued global cooperation and
shared commitment to the reduction of the burden of H. pylori-related
diseases (Shah et al., 2025; Suzuki et al., 2025;
Kamboj et al., 2025).
Conflict of
interest Author declares
that there is no conflict of interest.
Funding
information not applicable.
Ethical approval not applicable.
References
Ali, A., & AlHussaini, K. I. (2024). Helicobacter pylori:
a contemporary perspective on pathogenesis, diagnosis and treatment
strategies. Microorganisms, 12(1), 222.
Athavale,
V. S., Singh, V., Khandalkar, S. N., Nirhale, D. S., Lad, A., & Shetty, I.
(2017). Comparative study of rapid urease test and histopathological
examination for detection of H. pylori infection. International Surgery
Journal, 4(12), 4071.
Baj,
J., Forma, A., Sitarz, M., Portincasa, P., Garruti, G., Krasowska, D., &
Maciejewski, R. (2020). Helicobacter pylori virulence factors—mechanisms of
bacterial pathogenicity in the gastric microenvironment. Cells, 10(1), 27.
Bordin,
D. S., Voynovan, I. N., Andreev, D. N., & Maev, I. V. (2021). Current
Helicobacter pylori Diagnostics. Diagnostics, 11(8), 1458. https://doi.org/10.3390/diagnostics11081458
Charitos, I. A., D’Agostino, D., Topi, S., & Bottalico,
L. (2021). 40 years of Helicobacter pylori: a revolution in biomedical
thought. Gastroenterology
Insights, 12(2),
111-135.
Chen,
D., Wang, W., Chen, X., Liang, N., Li, J., Ding, W., ... & Liu, Z. (2025).
Plant-derived extracts or compounds for Helicobacter-associated gastritis: a
systematic review of their anti-Helicobacter activity and anti-inflammatory
effect in animal experiments. Chinese Medicine, 20(1), 53.
Chen, Y. C., Malfertheiner, P., Yu, H. T., Kuo, C. L., Chang,
Y. Y., Meng, F. T., ... & Liou, J. M. (2024). Global prevalence of
Helicobacter pylori infection and incidence of gastric cancer between 1980 and
2022. Gastroenterology, 166(4), 605-619.
Cheok, Y. Y., Lee, C. Y. Q., Cheong, H. C., Vadivelu, J.,
Looi, C. Y., Abdullah, S., & Wong, W. F. (2021). An overview of
Helicobacter pylori survival tactics in the hostile human stomach
environment. Microorganisms, 9(12), 2502.
Chmiela,
M., Walczak, N., & Rudnicka, K. (2018). Helicobacter pylori outer membrane
vesicles involvement in the infection development and Helicobacter
pylori-related diseases. Journal
of biomedical science, 25,
1-11.
Dieye,
Y., Nguer, C. M., Thiam, F., Diouara, A. A. M., & Fall, C. (2022).
Recombinant helicobacter pylori vaccine delivery vehicle: a promising tool to
treat infections and combat antimicrobial resistance. Antibiotics, 11(12),
1701.
Doig, P., de Jonge, B. L., Alm, R. A., Brown, E. D.,
Uria-Nickelsen, M., Noonan, B., Mills, S. D., Tummino, P., Carmel, G., Guild,
B. C., Moir, D. T., Vovis, G. F., & Trust, T. J. (1999). Helicobacter
pylori physiology predicted from genomic comparison of two strains. Microbiology and molecular biology reviews:
MMBR, 63(3), 675–707.
https://doi.org/10.1128/MMBR.63.3.675-707.1999
Duan, Y., Xu, Y., Dou, Y., & Xu, D. (2025). Helicobacter
pylori and gastric cancer: mechanisms and new perspectives. Journal of Hematology & Oncology, 18(1), 10.
Elbaiomy,
R. G., Luo, X., Guo, R., Deng, S., Du, M., El-Sappah, A. H., ... & Zhang,
Z. (2025). Antibiotic resistance in Helicobacter pylori: a genetic and
physiological perspective. Gut
Pathogens, 17(1),
1-20.
Evans
Jr, D. J., Evans, D. G., Takemura, T., Nakano, H., Lampert, H. C., Graham, D.
