An innovative laboratory model that mimics the human stomach lining could help better understand how common bacteria cause infections that can lead to serious conditions such as gastric cancer. Researchers funded in part by the NCCR Bio-Inspired Materials have created a miniature version of the stomach tissue with a realistic 3D structure, maintaining the natural organization of different cell types. Unlike previous models, this system can sustain healthy stomach tissue with both stem and mature cells, while producing protective mucus.

Helicobacter pylori (H. pylori) is a bacterium that infects about half the world's population and can cause ulcers, or even worse, gastric cancer. Until now, scientists have struggled to create laboratory models that accurately replicate how these bacteria interact with stomach cells. Current models are either too simplistic (flat cell layers) or too complex (three-dimensional structures that are difficult to work with).

Researchers from Switzerland and the United States led by NCCR Bio-Inspired Materials Associate PI Matthias Lutolf have developed an innovative "organoid-on-a-chip" system that overcomes these limitations. This model creates a miniature version of the stomach lining with a realistic three-dimensional structure that maintains the natural organization of different cell types.

When infected with H. pylori, the model allowed researchers to observe how the bacteria established themselves and persisted for up to six days, even in acidic conditions similar to the stomach environment. The bacteria attached to the junctions between cells and formed small colonies without immediately destroying the tissue.

Using advanced genetic analysis, the researchers discovered that different cell types in the stomach lining respond to H. pylori infection in unique ways. Immature cells showed the expected inflammatory response, while mature surface cells responded differently than previously thought. Rather than producing strong inflammatory signals, these cells strengthened their cell-to-cell connections and produced antimicrobial compounds, particularly activating a system called DUOX2/DUOXA2 that generates hydrogen peroxide to kill bacteria.

This new model provides scientists with a powerful tool to study how H. pylori cause long-term infections that can eventually lead to disease. By revealing previously unknown defense mechanisms in mature stomach cells, particularly under realistic acidic conditions, this research opens new avenues for understanding gastric diseases and potentially developing treatments.

Reference:  Hofer, M.; Kim, Y.; Broguiere, N.; Gorostidi, F.; Klein, J. A.; Amieva, M. R.; Lutolf, M. P. Accessible Homeostatic Gastric Organoids Reveal Secondary Cell Type-Specific Host-Pathogen Interactions in Helicobacter Pylori Infections. Nat Commun 2025, 16 (1), 2767. https://doi.org/10.1038/s41467-025-57131-y