Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here we identified members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as novel receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human CEACAM1, CEACAM3, CEACAM5 and CEACAM6. HopQ-CEACAM binding is glycan-independent and targeted to the N-domain. H. pylori binding induces CEACAM1 mediated signaling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells, and enhances the release of proinflammatory mediators such as interleukin-8. Based on the crystal structure of HopQ, we found that a β-hairpin insertion (HopQ-ID) in HopQ's extracellular 3+4 helix bundle domain is important for CEACAM binding. A peptide derived from this domain competitively inhibits HopQ-mediated activation of the Cag virulence pathway, as genetic or antibodymediated abrogation of the HopQ function shows. Together, our data imply the HopQ-CEACAM1 interaction as potentially promising novel therapeutic target to combat H. pyloriassociated diseases. Helicobacter pylori (H. pylori) is one of the most prevalent human pathogens, colonizing half of the world's population. Chronic inflammation elicited by this bacterium is the main cause of gastric cancer 1. During co-evolution with it's human host over more than 60.000 years 2 , the bacterium has acquired numerous adaptations for the long-term survival within its unique niche, the stomach. This includes the ability to buffer the extreme acidity of this environment, the interference with cellular signaling pathways, the evasion of the human immune response and a strong adhesive property to host cells 3. Specifically, H. pylori persistence is facilitated by the binding of BabA and SabA adhesins to the human blood group antigen Leb and the sLex antigen, respectively 4-6. However, adhesion to blood group antigens is not universal, is dynamically regulated during the course of infection and can also be turned off 7. We observed that H. pylori was capable of binding to human gastric epithelium of nonsecretors. Therefore, we hypothesized that the bacterium might be able to interact with other cell surface receptors to ensure persistent colonization. We here show that the H. pylori adhesin HopQ specifically interacts with human carcinoembryonic antigen-related cell adhesion molecules (CEACAMs). CEACAMs embrace a group of immunoglobulin superfamily-related glycoproteins with a wide tissue distribution. CEACAM1 can be expressed in leukocytes, endothelial and epithelial cells, CEACAM3 and CEACAM8 in granulocytes, CEACAM5 and CEACAM7 in epithelial cells and CEACAM6 in epithelia and granulocytes. In epithelial cells, transmembrane anchored CEACAM1 as well as glycosylphosphatidylinositol-linked CEACAM5, CEACAM6 and CEACAM7 localize to the apical membrane 8. CEACAMs modulate diverse cellular functions such as cell adhesion, differentiation,...

ObjectiveGastrointestinal microbiota may be involved in Helicobacter pylori-associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from H. pylori infection.DesignDeep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti-H. pylori treatment, relative to 49 H.pylori negative subjects.ResultsIn H. pylori positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in H. pylori positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between Helicobacter and Fusobacterium, Neisseria, Prevotella, Veillonella, Rothia were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased Bifidobacterium after successful H. pylori eradication and more upregulated drug-resistant functional orthologs after failed treatment.ConclusionH. pylori infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful H. pylori eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.

Infection with the gram-negative bacterium Helicobacter pylori is the most prevalent chronic bacterial infection, affecting ∼50% of the world’s population, and is the main risk factor of gastric cancer. The proinflammatory cytokine IL-1β plays a crucial role in the development of gastric tumors and polymorphisms in the IL-1 gene cluster leading to increased IL-1β production have been associated with increased risk for gastric cancer. To be active, pro–IL-1β must be cleaved by the inflammasome, an intracellular multiprotein complex implicated in physiological and pathological inflammation. Recently, H. pylori was postulated to activate the inflammasome in murine bone marrow–derived dendritic cells; however, the molecular mechanisms as well as the bacterial virulence factor acting as signal 2 activating the inflammasome remain elusive. In this study, we analyzed the inflammasome complex regulating IL-1β upon H. pylori infection as well as the molecular mechanisms involved. Our results indicate that H. pylori–induced IL-1β secretion is mediated by activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain–containing 3 inflammasome. We also show that reactive oxygen species, potassium efflux, and lysosomal destabilization are the main cellular mechanisms responsible of nucleotide-binding oligomerization domain family, pyrin domain–containing 3 inflammasome activation upon H. pylori infection, and identify vacuolating cytotoxin A and cag pathogenicity island as the bacterial virulence determinants involved. Moreover, in vivo experiments indicate an important role for the inflammasome in the onset and establishment of H. pylori infection and in the subsequent inflammatory response of the host.