Y., ... & Kvietys, P. R. (1995). Characterization of a Helicobacter pylori
neutrophil-activating protein. Infection
and immunity, 63(6),
2213-2220.
Fontenot,
T., & Barber, A. E. (2024). Invasive and Non-Invasive Methods of Diagnosing
H. pylori Infection: A Review of Current Practice. Towards the Eradication of
Helicobacter pylori Infection-Rapid Diagnosis and Precision Treatment.
Fontenot,
T., & E. Barber, A. (2024). Invasive and Non-Invasive Methods of Diagnosing
H. pylori Infection: A Review of Current Practice. IntechOpen. doi:
10.5772/intechopen.1004779.
Gao,
W., Wang, Q., Zhang, X., & Wang, L. (2024). Ten-day vonoprazan-based versus
fourteen-day proton pump inhibitor-based therapy for first-line Helicobacter
pylori eradication in China: A meta-analysis of randomized controlled trials.
International Journal of Immunopathology and Pharmacology, 38,
03946320241286866.
Goh,
K. L., Parasakthi, N., Peh, S. C., Puthucheary, S. D., & Wong, N. W.
(1994). The rapid urease test in the diagnosis of Helicobacter pylori
infection. Singapore medical journal, 35(2), 161-162.
Gong, J., Wang, Q., Chen, X., & Lu, J.
(2025). Helicobacter pylori Vaccine: Mechanism of Pathogenesis, Immune Evasion
and Analysis of Vaccine Types. Vaccines, 13(5), 526.
Guerra-Valle,
M., Orellana-Palma, P., & Petzold, G. (2022). Plant-Based Polyphenols:
Anti-Helicobacter pylori Effect and Improvement of Gut Microbiota.
Antioxidants, 11(1), 109.
Gupta,
N., Beliya, E., Tiwari, S., Paul, J. S., & Jadhav, S. K. (2021). Combating
SARS-CoV-2 and other infectious diseases with enhanced immunity by herbs and
spices, and preventing its community transfer via ancient Indian traditions and
culture. NewBioWorld, 3(2), 13-21.
Hasanuzzaman,
M., Bang, C. S., & Gong, E. J. (2024). Antibiotic resistance of
Helicobacter pylori: Mechanisms and clinical implications. Journal of Korean Medical Science, 39(4).
Hooi,
J. K., Lai, W. Y., Ng, W. K., Suen, M. M., Underwood, F. E., Tanyingoh, D., ...
& Ng, S. C. (2017). Global prevalence of Helicobacter pylori infection:
systematic review and meta-analysis. Gastroenterology, 153(2),
420-429.
Horemans, T. (2014). A quest for novel therapeutic and diagnostic approaches in Helicobacter
pylori infections (Doctoral dissertation, University of Antwerp).
Hu, L.
T., Foxall, P. A., Russell, R. O. B. E. R. T., & Mobley, H. L. (1992).
Purification of recombinant Helicobacter pylori urease apoenzyme encoded by
ureA and ureB. Infection and
immunity, 60(7),
2657-2666.
Huang,
T. T., Cao, Y. X., & Cao, L. (2024). Novel therapeutic regimens against
Helicobacter pylori: An updated systematic review. Frontiers in Microbiology, 15, 1418129.
Ierardi, E., Losurdo, G., Mileti, A., Paolillo, R., Giorgio,
F., Principi, M., & Di Leo, A. (2020). The puzzle of coccoid forms of
Helicobacter pylori: beyond basic science. Antibiotics, 9(6),
293.
Illustration from NIAID NIH BIOART Source
(bioart.niaid.nih.gov/bioart/###)
Jaiswal,
S., Agrawal, S., & Rajwade, D. (2024). Nature’s Defender: The Antimicrobial
Potential of spices–An Overview. NewBioWorld, 6(1), 28-32.
Jearth,
V., Yadav, A. I., Shah, J., Singh, A. K., Sundaram, S., Sharma, V., ... &
Panigrahi, M. K. (2025). A survey of practice patterns and adherence to
national and international guidelines on the management of Helicobacter pylori
infection among gastroenterologists and gastroenterology fellows in India.
Indian Journal of Gastroenterology, 44(2), 208-219.
Kamboj, A. K., Cotter, T. G., & Oxentenko, A. S. (2017,
April). Helicobacter pylori: the past, present, and future in management.
