Phytochemicals as Promising Anti-H. pylori Agents: ­Molecular ­Insights and Therapeutic Potential

Qin Honghan^1,2, Sher Zaman Safi³  and Shalini Vellasamy¹
1. Department of Microbiology and Parasitology, Faculty of Medicine, MAHSA University, Bandar Saujana Putra, Selangor, Malaysia
2. School of Pharmacy, Youjiang Medical University for Nationalities, Baise, Guangxi, China
3. Department of Biochemistry, Faculty of Medicine, MAHSA University, Bandar Saujana Putra, Selangor, Malaysia
Correspondence to: Sher Zaman Safi, safisher@mahsa.edu.my

DOI: https://doi.org/10.70389/PJS.100281

Additional information

• Ethical approval: N/a
• Consent: N/a
• Funding: Guangxi Natural Science Foundation Project (2025GXNSFHA069164)
• Conflicts of interest: N/a
• Author contribution: Qin Honghan: Writing – original draft preparation; Sher Zaman Safi and Shalini Vellasamy: Writing – review and editing. All authors reviewed the final version of the manuscript
• Guarantor: Sher Zaman Safi
• Provenance and peer-review: Unsolicited and externally peer-reviewed
• Data availability statement: N/a

Keywords: Biofilm attenuation, Caga, Gastric mucosal anti-inflammatory activity, Plant-derived anti-helicobacter agents, Urease inhibition, Vaca virulence modulation.

Peer Review
Received: 14 January 2026
Last revised: 01 July 2026
Accepted: 21 September 2026
Version accepted: 3
Published: 28 September 2026

Plain Language Summary Infographic

Introduction

Helicobacter pylori (H. pylori) infection remains one of the most widespread bacterial infections worldwide, with recent pooled meta-analysis data indicating an overall global prevalence of approximately 43.1% in 2011–2022 across diverse populations.¹ Transmission occurs through multiple routes, including fecal–oral, oral–oral, gastro–oral, anal–oral, and genital–oral pathways, with the fecal–oral route being predominant.² Other transmission modes include human-to-human, animal-to-human, foodborne, and occupational exposures. Mother-to-child transmission is also possible, with poor hand hygiene being a key factor.³ The prevalence of infection varies geographically and can reach up to 80% in certain regions.⁴ In China, the infection rate is reported to be 42.8%.⁵ While the prevalence of H. pylori infection has declined in adults over the past 30 years, it has not declined in children and adolescents.⁶ H. pylori infection is associated with numerous gastric pathologies, such as inflammation, gastroduodenal ulcers, and gastric cancer,⁷ as well as other diseases like rosacea,⁸ non-alcoholic fatty liver disease,⁹ and rheumatic arthritis.¹⁰

Gastric ulcers occur in 10%–15% of patients infected with H. pylori, and 1%–3% develop gastric adenocarcinoma.¹¹ Patients often seek medical treatment for diagnostic procedures (such as gastroscopy and H. pylori detection) and treatment, leading to significant healthcare costs. In addition, patients may experience a decrease in work efficiency, absenteeism, or even loss of labor capacity due to the disease, negatively impacting their financial situation and that of their families. Meanwhile, society must invest substantial resources in disease prevention, research, and medical infrastructure. Reports indicate that in East Asia, the high burden of infectious cancers is primarily due to H. pylori (17.6 cases per 100,000 person-years). Notably, in China alone, there were 780,000 (35%) of the 2.2 million new infectious cancer cases globally in 2018, of which cancers caused by H. pylori accounted for 340,000 cases (42%). The high burden in China is attributed not only to the large population but also to cancers triggered by H. pylori invasion.¹² H. pylori infection has placed a heavy burden on the social economy. For instance, some studies have demonstrated that the expected costs of economic models for successful eradication after a 7-day or 14-day empirical treatment are $93.8 to $111.4 and $126.3 to $149.9, ­respectively.¹³

This review maps and critically interprets recent evidence on phytochemicals with reported anti-H. pylori activity. Because the literature encompasses ­heterogeneous compounds, extracts, experimental models, outcomes, and mechanistic endpoints, the objective was evidence mapping and mechanism-oriented synthesis rather than estimation of a single pooled treatment effect. The conclusions therefore rely mainly on in vitro studies and small in vivo studies, with limited clinical evidence, and should not be interpreted as demonstrating clinical efficacy or causality.

Methods

Review Design and Rationale

This study was conducted as a structured narrative review informed by selected principles of scoping-review methodology. It aimed to map phytochemicals investigated against H. pylori, describe the experimental models and antimicrobial outcomes used, and synthesize their proposed molecular mechanisms and translational implications. A conventional systematic review and meta-analysis were not considered appropriate because the available evidence comprises purified compounds, complex plant extracts, multiple bacterial strains, diverse in vitro and in vivo models, non-uniform exposure conditions, and heterogeneous mechanistic outcomes. The organization and reporting of the review were informed, where applicable, by selected principles from the JBI methodology for scoping reviews and PRISMA-ScR, while retaining the interpretive approach of a structured narrative review.^14,15

Information Sources and Literature Identification

PubMed, Scopus, and Web of Science were consulted for literature published from database inception through April 30, 2025. The principal search term was “Helicobacter pylori.” Titles, abstracts, and, where necessary, full texts were screened to identify studies of phytochemicals, plant-derived compounds, phytochemical-rich preparations, or plant extracts with ­potential anti-H. pylori activity. Particular attention was given to studies reporting MIC, MBC, adhesion or colonization, motility, urease activity, virulence factors, inflammatory or oxidative-stress responses, biofilm formation, antibiotic interactions, in vivo gastric outcomes, clinical eradication, or safety. Reference lists of eligible studies and relevant reviews were also manually examined. Because the search was conducted iteratively during manuscript development, complete historical database-specific search logs were not retained.

Eligibility Criteria

Primary in vitro, in vivo, and clinical studies were considered eligible when they evaluated a defined phytochemical, plant-derived compound, preparation, extract, or formulation against H. pylori and reported at least one relevant antimicrobial, mechanistic, translational, pharmacokinetic, formulation-related, or safety outcome. Reviews were used for background interpretation and reference-list screening but were not treated as primary evidence. Editorials, case reports, conference ­abstracts without sufficient data, duplicate publications, studies unrelated to H. pylori, and reports lacking relevant ^­antimicrobial or mechanistic information were excluded. Negative or non-significant findings were not excluded solely on the basis of study outcome.

