Glycophenotypic Alterations Induced by Pteridium aquilinum in Mice Gastric Mucosa: Synergistic Effect with Helicobacter pylori Infection

The bracken fern Pteridium aquilinum is a plant known to be carcinogenic to animals. Epidemiological studies have shown an association between bracken fern exposure and gastric cancer development in humans. The biological effects of exposure to this plant within the gastric carcinogenesis process are not fully understood. In the present work, effects in the gastric mucosa of mice treated with Pteridium aquilinum were evaluated, as well as molecular mechanisms underlying the synergistic role with Helicobacter pylori infection. Our results showed that exposure to Pteridium aquilinum induces histomorphological modifications including increased expression of acidic glycoconjugates in the gastric mucosa. The transcriptome analysis of gastric mucosa showed that upon exposure to Pteridium aquilinum several glycosyltransferase genes were differently expressed, including Galntl4, C1galt1 and St3gal2, that are mainly involved in the biosynthesis of simple mucin-type carbohydrate antigens. Concomitant treatment with Pteridium aquilinum and infection with Helicobacter pylori also resulted in differently expressed glycosyltransferase genes underlying the biosynthesis of terminal sialylated Lewis antigens, including Sialyl-Lewisx. These results disclose the molecular basis for the altered pattern of glycan structures observed in the mice gastric mucosa. The gene transcription alterations and the induced glycophenotypic changes observed in the gastric mucosa contribute for the understanding of the molecular mechanisms underlying the role of Pteridium aquilinum in the gastric carcinogenesis process

Docosahexaenoic acid inhibits Helicobacter pylori growth in vitro and mice gastric mucosa colonization

H. pylori drug-resistant strains and non-compliance to therapy are the major causes of H. pylori eradication failure. For some bacterial species it has been demonstrated that fatty acids have a growth inhibitory effect. Our main aim was to assess the ability of docosahexaenoic acid (DHA) to inhibit H. pylori growth both in vitro and in a mouse model. The effectiveness of standard therapy (ST) in combination with DHA on H. pylori eradication and recurrence prevention success was also investigated. The effects of DHA on H. pylori growth were analyzed in an in vitro dose-response study and n in vivo model. We analized the ability of H. pylori to colonize mice gastric mucosa following DHA, ST or a combination of both treatments. Our data demonstrate that DHA decreases H. pylori growth in vitro in a dose-dependent manner. Furthermore, DHA inhibits H. pylori gastric colonization in vivo as well as decreases mouse gastric mucosa inflammation. Addition of DHA to ST was also associated with lower H. pylori infection recurrence in the mouse model. In conclusion, DHA is an inhibitor of H. pylori growth and its ability to colonize mouse stomach. DHA treatment is also associated with a lower recurrence of H. pylori infection in combination with ST. These observations pave the way to consider DHA as an adjunct agent in H. pylori eradication treatment.publishe

La phosphatase acide de pH optimum 2,5 d'Escherichia coli : un systeme pour l'etude des effets negatifs de l'AMP cyclique

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

When bacteria become mutagenic and carcinogenic: Lessons from H. pylori

International audienceMore and more convincing data link bacteria to the development of cancers. How bacteria act as mutagens by altering host genomes, what are the different strategies they develop and what consequences do they have on infection-associated pathogenesis are the main questions addressed in this review, which focuses in particular on Helicobacter pylori infection. H. pylori is a major risk factor for gastric cancer development. Its oncogenic role is mediated by the chronic active inflammation it elicits in the gastric mucosa, associated with its capacity to persistently colonize the human stomach. However, direct genotoxicity of H. pylori through the action of bacterial cytotoxin or resulting from a DNA damaging effect of its metabolic derivatives as nitroso compounds cannot be excluded. Numerous studies have investigated inflammation-associated DNA damaging activity and mutagenic response due to H. pylori infection in both human and animal models. Recent findings on its mutagenic effects at the nuclear and mitochondrial genome and related DNA damage are reviewed. This genotoxic activity associated with oxidative species produced during inflammation is linked to the decreased efficiency of DNA repair systems. DNA methylation, which plays an important role in the regulation of the host response to H. pylori infection, is also documented. Furthermore, H. pylori affects genome integrity by increasing activation-induced cytidine deaminase (AID), a DNA/RNA editing cytidine deaminase linking mutagenesis and tumorigenesis. These different strategies occurring during bacteria–host cell interaction, lead to nucleotide modifications and genome instabilities recognized as early events in the carcinogenesis process and contribute to the oncogenic properties of H. pylori infection

Les nitrofuranes (place en thérapeutique, mutagénèse et application dans un modèle de souris transgéniques lacI/cII)

PARIS-BIUP (751062107) / SudocSudocFranceF

Mitochondrial Function in Health and Disease: Responses to Helicobacter pylori Metabolism and Impact in Gastric Cancer Development

