Effects of a Potential Probiotic Strain Lactobacillus gasseri ATCC 33323 on Helicobacter pylori-Induced Inflammatory Response and Gene Expression in Coinfected Gastric Epithelial Cells

ABSTRACT Helicobacter pylori is a bacterial pathogen that colonizes the human stomach, causing inflammation which, in some cases, leads to gastric ulcers and cancer. The clinical outcome of infection depends on a complex interplay of bacterial, host genetic, and environmental factors. Although H. pylori is recognized by both the innate and adaptive immune systems, this rarely results in bacterial clearance. Gastric epithelial cells are the first line of defense against H. pylori and alert the immune system to bacterial presence. Cytosolic delivery of proinflammatory bacterial factors through the cag type 4 secretion system ( cag -T4SS) has long been appreciated as the major mechanism by which gastric epithelial cells detect H. pylori . Classically attributed to the peptidoglycan sensor NOD1, recent work has highlighted the role of NOD1-independent pathways in detecting H. pylori ; however, the bacterial and host factors involved have remained unknown. Here, we show that bacterially derived heptose-1,7-bisphosphate (HBP), a metabolic precursor in lipopolysaccharide (LPS) biosynthesis, is delivered to the host cytosol through the cag -T4SS, where it activates the host tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA)-dependent cytosolic surveillance pathway. This response, which is independent of NOD1, drives robust NF-κB-dependent inflammation within hours of infection and precedes NOD1 activation. We also found that the CagA toxin contributes to the NF-κB-driven response subsequent to TIFA and NOD1 activation. Taken together, our results indicate that the sequential activation of TIFA, NOD1, and CagA delivery drives the initial inflammatory response in gastric epithelial cells, orchestrating the subsequent recruitment of immune cells and leading to chronic gastritis. IMPORTANCE H. pylori is a globally prevalent cause of gastric and duodenal ulcers and cancer. H. pylori antibiotic resistance is rapidly increasing, and a vaccine remains elusive. The earliest immune response to H. pylori is initiated by gastric epithelial cells and sets the stage for the subsequent immunopathogenesis. This study revealed that host TIFA and H. pylori -derived HBP are critical effectors of innate immune signaling that account for much of the inflammatory response to H. pylori in gastric epithelial cells. HBP is delivered to the host cell via the cag -T4SS at a time point that precedes activation of the previously described NOD1 and CagA inflammatory pathways. Manipulation of the TIFA-driven immune response in the host and/or targeting of ADP-heptose biosynthesis enzymes in H. pylori may therefore provide novel strategies that may be therapeutically harnessed to achieve bacterial clearance.

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Helicobacter pylori infection increases sirt2 gene expression in gastric epithelial cells of gastritis patients

Microbial Pathogenesis ◽

10.1016/j.micpath.2017.12.078 ◽

2018 ◽

Vol 116 ◽

pp. 120-123 ◽

Cited By ~ 6

Author(s):

Seiran Zandi ◽

Manouchehr A. Hedayati ◽

Ebrahim Mohammadi ◽

Farshad Sheikhesmaeili

Keyword(s):

Gene Expression ◽

Helicobacter Pylori ◽

Epithelial Cells ◽

Helicobacter Pylori Infection ◽

Gastric Epithelial Cells ◽

Sirt2 Gene

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Inhibitory Effect of β-Carotene on Helicobacter pylori-Induced TRAF Expression and Hyper-Proliferation in Gastric Epithelial Cells

Antioxidants ◽

10.3390/antiox8120637 ◽

2019 ◽

Vol 8 (12) ◽

pp. 637 ◽

Cited By ~ 2

Author(s):