Study Selection, Data Charting, and Evidence Interpretation

The first author screened potentially relevant publications by title and abstract and reviewed full texts when necessary. Study selection and data charting were performed by a single reviewer without independent duplicate screening or extraction. Relevant studies were organized according to phytochemical identity and source, chemical class, H. pylori strain, experimental model, culture conditions, dose, antimicrobial activity, molecular targets, major outcomes, antibiotic interactions, pharmacokinetic or delivery information, and safety. MIC and MBC values and experimental conditions were recorded when reported. Units were converted to μg/mL or μM only when valid conversion was possible; otherwise, values were retained as originally reported. NR indicates “not reported,” whereas N/A indicates “not applicable.”

No meta-analysis was conducted because of substantial methodological and outcome heterogeneity. Formal risk-of-bias scores were not used as exclusion criteria; instead, greater interpretive weight was assigned to studies using defined compounds, characterized strains, appropriate controls, replicated experiments, clinically relevant models, and clearly described methods. The limitations arising from single-reviewer screening and incomplete historical search records are acknowledged in the Strengths and Limitations section.

Overview of H. pylori Resistance and Treatment Strategies

H. pylori infection is a global health problem, with increasing antibiotic resistance, particularly to commonly used antibiotics such as clarithromycin, metronidazole, and amoxicillin. The growing resistance to these antibiotics presents significant challenges in treating H. pylori infection. Eliminating H. pylori has been shown to significantly reduce the incidence and mortality rates of gastric cancer.¹⁶ However, many individuals infected with H. pylori do not exhibit noticeable clinical symptoms in the early stages of infection. Eradicating H. pylori is the preferred strategy for the long-term prevention of chronic gastritis, peptic ulcers, and other gastroduodenal complications.¹⁷

Nevertheless, eradicating H. pylori remains difficult, as it requires a combination of multiple antibiotics over a prolonged treatment period. This complexity increases the risk of adverse drug reactions and the development of resistance, which may ­ultimately lead to treatment failure. According to statistics, the resistance rates of metronidazole, levofloxacin, and clarithromycin in China are all higher than 15%. In China, triple therapy is no longer considered the most effective treatment for H. pylori eradication. Instead, Bismuth Quadruple Therapy (BQT) combined with vonoprazan, high-dose amoxicillin, or BQT with proton pump inhibitors has shown better efficacy. Current ­Chinese guidelines recommend BQT as the primary empirical eradication regimen for Chinese patients.¹⁸

A clinical meta-analysis showed that in India, the highest resistance rate was observed for metronidazole (77.65%), followed by amoxicillin (37.78%), levofloxacin (32.8%), clarithromycin (35.64%), furazolidone (12.03%), and tetracycline (11.63%). Notably, 14.7% of H. pylori isolates were found to be multidrug-resistant.¹⁹ Overexpression of efflux pump genes hefA and hefD is significantly associated with multidrug-resistant H. pylori isolates, and these pumps interact with resistance-related gene mutations (e.g., 23S rRNA, gyrA, rdxA), highlighting a combined role of efflux activity and genetic mutations in antibiotic resistance.²⁰ As noted, one of the main obstacles in treating H. pylori infections in the gastrointestinal tract is antibiotic resistance.²¹

Given the growing problem of H. pylori resistance, treatment strategies should be individually tailored according to the patient’s specific condition.^{22 ­}Approaches such as combination therapy,²³ sequential therapy,²⁴ Chinese–Western medicine combined therapy,²⁵ and probiotic-assisted therapy²⁶ can increase the H. pylori eradication rate and reduce the emergence of drug-resistant strains. Moreover, monitoring H. pylori resistance and developing new treatment options are key areas for future research.

Molecular Mechanisms of Phytochemicals Against H. pylori

The pathogenesis of H. pylori can be outlined in three key aspects: attachment and colonization in the gastric mucosa, triggering and evading the host immune response, and ultimately leading to the establishment of disease.²⁷ The mechanisms of anti-H. pylori action mainly include the following: Inhibition of bacterial growth through structural and metabolic disruption: Phytochemicals can damage the cell walls and membranes of bacteria, disrupting their structure and inhibiting bacterial growth. Additionally, interfering with key metabolic pathways in H. pylori can prevent the bacteria from growing and reproducing normally.

Suppression of virulence and disruption of survival conditions: Inhibiting the expression of virulence factors (CagA and VacA) can reduce bacterial virulence. Inhibition of urease activity also harms the survival conditions of H. pylori, decreasing its ability to colonize and grow in the stomach. Regulation of the host’s immune response and enhancement of immune function: Certain anti-H. pylori substances may stimulate the host’s immune system and enhance the functioning of immune cells such as macrophages, T cells, and B cells, thereby improving the body’s ability to clear H. pylori. For instance, some probiotics can regulate intestinal flora and strengthen the intestinal immune barrier, indirectly aiding the fight against H. pylori infection.

Destruction of the bacterial biofilm: Some enzyme-based substances can disrupt biofilm formation, exposing bacteria and making them more susceptible to elimination. Additionally, several studies have identified specific molecular pathways that can be targeted to restrict H. pylori proliferation, such as IMPDH²⁸ and the H. pylori ureI channel.²⁹ Collectively, these mechanisms indicate that phytochemicals may act at several stages of H. pylori persistence and host injury; however, the strength of evidence differs substantially among compounds and endpoints.

Phytochemicals are chemical components found in plants, including flavonoids, terpenoids, ­alkaloids, phenols, and others. They are widely distributed in plants and are typically isolated as individual ­compounds or classes of chemicals through extraction, separation, and other techniques, possessing clear chemical structures and relatively stable physicochemical properties. Their effects are often more specific and can target particular biological processes or physiological targets. The following sections organize the available evidence by the principal bacterial or host process investigated.

