H. pylori Infection, Gastritis and Stomach Cancer

by John G. Connor, M.A., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.
 
Table of Contents
  • Background
  • Herbs Which have been Shown to Inhibit H. pylori
  • Other Herbs Which may Assist in Inhibiting H. pylori
  • Research into the Different Pathways Involved in H. Pylori Inflammation
  • References 
Background
· The gram-negative bacterium Helicobacter pylori (HP), identified in 1982, is now recognized as the primary etiological factor associated with the development of gastritis and peptic ulcer disease. In addition, HP infections are also associated with chronic gastritis, gastric carcinoma and primary gastric B-cell lymphoma. (Mahady et al, 2005).

· H. pylori lives between the protective lining of the stomach and the stomach cells, where the phagocytic cells that attack this bacteria create a chronic inflammatory/oxidative state.  H. pylori lives in the gastric mucus layer and does not typically breach the gastric epithelial layer.  Interactions between H. pylori and phagocytic cells probably occur when there are disruptions in the gastric epithelial  barrier or in the setting of gastric mucosal injury. Activation of mast cells by H. pylori may contribute to the inflammatory response associated with H. pylori infection. (Algood & Cover 2006)· Heliobacter pylori infection stimulates TLR4* glycosylation, which initiates intracellular signaling in the infected host cell causing oxidative damage.  (Singh and Agarwal 2006)

*TLRs Toll-like receptors – are among important mediators of inflammation and they are important for the recognition of a broad range of microbial pathogens, including bacteria and viruses.  TLRs interact with various adaptor proteins activating various transcription factors, such as NF-κB and AP-1, and induce innate and adaptive immune response.  (Singh and Agarwal 2006)

· H. pylori-induced chronic inflammation, after twenty years can cause ulcers and stomach cancer or gastric lymphoma.

· Helicobacter pylori is a type I carcinogen, and infection with this pathogenic bacterium is the leading cause of gastric cancer worldwide. It has been postulated that infection by H. pylori may contribute to this disease in two distinct ways. One way is by activating a chronic inflammatory response which causes a cascade of molecular and morphological changes in the inflamed epithelium, leading to mucosal atrophy, metaplasia, dysplasia, and eventually gastric cancer. The other is that this bacterium may directly modify epithelial-cell function and promote carcinogenesis by interfering with genes such as those regulating apoptosis, cell cycle control, tumor suppression, and cell-to-cell contacts. (Keates et al 2008)

· The carcinogenic potential of H. pylori is also implicated in the endogenous synthesis of nitric oxide (NO) in macrophages by the induction of inducible nitric oxide synthase (iNOS). (Cancer res. 1996, 56, 3228-3243)

· One way in which H. pylori might resist being killed by macrophages is by blocking the production of nitric oxide.  This effect is mediated by H. pylori arginase, which competes with nitric oxide synthase (NOS) for Arginine.  Also in vivo experiments indicate H. pylori can induce macrophage apoptosis.  H. pylori is also reported to have several inhibitory effects on B lymphocytes.  H. pylori can also interfere with multiple functions of T lymphocytes. And one report indicated it can have proapoptotic effects on T cells.  H. pylori arginase also contributes to inhibition of T-cell proliferation. (Algood & Cover 2006)

· Helicobacter pylori (H. pylori) infection induces nitric acid (NO) overproduction through inducible NO synthase (iNOS) expression, subsequent DNA damage and enhanced anti-apoptosis signal transduction sequence in the human gastric mucosa, whereas its possible effect on endothelial nitric oxide synthase (eNOS) expression has not as yet been investigated. The authors concluded that H. pylori infection upregulates eNOS, and induces angiogenesis, contributing to H. pylori-associated pathophysiology in gastric mucosa. (Lazaraki et al 2008)

