Enhancement of Gastric Mucosal Defense by Phytomedicine in the Context of H. pylori–Associated Ulcer Disease

Introduction

Gastric ulcers remain a major global health issue, primarily associated with Helicobacter pylori (H. pylori) infection. The pathogen contributes to mucosal damage through multiple virulence factors and inflammatory responses (Figure 1). Phytomedicine, comprising bioactive compounds derived from medicinal plants, has gained attention due to its diverse pharmacological properties, including antimicrobial, antioxidant, and anti-inflammatory effects. These properties make phytomedicine a promising candidate for targeting multiple pathways involved in gastric ulcer pathogenesis.^1–7

Figure 1 Mechanisms of Gastric Ulcer Formation Induced by H. pylori. Schematic representation of the mechanisms underlying H. pylori–induced gastric ulcer formation. The figure highlights the role of bacterial virulence factors such as CagA and VacA in disrupting gastric epithelial integrity, inducing oxidative stress, and triggering inflammatory responses. Activation of immune cells and release of pro-inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) contribute to mucosal damage, while impairment of protective factors including mucus, bicarbonate secretion, and mucosal blood flow further exacerbates ulcer development. The red arrows indicate the upward migration and activity of immune cells (e.g., neutrophils) and the associated release of reactive oxygen species (ROS), contributing to epithelial damage and inflammation.

In clinical practice, standard regimens such as triple and quadruple therapies remain the first-line treatment; however, their declining eradication rates and side-effect profiles have led to increasing exploration of adjunctive strategies, including phytomedicine. Despite promising preclinical and limited clinical evidence, phytomedicines are not yet incorporated into standard clinical guidelines, highlighting the need for further translational research.

Current international consensus guidelines recommend proton pump inhibitor–based triple or quadruple antibiotic therapy as first-line management for H. pylori infection. However, increasing global antibiotic resistance, regional variability in eradication rates, and therapy-associated adverse effects have reduced treatment success. These clinical challenges have stimulated growing interest in adjunctive strategies that target bacterial virulence and host mucosal defense mechanisms rather than relying solely on antimicrobial eradication.

However, phytomedicine is not yet incorporated into international consensus guidelines, primarily due to the lack of large-scale, well-controlled clinical trials.

By integrating current knowledge on H. pylori pathogenesis and phytomedicine-based interventions, this review aims to provide a mechanistic framework for developing novel strategies that enhance gastric mucosal defense.

Currently, phytomedicine is not included in standard clinical guidelines for H. pylori management, such as those recommended by international consensus groups. However, increasing evidence from preclinical and limited clinical studies supports its role as a complementary strategy. Integrating phytomedicine into clinical practice will require standardized formulations, safety validation, and well-designed clinical trials.

Pathophysiology of Gastric Ulcer and Mucosal Defense Imbalance

The epithelial barrier of the human gastrointestinal tract serves as the first line of defence by forming a tightly regulated structure that prevents pathogen adhesion, growth, and invasion. To establish colonization and cause infections such as gastric ulcers (GUs), pathogens such as H. pylori employ specialized mechanisms that allow them to survive in the harsh conditions of the gastric lumen. GUs are lesions of the gastric mucosa that arise from an imbalance between aggressive factors, such as gastric acid and pepsin, and protective mechanisms, including mucus and bicarbonate secretion and adequate blood flow.⁸ Gastric ulcers (GUs) are common gastrointestinal disorders that are associated with significant morbidity. Chronic GUs can lead to complications such as pain, bleeding, perforation, and, in severe cases, gastric cancer. The leading cause worldwide is H. pylori infection, which compromises the mucosal barrier, triggers chronic inflammation, induces oxidative stress, and disrupts gastric acid secretion.^9–11 Other causative factors include the use of non-steroidal anti-inflammatory drugs (NSAIDs), which suppress prostaglandin (PGs) synthesis, reduce mucus and bicarbonate production; excess gastric acid from conditions like hypergastrinemia;^12–14 lifestyle factors such as smoking, alcohol consumption, stress, and spicy foods;^15–19 genetic predisposition; and certain chronic illnesses that can also increase susceptibility.^16,20–22 However, multiple factors contribute to H. pylori being the most important etiological agent, making it central to prevention and management strategies.^23–27

This review emphasizes H. pylori infection as a key etiological factor while focusing on the critical role of gastric mucosal defense in disease pathogenesis and therapy. In particular, it explores how phytomedicines enhance mucosal protection through multi-target mechanisms, including modulation of inflammation, oxidative stress, and epithelial integrity. Colonization by H. pylori initiates a cascade of pathological events including disruption of the gastric mucosal barrier, sustained inflammation, oxidative stress, and disturbances in gastric acid secretion.^11,28–31 Understanding the molecular mechanisms by which H. pylori damages gastric mucosa is critical for developing effective therapeutic strategies. In this context, phytomedicine has emerged as a promising approach that offers multi-targeted protective effects against bacterial colonization, inflammation, and oxidative stress. This review highlights the current understanding of the role of H. pylori in gastric ulcer formation, with an emphasis on the underlying mechanisms, clinical implications, and potential plant-based therapeutic interventions.

Native Gastric Mucosal Defense Mechanisms

The gastric mucosal defense system is a highly coordinated network consisting of pre-epithelial, epithelial, and subepithelial components. The pre-epithelial barrier includes mucus and bicarbonate secretion, which neutralize gastric acid. The epithelial layer maintains integrity through tight junctions, rapid cell turnover, and restitution mechanisms. Subepithelial defense involves adequate mucosal blood flow and prostaglandin-mediated cytoprotection. Disruption of these defense mechanisms by H. pylori leads to increased susceptibility to mucosal injury and ulcer formation. Understanding these native defense systems is essential to contextualize the therapeutic role of phytomedicine in enhancing mucosal protection.