Inhibition of Adhesion

The attachment of H. pylori to host epithelial cells is crucial for its survival and successful colonization under the harsh conditions of the stomach. Adhesion helps protect H. pylori from being expelled by mechanisms such as gastrointestinal motility and mucus flow. H. ­pylori adhesion to host epithelial cells is mediated by specific outer membrane adhesins, such as BabA, SabA, HopQ, and other OMPs that bind host receptors (e.g., mucins and CEACAMs), facilitating persistent colonization of the gastric mucosa through ­protein–protein and protein–ligand interactions.³⁰

Table 1 lists the impacts and mechanisms of action of some phytochemicals against H. pylori in recent years, particularly focusing on inhibiting adhesion genes such as alpA, alpB, babA, ureI, sabA, hpaA, and hopZ. Table 2 outlines the functions of some related adhesion genes. Based on the literature, there are limited studies on genes targeted by phytochemicals for H. pylori adhesion, likely due to limitations in experimental techniques and the infrequent detection of these genes. Specific probiotic strains and antimicrobial peptides have been shown to inhibit H. pylori adhesion to gastric epithelial cells.^31,32 Whether combining probiotics and antimicrobial peptides with phytochemicals will result in greater efficacy remains to be explored, representing a potential new direction for future research.

Table 1: Inhibitors of H. pylori adhesion, motility, virulence, replication, and transcription: Phytochemicals.
Number	Phytochemicals/Ref.	Model	MIC/MBC	Molecular Targets	Key Outcomes	Synergy with Antibiotics	Safety Notes
1	Daphnetin33	In vitro	MIC: 25–100 µg/mL	¯ babA and ureI; ­ recA	¯ adherence, ­ DNA damage in H. pylori	NR	No significant cytotoxicity to the GES-1 cell line, consistent with published data
2	Hesperetin34	In vitro	MIC: 50–100 µM	¯ dnaE, dnaN, dnaQ, holB, rpoA, rpoB, rpoD, rpoN, flhA, flaA, flgE, sabA, alpA, alpB, hpaA, hopZ, ureA, and ureB; ¯ CagA and VacA	¯ Replication, ¯ Flagellar movement, ¯ Adhesion, ¯ Urease	NR	NR
3	Urolithin B35	In vivo, In vitro	NR	¯ CXCL1, CCL2, IL-6, and IL-8	¯ Adhesion, ¯ Inflammation, ¯ Gastric tissue lesions in mice, ¯ oxidative stress	NR	NR
4	Protocatechuic acid36	In vitro, In vivo	NR	¯ IL-6 and TNF-α; ¯ alpA, alpB, and cagA	¯ Inflammation, ¯ Adhesion	NR	NR
5	1,3,6-Trigalloylglucose37	In vitro	MIC: 116–128 µg/mL, MBC: >256 µg/mL	¯ CagA	¯ Urease activity, ¯ Adhesion	NR	No toxic side effects on normal cells at antibacterial concentrations
6	Resveratrol38	In vitro	MIC: 64 µg/mL	¯ rplJ, rpsC, sabA, and hopD; ­ trxR, sodB, napA, cagA, and ureB; ¯ HP1542	¯ OMPs affect pathogenesis, nutrient absorption, bacterial adhesion, and colonization. Antioxidant. ¯ Ribosomes	NR	NR
7	Kaempferol39	In vitro	MIC: 50 µM	¯ TNF-α, IL-1β, and IL-8; ¯ vacA, secA, virB5, virB6, virB8, virB9, and virD4	¯ AGS cells produce proinflammatory cytokines. ¯ Virulence factor expression, ¯ the transfer of VacA and CagA to AGS cells associated with T4SS and T5SS	NR	NR
8	Baicalin40–43	In vitro, In vivo	MIC50: 1.04 mg/mL, MIC90: 1.30 mg/mL	¯ hefA and vacA; ¯ IL-8, IL-1, IgM, and IgA	¯ Genes for multidrug resistance in pylori, ¯ Urease	Reduced the MICs of amoxicillin and tetracycline against H. pylori strains	No disruption of gut microbiota balance
9	Curcumin44	In vitro, In vivo	NR	¯ cagE and cagF; ¯ phosphorylated CagA, phosphorylated c-Src, IL-8, and CXCL8	¯ Shift and phosphorylation of CagA	NR	NR
10	Hezi Qingyou formula (chebulic acid, gallic acid, corilagin, chebulanin, and ellagic acid)45	In vitro	MIC: 80–160 µg/mL, MBC: 160–320 µg/mL	¯ ureE, ureF, flaA, flaB, alpB, babA, and alpA	¯ Expression of adhesion-, urease-, and flagellar-associated genes; ­ bacterial membrane permeability; ¯ urease activity	No synergistic or antagonistic interactions with clarithromycin, metronidazole, levofloxacin, or amoxicillin	NR
Abbreviations: MBC, minimum bactericidal concentration; MIC, minimum inhibitory concentration; NR, not reported in the cited primary study; OMPs, outer-membrane proteins; T4SS, type IV secretion system; T5SS, type V secretion system. MIC and MBC values and experimental conditions are presented as reported in the cited primary studies unless a valid unit conversion was possible. Gene symbols are italicized, whereas protein names are presented in roman type. All gene/protein annotations, strain information, culture media, pH, oxygen conditions, exposure durations, synergy methods, and safety findings should be verified against the corresponding primary sources before submission.

Table 2: Relevant genes and functions of phytochemicals to inhibit adhesion, motility, virulence, replication, and transcription of Helicobacter pylori.
Gene	Function
RecA	Induces cell death and negatively regulates babA expression33
BabA	Adhesion protein in H. pylori helps adhere to gastric epithelial cells33
SabA	Promotes adhesion to persistent infections via interaction with Lewis antigen33
UreI	Proton-gated urea channels, essential for colonization of acidic gastric surfaces33
OipA (HopH)	Outer inflammatory protein A (HopH), an outer-membrane protein associated with epithelial adhesion, IL-8 induction, inflammation, and disease severity34
DnaA and DnaB	DnaA: replication initiator protein that promotes origin recognition and initiation of chromosomal DNA replication. DnaB: replicative helicase that unwinds DNA at the replication fork34
FlaA and FlaB	Flagellin: mutations lead to a lack of motility34
FlgE	Hook proteins for flagellar filament attachment, necessary for motility34
FlhA	Core flagellar export apparatus protein required for flagellar assembly and motility34
AlpA and AlpB	Mediate adhesion to gastric mucosa, induce gastric injury34; induce intracellular signaling cascades34
NapA	Protects H. pylori DNA from oxidative damage38
HopD	Ensures nutrient supply for H. pylori survival and proliferation38
VirB6, VirB8, VirB9	Parts of the T4SS that facilitate bacterial protein transport39
VirB5	Minor pilus-tip component of the Cag type IV secretion system that contributes to host–cell contact and effector delivery39
SecA	ATPase of the Sec protein-export pathway; it is not a regulatory protein of the type V secretion system39

