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Pritchard, D. M.

Publications and source records attributed to Pritchard, D. M..

2 recordsLinked to original sources
bioRxiv2017

Comparison Of The Human Gastric Microbiota In Hypochlorhydric States Arising As A Result Of Helicobacter pylori-Induced Atrophic Gastritis, Autoimmune Atrophic Gastritis And Proton Pump Inhibitor Use

ObjectiveSeveral conditions associated with reduced gastric acid secretion confer an altered risk of developing a gastric malignancy. Helicobacter pylori-induced atrophic gastritis predisposes to gastric adenocarcinoma, autoimmune atrophic gastritis is a precursor of type I gastric neuroendocrine tumours, whereas proton pump inhibitor (PPI) use does not affect stomach cancer risk. We hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota and that this influenced subsequent tumour risk.\n\nDesign95 patients (in groups representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis and autoimmune atrophic gastritis) were selected from a cohort of 1400. RNA extracted from gastric corpus biopsies was analysed using 16S rRNA sequencing (MiSeq).\n\nResultsSamples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. Patients with autoimmune atrophic gastritis also exhibited relatively high microbial diversity, but with samples dominated by Streptococcus. H. pylori colonisation was associated with decreased microbial diversity and reduced complexity of co-occurrence networks. H. pylori-induced atrophic gastritis resulted in lower bacterial abundances and diversity, whereas autoimmune atrophic gastritis resulted in greater bacterial abundance and equally high diversity compared to normal stomachs. Pathway analysis suggested that glucose-6-phospahte1-dehydrogenase and D-lactate dehydrogenase were over represented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase.\n\nConclusionAutoimmune and H. pylori-induced atrophic gastritis were associated with different gastric microbial profiles. PPI treated patients showed relatively few alterations in the gastric microbiota compared to healthy subjects.\n\nSIGNIFICANCE OF THIS STUDY 1. What is already known about this subject?O_LISome conditions which result in reduced gastric acid secretion and hypochlorhydria are associated with an increased risk of gastric tumourigenesis.\nC_LIO_LIThis risk is different in patients with H. pylori-induced atrophic gastritis, autoimmune atrophic gastritis and chronic proton pump inhibitor use.\nC_LIO_LIHypochlorhydria and H. pylori infection cause alterations in the composition of the gastric microbiota.\nC_LI\n\n2. What are the new findings?O_LIWe used 16S rRNA sequencing to characterise the microbiota in gastric corpus biopsies from a well characterised cohort of patients.\nC_LIO_LIThe gastric microbiota was different in patients who were hypochlorhydric as a result of H. pylori-induced atrophic gastritis, autoimmune atrophic gastritis and proton pump inhibitor use.\nC_LIO_LIBiochemical pathways associated with gastric carcinogenesis such as the fumarate reductase pathway were predicted to be altered in patients with atrophic gastritis.\nC_LI\n\n3. How might it impact on clinical practice in the foreseeable future?O_LIUnderstanding how the microbiota that colonise the hypochlorhydric stomach influence gastric carcinogenesis may ultimately permit stratification of patients subsequent tumour risk.\nC_LIO_LIInterventions that alter the composition of the gastric microbiome in hypochlorhydric patients with atrophic gastritis should be tested to investigate whether they alter the subsequent risk of developing gastric malignancy.\nC_LI

microbiology↗
bioRxiv2017

Mice lacking NF-κB1 exhibit marked DNA damage responses and more severe gastric pathology in response to parenteral tamoxifen administration.

BackgroundTamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-{kappa}B subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-{kappa}B subunits.\n\nMethodsGroups of 5 female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150mg/kg TAM by IP injection. 72 hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of 6 female WT and Nfkb1-/- mice were exposed to 12Gy {gamma}-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 hours after irradiation.\n\nResultsTAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by {gamma}H2AX. To determine investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to TAM induced DNA damage, or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following {gamma}-irradiation. 6 hours after {gamma}-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice.\n\nConclusionsNF-{kappa}B1 mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage.

immunology↗