Dr. Ron’s Research Review – December 12, 2012

This week’s research review focuses on H. pylori

In 1996, Martin J. Blaser advanced the hypothesis that H. pylori is normal flora of the stomach that has a beneficial effect. By regulating the acidity of the stomach contents, it lowers the impact of regurgitation of gastric acid into the esophagus. (Saha, Hammond et al. 2010)

Humans have been colonized by H pylori for at least 50,000 years - throughout their evolution. H. pylori has adapted to humans, colonizing children and persisting throughout life. Despite  the  fact  that  about  half  the  world’s  population  carries  H. pylori, only a small proportion develop ulcers or gastric cancer. Absence of H. pylori causes hyperchlorhydria, and hence worsens acid-related esophageal diseases. (Atherton and Blaser 2009)

Recent research shows that H pylori has beneficial effects.

Helicobacter pylori colonization is inversely associated with childhood asthma and allergies. (Chen and Blaser 2008) (Chen and Blaser 2007)

In mice with diet-induced obesity, Helicobacter pylori colonization had a beneficial effect on glucose homeostasis. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain.   (Bassaganya-Riera, Dominguez-Bello et al. 2012)

Dr. Ron


Articles

Coadaptation of Helicobacter pylori and humans: ancient history, modern implications

            (Atherton and Blaser 2009) Download

Humans have been colonized by Helicobacter pylori for at least 50,000 years and probably throughout their evolution. H. pylori has adapted to humans, colonizing children and persisting throughout life. Most strains possess factors that subtly modulate the host environment, increasing the risk of peptic ulceration, gastric adenocarcinoma, and possibly other diseases. H. pylori genes encoding these and other factors rapidly evolve through mutation and recombination, changing the bacteria-host interaction. Although immune and physiologic responses to H. pylori also contribute to pathogenesis, humans have evolved in concert with the bacterium, and its recent absence throughout the life of many individuals has led to new human physiological changes. These may have contributed to recent increases in esophageal adenocarcinoma and, more speculatively, other modern diseases.

Helicobacter pylori Colonization Ameliorates Glucose Homeostasis in Mice through a PPAR gamma-Dependent Mechanism

            (Bassaganya-Riera, Dominguez-Bello et al. 2012) Download

BACKGROUND: There is an inverse secular trend between the incidence of obesity and gastric colonization with Helicobacter pylori, a bacterium that can affect the secretion of gastric hormones that relate to energy homeostasis. H. pylori strains that carry the cag pathogenicity island (PAI) interact more intimately with gastric epithelial cells and trigger more extensive host responses than cag(-) strains. We hypothesized that gastric colonization with H. pylori strains differing in cag PAI status exert distinct effects on metabolic and inflammatory phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we examined metabolic and inflammatory markers in db/db mice and mice with diet-induced obesity experimentally infected with isogenic forms of H. pylori strain 26695: the cag PAI wild-type and its cag PAI mutant strain 99-305. H. pylori colonization decreased fasting blood glucose levels, increased levels of leptin, improved glucose tolerance, and suppressed weight gain. A response found in both wild-type and mutant H. pylori strain-infected mice included decreased white adipose tissue macrophages (ATM) and increased adipose tissue regulatory T cells (Treg) cells. Gene expression analyses demonstrated upregulation of gastric PPAR gamma-responsive genes (i.e., CD36 and FABP4) in H. pylori-infected mice. The loss of PPAR gamma in immune and epithelial cells in mice impaired the ability of H. pylori to favorably modulate glucose homeostasis and ATM infiltration during high fat feeding. CONCLUSIONS/SIGNIFICANCE: Gastric infection with some commensal strains of H. pylori ameliorates glucose homeostasis in mice through a PPAR gamma-dependent mechanism and modulates macrophage and Treg cell infiltration into the abdominal white adipose tissue.

Inverse associations of Helicobacter pylori with asthma and allergy

            (Chen and Blaser 2007) Download

BACKGROUND: Acquisition of Helicobacter pylori, which predominantly occurs before age 10 years, may reduce risks of asthma and allergy. METHODS: We evaluated the associations of H pylori status with history of asthma and allergy and with skin sensitization using data from 7663 adults in the Third National Health and Nutrition Examination Survey. Adjusted odds ratios (ORs) for currently and ever having asthma, allergic rhinitis, allergy symptoms in the previous year, and allergen-specific skin sensitization were computed comparing participants seropositive for cagA(-) or cagA(+) strains of H pylori with those without H pylori. RESULTS: The presence of cagA(+) H pylori strains was inversely related to ever having asthma (OR, 0.79; 95% confidence interval [CI], 0.63-0.99), and the inverse association of cagA positivity with childhood-onset (age </=15 years) asthma was stronger (OR, 0.63; 95% CI, 0.43-0.93) than that with adult-onset asthma (OR, 0.97; 95% CI, 0.72-1.32). Colonization with H pylori, especially with a cagA(+) strain, was inversely associated with currently (OR, 0.77; 95% CI, 0.62-0.96) or ever (OR, 0.77; 95% CI, 0.62-0.94) having a diagnosis of allergic rhinitis, especially for childhood onset (OR, 0.55; 95% CI, 0.37-0.82). Consistent inverse associations were found between H pylori colonization and the presence of allergy symptoms in the previous year and sensitization to pollens and molds. CONCLUSION: These observations support the hypothesis that childhood acquisition of H pylori is associated with reduced risks of asthma and allergy.