Yongchae Park ◽

Hanbit Lee ◽

Joo Weon Lim ◽

Hyeyoung Kim

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Helicobacter Pylori ◽

Epithelial Cells ◽

Nadph Oxidase ◽

Gastric Epithelial Cells ◽

Gastric Cancer Cells ◽

Ags Cells ◽

H Pylori ◽

Β Carotene

Helicobacter pylori infection causes the hyper-proliferation of gastric epithelial cells that leads to the development of gastric cancer. Overexpression of tumor necrosis factor receptor associated factor (TRAF) is shown in gastric cancer cells. The dietary antioxidant β-carotene has been shown to counter hyper-proliferation in H. pylori-infected gastric epithelial cells. The present study was carried out to examine the β-carotene mechanism of action. We first showed that H. pylori infection decreases cellular IκBα levels while increasing cell viability, NADPH oxidase activity, reactive oxygen species production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, and TRAF1 and TRAF2 gene expression, as well as protein–protein interaction in gastric epithelial AGS cells. We then demonstrated that pretreatment of cells with β-carotene significantly attenuates these effects. Our findings support the proposal that β-carotene has anti-cancer activity by reducing NADPH oxidase-mediated production of ROS, NF-κB activation and NF-κB-regulated TRAF1 and TRAF2 gene expression, and hyper-proliferation in AGS cells. We suggest that the consumption of β-carotene-enriched foods could decrease the incidence of H. pylori-associated gastric disorders.

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Helicobacter pylori-Induced Histone Modification, Associated Gene Expression in Gastric Epithelial Cells, and Its Implication in Pathogenesis

PLoS ONE ◽

10.1371/journal.pone.0009875 ◽

2010 ◽

Vol 5 (4) ◽

pp. e9875 ◽

Cited By ~ 59

Author(s):

Song-Ze Ding ◽

Wolfgang Fischer ◽

Maria Kaparakis-Liaskos ◽

George Liechti ◽

D. Scott Merrell ◽

...

Keyword(s):

Gene Expression ◽

Helicobacter Pylori ◽

Epithelial Cells ◽

Histone Modification ◽

Gastric Epithelial Cells

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Effect of rebamipide on gene expression in gastric epithelial cells induced by Helicobacter pylori water extract

Gastroenterology ◽

10.1016/s0016-5085(03)83000-7 ◽

2003 ◽

Vol 124 (4) ◽

pp. A592

Author(s):

Norimasa Yoshida ◽

Takeshi Ishikawa ◽

Eiichiro Ichiisi ◽

Masasi Kuchide ◽

Kazuhiko Uchiyama ◽

...

Keyword(s):

Gene Expression ◽

Helicobacter Pylori ◽

Epithelial Cells ◽

Water Extract ◽

Gastric Epithelial Cells

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Phylogeographic Origin of Helicobacter pylori Determines Host-Adaptive Responses upon Coculture with Gastric Epithelial Cells

Infection and Immunity ◽

10.1128/iai.01182-12 ◽

2013 ◽

Vol 81 (7) ◽

pp. 2468-2477 ◽

Cited By ~ 16

Author(s):

Alexander Sheh ◽

Rupesh Chaturvedi ◽

D. Scott Merrell ◽

Pelayo Correa ◽

Keith T. Wilson ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Helicobacter Pylori ◽

Epithelial Cells ◽

Gastric Disease ◽

Gastric Epithelial Cells ◽

Gastric Cancer Risk ◽

Content Type ◽

H Pylori ◽

Induced Apoptosis

ABSTRACTWhileHelicobacter pyloriinfects over 50% of the world's population, the mechanisms involved in the development of gastric disease are not fully understood. Bacterial, host, and environmental factors play a role in disease outcome. To investigate the role of bacterial factors inH. pyloripathogenesis, global gene expression of sixH. pyloriisolates was analyzed during coculture with gastric epithelial cells. Clustering analysis of six Colombian clinical isolates from a region with low gastric cancer risk and a region with high gastric cancer risk segregated strains based on their phylogeographic origin. One hundred forty-six genes had increased expression in European strains, while 350 genes had increased expression in African strains. Differential expression was observed in genes associated with motility, pathogenicity, and other adaptations to the host environment. European strains had greater expression of the virulence factorscagA,vacA, andbabBand were associated with increased gastric histologic lesions in patients. In AGS cells, European strains promoted significantly higher interleukin-8 (IL-8) expression than did African strains. African strains significantly induced apoptosis, whereas only one European strain significantly induced apoptosis. Our data suggest that gene expression profiles of clinical isolates can discriminate strains by phylogeographic origin and that these profiles are associated with changes in expression of the proinflammatory and protumorigenic cytokine IL-8 and levels of apoptosis in host epithelial cells. These findings support the hypothesis that bacterial factors determined by the phylogeographic origin ofH. pyloristrains may promote increased gastric disease.