* Increased production of nitric oxide (NO) is reported in several inflammatory disorders, such as sepsis, arthritis, thrombotic thrombocytopenic purpura and anti-phospholipid syndrome.  In addition NO upregulates cyclo-oxygenase-2 (COX-2) and the synthesis of several other inflammatory cytokines.  Inflammation and thrombotic complications are usually associated with malignancy.  Earlier reports indicate the upregulation of tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP) and tissue factor (TF) in patients with malignancy.  These data suggest that the pathogenesis associated with malignancy/hypercoagulable state is associated with an inflammatory component. (Fareed et al 2004)

* iNOSinducible nitric oxide synthase – contributes to enhanced microvascular permeability and density in response to proinflammatory mediators and VEGF*

.  The iNOS gene is under the transcriptional control of a variety of inflammatory mediators such as cytokines, lipopolysaccharides (LPS) and others.  iNOS expression has been described in rheumatoid arthritis, multiple sclerosis and Sjogren’s syndrome.  iNOS expression has also been found in chronically inflammatory disease of the airways, the vessels, the bowels, the kidney, the heart, the skin and the apex of the teeth.  In these various disease iNOS immunoreactivity has sometimes been localized to macrophages, but in most cases is found associated with epithelial cells around inflammatory foci. (Kroncke, Fehsel and Kolb-Bachofen 1998)

* VEGFvascular endothelial growth factor is one of the most powerful stimulants of tumor angiogenesis.· In a recent study VEGF was shown to be critical to the invasive process in human gastric cancer. (Zhao et al 2009)· The virulence of H. pylori is determined by the genotypes, particularly the cytotoxin-associated gene A (cagA), which encodes a high molecular weight immunodominant antigen, and vacA (vacuolating cytoxin A).

· While certain tumor markers for gastric cancer may be elevated (CEA, CA 19-9, CA 72-4), they are unreliable for diagnosis.  Upper gastrointestinal endoscopy is the gold standard in diagnosis. (Phytopharmaceuticals in Cancer Chemoprevention, page 146, 2005)

· Several nutritional factors have been suggested as risk factors for gastric cancer.  Foods with a high nitrate content (preserved foods) and high salt content (particularly pickled foods and salted fish and meat) may increase cancer risk. Fresh fruits and vegetables, on the other hand, particularly in the uncooked form, reduce cancer risk, perhaps through their antioxidant content. (Phytopharmaceuticals in Cancer Chemoprevention, page 144, 2005)

· Chemotherapy for gastric cancer may be used as adjuvant or for palliation, although gastric cancer is a relatively resistant tumor to this therapeutic modality.  The currently available drugs yield disappointing results both alone and in combination, though clinical trials are ongoing with new agents. (Phytopharmaceuticals in Cancer Chemoprevention, page 149, 2005)

Herbs Which Have Been Shown to Inhibit H. pylori·   
Whey protein concentrate produced with milk from H. pylori-immunized cows contains antibodies that are active at the pH of the stomach, and bactericidal against H. pylori in vitro, via the classical complement pathway. This study has demonstrated the potential for use of WPC in the prevention/treatment of H. pylori infections. (Early et al 2001)

· Ginger root (Zingiber officinale) has been used traditionally for the treatment of gastrointestinal ailments such as motion sickness, dyspepsia and hyperemesis gravidarum, and is also reported to have chemopreventative activity in animal models. Since Helicobacter pylori (HP) is the primary etiological agent associated with dyspepsia, peptic ulcer disease and the development of gastric and colon cancer, the anti-HP effects of ginger and its constituents were tested in vitro. RESULTS: The methanol extract of ginger rhizome inhibited the growth of all 19 strains in vitro with a minimum inhibitory concentration range of 6.25-50 micrograms/ml. One fraction of the crude extract, containing the gingerols, was active and inhibited the growth of all HP strains with an MIC range of 0.78 to 12.5 micrograms/ml and with significant activity against the CagA+ strains. CONCLUSION: These data demonstrate that ginger root extracts containing the gingerols inhibit the growth of H. pylori CagA+ strains in vitro and this activity may contribute to its chemopreventative effects. (Mahady et al 2003)·

