H. pylori Infection, Gastritis and Stomach Cancer

Compiled by John Connor, L.Ac. from articles and lectures by Donald Yance and other selected sources – August 6, 2009

 

Table of Contents

• Background
• Herbs Which Have Been Shown to Inhibit H. pylori
• Other Herbs Which May Assist in Inhibiting H. pylori
• Possible Tests to Determine the Extent of H. pylori Progression
• Research into the Different Pathways Involved in H. Pylori Inflammation

 

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)

 

* iNOS – inducible 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)

 

* VEGF – vascular 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

·        Ginger

·        Resveratrol

·        Curcumin

·        Garlic

·        Bloodroot

·        Goldenseal

·        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)

·        Stilbenes eg. (Resveratrol) – activate sirtuin enzymes present within our genes and are responsible for preserving the lives of cells.  Stilbenes effectively downgrade the signaling pathway of NF-kB* activation, which results in an inhibition of prostaglandin production and inhibition of iNOS, COX-1, COX-2 and AP-1.

 

* NF-κB – nuclear factor kappa beta - up-regulation has been found to be associated with almost every kind of cancer.

 

·        Resveratrol -- scavenges nitric oxide free radicals, effectively inhibiting iNOS and COX-2, causing a down-regulation of NF-κB activation, and thereby reducing vascular flow and tumor permeability and minimizing tumor growth.

·        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 leaf

·        Rosemary leaf

·        Silymarin (Milk Thistle)

·        Boswellia serrata

·        Nutmeg seeds

·        Yarrow

·        Fennel seed

·        Marjoram

·        Caraway seeds

·        Bitterroot

·        Juniper Berry

·        Lavender flower

·        Lemon Balm leaves

·        Peppermint leaves

·        Anise seeds

·        Chamomile flowers

·        Passion Flower

·        Cardamom seeds

·        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)

 

·        Carnosol (in holy basil and rosemary) – acts as an antioxidant and anti-carcinogen, and is a potent modulator of NF-κB. Carnosol has been shown to inhibit cancer-inducing NF-κB, iNOS, and MAPK* activity.  

 

* MAPK - mitogen-activated protein  kinases - are serine/threonine-specific protein kinases that respond to extracellular stimuli (mitogens) and regulate various cellular activities, such as gene expression, mitosis, differentiation, and cell survival/apoptosis.

 

·        Pterostilbene – an active constituent of blueberries – was able to inhibit cell proliferation and induce apoptosis in a concentration and time-dependent manner in human gastric carcinoma cells.  (Pan MH, et al 2007)

 

·        Ursolic acid (in holy basil and rosemary) – inhibits cancer through multiple mechanisms, including down-regulating NF-κB. 

 

·        Chelidonium majus extract exerts inhibitory effects on glandular stomach carcinogenesis in the rat, so that it may have potential as a chemopreventive agent for stomach cancer in man.

 

·        Glutamine -- supplementation prevents immuno-supppression, muscle atrophy during periods of stress, heals gastric and peptic ulcers, and is a chemotherapy and radiation therapy protectant compound.  Glutamine’s ability to reduce toxicity involves mediation through changes in glutathione metabolism.

 

·        Willow bark – is rich in salicin.  It has fewer side effects than aspirin.  Salicin is a potent anti-inflammatory agent, that also inhibits over expression of NF-κB, which is involved in both inflammation and abnormal gene expression.

 

·        Gotu kola can also stimulate the production of tissue plasminogen activator (tPA), which is associated with the ability to break down fibrin.  Fibrin formation and platelet aggregation are important steps to tumor formation.

 

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

 

·        Natural compounds shown to block EGF (Epithelial Growth Factor) receptor activation and its downstream effectors include:

·        Resveratrol

·        Vitamin D-3

·        Licorice

·        Quercetin (inhibits both EGF and HER2-neu expression).

·        Cysteine (un-denatured whey protein concentrate)

·        Selenium

·        Curcumin

·        I-3-C/DIM – indole-3-carbinol,  di-indolemethane

·        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)

 

·        Natural Compounds that Down-Regulate COX-2

·        EPA/DHA in n-3 fatty acids from fish oils

·        Baicalein, from Chinese skullcap (ICII >95%)

·        Curcumin

·        Transresveratrol

·        Pterostilbene

·        Quercetin

·        Salicin (Corydalis 30%) Will bark extract (WBE)

·        WBE inhibits the dell growth and promote apoptosis in human colon and lung cancer both through COX-selectivity and nonCOX-2. Other synergistic compound WBE include other salicyl alcohol derivates, flavonoids, proanthocyanidins.