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Inhibition of Helicobacter pylori-induced Nuclear Factor-kappa B Activation and Interleukin-8 Gene Expression by Ecabet Sodium in Gastric Epithelial Cells

Helicobacter ◽

10.1046/j.1523-5378.2003.00175.x ◽

2003 ◽

Vol 8 (5) ◽

pp. 542-553 ◽

Cited By ~ 17

Author(s):

Jung Mogg Kim ◽

Joo Sung Kim ◽

Hyun Chae Jung ◽

Yu-Kyoung Oh ◽

Nayoung Kim ◽

...

Keyword(s):

Gene Expression ◽

Helicobacter Pylori ◽

Epithelial Cells ◽

Nuclear Factor Kappa B ◽

Interleukin 8 ◽

Nuclear Factor ◽

Gastric Epithelial Cells ◽

Ecabet Sodium ◽

Nuclear Factor Kappa

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Chemokines and Antimicrobial Peptides Have acag-Dependent Early Response to Helicobacter pylori Infection in Primary Human Gastric Epithelial Cells

Infection and Immunity ◽

10.1128/iai.01517-13 ◽

2014 ◽

Vol 82 (7) ◽

pp. 2881-2889 ◽

Cited By ~ 19

Author(s):

Pascale Mustapha ◽

Isabelle Paris ◽

Magali Garcia ◽

Cong Tri Tran ◽

Julie Cremniter ◽

...

Keyword(s):

Helicobacter Pylori ◽

Epithelial Cells ◽

Inflammatory Response ◽

Antimicrobial Peptides ◽

Virulence Factors ◽

Inflammatory Mediator ◽

Host Cells ◽

Gastric Epithelial Cells ◽

Content Type ◽

H Pylori

ABSTRACTHelicobacter pyloriinfection systematically causes chronic gastric inflammation that can persist asymptomatically or evolve toward more severe gastroduodenal pathologies, such as ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. Thecagpathogenicity island (cagPAI) ofH. pyloriallows translocation of the virulence protein CagA and fragments of peptidoglycan into host cells, thereby inducing production of chemokines, cytokines, and antimicrobial peptides. In order to characterize the inflammatory response toH. pylori, a new experimental protocol for isolating and culturing primary human gastric epithelial cells was established using pieces of stomach from patients who had undergone sleeve gastrectomy. Isolated cells expressed markers indicating that they were mucin-secreting epithelial cells. Challenge of primary epithelial cells withH. pyloriB128 underscored early dose-dependent induction of expression of mRNAs of the inflammatory mediators CXCL1 to -3, CXCL5, CXCL8, CCL20, BD2, and tumor necrosis factor alpha (TNF-α). In AGS cells, significant expression of only CXCL5 and CXCL8 was observed following infection, suggesting that these cells were less reactive than primary epithelial cells. Infection of both cellular models withH. pyloriB128ΔcagM, acagPAI mutant, resulted in weak inflammatory-mediator mRNA induction. At 24 h after infection of primary epithelial cells withH. pylori, inflammatory-mediator production was largely due tocagPAI substrate-independent virulence factors. Thus,H. pyloricagPAI substrate appears to be involved in eliciting an epithelial response during the early phases of infection. Afterwards, other virulence factors of the bacterium take over in development of the inflammatory response. Using a relevant cellular model, this study provides new information on the modulation of inflammation duringH. pyloriinfection.

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