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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.