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Colonization by Helicobacter pylori is associated with gastric diseases, ranging from superficial gastritis to more severe pathologies, including intestinal metaplasia and adenocarcinoma. The interplay of the host response and the pathogen affect the outcome of disease. One major component of the mucosal response to H. pylori is the activation of a strong but inefficient immune response that fails to control the infection and frequently causes tissue damage. We have shown that polyamines can regulate H. pylori–induced inflammation. Chemical inhibition of ornithine decarboxylase (ODC), which generates the polyamine putrescine from l-ornithine, reduces gastritis in mice and adenocarcinoma incidence in gerbils infected with H. pylori. However, we have also demonstrated that Odc deletion in myeloid cells enhances M1 macrophage activation and gastritis. Here we used a genetic approach to assess the specific role of gastric epithelial ODC during H. pylori infection. Specific deletion of the gene encoding for ODC in gastric epithelial cells reduces gastritis, attenuates epithelial proliferation, alters the metabolome, and downregulates the expression of immune mediators induced by H. pylori. Inhibition of ODC activity or ODC knockdown in human gastric epithelial cells dampens H. pylori–induced NF-κB activation, CXCL8 mRNA expression, and IL-8 production. Chronic inflammation is a major risk factor for the progression to more severe pathologies associated with H. pylori infection, and we now show that epithelial ODC plays an important role in mediating this inflammatory response.

Introduction Hypusine is an amino acid found only in the eukaryotic translation initiation factor 5A (EIF5A). Hypusine is synthesized by the enzyme deoxyhypusine synthase (DHPS) that transfers the N-moiety of spermidine to a lysine residue in EIF5A. This post-translational modification (hypusination) is essential to binding specific mRNAs. The EIF5AHyp/mRNA complex is translocated to the cytoplasm, reaches ribosomes, and allows for translation. We analyzed the role of hypusination in the innate response of macrophages. Results The gastric pathogen Helicobacter pylori stimulated DHPS expression and hypusination in murine bone marrow-derived macrophages (BMmacs). We generated myeloid-specific Dhps knockout mice (DhpsΔmye) by crossing Dhpsfl/fl mice to Lyz2-cre mice. By iTRAQ proteomics, 29 of the proteins induced by H. pylori in BMmacs from Dhpsfl/fl mice were significantly less expressed in infected DhpsΔmye mice. These included antibacterial effectors (IRG1, NOS2), cytokines (TNF-α, IL-1β), and mediators of autophagy (SQSTM, IRGM1). These findings were confirmed by Western blot. DhpsΔmye mice infected with H. pylori exhibited increased colonization (p Conclusions Hypusination in myeloid cells is critical for host innate immunity to limit the infectivity of pathogenic bacteria.