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Development of an innovative Airway-on-Chip microbiome cell culture model to investigate host-microbiome interactions at the airway epithelial surface

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Lung microbes in a chip model elucidate the host-microbiota battle in chronic respiratory disease

Recent studies show that the airway microbiota of patients with asthma and chronic obstructive pulmonary disease (COPD) is very different to that of patients with no chronic respiratory disease.

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The problem facing scientists and healthcare practitioners is the lack of understanding whether, and how, changes in lung microbial composition contribute to susceptibility to respiratory infections, as well as progression of asthma and COPD. In mouse lungs, changes result in airway inflammation and lung function loss but it’s still unclear what drives these changes and how they lead to increased predisposition to lung infections and damage. The need to understand this link is paramount as current treatment of asthmatic and COPD patients is limited to symptom reduction and prevention of disease progression. Unfortunately, this approach is hampered by the large number of patients resistant to corticosteroid treatment.

Airway-on-chip to the rescue

“Our core goals were to develop a human ‘Airway Lung-Chip’ microbiota model and to study host-microbiota interactions in the lungs,” outlines Pieter Hiemstra, project coordinator of the EU-funded EpiCBiome project and professor of respiratory cell biology and immunology at Leiden University Medical Center. The researchers focused their attention on the role of host defence peptides and proteins in the context of asthma and COPD. EpiCBiome researchers successfully applied organ-chip technology in their laboratory and optimised the ‘Airway Lung-Chip’ and ‘Alveolus Lung-Chip’ with use of cells from Hiemstra’s laboratory. The research was undertaken with the support of the Marie Skłodowska-Curie programme. “It was exciting to learn to work with our partner Emulate’s organ-chip platform,” Hiemstra recalls. “And the on-site training of the fellow Anne van der Does at Emulate has proven to be highly valuable.” In addition, during the grant period the team optimised a more simplified Transwell lung epithelial microbiota co-culture system. They have also studied how remodelling of the airway epithelium affects microbial load of a complex microbial mixture.

Issues posed by microbes

“The biggest problem we had to overcome was to obtain a complex microbial mixture that is representative of a stable microbiota that we could apply to the cell cultures,” Hiemstra explains. This difficulty remained a limitation throughout the project and work to improve this is still ongoing at the lab. Another issue is that the microbiota numbers in the lungs are really low and trying to reproduce that level in vitro creates challenges for reliable read-outs. “As a result, we have focused on the epithelial response more than on the microbiota composition in the project,” Hiemstra summarises. The final challenge was transferring the ‘Airway Lung-Chip’ model to the Dutch lab and optimising cell culture conditions to ensure the reliability and robustness of the model, which took longer than anticipated.

Future for airway-on-chip applications

The research team will continue to incorporate microbes in the cultures, especially on the chip as the work has not extended to that point yet. This ties in with plans to extend the investigations to include lung cancer. “In addition, the experiments with Transwells have given us valuable clues on how remodelling may affect the lung microbiota and this will be the main focus of our future research.” Anne van der Does has established herself as an independent scientist in the department, and she recently obtained the first major grants that are based on the introduction of the ‘Airway Lung-Chip’ in the Hiemstra laboratory. He summarises the value of the work: “The project has been instrumental in the career development of van der Does and has also resulted in the introduction of a highly valuable method in our laboratory.”


EpiCBiome, lung, chip, microbiome, microbiota, COPD, culture, respiratory disease

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