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 Δhyd 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 H2-utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H2-generated transmembrane potential is a contributor to toxin translocation. The Δhyd 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 Δhyd 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 Δhyd 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 (H2/O2) 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 H2-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 H2 oxidation to include transport of a carcinogenic toxin. The work provides a new avenue for exploratory treatment of some
cancers via microflora alterations.