International audienceMitochondria are major cellular organelles that play an essential role in metabolism, stress response, immunity, and cell fate. Mitochondria are organized in a network with other cellular compartments, functioning as a signaling hub to maintain cell´s health. Mitochondrial dysfunctions and genome alterations are associated with diseases including cancer. Mitochondria are a preferential target for pathogens, which have developed various mechanisms to hijack cellular functions for their benefit. Helicobacter pylori (H. pylori) is recognized as the major risk factor for gastric cancer. H. pylori induces oxidative stress and chronic gastric inflammation with mitochondrial dysfunction. Its pro-apoptotic cytotoxin VacA interacts with the mitochondrial inner membrane, leading to increased permeability and decreased ATP production. Furthermore, H. pylori induces mitochondrial DNA damage and mutation, concomitant with the development of gastric intraepithelial neoplasia as observed in infected mice. In this chapter, we present diverse aspects of the role of mitochondria as energy supplier and signaling hub and their adaptation to stress conditions. The metabolic activity of mitochondria is directly linked to biosynthetic pathways. Whereas H. pylori virulence factors and derived metabolites are essential for gastric colonization and niche adaptation, they may also impact mitochondrial function and metabolism, and may have consequences in gastric pathogenesis. Importantly, during its long way to reach the gastric epithelium, H. pylori faces various cellular types along the gastric mucosa. We discuss how the mitochondrial response of these different cells is affected by H. pylori and impacts the colonization and bacterium niche adaptation and point to areas that remain to be investigated

Membrane-lipids anti-bacterial and anti-tumoral therapies revisited: an example with Helicobacter pylori infection.

International audienc

Pathogenesis of Helicobacter pylori infection

International audienceThe original strategies developed by Helicobacter pylori to persistently colonise its host and to deregulate its cellular functions make this bacterium an outstanding model to study host-pathogen interaction and the mechanisms responsible for bacterial-induced carcinogenesis. During the last year, significant results were obtained on the role of bacterial factors essential for gastric colonisation such as spiral shape maintenance, orientation through chemotaxis and the formation of bacteria clonal population islands inside the gastric glands. Particularities of the H pylori cell surface, a structure important for immune escape, were demonstrated. New insights in the bacterial stress response revealed the importance of DNA methylation-mediated regulation. Further findings were reported on H pylori components that mediate natural transformation and mechanisms of bacterial DNA horizontal transfer which maintain a high level of H pylori genetic variability. Within-host evolution was found to be niche-specific and probably associated with physiological differences between the antral and oxyntic gastric mucosa.In addition, with the progress of CryoEM, high-resolution structures of the major virulence factors, VacA and CagT4SS, were obtained. The use of gastric organoid models fostered research revealing, preferential accumulation of bacteria at the site of injury during infection. Several studies further characterised the role of CagA in the oncogenic properties of H pylori, identifying the activation of novel CagA-dependent pathways, leading to the promotion of genetic instabilities, epithelial-to-mesenchymal transition and finally carcinogenesis. Recent studies also highlight that microRNA-mediated regulation and epigenetic modifications, through DNA methylation, are key events in the H pylori-induced tumorigenesis process

Biomarqueurs sanguins des lésions gastriques pré-néoplasiques

National audienceCurrently, gastric pre-neoplastic lesions (glandular atrophy, intestinal metaplasia, dysplasia) can only be detected during an upper GI endoscopy. Depending on their extent and severity, follow-up is proposed in order to detect the appearance of gastric adenocarcinoma as early as possible. When there is no indication for endoscopy, pre-neoplastic lesions may be present and evolve silently. In countries with a low risk of gastric cancer such as France, where there is no systematic endoscopic screening, patients not at high risk of gastric adenocarcinoma in whom pre-neoplastic lesions exist therefore have a loss of chance with a risk of developing gastric adenocarcinoma at a symptomatic stage, with a poor prognosis. Several serum biomarkers of pre-neoplastic lesions have been proposed, deriving from the histological characteristics of these lesions. The TFF3 peptide is a biomarker of intestinal metaplasia, and the pepsinogen I/II ratio of glandular atrophy. The place of these biomarkers in a national screening strategy remains to be clarified.Les lésions pré-néoplasiques gastriques (atrophie glandulaire, métaplasie intestinale, dysplasie) ne peuvent être détectées que lors d’une endoscopie œso-gastro-duodénale. En fonction de leur étendue et de leur sévérité, une surveillance est proposée, afin de détecter le plus précocement possible l’apparition d’un adénocarcinome gastrique. Lorsqu’il n’existe pas d’indication d’endoscopie, les lésions pré-néoplasiques peuvent être présentes et évoluer silencieusement. Dans les pays à bas risque de cancer gastrique comme la France, où il n’existe pas de dépistage endoscopique systématique, les patients non à haut risque d’adénocarcinome gastrique chez qui des lésions pré-néoplasiques existent ont donc une perte de chance avec un risque de développer un adénocarcinome gastrique à un stade symptomatique, de mauvais pronostic. Plusieurs biomarqueurs sériques des lésions pré-néoplasiques ont été proposés, dérivant des caractéristiques histologiques de ces lésions. Le peptide TFF3 est un biomarqueur de métaplasie intestinale, et le ratio pepsinogène I/II d’atrophie glandulaire. La place de ces biomarqueurs dans une stratégie nationale de dépistage reste à préciser