Modification of the Gastric Mucosal Microbiota by a Strain-Specific <named-content content-type="genus-species">Helicobacter pylori</named-content> Oncoprotein and Carcinogenic Histologic Phenotype
ABSTRACT Helicobacter 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....
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2019-06-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00955-19 |
| _version_ | 1819004426607656960 |
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| author | Jennifer M. Noto Joseph P. Zackular Matthew G. Varga Alberto Delgado Judith Romero-Gallo Matthew B. Scholz M. Blanca Piazuelo Eric P. Skaar Richard M. Peek |
| author_facet | Jennifer M. Noto Joseph P. Zackular Matthew G. Varga Alberto Delgado Judith Romero-Gallo Matthew B. Scholz M. Blanca Piazuelo Eric P. Skaar Richard M. Peek |
| author_sort | Jennifer M. Noto |
| collection | DOAJ |
| description | ABSTRACT Helicobacter 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 α-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 α- or β-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 α- and β-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. |
| first_indexed | 2024-12-20T23:36:43Z |
| format | Article |
| id | doaj.art-4e1d7e064e0343d7a2ef53ea353bd1c7 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-20T23:36:43Z |
| publishDate | 2019-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-4e1d7e064e0343d7a2ef53ea353bd1c72022-12-21T19:23:11ZengAmerican Society for MicrobiologymBio2150-75112019-06-0110310.1128/mBio.00955-19Modification of the Gastric Mucosal Microbiota by a Strain-Specific <named-content content-type="genus-species">Helicobacter pylori</named-content> Oncoprotein and Carcinogenic Histologic PhenotypeJennifer M. Noto0Joseph P. Zackular1Matthew G. Varga2Alberto Delgado3Judith Romero-Gallo4Matthew B. Scholz5M. Blanca Piazuelo6Eric P. Skaar7Richard M. Peek8Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USADepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USADepartment of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, USADivision of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USADivision of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USAVanderbilt Technologies for Advanced Genomics, Vanderbilt University Medical Center, Nashville, Tennessee, USADivision of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USADepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USADivision of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USAABSTRACT Helicobacter 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 α-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 α- or β-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 α- and β-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.https://journals.asm.org/doi/10.1128/mBio.00955-19CagAHelicobacter pylorigastric cancergastric microbiotairon deficiency |
| spellingShingle | Jennifer M. Noto Joseph P. Zackular Matthew G. Varga Alberto Delgado Judith Romero-Gallo Matthew B. Scholz M. Blanca Piazuelo Eric P. Skaar Richard M. Peek Modification of the Gastric Mucosal Microbiota by a Strain-Specific <named-content content-type="genus-species">Helicobacter pylori</named-content> Oncoprotein and Carcinogenic Histologic Phenotype mBio CagA Helicobacter pylori gastric cancer gastric microbiota iron deficiency |
| title | Modification of the Gastric Mucosal Microbiota by a Strain-Specific <named-content content-type="genus-species">Helicobacter pylori</named-content> Oncoprotein and Carcinogenic Histologic Phenotype |
| title_full | Modification of the Gastric Mucosal Microbiota by a Strain-Specific <named-content content-type="genus-species">Helicobacter pylori</named-content> Oncoprotein and Carcinogenic Histologic Phenotype |
| title_fullStr | Modification of the Gastric Mucosal Microbiota by a Strain-Specific <named-content content-type="genus-species">Helicobacter pylori</named-content> Oncoprotein and Carcinogenic Histologic Phenotype |
| title_full_unstemmed | Modification of the Gastric Mucosal Microbiota by a Strain-Specific <named-content content-type="genus-species">Helicobacter pylori</named-content> Oncoprotein and Carcinogenic Histologic Phenotype |
| title_short | Modification of the Gastric Mucosal Microbiota by a Strain-Specific <named-content content-type="genus-species">Helicobacter pylori</named-content> Oncoprotein and Carcinogenic Histologic Phenotype |
| title_sort | modification of the gastric mucosal microbiota by a strain specific named content content type genus species helicobacter pylori named content oncoprotein and carcinogenic histologic phenotype |
| topic | CagA Helicobacter pylori gastric cancer gastric microbiota iron deficiency |
| url | https://journals.asm.org/doi/10.1128/mBio.00955-19 |
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