The antibacterial activity of sixteen Chilean red wines (Cabernet Sauvignon, Cabernet Merlot, Cabernet Organic and Pinot Noir), and the active extracts of two randomly selected wines were assayed for their antibacterial activity on six strains of Helicobacter pylori isolated from gastric biopsies. All the red wines studied showed some antibacterial activity on the six strains of H. pylori, although the strains were heterogeneous in their susceptibility to each particular wine. The active fraction of the two wines selected also showed good activity against the strains tested. The main active compound was identified as resveratrol. The results presented indicate that Chilean red wines have antibacterial activity against H. pylori, which depends mainly on the presence of resveratrol. (Daroch et al, 2001)·

· Curcumin, a polyphenolic chemical constituent derived from turmeric (Curcuma longa), has been shown to prevent gastric and colon cancers in rodents. Many mechanisms have been proposed for the chemopreventative effects, although the effect of curcumin on the growth of Helicobacter pylori has not been reported. H. pylori is a Group 1 carcinogen and is associated with the development of gastric and colon cancer. These data demonstrate that curcumin inhibits the growth of H. pylori cagA+ strains in vitro, and this may be one of the mechanisms by which curcumin exerts its chemopreventative effects. (Mahady et al, 2002)

· Curcumin, diferuloylmethane from turmeric, has recently been shown to arrest H. pylori growth. Curcumin showed immense therapeutic potential against H. pylori infection as it was highly effective in eradication of H. pylori from infected mice as well as in restoration of H. pylori-induced gastric damage. (De et al, 2009)

· Allixin, a phytoalexin from garlic, inhibits the growth of Heliobacter pylori in vitro.  (Mahady et al 2001)

· Methanol extracts of the rhizomes of Sanguinaria Canadensis (Bloodroot), and the roots and rhizomes of Hydrastis Canadensis (Goldenseal), two plants used traditionally for the treatment of gastrointestinal ailments, were screened for in vitro antibacterial activity against 15 strains of Helicobacter pylori. The rhizome extracts, as well as a methanol extract of S. canadensis suspension-cell cultures inhibited the growth of H. pylori in vitro, with a MIC50 range of 12.5-50.0 microg/ml. Three isoquinoline alkaloids were identified in the active fraction. Sanguinarine and chelerythrine, two benzophenanthridine alkaloids, inhibited the growth of the bacterium, with an MIC50 of 50.0 and 100.0 microg/ml, respectively. Protopine, a protopine alkaloid, also inhibited the growth of the bacterium, with a MIC50 of 100 microg/ml. The crude methanol extract of H. canadensis rhizomes was very active, with an MIC50 of 12.5 microg/ml. Two isoquinoline alkaloids, berberine and beta-hydrastine, were identified as the active constituents, and having an MIC50 of 12.5 and 100.0 microg/ml, respectively. (Mahady et al, 2003)

· Cancer prevention requires avoidance of tobacco, alcohol, high-fat diet, polluted air and water, sedentary lifestyle, and of mechanical, physical, psychological, or chemical stress. How these factors can cause cancer, is suggested by the transcription nuclear factor-kappa B (NF-kappa B), that is activated by tobacco, alcohol, high-fat diet, environment pollutants, cancer-causing viruses (human papillomavirus, hepatitis B and C viruses, HIV) and bacteria (Helicobacter pylori), ultraviolet light, ionizing radiation, obesity, and stress. Furthermore, NF-kappa B-regulated gene products have been implicated in transformation of cells, and in proliferation, survival, invasion, angiogenesis, and metastasis. Suppression of NF-kappa B activation by the phytochemicals present in fruits and vegetables provides the molecular basis for their ability to prevent cancer. Other agents identified from spices and Ayurvedic and traditional Chinese medicines also been found to suppress NF-kappa B activation and thus may have potential for cancer prevention. These classic chemopreventive agents should offer long-term safety, low cost, and efficacy. The current review discuses in detail numerous agents such as curcumin, resveratrol, silymarin, catechins and others as potential chemopreventive agents. Thus, cancer, an ancient problem, may have an ancient solution. (Ralhan et al, 2009)

