Mapping the interdependency of the gut-lung-axis and hydrogel barrier in health and disease (A05)

• Subject Area: Pharmacy
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431232613

The gut and lungs are anatomically distinct, yet potential anatomic communications and complex pathways involving their respective microbiota have unveiled the existence of a gut–lung axis (GLA). This inter-tissue crosstalk putatively contributes to healthy and diseased states. In fact, chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD) often occur together with chronic gastrointestinal tract diseases, such as inflammatory bowel disease (IBD). Up to 50% of adults with IBD have pulmonary involvement, such as inflammation or impaired lung function, and patients with COPD are 2-3 times more likely to be diagnosed with IBD. Further, the GLA also modulates the response to acute bacterial and viral lung infections, the latter of which has been recently highlighted through the COVID-19 pandemic. So far, gut-microbe-derived components and metabolites such as short-chain fatty acids have been identified as putative mediators of the GLA. Yet, mechanism beyond the microbiome are highly likely and many questions remain as to how this crosstalk impacts lung and intestinal hydrogels and, thus potentially contributes to the manifestation of comorbidities.Hence, in this supplementary proposal to the recently installed CRC1449, we propose the development of a microphysiological system (MPS) allowing a long-term co-cultivation of intestinal and pulmonary epithelial tissue models to emulate the GLA in a human-based ex vivo system. This MPS will then be employed to test our main hypothesis which is that the gut-lung crosstalk governs the composition and function of epithelial hydrogels. To trial this hypothesis, the following three aims have been defined: 1. Characterization of epithelial hydrogels in human-based intestinal and pulmonary tissue models.2. Characterization of the impact of gut-lung crosstalk on epithelial hydrogels in steady-state.3. Determine down-stream effects of pathophysiological conditions and stimuli on intestinal and pulmonary hydrogels.This project adds an important and so far, missing layer to the CRC1449 as it bridges projects with lung and gut focus. More specifically, the proposed multi-organ chip will allow investigating the impact of gut-lung crosstalk on epithelial hydrogel composition, function, and maintenance in health and disease. Therefore, the proposed development and characterization of a gut-lung MPS sets the stage for a prospective second funding period in which the focus will be on unraveling the impact of pathophysiological stimuli such as infections or inflammation on epithelial hydrogels in the context of the gut-lung crosstalk.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1449: Dynamic Hydrogels at Biointerfaces
• Applicant Institution: Freie Universität Berlin
• Project Head: Professorin Dr. Sarah Hedtrich