H. pylori Biology and Virulence Mechanisms

Helicobacter pylori was first identified by the microbiologists Barry Marshall and Robin Warren in 1982. It was reclassified from Campylobacter pylori in 1989, and its genome was sequenced in 1997, providing valuable insights into its virulence mechanisms.^32–35 Having co-evolved with humans over the millennia, H. pylori exists as genetically diverse populations capable of establishing persistent infections associated with various gastrointestinal disorders. It is a microaerophilic, curved or spiral-shaped, Gram-negative, multi-flagellated bacterium with a relatively small genome of 1.6 million base pairs, encoding approximately 1,600 proteins. H. pylori infects nearly 50% of the global population.^34,36,37 H. pylori possesses a core genome of approximately 1,100 conserved genes, and accessory genes contribute to its genetic diversity via high rates of mutation and recombination. Absence of the classical mismatch repair system, along with the characteristics of DNA polymerase I, results in frequent mutations. Additionally, this bacterium can acquire foreign DNA via a type IV secretion system. The presence of the cag pathogenicity island (cagPAI) markedly enhances its inflammatory potential, with cagPAI-positive strains inducing more severe inflammation than cagPAI-negative strains.^38–41

Different H. pylori genotypes show distinct geographical distributions, with the severity of the associated disorders varying according to the predominant genotype. Infection is especially common in developing countries and is characterized by the capacity of the bacterium to colonize and persist in the stomach. H. pylori utilizes urease activity to neutralize gastric acid and employs its flagella to navigate toward the gastric epithelium.^42–46 H. pylori produces toxins that damage the host tissues and activate the innate immune response. Biofilm formation contributes to persistent infections and enhances antibiotic resistance. The clinical manifestations of the infection include vomiting, nausea, and loss of appetite. Diagnosis can be achieved using various methods, each with specific advantages and limitations, while treatment typically involves a combination of proton pump inhibitors and antibiotics.^47–51

H. pylori colonizes the stomach, survives under acidic conditions, and adheres to the gastric epithelium. It disrupts the mucosal barrier by reducing mucus and bicarbonate secretion and weakening tight junctions. The bacterium also induces chronic inflammation by stimulating the production of cytokines such as TNF-α, IL-1β, and IL-6 and IL-8.^52–54 H. pylori infection induces oxidative stress leading to DNA, protein, and lipid damage. It also disrupts gastric acid secretion and diminishes prostaglandin-mediated mucosal protection.^{10,28,55–57} These therapeutic limitations underscore the urgent need for adjunctive strategies targeting both bacterial virulence and restoration of host mucosal defense. A thorough understanding of the role of H. pylori in gastric ulcer pathogenesis is essential for effective prevention, management, and development of novel therapeutic approaches.^58–62

Currently, standard treatment for H. pylori infection involves combination antibiotic therapies; however, increasing antibiotic resistance, high recurrence rates, and treatment-associated side effects have limited their long-term effectiveness. Despite growing preclinical evidence supporting phytomedicines, their integration into clinical practice remains limited, highlighting the need for further translational and clinical investigations.

Disruption of Gastric Mucosal Defense by H. pylori

The gastric epithelial layer functions as the first line of defense; however, H. pylori overcomes this barrier through morphological “shape switching”, active motility, and deep mucosal penetration. The bacterium firmly adheres to epithelial receptors via various adhesins, including NapA, blood group antigen-binding adhesin A/B (BabA/B), sialic acid-binding adhesin A (SabA), heat shock protein 60 (Hsp60), and other outer membrane proteins (OMPs), thereby enhancing colonization stability. After attachment, H. pylori secretes potent virulence factors that compromise the integrity of host cells. Notably, cytotoxin associated gene A (CagA) triggers inflammation and oncogenic signaling, whereas vacuolating cytotoxin A (VacA) induces vacuolation and facilitates immune evasion. Together, these mechanisms promote persistent infection, chronic inflammation, and progressive gastric tissue damage (Figure 2).^8,11,63–67

Figure 2 Molecular Mechanisms Underlying H. pylori–Induced Gastric Ulceration. Illustration of the intracellular signaling pathways activated during H. pylori infection. The figure depicts activation of key pathways such as NF-κB and MAPK, leading to increased expression of inflammatory mediators, chemokines, and adhesion molecules. These events promote epithelial cell apoptosis, oxidative stress generation, and sustained inflammation, ultimately contributing to gastric mucosal injury and ulcer formation. Green arrows and upward symbols (↑) indicate upregulation/activation of molecular pathways and mediators, including inflammatory signaling (e.g., NF-κB, MAPK), cytokine production, oxidative stress, and apoptosis. Red arrows and upward symbols (↑ in red) highlight strong induction or overexpression of key pathogenic factors. Downward arrows (↓) indicate inhibition or suppression of signaling components or biological processes. Blue arrows represent the direction of signaling flow and pathway interactions between molecular components.

