Hydrogen Metabolism in Helicobacter pylori Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation

Author:

Wang Ge1,Romero-Gallo Judith2,Benoit Stéphane L.1,Piazuelo M. Blanca2,Dominguez Ricardo L.3,Morgan Douglas R.2,Peek Richard M.24,Maier Robert J.1

Affiliation:

1. Department of Microbiology, University of Georgia, Athens, Georgia, USA

2. Division of Gastroenterology, Department of Medicine, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

3. Hospital de Occidente, Ministry of Health, Santa Rosa de Copan, Honduras

4. Departments of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Abstract

ABSTRACT A known virulence factor of Helicobacter pylori that augments gastric cancer risk is the CagA cytotoxin. A carcinogenic derivative strain, 7.13, that has a greater ability to translocate CagA exhibits much higher hydrogenase activity than its parent noncarcinogenic strain, B128. A Δ hyd mutant strain with deletion of hydrogenase genes was ineffective in CagA translocation into human gastric epithelial AGS cells, while no significant attenuation of cell adhesion was observed. The quinone reductase inhibitor 2- n -heptyl-4-hydroxyquinoline- N -oxide (HQNO) was used to specifically inhibit the H 2 -utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H 2 -generated transmembrane potential is a contributor to toxin translocation. The Δ hyd strain showed a decreased frequency of DNA transformation, suggesting that H. pylori hydrogenase is also involved in energizing the DNA uptake apparatus. In a gerbil model of infection, the ability of the Δ hyd strain to induce inflammation was significantly attenuated (at 12 weeks postinoculation), while all of the gerbils infected with the parent strain (7.13) exhibited a high level of inflammation. Gastric cancer developed in 50% of gerbils infected with the wild-type strain 7.13 but in none of the animals infected with the Δ hyd strain. By examining the hydrogenase activities from well-defined clinical H. pylori isolates, we observed that strains isolated from cancer patients ( n = 6) have a significantly higher hydrogenase (H 2 /O 2 ) activity than the strains isolated from gastritis patients ( n = 6), further supporting an association between H. pylori hydrogenase activity and gastric carcinogenesis in humans. IMPORTANCE Hydrogen-utilizing hydrogenases are known to be important for some respiratory pathogens to colonize hosts. Here a gastric cancer connection is made via a pathogen’s ( H. pylori ) use of molecular hydrogen, a host microbiome-produced gas. Delivery of the known carcinogenic factor CagA into host cells is augmented by the H 2 -utilizing respiratory chain of the bacterium. The role of hydrogenase in carcinogenesis is demonstrated in an animal model, whereby inflammation markers and cancer development were attenuated in the hydrogenase-null strain. Hydrogenase activity comparisons of clinical strains of the pathogen also support a connection between hydrogen metabolism and gastric cancer risk. While molecular hydrogen use is acknowledged to be an alternative high-energy substrate for some pathogens, this work extends the roles of H 2 oxidation to include transport of a carcinogenic toxin. The work provides a new avenue for exploratory treatment of some cancers via microflora alterations.

Funder

University of Georgia Research Foundation

Publisher

American Society for Microbiology

Subject

Virology,Microbiology

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