The gram-negative bacteria Helicobacter pylori have evolved to colonize and persist in the stomach for decades. Although most patients remain asymptomatic, infection represents the main risk factor for gastric cancer. I have found that H. pylori colonizes not only the mucus layer that covers the epithelium but also the intercellular junctions of specialized epithelial cells deep in gastric glands and demonstrated that this subpopulation of H. pylori directly interact with progenitor and stem cells. The presented studies reveal that H. pylori actively sense the epithelium and use urea as chemoattractant to swim towards epithelial cells. Of note, isogenic chemotaxis mutants of H. pylori have an impaired ability to colonize the glands, indicating that H. pylori possesses sophisticated tools to locate and swim towards the gland to establish a colonization niche. Once infection is established, gland-associated bacteria, which interact with stem cells, trigger specific epithelial responses. Increased stem cell turnover and proliferation are responsible for gland hyperplasia and metaplasia, which are specifically observed in areas of the stomach with gland-associated bacteria. In addition to the overall increased proliferation in the stem and progenitor cell compartment, a subpopulation of gland-base stem cells that express Lgr5 are differentiating into antimicrobial cells and are able to counterbalance infections by secretion of antimicrobial compounds into the gland lumen such as Intelectin 1. Depletion of these cells leads to an increased colonization and deeper invasion of H. pylori. We demonstrate that both stem cell turnover and antimicrobial gland base cell differentiation are driven by the same factor that is expressed in the stromal stem cell niche of the stomach gland. This factor is R-spondin 3 and is secreted by stromal myofibroblasts. R-spondin 3 stabilizes Wnt signaling in gland epithelial cells, leading to an increased expression of Wnt target genes. While overall it acts as a mitogen, gland base cells indeed require Rspo3 to differentiate into secretory cells and depletion of R-spondin 3 leads to a loss of this cell type and an inability of the glands to counterbalance gland colonization. Our data demonstrate that H. pylori infection alters the epithelial gland homeostasis. R-spondin 3 expression is increased upon infection, leading to both, epithelial regeneration and antimicrobial epithelial responses to infection. Together we demonstrate how the gland colonization by H. pylori creates an ongoing battle between the bacteria and the host. We propose that this battle, which usually continues for decades in infected individuals, can result in dysfunctions of the epithelium and increase the risk for gastric malignancies. Further studies will reveal whether we can use host-derived strategies to win such battles against bacteria in the stomach or at other sites in the body.