Inhibition of Motility

The motility of H. pylori is associated with its flagella. For H. pylori infections, flagella play an important role because flagellar motility is essential for H. pylori to colonize the host. Previous studies have shown that knocking out the flagellar gene flhF results in a reduced number of flagella, improper localization, and reduced motility.⁴⁶ H. pylori swims faster depending on the quantity and shape of its flagella, which it uses to break through the gastric mucus layer. The more flagella it has, and the more spirally shaped its cell body is, the faster it swims.⁴⁷ The implantation of H. pylori in the human stomach, facilitated by flagellum-driven motility, can lead to the development of multiple ­diseases, such as chronic gastritis, peptic ulcer disease, and gastric cancer.⁴⁸

Appropriate concentrations of zinc are essential for the propagation of H. pylori, with an MIC of 105 μg/mL. It was reported that high zinc concentrations ­downregulated the expression of flagellar genes flaA, flaB, flgK, fliD, and flgL, causing H. pylori to become immobile and weakly colonize.⁴⁹ Table 1 lists the impacts and mechanisms of action of some phytochemicals that have inhibited H. pylori motility in recent years. These phytochemicals mainly target H. pylori flagellar motility genes: flaA, flaB, flhA, and flgE. Table 2 outlines the functions of some relevant flagellar genes.

Inhibition of CagA and VacA

When H. pylori infects the gastric mucosa, it secretes several virulence factors that damage gastric epithelial cells while inducing and modulating inflammatory responses. CagA and VacA are the most extensively studied virulence factors. Their production disrupts the balance between gastric mucosal epithelial cell growth and regulation. CagA binds to gastric mucosal epithelial cells via the Type IV secretion system, where it becomes phosphorylated. This phosphorylation interferes with cellular signaling pathways, leading to tissue inflammation and immune responses. This includes rearrangement of the cellular actin skeleton and the emergence of a “hummingbird-like” morphology. VacA also adheres to gastric epithelial cells and enters the cells, causing damage to lysosomes and the endoplasmic reticulum, which leads to the death of gastric epithelial cells. The combined effects of CagA and VacA result in vacuole formation inside gastric epithelial cells, impairing immune function and causing a series of pathological changes.⁵⁰

Both CagA and VacA can inhibit the autophagy of gastric mucosal epithelial cells, reducing the ability of the cells to eliminate H. pylori and its virulence factors. Additionally, H. pylori survival allows the continued pathogenic effects of CagA and VacA, facilitating the transformation of gastritis into gastric cancer.⁵¹ Table 1 lists the genes related to H. pylori virulence factors that have been inhibited by certain phytochemicals in recent years: CagA, VacA, virB6, virB8, and virB9, while Table 2 outlines the functions of these genes.

Inhibition of Urease Activity

Among the virulence factors contributing to gastric mucosal colonization and bacterial metabolism, ­urease is crucial for the survival of H. pylori. By catalyzing the hydrolysis of urea, urease produces NH3 and CO2, where NH3 neutralizes gastric acid and creates ­favorable conditions for H. pylori to survive in the ­highly acidic environment. Urease, a Ni²+-dependent metalloenzyme, is abundantly produced by H. pylori, constituting approximately 10%–15% of the bacterium’s total protein content and is essential for both initial colonization and maintenance of chronic infection in the gastric mucosa.⁵² The active site of urease contains two nickel ions, which are essential for catalysis.

Macrophages can inhibit H. pylori by fusing phagosomes with lysosomes to form phagolysosomes. ­However, H. pylori inhibits phagocytosis through urease, delaying the phagocytosis process.⁵³ UreG, a SIMIBI-like GTPase, is involved with the UreF-UreH complex in nickel regulation during urease activation. The biological function of UreG is often modulated by dimerization, and the dimers deliver nickel ions for urease maturation.⁵⁴ For example, an extract from a medicinal plant in the Middle East contains D-glucosamine, which serves as a urease inhibitor against H. pylori infection.⁵⁵ ­Additionally, an aqueous extract from the roots of Z. nitidum inhibits urease activity by targeting the sulfhydryl active site.⁵⁶

As shown in Table 1, Hesperetin, 1,3,6-trigalloyl glucose, and Baicalin also inhibit urease activity. Furthermore, Table 3 shows that Epiberberine, Coptisine, Patchouli alcohol, and Palmatine significantly inhibit H. pylori urease activity. Previous studies have demonstrated that phytochemicals have a strong inhibitory effect on H. pylori urease activity in in vitro experiments. However, there are relatively few studies conducted on animals or patients. The inhibition of H. pylori is still in the early stages, and further investigation into the mechanisms of action, specifically the effects on related genes and protein expression, is needed. For example, it was found that patchouli alcohol, when combined with clarithromycin and metronidazole, had a ­remarkable inhibitory effect on H. pylori growth. This approach could potentially serve as a new way to tackle H. pylori resistance.⁵⁷ Cedarwood has also been found to inhibit urease at an MIC of 15.6 mg/L, and as an essential oil, it may be used as a solvent to dissolve drugs targeting H. pylori or phytochemicals, thus enhancing their effectiveness.58 This idea warrants further research.