Epithelial Cell Defenses: Foundation of Gastric Mucosal Protection

H. pylori colonization involves adaptation to the acidic gastric environment using flagella to penetrate epithelial cells and attachment to host receptors via adhesins, thereby causing tissue damage through cytotoxic proteins. The bacterium persists by adhering to cells and releasing virulence factors such as BabA, OipA, and VacA. The HomB protein may contribute to carcinogenesis by inducing IL-8 secretion, whereas the lipoproteins AlpA and AlpB may facilitate colonization. Additional cytotoxins further support the establishment and persistence of H. pylori infection.^8,68,69

Urease production enables bacteria, such as H. pylori, to survive and adapt to the acidic gastric environment. Ni serves as an essential cofactor for urease and hydrogenase enzymes, whereas bacterial proteins such as FecA3 and FrpB4 facilitate the acquisition of metal ions necessary for these enzymatic functions.^70,71 Urease catalyzes the breakdown of urea into ammonia and carbon dioxide, which helps neutralize gastric acidity and facilitates H. pylori colonization. The expression of urease genes is induced under acidic conditions, and bacterial morphology influences urease activity, with spiral-shaped strains exhibiting higher activity than coccoid strains. Furthermore, pH of the gastrointestinal tract modulates both urease production and enzymatic function.^72–76

H. pylori Shape Switching: An Adaptation for Survival and Colonization

H. pylori can alternate between spiral (SVCF) and coccoid (CVNCF) forms in response to adverse conditions such as nutrient deprivation and antibiotic exposure. The coccoid form is non-culturable, resistant to antibiotics, and retains its pathogenic potential, whereas the spiral form can be easily cultured. Traditional culture methods often fail to detect coccoid forms, necessitating the use of molecular techniques for their accurate identification. In a study by Elhariri et al, 13 of 75 H. pylori samples contained spiral forms, whereas the remainder were coccoid, with the latter surviving in cultured milk for over 30 days. Both forms share identical genotypes, confirming that coccoid cells arise from the spiral form.^77–79

Navigating the Gastric Mucosa: The Penetrative Behavior of H. pylori

H. pylori is a Gram-negative, flagellated bacterium capable of penetrating the gastric mucosa. It is composed of essential structural components, such as the basal body, hook, and filament, as well as proteins such as FlaA and FlaB. Flagella facilitate both motility and adhesion to epithelial cells, with enhanced movement in the acidic gastric environment driven by a proton motive force. Mutations in flagellar genes, including FlaA, FlaB, and FliD, impair the ability of the bacterium to colonize the stomach, as non-flagellated strains exhibit reduced motility and diminished adhesion to the gastric mucosa.^80–83

Receptor-Specific Adhesion: A Key Step in H. pylori Mucosal Colonization

H. pylori initiates infection by adhering to gastric epithelial cells via specific adhesins that bind to the mucus layer. Key adhesins include blood-antigen binding protein A (BabA) and sialic acid-binding adhesin (SabA); however, some strains lack these. Other important adhesins include heat shock protein 60 (Hsp60), AlpA, AlpB, H. pylori outer membrane protein (HopZ), lac di NAc-binding adhesins (LabA), and neutrophil-activating proteins (NAP). These molecules not only facilitate bacterial attachment but also contribute to nutrient acquisition, cytotoxin release, and generation of harmful substances within host cells.^84,85

NapA as a Critical Mediator of Neutrophil Chemotaxis and Gastric Mucosal Damage

H. pylori secretes neutrophil-activating protein (NAP), which protects bacterial DNA and shares structural similarities with iron-storing proteins. NAP stimulates the production of neutrophil-derived reactive oxygen species (ROS), leading to cellular damage and enhanced adhesion of neutrophils to endothelial cells via β2 integrin receptors. It also induces the production of IL-8 and macrophage inflammatory proteins, thereby contributing to chronic gastritis, and promotes immune cell recruitment to the gastric mucosa during infection. By interacting with neutrophil receptors and facilitating adhesion to host cells, NAP prevents bacterial DNA damage and promotes T helper cell differentiation. These properties suggest its potential as a vaccine adjuvant and in cancer immunotherapy, although further research is needed to explore its role in glucose analogue (2-Deoxy-D-Glucose) activation.^86–89

Blood Group Antigen-Binding Proteins (babA/B): Critical Determinants of H. pylori Adhesion

H. pylori expresses three types of blood group antigen-binding adhesin: babA1, babA2, and babB. BabA2 plays a critical role in binding to the fucosylated Lewis B (Leb) antigen on gastric epithelial cells, whereas babA1 is non-functional because of the absence of a start codon. The central sequence of babA is essential for adhesion and is associated with an increased risk of gastric cancer. The function of babB remains unclear, although its expression has been linked to gastric disorders. Some strains possess a chimeric form (babB/A) that can bind to Leb in the absence of babA2, reflecting genetic recombination. Notably, the BabA–Leb interaction remained robust during chronic infections.^90–93

SabA: A Key Sialic Acid-Binding Adhesin Driving H. pylori Adherence

The sialyl-Lewis x (sLex) antigen is upregulated during severe H. pylori-induced inflammation, highlighting the role of SabA adhesin in bacterial attachment to gastric epithelial cells. Approximately 80% of clinical H. pylori strains harbor the sabA gene, with variations in CT dinucleotide repeats influencing SabA expression. Longer repeats produce full-length proteins, whereas shorter repeats generate truncated forms. The poly T tract in the promoter region further regulates sabA expression. Patients infected with SabA-positive strains exhibit higher bacterial loads because SabA binds to the sLex antigen, facilitating colonization, particularly when Lewis B (Leb) expression is low. Moreover, phase variation in sabA allows H. pylori to evade host immune responses, contributing to chronic infection.^94–96

Role of Heat Shock Protein 60 in H. pylori Survival and Host Interaction

Physical stresses such as temperature and acidity stimulate the production of heat shock proteins (Hsps) in H. pylori, particularly Hsp10/60. Increased Hsp60 levels at low pH values suggest that acid stress influences receptor selectivity. Hsp60 also triggers immune responses, causing human monocytes to release pro-inflammatory cytokines. Infected individuals produce anti-Hsp60 antibodies, which are linked to gastritis and stomach cancer, potentially serving immunological functions, rather than directly eliminating bacteria. To fully understand the significance of these antibodies in gastrointestinal illnesses associated with H. pylori infection, further research is required.^97,98