Other Herbs Which May Assist in Inhibiting H. pylori
· Ginkgo reduced gastric cancer tumors by 73.4% in patients with gastric cancer.  It also improves the mucosal healing of duodenal ulcers.  It inhibited cancer induced from proton-pump inhibiting drugs. (Med Hypotheses. 2006;66(6):1244 Epup 2006 Feb 28)

· In addition to gastritis and peptic ulcer disease, Heliobacter pylori  infections are associated with chronic gastritis, gastric carcinoma and primary gastric B-cell lymphoma. For centuries, herbals have been used in traditional medicine to treat a wide range of ailments, including gastrointestinal (GI) disorders such as dyspepsia, gastritis and peptic ulcer disease (PUD). However, the mechanism of action by which these botanicals exert their therapeutic effects has not been completely elucidated. As part of an ongoing screening program, the study assessed the in vitro susceptibility of 15 HP strains to botanical extracts, which have a history of traditional use in the treatment of GI disorders. Methanol extracts of Myristica fragrans (nutmeg seed) had a MIC of 12.5 microg/mL; Zingiber officinale (ginger rhizome/root) and Rosmarinus officinalis (rosemary leaf) had an MIC of 25 microg/mL. Methanol extracts of botanicals with a MIC of 50 microg/mL included Achillea millefolium (yarrow), Foeniculum vulgare (fennel seed), Passiflora incarnata (passion flower herb), Origanum majorana (marjoram herb) and a (1:1) combination of Curcuma longa (turmeric root) and ginger rhizome. Botanical extracts with a MIC of 100 microg/mL included Carum carvi (caraway seeds), Elettaria cardamum (seed), Gentiana lutea (bitterroot), Juniper communis (berry), Lavandula angustifolia (flowers), Melissa officinalis (lemon balm leaves), Mentha piperita (peppermint leaves) and Pimpinella anisum (anise seed). Methanol extracts of Matricaria recutita (chamomile flowers) and Ginkgo biloba (leaves) had a MIC > 100 microg/mL.  (Mahady et al, 2005)

· Boswellic acids inhibited ulcer production non-specifically in all the experimental models, whereby, it is not possible to propose a single specific mechanism. Nevertheless it is possible that Boswellic acids might be acting by increasing the gastric mucosal resistance and local synthesis of cytoprotective prostaglandins and inhibiting the leukotriene synthesis. (Singh et al 2008)

· H. pylori infection is associated with epidermal growth factor (EGF) receptor (EGFR) activation. (Yan et al 2009)

· Helicobacter pylori (H. pylori) infection induces nitric acid (NO) overproduction through inducible NO synthase (iNOS) expression. (Lazaraki et al 2008)

* Increased production of nitric oxide (NO) is reported in several inflammatory disorders.  In addition NO upregulates cyclo-oxygenase-2 (COX-2) and the synthesis of several other inflammatory cytokines.  (Fareed et al 2004)

Research into the Different Pathways Involved in H. Pylori Inflammation & Carcinogenesis
· Work from a number of laboratories has led to the hypothesis that T-cells and the Th1 immune response, governed largely by host genetic factors, are strongly associated with the H. pylori-mediated induction of atrophy and cancer. The induction by H. pylori of cytokines and chemokines and growth-related genes is mediated by the MAPK and NF-κB signaling pathway. Recent studies have shown that NF-kappaB is activated through a NF-κB-inducing kinase/p21-activated kinase 1 pathway. H. pylori can also promote cellular apoptosis through a number of mechanisms, the most important of which is upregulation of the Fas/FasL* pathway. (Fox & Wang, 2002)

*The Fas/Fas Ligand system plays a crucial role in modulating immune response by inducing cell apoptosis to maintain homeostasis, self-tolerance of lymphocytes, and immune privilege.  