Table 3: Phytochemicals that inhibit urease activity.
Number	Phytochemicals/Ref.	Model	MIC/MBC	Molecular Targets	Key Outcomes	Synergy with Antibiotics	Safety Notes
1	Epiberberine59,60	In vitro, In vivo	MIC: 32–64 µg/mL; MBC: 64–128 µg/mL	¯ ureB	¯ Urease activity; anti-inflammatory effects; induction of H. pylori structural disruption and bacterial death	NR	NR
2	Coptisine54	In vitro	MIC: 25–50 µg/mL; MBC: 37.5–125 µg/mL	¯ ureG expression	¯ H. pylori growth; ¯ urease activity; promoted nickel dissociation from the UreG dimer	NR	No significant cytotoxicity in the tested cell model at the evaluated concentrations
3	Palmatine61	In vitro	MIC: 100–200 µg/mL at pH 7.4; MIC: 75–100 µg/mL at pH 5.3	Interaction with urease sulfhydryl groups	¯ Urease activity	NR	NR
4	Patchouli alcohol53, 57, 62,63	In vitro, In vivo	MIC: 12.5–75 µg/mL at pH 5.3–9.0; MBC: 25–75 µg/mL	¯ ureB, ureE, ureI, nixA, alpA, alpB, flaA, flaB, hp0605, hp1327, and hp1489; ¯ TNF-α, IL-1β, IL-6, iNOS, MDA, MCP-1, TXNIP, pro-caspase-1, cleaved caspase-1, and NLRP3; ­ NP-SH and ­ GSH/GSSG ratio	Impaired urease function and maturation; enhanced macrophage-mediated bacterial clearance; ¯ NLRP3 inflammasome activation; ¯ adhesion and motility; disruption of bacterial ultrastructure and flagellar integrity; ¯ ROS production	Synergistic activity with clarithromycin	No significant effect on GES-1 cell proliferation at the tested concentrations
5	Sanguinarine64	In vitro	NR	Interaction with urease thiol groups and the Ni2+-associated catalytic system	¯ Urease activity	NR	NR
Abbreviations: GSH/GSSG, reduced-to-oxidized glutathione ratio; MBC, minimum bactericidal concentration; MDA, malondialdehyde; MIC, minimum inhibitory concentration; NP-SH, non-protein sulfhydryl groups; NR, not reported in the cited primary study; ROS, reactive oxygen species. MIC and MBC values and experimental conditions are presented as reported in the cited primary studies unless a valid unit conversion was possible. Gene symbols are italicized, whereas protein names are presented in roman type.

Inhibition of ROS and Inflammatory Response

Upon attachment to host cells, H. pylori immediately initiates signal transduction, leading to the transcription and translation of relevant inflammatory proteins. H. pylori infection elicits a robust host inflammatory response, stimulating gastric epithelial cells and infiltrating immune cells to produce pro-inflammatory cytokines (such as IL-1β, IL-6, IL-8, and TNF-α), which contribute to mucosal inflammation and gastric tissue damage.⁶⁵ If the gastric mucosa is excessively damaged, diseases such as tumors or gastric cancer may develop. Therefore, it is crucial to protect the gastric mucosa from such damage.

CagA plays a key role in initiating the NF-κB, MAPK, and SHP-2/ERK pathways in host cells, which leads to the production of pro-inflammatory cytokines, including IL-6, IL-8, IFN-γ, and TNF-α.⁶⁶ Specifically, CagA is translocated to gastric epithelial cells via the T4SS and promotes IL-8 secretion by activating the Ras-Raf-Mek-Erk-NF-κB signaling pathway. At the same time, VacA enhances the expression of pro-inflammatory cytokines by influencing the ERK1/2 signaling ­pathway.⁶⁷ H. ­pylori also increases the synthesis of ROS and the expression of IL-8 in gastric epithelial cells.68 ­Mitochondria are primarily responsible for cellular ROS synthesis, and excessive ROS production leads to mitochondrial dysfunction.⁶⁸ NO (nitric oxide) is an important biologically active substance involved in immune and inflammatory responses. Upon H. pylori infection, macrophages produce ROS and NO as part of the innate immune response, which contribute both to pathogen elimination and to modulation of inflammatory signaling, including the activation of the NLRP3 inflammasome.⁶⁹

Table 4 summarizes the monomers obtained from plant extracts or isolated from plants in recent years. The studies have verified that these monomers can effectively inhibit H. pylori-induced gastric mucosal inflammatory responses. To provide a clearer understanding of the relationship between ROS, signaling pathways, oxidative stress, and the inflammatory response during H. pylori invasion, we have illustrated this in Figure 1. Based on the literature, inflammatory markers are primarily tested, including TNF-α, IL-1β, IL-6, IL-8, etc., and associated signaling pathways like Nrf2 and NF-κB are examined to assess anti-inflammatory effects. However, other inflammatory factors and signaling pathways are less extensively studied.