Host–Pathogen Interactions Driven by H. pylori Outer Membrane Proteins

H. pylori contains approximately 65 outer membrane proteins (OMPs) categorized into five gene families. Family 1 includes adhesion proteins (AlpA/B, SabA/B, BabA/B/C) that help the bacterium attach to host cells. Gene recombination and sliding strand mispairing control the synthesis of OMPs. Furthermore, efflux pump proteins, which contribute to antibiotic resistance, are produced by the five OMP family genes. Many OMPs are crucial for H. pylori pathogenicity and they impact host epithelial cells.^99–101

Toxin-Driven Host Cell Damage: A Central Feature of H. pylori Pathogenesis

H. pylori induces infection and damages host cells by adhering to gastric epithelial cells and releasing toxins, notably cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), after breaching the mucosal barrier. CagA-positive strains are highly prevalent in Asia (approximately 90%) compared to Europe and North America (approximately 60%) and are associated with severe gastric conditions, including ulcers and cancer. CagA protein is classified into European, North American, and East Asian types, with East Asian variants linked to more severe disease. The H. pylori genome contains the cag pathogenicity island (cagPAI), which encodes a type IV secretion system (T4SS) that transfers CagA into host cells. CagA modulates multiple signaling pathways that influence cell behavior and inflammation, although the effects of its non-phosphorylated form are not yet fully understood.^102–104

Vacuolating Cytotoxin A: A Key Effector of H. pylori-Induced Tissue Injury

H. pylori produces two major toxins, CagA and VacA, which cause vacuolation in host cells, leading to cellular damage and disrupted functions, including the immune response. The VacA protein, processed from a 140 kDa precursor to an 88 kDa active form, binds to epithelial cell receptors and inhibits T-lymphocyte activation. Variations in vacA affect toxicity and are associated with conditions such as gastritis and peptic ulcer disease. Overall, VacA significantly influences host cell function and immune responses, contributing to diseases caused by H. pylori.^104–107

Activation of Inflammation and Oxidative Stress During H. pylori Infection

Persistent H. pylori infection leads to significant inflammation through elevated pro-inflammatory mediators like TNF-α, IL-1β, and IL-8, which attract immune cells like neutrophils, and macrophages. This results in excessive ROS production, causing oxidative stress that damages the gastric mucosa and promotes lipid peroxidation (LPO) and DNA damage. The resulting oxidative inflammation impairs the healing of the gastric lining by inhibiting cell proliferation and migration, creating a persistent cycle of inflammation and damage that contributes to gastric diseases linked to H. pylori (Figure 3).^108–110

Figure 3 Protective and Healing Mechanisms of Phytomedicines in H. pylori–Induced Gastric Ulcers. Overview of the therapeutic mechanisms of phytomedicines in H. pylori–induced gastric ulcers. Phytocompounds exert antimicrobial effects by disrupting bacterial membrane integrity, inhibiting urease activity, preventing adhesion, and attenuating CagA/VacA signaling. Anti-inflammatory actions include suppression of NF-κB activation, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), immune cell infiltration, and COX-2/iNOS expression. Antioxidant effects involve scavenging of reactive oxygen species (ROS), enhancement of SOD, CAT, and GPx activity, and protection against lipid peroxidation. Mucosal defense is strengthened through increased mucus and bicarbonate secretion, maintenance of gastric pH, restoration of PGE2, and improved tight junction integrity. Phytomedicines also promote fibroblast proliferation, collagen synthesis, epithelial cell survival and migration, angiogenesis (VEGF, HIF-1α), and extracellular matrix remodeling, thereby facilitating ulcer healing and reducing recurrence. Upward (↑) arrows indicate upregulation or enhancement, while downward (↓) arrows indicate inhibition or suppression.

Impaired Mucosal Protection as a Driver of Gastric Injury and Ulceration

Gastric mucosal protection involves mucus bicarbonate secretion, epithelial buffering, prostaglandin synthesis and blood flow. H. pylori infection disrupts these defenses by causing direct epithelial damage and altering cellular processes, leading to decreased mucus production, weakened tight junctions, and impaired bicarbonate secretions. These changes compromise the gastric mucosal barrier, increasing the risk of acid injury and contributing to conditions such as chronic gastritis and ulcers. H. pylori infection severely impairs gastric mucosal defense by disrupting mucin secretion, altering tight junctions, and reducing prostaglandin protection.^111–113 This necessitates therapeutic strategies to restore barrier function and reduce inflammation.

Phytomedicine offers a promising solution because various plant-derived compounds can enhance mucin production, boost mucus secretion, restore prostaglandins, and exert antioxidant and anti-inflammatory effects. These compounds can improve tight junction integrity and may serve as effective adjuncts or alternatives to traditional therapies against H. pylori, highlighting the potential of phytomedicines as gastroprotective agents.^114–117

Having established the mechanisms of H. pylori–induced mucosal damage, the following section focuses on how phytomedicines counteract these processes and enhance gastric mucosal defense.

