Berlin, 11.04.2022 – An infection of the stomach lining with the Helicobacter bacterium leads to gastric inflammation and also increases the risk of stomach cancer. A research team from Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has now been able to elucidate characteristic changes in the gastric glands in the course of an infection. The scientists have found a previously unknown mechanism that limits cell division in healthy tissue and thus protects against cancer development. However, a stomach infection cancels this mechanism so that cells can grow uncontrollably. These findings, published in the journal Nature Communications*, may be the basis for the development of new cancer therapies.
A colonisation of the stomach with Helicobacter pylori occurs in about half of humanity worldwide. This makes it one of the most common chronic bacterial infections. As a result, inflammation of the stomach (gastritis) or stomach cancer can develop. Due to the constant contact with gastric acid, the healthy stomach lining completely renews itself within a few weeks, whereby its structure and composition always remain unchanged. “Until now, it was assumed that a Helicobacter infection directly damages the glandular cells of the gastric mucosa,” explains Prof. Dr. Michael Sigal, last author of the study. “Our team has now found that the complex interactions of different cells and signals that ensure tissue stability are disrupted by infection.” Prof. Sigal is Emmy Noether research group leader at the Charité’s Department of Medicine with a focus on hepatology and gastroenterology and at the Berlin Institute for Medical Systems Biology (BIMSB), which is part of the MDC.
In order to track the changes in the gastric glands caused by a Helicobacter infection, the research team, together with scientists at the Max Planck Institute for Infection Biology, made use of complex mouse models in which certain cells of the gastric glands can be visualised, isolated and examined in detail using state-of-the-art technologies – such as imaging and single-cell sequencing on tissue. In addition, they developed special organ-like microstructures – so-called organoids – in the laboratory to limit the use of animal models. With the help of these tiny miniature stomachs, they were able to recreate many of the glands’ properties and investigate the influence of diverse signals on the stem cells there, which can give rise to different cell types.
“We found out that the so-called stromal cells surrounding the glands are not – as previously thought – only responsible for mechanical stability. They also produce messenger substances that significantly influence the behaviour of the glands,” describes Prof. Sigal. These messenger substances also include the “Bone Morphogenetic Protein” (BMP), which is important for tissue development. The researchers were able to show that stromal cells surrounding the base of the gland continuously suppress the BMP signalling pathway and thus stimulate the division of the stem cells there. In contrast, stromal cells at the tip of the gland activate the signalling pathway and thus prevent cell division there.
This environmental influence is the basis for the stable glandular structure. A Helicobacter infection leads to the release of end-inflammatory substances such as interferon-gamma (IFN-γ). In the course of this inflammatory reaction, increased messenger substances are now produced that stimulate the cell division of the stem cells in the glands. This eventually leads to so-called hyperplasia – i.e. the tissue enlarges and cancer precursors can develop.
“Our findings show that an infection and associated inflammation has many more effects in the tissue than previously thought: classical inflammatory substances such as IFN-γ not only have a direct antimicrobial effect, but also influence cell division and the behaviour of stem cells in the tissue. In the case of tissue damage, rapid cell division can be very useful to enable rapid healing. However, in the case of chronic inflammation in the course of a Helicobacter infection, it could favour the development of cancer precursors,” summarises Prof. Sigal. The signalling pathways in the interaction between the immune system and stem cells, which could also be significant for organs other than the stomach, thus represent a starting point for new therapies – both in cancer prevention and in regenerative medicine.
*Kapalczynska M et al. BMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation. Nat Commun (2022). doi: 10.1038/s41467-022-29176-w
Caption: Gastric tissue infected with Helicobacter bacteria. Dividing cells are shown in green, cell nuclei in blue. © Charité | Michael Sigal