Table 4: Phytochemicals that attenuate H. pylori-induced inflammatory response and ROS.
Number	Phytochemicals/Ref.	Model	MIC/MBC	Molecular Targets	Key Outcomes	Synergy with Antibiotics	Safety Notes
1	Evodiamine72	In vitro	MIC: 1.52, 6.07, and 12.13 µg/mL	¯ ureA, ureB, dnaA, dnaB, dnaE, dnaN, dnaQ, rpoA, rpoB, rpoD, rpoN, vacA, secA, cagA, virB2, virB4, virB5, virB6, virB7, virB8, virB9, virD4; ¯ IL-8	¯ Urease activity; ¯ virulence-factor expression; ¯ NF-κB and MAPK signaling; ¯ bacterial replication and transcription; ¯ CagA and VacA translocation into AGS cells	NR	NR
2	Fagopyrum tataricum (L.) Gaertn. bran flavonoid extract73	In vitro	MIC: 25–100 mg/mL	¯ ureA and ureB; ¯ IL-6, IL-8, and CXCL1	¯ Urease activity; ¯ pro-inflammatory mediator production	NR	NR
3	Grape seed extract74	In vitro	MIC: 0.075–1.5 mg/mL	¯ IL-8	¯ Inflammatory responses; ¯ oxidative damage; ¯ ROS production	NR	NR
4	Ellagitannins from Castanea sativa Mill. leaf extracts75	In vitro	MIC: 100 µg/mL	¯ IL-8; altered expression of TFRC, SPRY4, GBP1, GBP3, PRAG1, AMIGO2, and PTPRE	¯ Inflammatory responses; modulation of NF-κB and Rho GTPase signaling; ¯ adhesion	NR	NR
5	Steamed ginger extract76	In vitro	MIC: 100 mg/mL	¯ IL-8, TNF-α, IL-6, IFN-γ, NF-κB p65, phosphorylated IκBα, iNOS, NO, and MPO	¯ Pro-inflammatory cytokine production; ¯ NF-κB signaling	NR	No detectable cytotoxicity in AGS cells after 24 h of exposure at the tested concentrations
6	Korean propolis77	In vivo	NR	¯ H. pylori 16S rRNA abundance; ¯ ureA and napA; ¯ CagA, NO, IL-8, TNF-α, IL-1β, phosphorylated IκBα, NF-κB p65, c-Myc, and A20	¯ Bacterial burden and virulence-associated markers; ¯ pro-inflammatory cytokine production; ¯ NF-κB signaling	NR	NR
7	Korean red ginseng extract68,78,79	In vitro, In vivo	NR	­ SOD1 expression, HO-1, total SOD activity, and phosphorylated or nuclear Nrf2; ¯ KC, IL-1β, iNOS, MPO, lipid peroxidation, and IL-8	¯ Mitochondrial dysfunction; ­ nuclear translocation of Nrf2; ¯ DNA damage; ¯ inflammation in mice; ¯ NF-κB activation; ¯ ROS production	NR	NR
8	Callicarpa nudiflora extract80	In vitro	MIC: 2.5 mg/mL	¯ NLRP3, TNF-α, IL-1β, IL-6, and IL-8	¯ NLRP3 inflammasome activation; ¯ ROS production; ¯ LDH release	NR	NR
9	Achillea millefolium L. extract81	In vitro	MIC: 0.08–0.14 mg/mL	¯ IL-8	¯ Inflammatory responses; ¯ oxidative stress; ¯ ROS production	NR	NR
10	β-Carotene82,83	In vitro	NR	­ IκBα; ¯ NADPH oxidase activity, TRAF1, TRAF2, phosphorylated GSK3β, β-catenin, c-Myc, and cyclin E	¯ NADPH oxidase activity; ¯ NF-κB activation; ¯ GSK3β/β-catenin signaling; ¯ oncogene expression; ¯ ROS production	NR	NR
11	α-Lipoic Acid84,85	In vitro	NR	­ Nrf2 and HO-1; ¯ IL-8, Keap1, MAPK, JAK–STAT, and NF-κB signaling	Enhanced antioxidant responses; ¯ inflammatory signaling; ¯ ROS production	NR	NR
12	Cinnamaldehyde86	In vitro, In vivo	MIC: 8–16 µg/mL	¯ IL-6, TNF-α, IL-1β, and intracellular ATP; ¯ GyrA, GyrB, AtpA, and TopA	¯ H. pylori adhesion, colonization, and biofilm formation; depletion of intracellular ATP; alteration of bacterial ROS responses	Additive effects with levofloxacin on 6 strains; synergistic effects with levofloxacin on 2 strains	Low toxicity: No cytotoxicity on GES-1 cells, no pathological damage or weight change in mice at a 70 mg/kg dose
13	Banxia Xiexin decoction87	In vitro, In vivo	MIC: 256–512 µg/mL	¯ IL-1β, IL-6, and TNF-α; ¯ Bax, CagA, and VacA	¯ Urease activity; ¯ virulence-factor expression; ¯ inflammatory responses	NR	NR
14	Olive leaf extract71	In vitro	NR	¯ IL-8	¯ inflammatory responses; ¯ oxidative stress; ¯ ROS production	NR	NR
15	Artemisinin and its derivatives88	In vitro	MIC: 0.5–10 µg/mL	¯ CagA, IL-8, and TNF-α	¯ H. pylori adhesion; ¯ ROS production in gastric cancer cells; ¯ NF-κB activation	NR	Minor cytotoxicity toward normal GES-1 cells; artesunate and dihydroartemisinin were less cytotoxic to GES-1 cells than to SGC-7901 cells, with cell viability >85% at 5–20 µM
16	Syzygium aromaticum aqueous extract89	In vitro	MIC: 320 µg/mL	¯ IL-8, TNF-α, and CXCL8; ­ TLR4 and phosphorylated NF-κB p65; ¯ Nrf2/HO-1 signaling	Enhanced innate immune and macrophage responses; ­ macrophage-mediated bacterial clearance; activation of TLR4/NF-κB signaling; suppression of Nrf2/HO-1 signaling	NR	NR
Abbreviations: HO-1, heme oxygenase-1; iNOS, inducible nitric oxide synthase; LDH, lactate dehydrogenase; MBC, minimum bactericidal concentration; MIC, minimum inhibitory concentration; MPO, myeloperoxidase; NO, nitric oxide; NR, not reported in the cited primary study; ROS, reactive oxygen species; SOD, superoxide dismutase. MIC and MBC values, strain information, and experimental conditions are presented as reported in the cited primary studies unless a valid unit conversion was possible. Gene symbols are italicized, whereas protein names are presented in roman type. All directional changes refer to comparisons reported in the corresponding primary studies.

The potential of phytochemicals to reduce inflammatory responses deserves further investigation, especially if these compounds are structurally modified to form derivatives that may enhance antimicrobial activity. Vitamin D3 has been reported to modulate the immune system, thereby attenuating the H. pylori-­induced ­inflammatory response in the stomach lining. This ­finding is particularly relevant for children infected with H. pylori.⁷⁰ It would be worth exploring whether the efficacy of Vitamin D3 can be enhanced when combined with phytochemicals. Monomers extracted from plants can sometimes be evaluated based on their chemical structure to assess their potential for redox reactions. For example, the chemical structure of hydroxytyrosol contains two adjacent phenolic hydroxyl groups, which are capable of scavenging free radicals, chelating metals,71 and exhibiting strong antioxidant activity.

Inhibition of biofilm

The H. pylori biofilm is composed of aggregates of quiescent cells. When the biofilm is formed, planktonic cells first attach to abiotic or biotic surfaces, and small colonies with a three-dimensional structure are subsequently established.⁹⁰ Biofilm growth is regarded as a major factor contributing to the chronic colonization of the host stomach by H. pylori, treatment failure, and the eventual development of gastric disease.⁹⁰ The formation of biofilms enhances H. pylori’s resistance to antibiotics,⁹¹ and may increase its resistance to antibiotics in vitro by approximately 4–20 times.⁹² H. pylori forms biofilms whose extracellular matrix protects the bacteria from reactive oxygen species (ROS)-mediated toxicity produced by host immune cells, thereby contributing to bacterial survival under oxidative stress.⁹³ ROS released by inflammatory cells may facilitate the formation of H. pylori biofilms within the stomach.⁹³

SpoT proteins have been shown to promote oxidative stress-induced biofilm formation and multidrug resistance in H. pylori, while upregulating the napA gene expression.⁹³ Outer membrane vesicles (OMVs) are involved in the development and stability of H. pylori biofilms.⁹⁴ OMP6 is regulated by non-phosphorylated ArsR and plays a role in the production of H. pylori biofilms.⁹⁵ The phytochemicals listed in Table 5 primarily function to inhibit biofilm formation and enhance membrane permeability, which, in turn, prevents or eradicates the growth of H. pylori.