Role of Phytomedicine in Enhancing Gastric Mucosal Defense

Mucosal Protective Mechanisms

Phytomedicine plays a significant role in restoring gastric mucosal integrity by enhancing mucus bicarbonate secretion, strengthening tight junction proteins, and promoting prostaglandin-mediated cytoprotection. Many plant-derived bioactive compounds also exhibit potent antioxidant and anti-inflammatory effects, counteracting oxidative and inflammatory damage induced by H. pylori. These multifaceted protective actions provide a strong rationale for evaluating selected phytoextracts with documented gastroprotective potential. A systematic review and meta-analysis of 61 preclinical studies showed that 36 plant extracts and 37 plant-derived compounds significantly improved H. pylori-associated gastritis in animal models by inhibiting H. pylori infection, suppressing inflammation, reducing oxidative stress, and regulating apoptosis and cell proliferation. Asteraceae, Fabaceae, and Rosaceae are important active families, with flavonoids, phenols, alkaloids, and terpenoids as the main bioactive classes. A meta-analysis confirmed significant anti-H. pylori and anti-inflammatory effects, with involvement of critical signaling pathways, including NF-κB, JAK2/STAT3, MAPK, TLR4/MyD88, PI3K/AKT, NLRP3/Caspase-1, and NRF2/HO-1. These findings highlight the potential of plant-derived substances as promising therapeutic agents for H. pylori-associated gastritis.¹¹⁸

Anti-H. pylori Activity

Mastic gum, a natural resin from Pistacia lentiscus, shows potent antibacterial action against H. pylori, killing both reference and clinical strains, including metronidazole-resistant isolates, at a minimal bactericidal concentration of 0.06 mg/mL. Even very low doses markedly inhibit growth and have a strong post-antibiotic effect. This anti-H. pylori action may explain the rapid healing of GUs with low-dose mastic, as clinically observed.¹¹⁹

As evidenced by stable¹³ C-UBT readings and no symptom reduction during treatment, garlic oil capsules (4 mg, administered four times daily for 14 days) had no effect on H. pylori eradication or symptom improvement in dyspepsia patients. Thus, garlic oil appeared to be ineffective against H. pylori at the tested dose and duration.¹²⁰ Another study found that garlic extract at varying concentrations (1, 2, and 4%) in the diet, administered 4 h after H. pylori inoculation, effectively reduced gastritis in Mongolian gerbils by reducing gastric inflammation and mucosal damage, as confirmed by improved gastric tissue integrity in histological analyses.¹²¹

Green tea extract, used at concentrations of 500, 1000, and 2000 ppm for 6 wks, was identified as the most effective urease inhibitor among 77 plant-derived foods, with an IC₅₀ of 13 µg/mL due to its active catechins, particularly the 5′-hydroxyl group. In gerbils infected with H. pylori, the extract significantly reduced gastritis severity and infection prevalence in a dose-dependent manner, indicating its potential to inhibit H. pylori urease and alleviate gastric issues.¹²² Mice were intragastrically inoculated with 1×10^8 CFU of H. pylori strain SB01/05C in sterile PBS three times at 2-day intervals to establish infection. Treatment with carotenoid-rich algal meal resulted in a significant reduction in H. pylori bacterial load and gastric inflammation, as confirmed by histological examination. Splenocyte assays have shown that the strong Th1 response (high IFN-γ) typically elicited by H. pylori shifts to a more balanced Th1/Th2 response with increased IL-4.¹²³ Methanol extracts of ginger rhizomes inhibited the growth of all 19 tested H. pylori strains, including the CagA-positive strains, with MICs of 6.25–50 µg/mL. A fraction enriched in gingerols showed stronger activity (MIC 0.78–12.5 µg/mL) against all strains, including the virulent CagA+ strains. These results indicate that gingerols are the active constituents responsible for anti-H. pylori activity in vitro, which may underlie the chemopreventive effects of ginger.¹²⁴

In a Mongolian gerbil model infected with H. pylori, treatment with rice extract resulted in a significant reduction in bacterial colonization, as well as decreased mucosal damage and inflammatory cell infiltration.¹²⁵ Fruit juice concentrate (0, 1, or 3% for 10 weeks) from Prunus mume effectively reduced H. pylori-induced gastric lesions in Mongolian gerbils by decreasing bacterial colonization and alleviating gastric inflammation and mucosal damage, as evidenced by histological analysis.¹²⁶

A study of Mongolian gerbils indicated that treatment with Japanese rice fluid (from 2 to 14 weeks after H. pylori inoculation) decreased H. pylori bacterial colonization and improved gastric inflammation and mucosal damage.¹²⁷ Selenium-enriched garlic protects against H. pylori-induced chronic gastritis in Mongolian gerbils by reducing gastric inflammation and mucosal lesions, while also modulating oxidative stress and enhancing antioxidant defenses in gastric tissues.¹²⁸ Chios mastic gum extracts exhibit significant anti-H. pylori activity, inhibit bacterial growth and adhesion in vitro, and reduce colonization in animal models. Treatment with these extracts also helps alleviate gastric inflammation and mucosal damage caused by H. pylori infection.¹²⁹ Citrus auraptene effectively reduced H. pylori colonization and bacterial load in the stomach of Mongolian gerbils, leading to decreased gastric inflammation and improved mucosal histology.¹³⁰

Clinical and Translational Evidence

A seven-day non-antibiotic treatment regimen with curcumin, lactoferrin, N-acetylcysteine, and pantoprazole only achieved H. pylori eradication in 12% of patients, indicating low effectiveness. However, the patient reported significant improvements in dyspeptic symptoms and reductions in serum pepsinogen levels I and II, suggesting decreased gastric inflammation. There were no significant changes in IgG-Hp and gastrin-17 levels. Overall, although the treatment did not eliminate H. pylori, it enhanced symptom relief and biochemical indicators of mucosal inflammation.¹³¹

Anti-Inflammatory and Antioxidant Effects

Red wine and green tea effectively reduced gastritis caused by H. pylori or VacA by decreasing gastric inflammation, lowering pro-inflammatory cytokine levels, and enhancing mucosal histology.¹³² Nordihydroguaiaretic acid inhibited gastric cancer linked to H. pylori in Mongolian gerbils by reducing inflammation, minimizing mucosal damage, and preventing precancerous lesions.¹³³

