Plant-derived extracts or compounds for Helicobacter-associated gastritis: a systematic review of their anti-Helicobacter activity and anti-inflammatory effect in animal experiments

Abstract

Background: Helicobacter infection, which is the leading cause of gastritis and stomach cancer, has become common worldwide. Almost all Helicobacter-infected patients have chronic active gastritis, also known as Helicobacter-associated gastritis (HAG). However, the eradication rate of Helicobacter is decreasing due to the poor efficacy of current medications, which causes infection to recur, inflammation to persist, and stomach cancer to develop. Natural components have robust antibacterial activity and anti-inflammatory capacity, as confirmed by many studies of alternative natural medicines.

Purpose: This article aimed to conduct a comprehensive search and meta-analysis to evaluate the efficacy of anti-Helicobacter and anti-inflammatory activities of plant-derived extracts or compounds that can treat HAG in animal experiments. We intended to provide detailed preclinical-research foundation including plant and compound information, as well as the mechanisms by which these plant-derived substances inhibit the progression of Helicobacter infection, gastritis and neoplasms for future study.

Methods: The systematic review is aligned with the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and the protocol was registered in PROSPERO (CRD42024527889). An extensive search was performed across multiple databases, including PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal database (VIP), the Wanfang database, and the China biomedical literature service system (SinoMed), up until November 2023. Meta-analysis on Review Manager software (RevMan 5.4) estimating anti-Helicobacter and anti-inflammatory activity was performed. We used the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias tool to evaluate the risk of bias of each study included.

Results: Our study encompassed 61 researches, comprised 36 extracts and 37 compounds improving HAG by inhibiting Helicobacter infection, the inflammatory response, oxidative stress, and regulating apoptosis and proliferation. Sixteen families especially Asteraceae, Fabaceae and Rosaceae and nine classes including Terpenoids, Alkaloids, Phenols, and Flavonoids may be promising directions for valuable new drugs. The Meta-analyse demonstrated the plant-base substance treatments possess significant anti-Helicobacter and anti-inflammation activity comparing to control groups. The included plants and compounds confirmed that signaling pathways NF-κB, JAK2/STAT3, MAPK, TLR4/MyD88, PI3K/AKT, NLRP3/Caspase-1 and NRF2/HO-1 play a key role in the progression of HAG.

Conclusion: Plant-derived extracts or compounds actively improve HAG by modulating relevant mechanisms and signaling pathways, particularly through the anti-Helicobacter and inflammatory regulation ways. Further researches to apply these treatments in humans are needed, which will provide direction for the future development of therapeutic drugs to increase eradication rate and alleviate gastritis.

Keywords: Compound; Helicobacter; Helicobacter-associated gastritis; Inflammation; Phytotherapy; Plant extract.

Fig. 1

PRISMA flow diagram for the systematic review

Fig. 2

Mouse or rat strains used in different studies

Fig. 3

Risk of bias graph

Fig. 4

Risk of bias summary

Fig. 5

Forest plots of anti-Helicobacter activity. [A Positive events of CLO; B Positive events of RUT]

Fig. 6

Forest plots of anti-inflammatory activity. [A IL-1β protein level (pg/mL), B IL-1β protein level (pg/ug), C TNF-α protein level (pg/mL), D TNF-α protein level (pg/ug)]

Fig. 7

Funnel plots of different studies. [(A Positive events of CLO; B Positive events of RUT; C IL-1β and TNF-α protein levels (pg/mL); D IL-1β and TNF-α protein levels (pg/ug)]

Fig. 8

Signaling pathways regulating HAG

Fig. 9

Phytomedicines act on Correa cascade. ( Created in BioRender. https://BioRender.com/daegq0t. Agreement number: OK28AFSX59)