Table 5: Phytochemicals and phytochemical-rich extracts inhibiting H. pylori biofilm formation.
Number	Phytochemicals/Ref.	Model	MIC/MBC	Molecular Targets	Key Outcomes	Synergy with ­Antibiotics	Safety Notes
1	Carvacrol and thymol94	In vitro	Carvacrol: MIC, 16–64 µg/mL; thymol: MIC, 64–128 µg/mL; MBC, 256 µg/mL	¯ HpCAα, ¯ HpCAβ	¯ Biofilm formation; ¯ outer-membrane vesicle release; ¯ vesicle-associated extracellular DNA content	NR	Carvacrol: low cytotoxicity, IC₅₀ = 300 ± 6.5 µM; thymol: low cytotoxicity, IC₅₀ = 200 ± 6.5 µM
2	Nimbolide96	In vitro	MIC: 1.25–5 µg/mL; MBC: 2.5–10 µg/mL	NR	Enhanced antibacterial and antibiofilm activity under acidic conditions	NR	Low cytotoxicity in the tested human cell model
3	Aloe-emodin95	In vitro	NR	¯ OMP6	Biofilm disruption	NR	NR
4	Extracts from Rubus idaeus and Rubus occidentalis97	In vitro	MIC: 7.2–7.8 mg/mL, depending on the extract	NR	¯ Biofilm formation	Synergistic interactions with doxycycline and levofloxacin; additive interactions with amoxicillin and clarithromycin	NR
5	Phillygenin98	In vitro	MIC: 16–32 µg/mL; MBC: 128 µg/mL	¯ spoT and hp1174; ¯ IL-6, TNF-α, and IL-1β; ¯ mdoB; ­ flaA and lptB	¯ biofilm formation; ¯ intracellular ATP	NR	Favorable safety profile in the reported in vitro and in vivo evaluations
6	Extracts from Corydalis cheilanthifolia and Chelidonium majus99	In vitro	Corydalis cheilanthifolia: MIC, 64 µg/mL; Chelidonium majus: MIC, 128 µg/mL.	NR	¯ Biofilm formation	Synergistic interaction with amoxicillin	Cytotoxicity was observed at elevated concentrations
Abbreviations: eDNA, extracellular DNA; IC₅₀, half-maximal inhibitory concentration; MBC, minimum bactericidal concentration; MIC, minimum inhibitory concentration; NR, not reported in the cited primary study; OMP, outer-membrane protein. MIC and MBC values and experimental conditions are presented as reported in the cited primary studies unless a valid unit conversion was possible. Gene symbols are italicized, whereas protein names are presented in roman type. All directional changes refer to comparisons reported in the corresponding primary studies.

Apparently, based on the literature, the phytochemical inhibition of H. pylori biofilms has progressed considerably. However, the molecular mechanisms of biofilm formation and its inhibition remain unclear. Complete elimination of biofilm formation still requires further research. Therefore, an in-depth exploration of the molecular mechanisms involved in H. pylori biofilm formation and its therapeutic inhibition is crucial for treating diseases related to H. pylori infection.

Nanoparticles themselves exhibit certain antibacterial activity, possess a strong ability to penetrate the ­mucus layer, and show good biocompatibility and stability. These characteristics may enhance the antibacterial effects if newly discovered phytochemicals are incorporated into nanocarriers using nanotechnology. For example, a study reported that curcumin, due to its structural instability and poor solubility in water, had limited antibacterial efficacy. However, when curcumin was encapsulated into nanocapsules using nanotechnology, its antibacterial effects were significantly improved.¹⁰⁰

According to relevant studies, probiotics may help inhibit the growth, adhesion, and colonization of pathogens, thereby reducing the formation of pathogen biofilms.¹⁰¹ One study found that Lactobacillus plantarum LN66, combined with levofloxacin, improved the elimination of H. pylori biofilm.¹⁰² It is worth exploring whether combining phytochemicals with probiotics could further improve efficacy. Bacteriophages encoding polysaccharide depolymerases can penetrate deeply into bacterial biofilms and degrade the extracellular polymeric matrix, enabling effective elimination of biofilm-associated cells.¹⁰³ The combination of phages and antibiotics has been shown to enhance the elimination rate of drug-resistant pathogens and mitigate prevalent antibiotic resistance.^104,105 If phytochemicals and phages are studied together, it may further improve therapeutic efficacy.

Future Perspectives in H. pylori Treatment With Phytochemicals

Current studies suggest that phytochemicals may provide multi-target antibacterial and host-modulating activities, and several traditional formulations, including the Hezi Qingyou formula and BanXiaXieXin ­decoction, warrant further standardized investigation. Nevertheless, apparent synergy among multiple constituents should not be assumed without compositional standardization, pharmacological interaction testing, and comparison with guideline-recommended therapy. Translation should prioritize reproducible chemical characterization, strain-specific susceptibility testing, clinically achievable exposure, and compatibility with established eradication regimens.

Key translational barriers include modest or variable antimicrobial potency, poor aqueous solubility, limited gastrointestinal permeability, chemical instability, low or inconsistent extraction yield, and insufficient pharmacokinetic information. Fermentation has been proposed as one approach to improve extraction yield or biological activity for selected phytochemical preparations.¹⁰⁶ Structural optimization, formulation technologies, and targeted delivery may also improve activity, but these approaches require direct comparison with the unmodified compound and rigorous assessment of stability, exposure, and toxicity.

Safety must be evaluated compound by compound rather than inferred from natural origin. High-dose exposure to certain flavonoids may be associated with gastrointestinal discomfort.¹⁰⁷ Allergic reactions may also occur in susceptible individuals, particularly when botanical preparations contain compounds structurally related to known plant allergens.¹⁰⁸ Some plant-derived alkaloids and herbal constituents have been associated with hepatotoxicity,¹⁰⁹ while high doses or particular chemical forms of selected phenolic compounds may pose potential nephrotoxicity risks.¹¹⁰ Future studies should report compound purity, formulation, dose, exposure duration, cytotoxicity, organ toxicity, microbiome effects, and interactions with antibiotics and acid-suppressive agents.