Calophyllum brasiliense Camb. showed significant anti-H. pylori inhibition of bacterial growth in laboratory tests and reduction of colonization in infected animals. It also helped alleviate gastric inflammation and mucosal damage caused by infection.¹³⁴ Caffeic acid phenethyl ester demonstrated anti-inflammatory effects in H. pylori-induced gastritis in Mongolian gerbils by reducing gastric inflammation, lowering pro-inflammatory cytokines, and enhancing mucosal histology.¹³⁵ Green tea demonstrated strong antibacterial effects against H. pylori and H. felis in vitro and reduced gastric mucosal inflammation in mice when administered before infection, indicating its preventive role against H. pylori-induced gastritis.¹³⁶

Apple peel polyphenols demonstrated strong anti-H. pylori effects in both laboratory tests and animal studies, inhibiting bacterial growth and reducing stomach colonization. They also alleviated gastric inflammation and oxidative stress, protecting the stomach lining from infection-related damage.¹³⁷

Muscadine grape skin and quercetin showed significant effectiveness against H. pylori infection in mice, reduced gastric inflammation and bacterial colonization, lowered pro-inflammatory cytokine levels, and improved gastric tissue histology.¹³⁸ Curcumin reduces gastric damage by H. pylori by lowering the activity of MMP-3/9, thereby suppressing inflammation and protecting gastric tissue in both cultured cells and mice.¹³⁹ Licorice extract exhibited strong anti-ulcer and anti-H. pylori effects, which were attributed to its glycyrrhizin and flavonoid components. It decreases bacterial levels, reduces inflammation, boosts mucus production, and aids in epithelial regeneration in infected gastric tissues, while also enhancing mucosal defense and promoting ulcer healing.¹⁴⁰

Raphanobrassica extracts reduced gastric inflammation and mucosal damage induced by H. pylori in Mongolian gerbils, lowering pro-inflammatory cytokine levels and markers of gastric injury.¹⁴¹ After six weeks of TASA administration in mice, H. pylori colonization significantly increased. However, post-treatment, TASA with either omeprazole or bismuth pectin exhibited strong antimicrobial effects comparable to those of standard triple therapy. Histological analysis revealed reduced gastric mucosal inflammation in the TASA-treated groups, and immunohistochemistry showed consistent suppression of H. pylori-induced IL-8, COX-2, and NF-κB expression induced by H. pylori.¹⁴²

Chenopodium ambrosioides L. (CAL) demonstrated strong antibacterial activity against H. pylori at a minimal inhibitory concentration (MIC) of 16 mg/L. Time-kill assays revealed complete bacterial inhibition at 1–2 × MIC within 24 h. In H. pylori-infected mice, CAL achieved eradication rates of 50–60%, similar to the 70% rate of standard triple therapy. Histopathological analysis indicated reduced bacterial colonization and minimal gastric inflammation in mice treated with CAL, highlighting its effectiveness against H. pylori in both in vitro and in vivo settings.¹⁴³ Flavonoid glycosides from Polygonum capitatum showed notable protective effects against inflammation caused by H. pylori infection, reduced pro-inflammatory cytokines, inhibited oxidative stress, alleviated mucosal damage, and improved histological outcomes in infected models.¹⁴⁴ Resveratrol enhances histological scores and reduces lipid peroxidation and myeloperoxidase activity in gastric mucosa. It lowers H. pylori-induced IL-8 and iNOS expression, inhibits IκBα phosphorylation, and increases HO-1 and Nrf2 levels.¹⁴⁵

In H. pylori-infected mice, supplementation with Angelica keiskei (AK) significantly reduced oxidative stress (lipid peroxide and myeloperoxidase activity) and suppressed inflammatory mediators (IFN-γ, COX-2, and iNOS) in gastric mucosa. AK also inhibited NF-κB activation and prevented IκBα degradation, leading to reduced gastric inflammation. These protective effects were comparable to those of the antioxidant N-acetylcysteine, suggesting that AK may prevent H. pylori-induced gastric inflammation via the NF–κB-mediated pathway.¹⁴⁶ Dietary supplements of Artemisia and green tea extracts help alleviate H. pylori-related chronic atrophic gastritis and lower the risk of gastric tumors. They reduce gastric inflammation, suppress pro-inflammatory cytokines, improve mucosal histology, and modulate oxidative stress while inhibiting carcinogenic pathways, showing anti-inflammatory and chemopreventive effects in infected models.¹⁴⁷

In mice infected with H. pylori, high-dose myrosinase-treated turnip roots significantly decreased bacterial colonization, increased anti-H. pylori IgG levels, and altered pro-inflammatory cytokines, leading to improved gastric health. This suggests that turnip has strong anti-H. pylori properties and could be used in dietary interventions or as a foundation for safe treatments against H. pylori infection.¹⁴⁸ It lowers pro-inflammatory cytokines, inhibits COX-2 and iNOS, decreases oxidative stress, and improves antioxidant activity in gastric tissues, thereby attenuating H. pylori-induced gastric inflammation.¹⁴⁶

Capsaicin and piperine have shown anti-inflammatory effects in H. pylori-induced chronic gastritis in Mongolian gerbils, significantly reducing gastric inflammation, lowering pro-inflammatory cytokines, and improving mucosal histology. Both compounds demonstrate strong gastroprotective and anti-inflammatory properties against H. pylori-related chronic gastritis.¹⁴⁹ In vitro, the extract inhibited 55 H. pylori clinical strains (MIC 0.125–8 mg/mL; maximum, ~2 mg/mL). In a C57BL/6 mouse model colonized with H. pylori, oral administration (50 mg/kg) for three weeks significantly reduced bacterial colonization in gastric mucosa with no observable toxicity.¹⁵⁰

