A New Organ-on-Chip Model Unveils Complex

Host-Pathogen Interactions in H. pylori Infection

Helicobacter pylori (H. pylori) infection is a significant global health concern, linked to various gastric diseases, including gastric cancer and peptic ulcers. Despite its high prevalence, many underlying mechanisms remain poorly understood. Current in vitro models either lack the complexity of the gastric environment or pose challenges for experimental access. This study of Hofer et al. introduces a novel human gastric organoid-on-chip model to address these limitations and gain insights into H. pylori infection dynamics.

A Novel Homeostatic Gastric Organoid-on-Chip Model:

Researchers developed a patterned homeostatic human gastric organ-on-chip system with bilateral access. This innovative model system incorporates a geometrically defined structure that enables more efficient cell seeding and long-term maintenance. The model allows for the simulation of physiological apical acidic conditions and an air-liquid interface (ALI). The inclusion of both progenitors and mature pit cells allows for a more complete representation of the human antrum [Fig. 1, see the link to the paper below]. Analysis by single cell RNA sequencing (scRNAseq) shows that this model generates higher maturity pit cells than other existing systems [Fig. 2, see the link to the paper below].

Unveiling Cell Type-Specific Responses to H. pylori Infection

Using this novel model, researchers investigated the cellular responses to H. pylori infection over both short (2 days) and extended (6 days) periods, under both physiological neutral and acidic conditions [Fig. 3 & 4, see the link to the paper below]. Their findings revealed distinctive responses among different gastric cell types:

• Progenitor, neck, and immature pit cells: These cells exhibited a cytokine-dominant response, aligning with previous observations .
• Mature pit cells: These cells showed upregulation of genes involved in cell junctions and antimicrobial responses, particularly under acidic conditions, including DUOX2 and DUOXA2 [Fig. 4 & Supplementary Fig. 5, see the link to the paper below].

Mechanistic Insights and Implications

The study demonstrates that mature pit cells respond to H. pylori infection by upregulating genes involved in cell junctions and an antimicrobial response (DUOX2/DUOXA2) particularly under acidic conditions [Fig. 4 & Supplementary Fig. 5, see the link to the paper below]. This enhanced model provides a powerful tool for investigating the interactions between H. pylori and the gastric epithelium under physiologically relevant conditions, and for understanding chronic infection dynamics and disease progression.

The findings of this study, utilizing a novel human gastric organ-on-chip model to investigate Helicobacter pylori infection, have significant implications for several areas of research and development:

1. Improved Understanding of H. pylori Pathogenesis

The study provides crucial insights into the complex interplay between H. pylori and the diverse cell types within the gastric epithelium. The identification of distinct responses among different cell populations (progenitor cells, neck cells, immature and mature pit cells) challenges previous understandings that focused on a more generalized inflammatory response. The finding that mature pit cells exhibit unique responses involving both antimicrobial mechanisms and changes in cellular junctions, particularly under acidic conditions (mimicking the physiological stomach environment), significantly advances our comprehension of how H. pylori establishes a persistent infection and induces chronic inflammation. This enhanced understanding is critical for developing effective therapeutic strategies.

2. Development of Novel Therapeutic Strategies

The identification of specific molecular pathways involved in the mature pit cell response to H. pylori infection opens new avenues for developing targeted therapies. The upregulation of DUOX2 and DUOXA2 in mature pit cells under acidic conditions suggests the potential for modulating these pathways to enhance the host’s antimicrobial defense and combat persistent infection. Further research could explore the development of drugs or other therapeutic interventions that either directly stimulate DUOX2/DUOXA2 activity or indirectly enhance this pathway to increase bacterial clearance and reduce inflammation.

3. Advancement of Gastric Disease Modeling

The novel organ-on-chip model system offers a significant improvement over traditional models by integrating the structural complexity and physiological conditions of the human gastric antrum. Its enhanced ability to generate mature pit cells, coupled with its bilateral accessibility, allows for more sophisticated investigations into the long-term effects of H. pylori infection. This refined model should facilitate a more comprehensive understanding of disease progression, from chronic inflammation to the development of peptic ulcers and gastric cancer. The ability to maintain a consistent bacterial burden over time in this model will provide opportunities to explore various interventions and assess their effects on disease development and progression.

4. Development of New Diagnostic Tools

The identification of specific gene expression patterns in different cell types in response to H. pylori infection may also contribute to the development of new diagnostic tools. The analysis of these specific markers in patient biopsies could improve early diagnosis of H. pylori infection and potentially predict the risk of developing more serious gastric diseases. Further research is needed to determine the clinical utility of these specific biomarkers in diagnosing and monitoring H. pylori infection and predicting disease outcomes.

5. Enhanced Drug Discovery and Development

This new model can be used to screen potential drug candidates for efficacy and safety, reducing the reliance on animal models. The ability to test drugs under physiologically relevant conditions in a human-relevant model offers opportunities to identify more promising drug candidates, optimize their use, and predict their efficacy and safety in humans more accurately. This will increase efficiency and reduce the costs associated with traditional drug development.

In summary, this research from Lutlof’s Lab represents a considerable advancement in our understanding of H. pylori pathogenesis and offers significant opportunities for developing improved diagnostic tools and therapeutic interventions. The innovative organ-on-chip model provides a powerful platform for more robust and physiologically relevant investigations into host-pathogen interactions and disease progression, accelerating progress in both research and clinical applications.

Link to the Hofer et al. publication: https://www.nature.com/articles/s41467-025-57131-y.epdf?sharing_token=yZ19lCIE1HZPRH8CC5bNkNRgN0jAjWel9jnR3ZoTv0MHRWGiatAfEdqkXHbBcEImrPll2n1vmyn-6aJOrUbWZxCmyeeC_gMOre6fa9eK5g8tF-2rgTOuWn-gEYerNmdWgwlxNTZEsd0zPmCw9X4YwqAN0snyxjbSdeoBA2O01p0%3D