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Modification of the Gastric Mucosal Microbiota by a Strain-Specific Helicobacter pylori Oncoprotein and Carcinogenic Histologic Phenotype

dc.contributor.authorNoto, Jennifer M.
dc.contributor.authorZackular, Joseph P.
dc.contributor.authorVarga, Matthew G.
dc.contributor.authorDelgado, Alberto
dc.contributor.authorRomero-Gallo, Judith
dc.contributor.authorScholz, Matthew B.
dc.contributor.authorPiazuelo, M. Blanca
dc.contributor.authorSkaar, Eric P.
dc.contributor.authorPeek, Richard M., Jr.
dc.identifier.citationNoto JM, Zackular JP, Varga MG,Delgado A, Romero-Gallo J, Scholz MB,Piazuelo MB, Skaar EP, Peek RM, Jr. 2019.Modification of the gastric mucosal microbiotaby a strain-specificHelicobacter pylorioncoprotein and carcinogenic histologicphenotype. mBio 10:e00955-19.
dc.description.abstractHelicobacter pylori is the strongest risk factor for gastric adenocarcinoma; however, most infected individuals never develop this malignancy. Strain-specific microbial factors, such as the oncoprotein CagA, as well as environmental conditions, such as iron deficiency, augment cancer risk. Importantly, dysbiosis of the gastric microbiota is also associated with gastric cancer. To investigate the combinatorial effects of these determinants in an in vivo model of gastric cancer, Mongolian gerbils were infected with the carcinogenic cag(+) H. pylori strain 7.13 or a 7.13 cagA isogenic mutant, and microbial DNA extracted from gastric tissue was analyzed by 16S rRNA sequencing. Infection with H. pylori significantly increased gastric inflammation and injury, decreased alpha-diversity, and altered microbial community structure in a cagA-dependent manner. The effect of iron deficiency on gastric microbial communities was also investigated within the context of infection. H. pylori-induced injury was augmented under conditions of iron deficiency, but despite differences in gastric pathology, there were no significant differences in alpha- or beta-diversity, phyla, or operational taxonomic unit (OTU) abundance among infected gerbils maintained on iron-replete or iron-depleted diets. However, when microbial composition was stratified based solely on the severity of histologic injury, significant differences in alpha- and beta-diversity were present among gerbils harboring premalignant or malignant lesions compared to gerbils with gastritis alone. This study demonstrates that H. pylori decreases gastric microbial diversity and community structure in a cagA-dependent manner and that as carcinogenesis progresses, there are corresponding alterations in community structure that parallel the severity of disease. IMPORTANCE Microbial communities are essential for the maintenance of human health, and when these communities are altered, hosts can become susceptible to inflammation and disease. Dysbiosis contributes to gastrointestinal cancers, and specific bacterial species are associated with this phenotype. This study uses a robust and reproducible animal model to demonstrate that H. pylori infection induces gastric dysbiosis in a cagA-dependent manner and further that dysbiosis and altered microbial community structure parallel the severity of H. pylori-induced gastric injury. Ultimately, such models of H. pylori infection and cancer that can effectively evaluate multiple determinants simultaneously may yield effective strategies for manipulating the gastric microbiota to prevent the development of gastric cancer.en_US
dc.description.sponsorshipWe acknowledge the following funding sources through the National Institutes of Health: F32 AI120553 (J.P.Z.), K22 AI7220 (J.P.Z.), T32 CA057726 (M.G.V.), R01 AI101171 (E.P.S.), R01 AI069233 (E.P.S.), R01 AI069233 (E.P.S.), R01 AI138581 (E.P.S.), R01 CA077955 (R.M.P.), R01 DK058587 (R.M.P.), P30 DK058404 (R.M.P.), and P01 CA116087 (R.M.P.).en_US
dc.rightsThis is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. You are not required to obtain permission to reuse this article.
dc.subjectHelicobacter pylorien_US
dc.subjectgastric canceren_US
dc.subjectgastric microbiotaen_US
dc.subjectiron deficiencyen_US
dc.subjectbacterial microbiotaen_US
dc.subjectmongolian gerbilsen_US
dc.subjectserum ferritinen_US
dc.subjectDNA damageen_US
dc.subject.lcshHelicobacter pylorien_US
dc.titleModification of the Gastric Mucosal Microbiota by a Strain-Specific Helicobacter pylori Oncoprotein and Carcinogenic Histologic Phenotypeen_US

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