Geniposide and its metabolite genipin effectively inhibit H. pylori-infection and reduce bacterial growth and adhesion to gastric cells. In animal models, they also decreased gastric inflammation and mucosal injury while suppressing pro-inflammatory cytokine expression, demonstrating their antibacterial and anti-inflammatory effects.¹⁵¹ Quercetin from Polygonum capitatum protects against H. pylori-associated gastric inflammation and apoptosis associated with H. pylori infection. Treatment modulated key signaling molecules, including p38MAPK, BCL-2, and BAX, reduced inflammatory responses and prevented gastric cell apoptosis.¹⁵²

Allium hookeri extract (AHE) showed strong in vitro anti-H. pylori activity, producing an inhibition zone of 20.6 mm, comparable or superior to standard antibiotics (CLR, AMX, and MTZ). AHE significantly reduced bacterial colonization in H. pylori-infected mice, as confirmed by the rapid urease test, and alleviated gastric mucosal inflammation and epithelial damage. These findings indicate that AHE effectively treats H. pylori infection and associated gastritis, suggesting its potential as a natural therapeutic agent for gastric complaints.¹⁵³

In H. pylori-infected mice, the combined plant extract RUG-com (Rubus crataegifolius, Ulmus macrocarpa, and Gardenia jasminoides) significantly reduced bacterial load and alleviated both acute and chronic gastric inflammation, including epithelial degeneration and erosion. The treatment downregulated the pro-inflammatory genes COX-2 and iNOS, indicating a molecular mechanism underlying its anti-inflammatory effect. These findings suggest that RUG-com effectively prevented H. pylori infection and mitigated H. pylori-induced gastric damage.¹⁵⁴

Mice infected with H. pylori and treated with Sida acuta leaf extracts for 2 wk with ethanol or cold-water extracts showed a marked decrease in bacterial load (from ~15.4 × 10^6 to ~3.5 × 10^6 CFU/mL for water extract and ~2.6 × 10^6 for ethanol), reduced ulcer severity and ulcer index level, lower gastric volume, and histological evidence of granulation (tissue repair).¹⁵⁵ Palmatine alleviated H. pylori-induced chronic atrophic gastritis by inhibiting MMP-10 via the ADAM17/EGFR pathway. Treatment reduced gastric inflammation, improved mucosal integrity, and suppressed tissue remodeling associated with infection.¹⁵⁶ Phytoncide extracts from Pinus koraiensis pinecones demonstrated gastroprotective effects in H. pylori-infected models. This treatment reduced bacterial colonization, suppressed gastric inflammation, and decreased pro-inflammatory cytokine levels. Histological analysis revealed improved mucosal integrity and reduced tissue damage.¹⁵⁷ The ethyl acetate extract of Alpinia officinarum Hance exerts protective effects against H. pylori-associated gastritis. Mechanistically, the extract suppresses pro-inflammatory cytokines by modulating the MAPK signaling pathway.¹⁵⁸

Individually, Rubus crataegifolius (RF) and Ulmus macrocarpa (UL) extracts showed moderate anti-H. pylori activity (MIC50 >100 and 200 µg/mL, respectively). Combined treatment exhibited significant synergy, reducing viable bacterial counts and achieving MIC₇₀–₉₀ at lower concentrations. In H. pylori-infected bALB/c mice, simultaneous administration of RF and UL (100 mg/kg each) significantly decreased gastric bacterial load and mucosal damage, whereas separate treatments were only moderately effective. These findings highlight the synergistic potential of RF and UL extracts as promising herbal therapies against H. pylori-induced gastritis.¹⁵⁹ Kaempferia parviflora (black ginger) ethyl acetate extract significantly suppressed H. pylori-stimulated pro-inflammatory cytokine production (eg., IL-8) and leukocyte chemotaxis in mammalian cells.¹⁶⁰ This study found that Rubus crataegifolius and Ulmus macrocarpa extracts exhibited a strong synergistic antibacterial effect against multiple H. pylori isolates. Their combination significantly inhibited bacterial growth to a greater extent than did either extract alone. In animal and cell models, the mixture also reduced gastric inflammation and protected gastric tissue from H. pylori-induced damage.¹⁵⁹ β-caryophyllene from clove extract promoted the eradication of H. pylori in a mouse model, significantly reduced bacterial colonization in the stomach, and alleviated gastric inflammation. Additionally, it decreased pro-inflammatory cytokine levels and improved gastric tissue histology.¹⁶¹

Pomegranate peel ethanol extract (PPEE) showed strong in vitro anti-H. pylori activity, with an MIC of 0.156 mg/mL and urease inhibition (IC₅₀ ≈ 6 mg/mL). PPEE exhibited a synergistic effect with metronidazole (FIC <0.5). In vivo, oral administration of PPEE for 8 days significantly reduced H. pylori-induced gastritis and decreased lymphocytic infiltration and chronicity in rats.¹⁶² Total triterpenoids from Chaenomeles speciosa demonstrated a protective effect against H. pylori-induced gastritis in mice by significantly reducing gastric inflammation, lowering pro-inflammatory cytokine levels, and alleviating mucosal damage.¹⁶³

In H. pylori-infected high-salt diet-promoted gastric cancer mice, dietary walnuts (100–200 mg/kg) significantly ameliorated chronic atrophic gastritis and reduced tumorigenesis. Walnut intake decreased pro-inflammatory and tumorigenic marker levels (COX-2, PGE2, NF-κB, c-Jun, IL-6, and STAT3) and preserved the expression of tumor-suppressive enzyme 15-PGDH. The protective proteins HO-1, Nrf2, and SOCS-1 were upregulated and proliferative indices (Ki-67 and PCNA) were controlled.¹⁶⁴