In Mayo Clinic Proceedings (Vol.
92, No. 4, pp. 599-604). Elsevier.
Keilberg,
D., & Ottemann, K. M. (2016). How H elicobacter pylori senses, targets and
interacts with the gastric epithelium. Environmental microbiology, 18(3), 791-806.
Kim,
S. Y., & Chung, J. W. (2020). Best Helicobacter pylori eradication strategy
in the era of antibiotic resistance. Antibiotics, 9(8),
436.
Kontizas,
E., & Sgouras, D. (2021). Review–pathogenesis of helicobacter pylori
infection. Microb Health Dis, 3(10.26355).
Kusters, J. G., Van Vliet, A. H., & Kuipers, E. J.
(2006). Pathogenesis of Helicobacter pylori infection. Clinical microbiology reviews, 19(3), 449-490.
Lee,
J. Y., & Kim, N. (2015). Diagnosis of Helicobacter pylori by invasive test:
histology. Annals of
translational medicine, 3(1),
10.
Liu, L., Guo, Y., Wang, B., Pan, Y., Zhao, C., Xiao, Z., ...
& Rao, L. (2025). Yogurt-inspired hybrid membrane vesicles for the
prevention and treatment of Helicobacter pylori infection. Cell Biomaterials, 1(4).
Liu,
M., Gao, H., Miao, J., Zhang, Z., Zheng, L., Li, F., ... & Sun, J. (2024).
Helicobacter pylori infection in humans and phytotherapy, probiotics, and
emerging therapeutic interventions: a review. Frontiers in Microbiology, 14, 1330029.
Liu, Q., Li, B., Ma, J., Lei, X., Ma, J., Da, Y., ... &
Zhang, C. (2025). Development of a Recombinant Outer Membrane Vesicles (OMVs)‐Based Vaccine Against Helicobacter pylori
Infection in Mice. Journal of
Extracellular Vesicles, 14(5),
e70085.
Malfertheiner,
P., Camargo, M. C., El-Omar, E., Liou, J. M., Peek, R., Schulz, C., ... &
Suerbaum, S. (2023). Helicobacter pylori infection. Nature reviews Disease primers, 9(1), 19.
Manna,
O. M., Caruso Bavisotto, C., Gratie, M. I., Damiani, P., Tomasello, G., &
Cappello, F. (2025). The Role of Helicobacter pylori Heat Shock Proteins in
Gastric Diseases’ Pathogenesis. International
Journal of Molecular Sciences, 26(11), 5065.
Mazzarello, P., Calligaro, A. L., & Calligaro, A. (2001).
Giulio Bizzozero: a pioneer of cell biology. Nature reviews Molecular cell biology, 2(10), 776-781.
Mezmale,
L., Coelho, L. G., Bordin, D., & Leja, M. (2020). Epidemiology of
Helicobacter pylori. Helicobacter, 25, e12734.
Michetti,
P., Kreiss, C., Kotloff, K. L., Porta, N., Blanco, J. L., Bachmann, D., ...
& Blum, A. L. (1999). Oral immunization with urease and Escherichia coli
heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori–infected
adults. Gastroenterology, 116(4), 804-812.
Mishra,
S., Kolla, A. P., Bajpai, R., Pandey, C., & Kolla, V. (2023). Formulation
and Evaluation of Herbal Toothpaste against Biofilm Producing Staphylococcus
aureus. NewBioWorld, 5(1), 37-44.
O'Connor,
A., Furuta, T., Gisbert, J. P., & O'Morain, C. (2020). Review–treatment of
Helicobacter pylori infection 2020. Helicobacter, 25, e12743.
Öztekin, M., Yılmaz, B., Ağagündüz, D., & Capasso, R.
(2021). Overview of Helicobacter pylori infection: clinical features,
treatment, and nutritional aspects. Diseases, 9(4), 66.
Puzhakkal,
S., Mittal, P., & Thiruchelvam, K. (2025). Prevalence of Helicobacter
pylori Infection in India: A Systematic Re-view and Meta-Analysis. Evidence
Synthesis in Healthcare Connect, 1(1), 1-10.
Rimbara,
E., Fischbach, L. A., & Graham, D. Y. (2011). Optimal therapy for
Helicobacter pylori infections. Nature
reviews Gastroenterology & hepatology, 8(2), 79-88.
