Human and Helicobacter pylori Interactions Determine the Outcome of Gastric Diseases

Abstract

The innate immune response is a critical hallmark of Helicobacter pylori infection. Epithelial and myeloid cells produce effectors, including the chemokine CXCL8, reactive oxygen species (ROS), and nitric oxide (NO), in response to bacterial components. Mechanistic and epidemiologic studies have emphasized that dysregulated and persistent release of these products leads to the development of chronic inflammation and to the molecular and cellular events related to carcinogenesis. Moreover, investigations in H. pylori-infected patients about polymorphisms of the genes encoding CXCL8 and inducible NO synthase, and epigenetic control of the ROS-producing enzyme spermine oxidase, have further proven that overproduction of these molecules impacts the severity of gastric diseases. Lastly, the critical effect of the crosstalk between the human host and the infecting bacterium in determining the severity of H. pylori-related diseases has been supported by phylogenetic analysis of the human population and their H. pylori isolates in geographic areas with varying clinical and pathologic outcomes of the infection.

Keywords: Chemokine; Coevolution; Nitric oxide; Reactive oxygen species.

Fig. 2.1

Hypothetical model for CXCL8-mediated gastric carcinogenesis. Gastric epithelial cells and macrophages produce CXCL8 (also referred to as IL-8) in response to different H. pylori factors; VacA, urease, and JHP940 have been shown to stimulate macrophages, whereas the T4SS-dependent injection of CagA or peptidoglycan (PG) have been involved in epithelial cell activation. CXCL8 chemoattracts PMNs and T cells to infiltrate to the site of infection and activates immune cells, thus favoring a persistent inflammatory state. Moreover, CXCL8 stimulates epithelial-mesenchymal transition (EMT) and angiogenesis. These events may contribute to H. pylori carcinogenesis. Lastly, tumor cells also produce CXCL8, further potentiating gastric cancer development.

Fig. 2.2

Structure, function, and cellular localization of the two NADPH complexes, NOX1 and NOX2, and SMOX. The type of gastric cells in which these enzymes have been detected during H. pylori infection is indicated in the boxes.

Fig. 2.3

A hypothesis to resolve the so-called Colombian enigma. The African strains (AA1 phylogenetic group) belonging to the low risk (LR) region induce less CXCL8 than European strains (AE2) of the high risk (HR) region. The methylation (Me, methyl) of the miR-124 gene is greater in gastric tissues from the HR vs. LR region; therefore miR-124 is less expressed and SMOX protein more translated in subjects from the HR region. Moreover, individuals with an African ancestry infected with AA1 isolates have less risk for developing more advanced gastric lesions than Amerindians infected with AE2 H. pylori strains.