Hydrogen Metabolism in <named-content content-type="genus-species">Helicobacter pylori</named-content> Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation

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 Δhyd muta...

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Autores principales:	Ge Wang, Judith Romero-Gallo, Stéphane L. Benoit, M. Blanca Piazuelo, Ricardo L. Dominguez, Douglas R. Morgan, Richard M. Peek, Robert J. Maier
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0bd3243815314c17a2bcffe12026516b
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spelling	oai:doaj.org-article:0bd3243815314c17a2bcffe12026516b2021-11-15T15:50:18ZHydrogen Metabolism in <named-content content-type="genus-species">Helicobacter pylori</named-content> Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation10.1128/mBio.01022-162150-7511https://doaj.org/article/0bd3243815314c17a2bcffe12026516b2016-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01022-16https://doaj.org/toc/2150-7511ABSTRACT 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.Ge WangJudith Romero-GalloStéphane L. BenoitM. Blanca PiazueloRicardo L. DominguezDouglas R. MorganRichard M. PeekRobert J. MaierAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 4 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Ge Wang Judith Romero-Gallo Stéphane L. Benoit M. Blanca Piazuelo Ricardo L. Dominguez Douglas R. Morgan Richard M. Peek Robert J. Maier Hydrogen Metabolism in <named-content content-type="genus-species">Helicobacter pylori</named-content> Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation
description	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 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.
format	article
author	Ge Wang Judith Romero-Gallo Stéphane L. Benoit M. Blanca Piazuelo Ricardo L. Dominguez Douglas R. Morgan Richard M. Peek Robert J. Maier
author_facet	Ge Wang Judith Romero-Gallo Stéphane L. Benoit M. Blanca Piazuelo Ricardo L. Dominguez Douglas R. Morgan Richard M. Peek Robert J. Maier
author_sort	Ge Wang
title	Hydrogen Metabolism in <named-content content-type="genus-species">Helicobacter pylori</named-content> Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation
title_short	Hydrogen Metabolism in <named-content content-type="genus-species">Helicobacter pylori</named-content> Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation
title_full	Hydrogen Metabolism in <named-content content-type="genus-species">Helicobacter pylori</named-content> Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation
title_fullStr	Hydrogen Metabolism in <named-content content-type="genus-species">Helicobacter pylori</named-content> Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation
title_full_unstemmed	Hydrogen Metabolism in <named-content content-type="genus-species">Helicobacter pylori</named-content> Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation
title_sort	hydrogen metabolism in <named-content content-type="genus-species">helicobacter pylori</named-content> plays a role in gastric carcinogenesis through facilitating caga translocation
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/0bd3243815314c17a2bcffe12026516b
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Hydrogen Metabolism in <named-content content-type="genus-species">Helicobacter pylori</named-content> Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation

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