Nanocarriers and other delivery systems may improve solubility, gastric retention, chemical stability, and mucosal penetration of poorly soluble phytochemicals,¹¹¹ but formulation benefits must be balanced against manufacturing complexity, carrier-related toxicity, and the need for reproducible quality control. Likewise, combinations with probiotics, antibiotics, or bacteriophages are hypothesis-generating strategies that require formal synergy testing and validation in clinically relevant models. Overall, phytochemicals represent a promising discovery platform and a potential adjunctive strategy for H. pylori management, but the current evidence is insufficient to support routine clinical substitution for recommended eradication regimens. Progress toward clinical use will require standardized methods, robust animal models, pharmacokinetic and toxicological characterization, randomized human studies, and transparent reporting of negative as well as positive findings.

Translational Considerations: Exposure, Delivery, Interactions, and Regulatory Limitations

Although several phytochemicals inhibit H. pylori at micromolar or microgram-per-millilitre concentrations in vitro, the translational relevance of these MIC values depends on whether comparable unbound concentrations can be achieved and maintained in the gastric lumen, mucus, or epithelial interface. Epiberberine and coptisine have reported MIC ranges of approximately 32–64 μg/mL and 25–50 μg/mL, respectively, but available oral pharmacokinetic data do not establish that conventional dosing achieves these concentrations in human gastric mucosa. Most pharmacokinetic studies measure plasma rather than gastric fluid, mucus, or tissue exposure; therefore, an in vitro MIC should not be interpreted as evidence that an orally administered dose will reach an effective concentration at the infection site.

Curcumin illustrates the same exposure problem. Its conventional oral use is limited by low aqueous solubility, poor absorption, rapid metabolism, and low systemic exposure. Formulation can substantially alter pharmacokinetics: an organogel-based nanoemulsion increased oral bioavailability approximately ninefold in mice, whereas submicron-dispersed curcumin produced approximately 18.4–20.5-fold higher Cmax and 35.9–42.6-fold higher AUClast than curcumin powder in healthy adults.^112,113 These formulation-specific increases in systemic exposure do not, however, demonstrate equivalent increases in gastric mucosal concentration or H. pylori eradication efficacy.

Nanoemulsions, polymeric or lipid nanoparticles, and mucoadhesive systems may improve solubility, chemical stability, gastric residence, and local mucosal exposure. Quantitative benefits should be reported separately for each formulation and should include changes in dissolution or solubility, gastric retention, plasma AUC, and concentrations in gastric fluid, mucus, and tissue. Future pharmacokinetic/pharmacodynamic studies should measure these exposure variables alongside MIC/MBC, bacterial burden, histological outcomes, and safety rather than relying solely on plasma pharmacokinetics.

Potential herb–drug interactions also require formal assessment. In a human study, repeated oral berberine administration reduced CYP2D6, CYP2C9, and CYP3A4 activities, indicating that exposure to concomitant medicines may be altered.¹¹⁴ Berberine-related modulation of P-glycoprotein and CYP enzymes, as well as experimentally reported transporter- and enzyme-related effects of curcumin, may depend on dose, formulation, and treatment duration. Consequently, phytochemical–antibiotic or phytochemical–acid-suppressant combinations should undergo dedicated interaction and safety studies, particularly when co-administered drugs have narrow therapeutic indices.

At present, the phytochemicals and advanced delivery systems discussed in this review remain investigational candidates and are not approved substitutes for guideline-recommended H. pylori eradication regimens. Clinical translation will require standardized composition and manufacturing, validated quality control, reproducible gastric exposure, toxicological and interaction assessment, and adequately powered randomized trials demonstrating eradication efficacy and acceptable safety.

Strengths and Limitations

A principal strength of this review is its mechanism- and translation-oriented mapping of a broad evidence base, integrating antibacterial activity, bacterial virulence and persistence, host inflammatory and oxidative responses, antibiotic interactions, formulation strategies, and safety. The structured tables also enable comparison of compounds across experimental models and help identify recurring targets and major knowledge gaps. Several limitations should be acknowledged. First, the review question and evidence base are broad and heterogeneous, and the article was not designed to generate a pooled treatment-effect estimate. Second, most included evidence is derived from in vitro experiments and small animal studies; clinical data are sparse, and efficacy in patients therefore cannot be inferred. Third, strain identity, culture medium, pH, oxygen conditions, exposure time, MIC methodology, compound purity, and safety reporting were incomplete or inconsistent in many primary studies, limiting direct comparison.

Fourth, study identification, eligibility assessment, and data charting were conducted by a single reviewer, without independent duplicate screening or extraction. Complete historical database-specific search logs were also unavailable because the literature search was conducted iteratively over an extended period. These factors may have introduced selection or extraction errors and limited the reproducibility of the review process. Fifth, a formal study-level risk-of-bias tool was not applied across all evidence types, and author judgment may have influenced interpretation. Relevant studies may also have been missed because of database coverage, search terminology, language restrictions, or incomplete reporting. These limitations support a cautious, non-causal interpretation and emphasize the need for standardized and clinically relevant research.

Abbreviations

BQT = Bismuth quadruple therapy

CAT = Increases

CXCL1 = CXC chemokine ligand 1

HO-1 = Heme oxygenase-1

IMPDH = Inosine monophosphate dehydrogenase

MBC = Minimum bactericidal concentration

MCP-1 = Monocyte chemoattractant protein-1

MIC = Minimum inhibitory concentration

MPO = Myeloperoxidase

NADPH = Reduced nicotinamide adenine dinucleotide phosphate

NO = Nitric oxide

NP-SH = Non-protein sulfhydryl

OMP6 = Outer membrane protein 6

OMVs = Outer membrane vesicles

ROS = Reactive oxygen species

T4SS = Type IV secretion system

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Cite this article as:
Honghan Q, Safi SZ, Vellasamy S. Phytochemicals as Promising Anti-H. pylori Agents: Molecular Insights and Therapeutic Potential. Premier Journal of Science 2026;25:100281

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