Rocha,
G. R., Lemos, F. F. B., de Oliveira Silva, L. G., Luz, M. S., Santos, G. L. C.,
Pinheiro, S. L. R., ... & de Melo, F. F. (2025). Overcoming
antibiotic-resistant Helicobacter pylori infection: Current challenges and
emerging approaches. World Journal of Gastroenterology, 31(10), 102289.
Salih, B. A. (2009). Helicobacter pylori infection in
developing countries: the burden for how long?. Saudi Journal of
Gastroenterology, 15(3), 201-207.
Sedarat,
Z., & Taylor-Robinson, A. W. (2024). Helicobacter pylori outer membrane
proteins and virulence factors: potential targets for novel therapies and
vaccines. Pathogens, 13(5), 392.
Shah, S. A. R., Mumtaz, M., Sharif, S., Mustafa, I., &
Nayila, I. (2025). Helicobacter pylori and gastric cancer: current insights and
nanoparticle-based interventions. RSC
advances, 15(7),
5558-5570.
Sharndama, H. C., & Mba, I. E. (2022). Helicobacter
pylori: an up-to-date overview on the virulence and pathogenesis
mechanisms. Brazilian Journal of
Microbiology, 53(1),
33-50.
Shih,
C. A., Shie, C. B., & Hsu, P. I. (2022). Update on the first-line treatment
of Helicobacter pylori infection in areas with high and low clarithromycin
resistances. Therapeutic Advances
in Gastroenterology, 15,
17562848221138168
Singh,
A., Verma, D., Tiwari, S., & Jadhav, S. K. (2021). Antimicrobial activity
of Azadirachta indica (Neem) leaf extract on gram positive and gram-negative
bacteria. NewBioWorld, 3(1), 11-17.
Soni,
P., & Gawri, S. (2023). Therapeutic Use of Some Common Medicinal Plants for
the Treatment of Major Life Style Diseases of Chhattisgarh. NewBioWorld, 5(2),
1-6.
Sutton, P., & Boag, J. M. (2019). Status of vaccine
research and development for Helicobacter pylori. Vaccine, 37(50),
7295-7299.
Suzuki,
S., Kusano, C., Horii, T., Ichijima, R., & Ikehara, H. (2022). The ideal
Helicobacter pylori treatment for the present and the future. Digestion, 103(1), 62-68.
Thorell, K., Muñoz-Ramírez, Z. Y., Wang, D., Sandoval-Motta,
S., Boscolo Agostini, R., Ghirotto, S., ... & Rabkin, C. S. (2023). The
Helicobacter pylori Genome Project: insights into H. pylori population
structure from analysis of a worldwide collection of complete genomes. Nature communications, 14(1), 8184.
Wizenty,
J., & Sigal, M. (2025). Helicobacter pylori, microbiota and gastric
cancer—principles of microorganism-driven carcinogenesis. Nature Reviews Gastroenterology &
Hepatology, 1-18.
Wu,
X., Gou, G., Wen, M., Wang, F., Liu, Y., Li, L., ... & Xie, R. (2025). The
immunoregulatory role of helper T cells in Helicobacter pylori infection.
Frontiers in Immunology, 16, 1593727.
Yamaoka,
Y. (2010). Mechanisms of disease: Helicobacter pylori virulence factors. Nature reviews Gastroenterology &
hepatology, 7(11),
629-641.
Yang, J., Chen, K., Zhu, Y., Xie, T., Fang, C., Wang, C.,
& Tang, T. (2025). Construction and evaluation of a Salmonella
minicell-based dendritic cell-targeted multi-epitope vaccine against
Helicobacter pylori. Frontiers in
Immunology, 16,
1595096.
Yi, M., Chen, S., Yi, X., Zhang, F., Zhou, X., Zeng, M.,
& Song, H. (2025). Helicobacter pylori infection process: From the
molecular world to clinical treatment. Frontiers in Microbiology, 16, 1541140.
Zhang, F., Ni, L., Zhang,
Z., Luo, X., Wang, X., Zhou, W., ... & Guo, L. (2024). Recombinant L.
lactis vaccine LL-plSAM-WAE targeting four virulence factors provides mucosal
immunity against H. pylori infection. Microbial Cell Factories, 23(1), 61.