In H. pylori-infected C57BL/6 mice, bamboo salt significantly reduced the expression of the bacterial virulence gene CagA and the pro-inflammatory cytokines TNF-α and IL-1β compared to that in infected controls. Solar salt showed only modest effects, while combining bamboo salt with standard triple therapy enhanced anti-H. pylori and anti-inflammatory effects, demonstrating a synergistic interaction.¹⁶⁵ In another study, infected mice treated with Korean propolis (KP) inhibited bacterial growth and suppressed virulence factors, including urease A, CagA, surface antigen gene, and NapA. KP treatment reduced pathological scores and gastric lesions, decreased pro-inflammatory cytokine and NO levels, and inhibited NF-κB signaling by repressing IκBα and p65 phosphorylation.¹⁶⁶

In vitro and in silico studies showed that Salvia officinalis metabolites, ethanolic extract, particularly essential oil and polyphenolic metabolites (rosmarinic acid, rutin, and quercitrin), inhibited H. pylori growth and showed anti-inflammatory effects via molecular docking analyses, supporting its potential as a multi-target anti-H. pylori agent.¹⁶⁷ Cudrania tricuspidata leaf extract (10–20 mg/kg/day for six weeks) significantly reduced H. pylori-infection markers in mice, including CLO scores and IgG antibody levels, in a dose-dependent manner. The extract suppressed pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6/-8), decreased gastric inflammation scores, and relieved erosions and ulcers.¹⁶⁸ Among Corydalis yanhusuo extracts, the chloroform extract (CECY) showed the strongest in vitro antibacterial activity against H. pylori. In infected C57BL/6 mice, CECY significantly decreased bacterial colonization, alleviated gastric damage, and lowered IgG levels, indicating anti-H. pylori activity as well as gastroprotective and anti-inflammatory effects. Among the isolated alkaloids, dehydrocorydaline (MIC 12.5 µg/mL) and berberine (MIC = 25 µg/mL) were the most active compounds.¹⁶⁹ Polygonum capitatum (PC) was found to act against HAG through the Akt/NF-κB/NLRP3 signaling pathway. PC treatment upregulated Akt and its phosphorylation, reduced NF-κB expression, and inhibited NLRP3 inflammasome activation, leading to decreased levels of the pro-inflammatory cytokines IL-1β and IL-18 in both HAG GES-1 cells and SD rats. Bioinformatics, molecular docking, and in vitro/in vivo experiments identified 52 hub genes involved in its anti-inflammatory effect, providing a mechanistic basis for PC’s therapeutic action in HAG.¹⁷⁰ Corn peptides with anti-adhesive activity alleviated gastric injury induced by H. pylori infection in vivo. This treatment reduced bacterial adherence to the gastric mucosa, decreased inflammation, and improved tissue histology.¹⁷¹

Epiberberine inhibits H. pylori growth and reduces host gastric apoptosis and inflammatory damage. This compound acts by downregulating bacterial urease expression, thereby diminishing H. pylori-induced pathogenic effects.¹⁷²

Salvia officinalis (sage) ethanolic extract in bioadhesive microparticles microencapsulated sage extract showed enhanced gastroprotective effects in rats with ethanol-induced ulcers, inhibiting ~89.7% of ulcers (vs. ~71.7% with free extract), with in vitro H. pylori MIC of ~50 μg/mL, and stronger inhibition of H^+/K^+-ATPase when encapsulated.¹⁷³

Although numerous plant extracts demonstrate anti-H. pylori activity in vitro and in animal models, direct comparison of efficacy remains challenging due to heterogeneity in extraction methods, phytochemical composition, dosing regimens, and experimental models. Flavonoid-rich extracts frequently exhibit strong antioxidant and NF-κB–modulating properties, whereas alkaloid-containing preparations often demonstrate direct antibacterial or urease-inhibitory activity. However, standardized head-to-head comparisons and pharmacokinetic analyses are limited. Future investigations should prioritize mechanistically guided evaluation strategies that correlate phytochemical composition with specific mucosal defense outcomes.

Despite extensive preclinical evidence, variations in study design, extraction methods, dosage, and experimental models limit direct comparison of efficacy among phytochemicals. Additionally, inconsistencies in bioavailability and pharmacokinetics remain significant challenges. Future studies should focus on standardized formulations, comparative efficacy analyses, and well-designed clinical trials to validate translational potential.

This highlights the need for mechanism-based classification of phytochemicals to better guide therapeutic development.

Conclusion

Phytomedicine represents a promising multi-target strategy for managing H. pylori–associated gastric ulcer disease, particularly through enhancement of gastric mucosal defense mechanisms. Beyond direct antibacterial activity, plant-derived bioactive compounds restore mucus–bicarbonate balance, preserve tight junction integrity, modulate prostaglandin-mediated cytoprotection, suppress oxidative stress, and attenuate pro-inflammatory signaling pathways provide a strong rationale for evaluating selected phytoextracts with documented gastroprotective potential (Table 1). By targeting both bacterial virulence and host mucosal vulnerability, phytochemicals provide a mechanistically integrated approach to disease management.

Table 1 Representative Phytomedicines Targeting Gastric Mucosal Defense in H. pylori Infection

Importantly, the therapeutic relevance of phytomedicine extends beyond eradication and emphasizes restoration of epithelial resilience and barrier function as central treatment goals. However, translation into clinical practice requires standardized formulations, pharmacokinetic validation, and rigorously designed clinical trials incorporating mucosal defense biomarkers as primary endpoints. Mechanism-driven clinical evaluation will be essential to define the precise role of phytomedicine as an adjunct or alternative strategy in H. pylori–associated gastric ulcer management.

Overall, enhancement of gastric mucosal defense represents a central therapeutic mechanism through which phytomedicine exerts its protective effects against H. pylori–associated gastric ulcer disease.