Possible Tests to Determine the Extent of H. pylori Progression

 

·          CEA  - Carcinoembryonic Antigen – levels are elevated in adenocarcimona of the colon, rectum, breast, lung, pancreas, and stomach; hepatocellular carcinoma; medullary carcinoma of the thyroid; inflammatory bowel disease,; chronic hepatitis; obstructive jaundice; liver abscess; emphysema; bronchitis. Laboratory Tests and Diagnostic Procedures, p. 293 (2008)

 

·         CA 19-9 – This test is used to monitor gastrointestinal, pancreatic and colorectal malignancies. Normal levels are <37 AU/mL.  Metastasis levels are >1000 AU/mL. Laboratory Tests and Diagnostic Procedures, p. 270 (2008)

 

·         CA 72-4 – Cancer Antigen 72-4 – This test can be used in combination with tumor marker M2-PK for detection of gastric cancer.  CA 72-4 is specific (100%) for esophageal, gastric and colorectal cancer, but not very sensitive (18%, 32% and 65% respectively) when tested alone.  When used in combination with M2-PK, there is increased sensitivity for gastric cancer up to 81% and increased sensitivity for esophageal cancer to 74% (Schneider et al, 2005).  The test is more sensitive than CA 125 for ovarian cancer.  CA 72-4 is not helpful in detecting micrometastasis of colorectal cancer, but is positive in advanced metastatic tumors.  It is being investigated for its usefulness as a prognostic indicator of survival in gastric cancer.  Positive tests may occur in 85% of invasive ductal breast carcinomas, more than 85% of gastrointestinal adenocarcinomas (gastric, colon, pancreatic and esophageal) and in ovarian and endometrial adenocarcinomas.  Specificity can be improved with concurrent testing for other tumor markers.  Laboratory Tests and Diagnostic Procedures, p. 272 (2008)

 

·        COX-2 expression is increased in early intestinal-type gastric cancer, suggesting that inhibition of the enzyme may help prevent this form of cancer according to a study in 2002 in Japan.

 

·        VEGF – vascular endothelial growth factor – Increased levels of VEGF have been associated with many forms of cancers.  When secreted, VEGF acts directly on endothelial cells to induce development of tiny blood vessels (angiogenesis) which helps provide the blood flow and nourishment necessary to enable continued growth of the tumor.  Because of its role in stimulating angiogenesis near tumors, VEGF is also thought to be an important factor in allowing metastasis to occur.  Platelet count and VEGF levels are normally positively correlated.  Thus VEGF levels must be corrected when platelets are elevated. Laboratory Tests and Diagnostic Procedures, p. 115 ( 2008)

 

·         p53 - The highest frequency of p53 mutations reported in human cancers are lung, 56%; colon, 50%; esophagus,45%; ovary, pancreas and skin, 44%; stomach, 41%; head and neck, 37%; bladder, 34%; prostate, 30% and breast, endometrium and mesothelioma, 22%.

 

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)

*Akt is known to protect cells from TGF-β-mediated apoptosis.  Bcl-2 is an NF-κB regulated gene that functions by blocking the apoptosis pathway, thus immortalizing cancer cells. It has been suggested that Bcl-2 over expression results in the up regulation of VEGF expression with increased neoangiogenesis in human cancer xenografts.

o        Natural Compounds that Reduce Bcl-2

§         Curcumin

§         EGCG and Theophylline - Green tea

§         Baicalin and baicalein - Scutellaria baicalensis

§         Hibiscus protocatechuic acid (PCA) - Hibiscus s.

§         Carnosol - Rosemary

§         Gingerol – Ginger

§         Echinocystic acid )EA) – Panax ginseng

§         OPCs – grape seed extract

§         Parthenolide – feverfew

§         Andrographolide – Andrographis, diterpenoid lactone

§         Beta-lapachone – Lapacho

§         EPA – from fish oil

§         Chelidonium alkaloids – Chelidonine

§         Casticin – Yarrow (Achillea millefolium)