Research

How to bacteria shape gastrointestinal stem cells to create a “healthy gut”

Prinicipal Investigator

Scientific interest within the context of the graduate college:

Helicobacter pylori is a human-specific bacterium that colonizes the stomachs of about 50% of the world’s population. We have previously found that H. pylori can invade gastric glands and colonize stem cell compartment1. This subpopulation of H. pylori induces an altered stem cell behavior. The stem cells increase their turnover kinetics, and in parallel promote a production of antimicrobial cells that secrete various antimicrobial compounds, that in turn shield the stem cells from invading bacteria. This counterbalances infection, while at the same time promoting changes in gland proliferation and cellular composition2,3. These data demonstrate the remarkable potential of our gastrointestinal epithelial lining to adapt to changes in the environment. The mechanisms that enable such adaptation have not been explored in detail and we have generated a substantial amount of preliminary data that will be used as a solid basis for this project (Jablonska et al., in revision). Using our Helicobacter model we would like to not only generate important insights in pathogenesis of gastric disorders, but to also generate fundamental, more general insights into the ability of mucosal tissues to respond to changes in the environment. In fact, we hypothesize that the behavior of stem cells already in the healthy state is significantly shaped by microbes and that the tissue structure, that we consider healthy, is under control of bacteria and their products.

Figure 1. Stem Cells are colonized by and respond to H. pylori.
a) Confocal microscopy of gland-associated H. pylori 2 weeks after infection (arrow indicates single bacteria in the base, where stem cells reside); b) Single molecule in situ hybridization (ISH) for Axin2 in the mouse stomach; c) 6-week lineage tracing in the antrum of Axin2CreER/Rosa-tdTomato (red: Axin2+ cell derived clones); d) Single molecule ISH for Rspo3 in uninfected and 2 month-infected mouse antrum; e) Axin2 expression in uninfected and 2 month-infected mouse antrum; f) Schematic demonstrating how gland-associated bacteria trigger Rspo3 –driven Axin2+ stem cell proliferation.
(Figure 1a from Sigal et al., 2015 Gastroenterology; Fig. 1b,d,e from Sigal et al., Nature 2017)

Project description:

The aim of the project will be to characterize the intercellular communication that promotes the mucosal response to H. pylori. We will combine well-established tools and novel techniques such as scRNAseq and spatial transcriptomics in collaboration with experts from the Berlin Institute for Medical Systems Biology. We will use organoids grown from primary gastric epithelial cells, in vivo infection models as well as human material from patients infected with H. pylori to explore how stem cells respond to Helicobacter infection. Our preliminary data suggest that the epithelial stem cells are primed to recognize and respond to infections and we will use various tools to explore this idea, characterize molecular pathways that control it and to address how such priming influences epithelial responses to infections.

Application details

References

  1. Sigal M, Rothenberg ME, Logan CY, […], Nusse R, Torres J, Amieva MR. Helicobacter pylori Activates and Expands Lgr5(+) Stem Cells Through Direct Colonization of the Gastric Glands. Gastroenterology. 2015; 148:1392-404.e21. doi: 10.1053/j.gastro.2015.02.049.
  2. Sigal M, Logan CY, Kapalczynska M, […], Nusse R, Amieva MR, Meyer TF. Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis. Nature. 2017; 548:451-455. doi: 10.1038/nature23642.
  3. Sigal M, Del Mar Reinés M, Müllerke S, […], Wiedenmann B, Sauer S, Meyer TF. 3 induces secretory, antimicrobial Lgr5 + cells in the stomach. Nat Cell Biol. 2019; 21:812-823. doi: 10.1038/s41556-019-0339-9.