· Corpus-predominant infection with Helicobacter pylori results in the activation of programmed cell death pathways in surface, parietal, and chief cells. (Hagen et al 2008)

· H. pylori infection is associated with epidermal growth factor (EGF) receptor (EGFR) activation through metalloproteinase-dependent release of EGFR ligands in gastric epithelial cells. EGFR activation by H pylori infection has an antiapoptotic effect in gastric epithelial cells that appears to involve Akt* signaling and Bcl family members. These findings provide important insights into the mechanisms of H. pylori-associated tumorigenesis. (Yan et al 2009)

In fact, in most cases of natural infection, the host immune response leads to a chronic inflammation within the gastric mucosa that actually promotes the development of atrophy and neoplasia. In most cases, eradication of the organism leads to resolution of inflammation, which in many instances can result in reduction in atrophy and gastric cancer risk. Work from a number of laboratories has led to the hypothesis that T-cells and the Th1 immune response, governed largely by host genetic factors, are strongly associated with the H. pylori-mediated induction of atrophy and cancer. (Fox and Wang, 2002)

 
· The authors have shown that PAI-1* is elevated both in patients with H. pylori gastritis and in AGS cells infected with H. pylori.  PAI-1 is upregulated by a number of known carcinogenic agents and plays a pivotal role in invasion, metastasis and angiogenesis.  Their findings suggest that increased PAI-1 production during H. pylori infection may contribute to H. pylori associated carcinogenesis. (Keates et al 2008) 

*Plasminogen activator inhibitor 1 (PAI-1) is a 50-kDa protein belonging to a family of serine protease inhibitors known as serpins. PAI-1 is synthesized by a variety of cells and is induced by growth factors, cytokines, hormones, and other stimuli, and high PAI-1 levels are present in plasma from patients with acute or chronic inflammatory conditions. The main function of PAI-1 in tissue is to inhibit the action of the urokinase-type plasminogen activator (uPA), a serine protease involved in tissue remodeling and cell migration. (Keates et al 2008)

Recent studies have shown that PAI-1 levels are elevated in tumors, and the extent of the increase correlates with an increased potential for the spread of the malignancy. It has also been noted that cancer patients with high PAI-1 levels have a poor prognosis for survival. High PAI-1 levels may promote the degradation of the extracellular matrix by decreasing the ability of cells to adhere to their substratum and detaching cells from the extracellular matrices by inactivating integrins. (Keates et al 2008)

Diet is one of the environmental factors that influences thrombosis and hemostasis. Macronutrients, micronutrients, and other bioactive food components alter the predisposition to thrombosis. The type and amount of dietary fat has been shown to alter thromboxane A2 production and platelet aggregation, bleeding time, factor VII, fibrinogen, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1). Both epidemiological studies and clinical trials indicate that the very long chain n-3 fatty acids lower thrombotic tendency and risk of heart disease. Other polyunsaturated fats and monounsaturated fat appear to have antithrombotic properties, but further studies are indicated. Hypercaloric diets and those with high glycemic loads are associated with elevations of PAI-1. Moderate consumption of alcohol is associated with decreased platelet aggregation. Low intakes of folate, vitamin B12, and vitamin B6 predispose to hyperhomocysteinemia, and the benefits of supplementation in decreasing vascular disease are under investigation. In a limited number of clinical and laboratory studies, vitamin E has been shown to decrease platelet aggregation and the concentration of PAI-1. (Margaret et al, 2005)

Coagulation – is also activated in inflammation.  The increase in hypercoagulation in cancer facilitates angiogenesis.
PAI-1 – plasminogen activator inhibitor 1 controls the proteolytic activity in cancer cells and cellular migration during angiogenesis.  (Anticancer Res. 2008 Jan-Feb;28(1B):415-8)


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2 Responses to H. pylori Infection, Gastritis and Stomach Cancer

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