Fig. 10

Various effects of traditional Chinese medicine in treating HAG

Fig. 11

Plants or compounds from a same family

Fig. 12

Compounds from a same class

Fig. 13

Mechanisms of HAG injuries. (Created in BioRender. https://BioRender.com/o86q708. Agreement number: GD27RQB2OM.) Helicobacter infects and survives in the stomach via various pathogenic factors. Helicobacter causes damage to the host and ultimately causes tumors via oxidative stress, inflammation, DNA damage, apoptosis, and proliferation ways. The order in which mechanisms are listed in the figure does not represent their order of occurrence in diseases. HopQ, Hop family adhesin HopQ; cagPAI, cytotoxin-associated gene pathogenicity island; T4SS, type IV secretion system; CagA, cytotoxin-associated gene A protein; HBP, heptose-1, 7-bisphosphate; T5SS, type V secretion system; VacA, vacuolating cytotoxin A; iNOS, isoform of nitric oxide synthase; COX-2, cyclooxygenase-2; MPO, myeloperoxidase; IL, interleukin; IFN-γ, interferon-gamma; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor-β; Bax, Bcl-2-associated X protein; Bad, Bcl-2-associated agonist of cell death; Apaf-1, apoptotic protease activating factor-1; Bcl-2, B-cell lymphoma-2 protein; Bcl-xl, Bcl-2-like protein-1; ROS, reactive oxygen species; LPO, lipid peroxide; MDA, malondialdehyde; LDH, lactatedehydrogenase; Keap1, kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid-2-related factor 2; HO-1, heme oxygenase-1; pH2AX, phospho-histone H2A. X; 8-OHdG, 8-hydroxydeoxyguanosine; Mcl-1, myeloid cell leukemia protein 1; EGFR, epidermal growth factor receptor; ADAM, a disintegrin and metalloproteinase; BrdU, 5’-bromodeoxyuridine; Ki-67, antigen identified by monoclonal antibody Ki-67.

Fig. 14

Signaling pathways regulating the HAG. (Created in BioRender. https://BioRender.com/m32b229. Agreement number: RT27ZDTNZS.) LPS, peptidoglycan, VacA, and CagA are bacterial fragments from Helicobacter, and these fragments cause the release of multiple factors that take part in inflammation, apoptosis, overproliferation, and tumors through different signaling pathways including NF-κB, JAK/STAT3, MAPK, TLR4/MyD88, PI3K/AKT, NLRP3/Caspase-1, and NRF2/HO-1. ROS, reactive oxygen species; IL-6R, interleukin 6 receptor; gp130, glycoprotein 130; JAK, janus kinase; STAT3, signal transducer and activator of transcription 3; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; TLR4, toll-like receptor 4; MyD88, myeloid differentiation primary response gene 88; TRAF6, tumor necrosis factor receptor-associated factor 6; IKK, IκB kinase; IκBα, inhibitor of kappa B; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; ASC, apoptosis associated speck-like protein containing a CARD; AP-1, activator protein 1; Keap1, kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid-2-related factor 2; HO-1, heme oxygenase-1; MKK, mitogen-activated protein kinase kinase; MEK, mitogen-activated extracellular signal-regulated kinase; MAPKK, MAP Kinase Kinase; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase 1/2; JNK, jun N-terminal kinase; LPS, lipopolysaccharides; CagA, cytotoxin-associated gene A protein; VacA, vacuolating cytotoxin A; NOD1, nucleotide-binding oligomerization domain-containing protein 1; HB-EGF, heparin-binding epidermal growth factor-like growth factor; ADAM17, a disintegrin and metalloproteinase 17; EGFR, epidermal growth factor receptor; MMP10, matrix metalloproteinase 10; Apaf-1, apoptotic protease activating factor-1; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8, interleukin-8; IL-17, interleukin-17; TNF-α, tumor necrosis factor α; IFN-γ, interferon γ; iNOS, inducible nitric oxide synthase; NO, nitric oxide; COX-2, cyclooxygenase-2; PGE₂, prostaglandin E₂.