Helicobacter pylori colonization is inversely associated with childhood asthma

            (Chen and Blaser 2008) Download

BACKGROUND: Asthma, a serious health problem worldwide, is becoming more common. Colonization with Helicobacter pylori, a major human indigenous (commensal) microbe, during early life may be relevant to the risk of childhood asthma. METHODS: We conducted cross-sectional analyses, using data from 7412 participants in the National Health and Nutrition Examination Survey (NHANES) 1999-2000, to assess the association between H. pylori and childhood asthma. RESULTS: H. pylori seropositivity was inversely associated with onset of asthma before 5 years of age and current asthma in children aged 3-13 years. Among participants 3-19 years of age, the presence of H. pylori was inversely related to ever having had asthma (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.45-1.06), and the inverse association with onset of asthma before 5 years of age was stronger (OR, 0.58; 95% CI, 0.38-0.88). Among participants 3-13 years of age, H. pylori positivity was significantly inversely associated with current asthma (OR, 0.41; 95% CI, 0.24-0.69). H. pylori seropositivity also was inversely related to recent wheezing, allergic rhinitis, and dermatitis, eczema, or rash. CONCLUSIONS: This study is the first to report an inverse association between H. pylori seropositivity and asthma in children. The findings indicate new directions for research and asthma prevention.

Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa

            (Saha, Hammond et al. 2010) Download

BACKGROUND AND AIMS: Helicobacter pylori infection of gastric mucosa causes gastritis and transient hypochlorhydria, which may provoke emergence of a mucosal precancer phenotype; H pylori strains containing a cag pathogenicity island (PAI) augment cancer risk. Acid secretion is mediated by the catalytic alpha subunit of parietal cell H,K-ATPase (HKalpha). In AGS gastric epithelial cells, H pylori induces nuclear factor-kappaB (NF-kappaB) binding to and repression of transfected HKalpha promoter activity. This study sought to identify bacterial genes involved in HKalpha repression and to assess their impact on acid secretion. METHODS AND RESULTS: AGS cells transfected with an HKalpha promoter construct or human gastric body biopsies were infected with wild-type (wt) or isogenic mutant (IM) H pylori strains. AGS cell HKalpha promoter activity, and biopsy HKalpha mRNA, protein and H(+) secretory activity were measured by luminometry, reverse transcription-PCR, immunoblotting and extracellular acidification, respectively. Wt H pylori and DeltavacA, DeltaureA, Deltaslt and DeltaflaA IM strains repressed HKalpha promoter activity by approximately 50%, a DeltacagA IM strain repressed HKalpha by approximately 33%, and DeltacagE, DeltacagM and DeltacagL IM strains elicited no HKalpha repression. Wt H pylori-infected biopsies had markedly reduced HKalpha mRNA and protein compared with IM strain infections or mock-infected controls. Histamine-stimulated, SCH28080-sensitive biopsy acid secretion was significantly inhibited by wt but not by DeltacagL IM H pylori infection compared with vehicle-only controls. CONCLUSIONS: It is concluded that H pylori cag PAI gene products CagE, CagM, CagL and, possibly, CagA are mechanistically involved in repression of HKalpha transcription. Further, acute H pylori infection of human gastric mucosa downregulates parietal cell H,K-ATPase expression, significantly inhibiting acid secretion.


References

Atherton, J. C. and M. J. Blaser (2009). "Coadaptation of Helicobacter pylori and humans: ancient history, modern implications." J Clin Invest 119(9): 2475-87.

Bassaganya-Riera, J., M. G. Dominguez-Bello, et al. (2012). "Helicobacter pylori Colonization Ameliorates Glucose Homeostasis in Mice through a PPAR gamma-Dependent Mechanism." PLoS One 7(11): e50069.

Chen, Y. and M. J. Blaser (2007). "Inverse associations of Helicobacter pylori with asthma and allergy." Arch Intern Med 167(8): 821-7.

Chen, Y. and M. J. Blaser (2008). "Helicobacter pylori colonization is inversely associated with childhood asthma." J Infect Dis 198(4): 553-60.

Saha, A., C. E. Hammond, et al. (2010). "Helicobacter pylori represses proton pump expression and inhibits acid secretion in human gastric mucosa." Gut 59(7): 874-81.