Inflammation promotes stomach epithelial defense by stimulating the secretion of antimicrobial peptides in the mucus
Megi Vllahu,
Antonia Voli,
Valerio Licursi,
Claudia Zagami,
Antonella D’Amore,
Jan Traulsen,
Sara Woelffling,
Monika Schmid,
Robbie Crickley,
Richard Lisle,
Alexander Link,
Alessandra Tosco,
Thomas F. Meyer,
Francesco Boccellato
Affiliations
Megi Vllahu
Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
Antonia Voli
Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
Valerio Licursi
Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR) of Italy c/o Department of Biology and Biotechnology ‘‘C. Darwin’’, Sapienza University, Rome, Italy
Claudia Zagami
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Antonella D’Amore
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Jan Traulsen
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Sara Woelffling
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
Monika Schmid
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
Robbie Crickley
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Richard Lisle
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Alexander Link
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
Alessandra Tosco
Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
Thomas F. Meyer
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
Francesco Boccellato
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
The mucus serves as a protective barrier in the gastrointestinal tract against microbial attacks. While its role extends beyond merely being a physical barrier, the extent of its active bactericidal properties remains unclear, and the mechanisms regulating these properties are not yet understood. We propose that inflammation induces epithelial cells to secrete antimicrobial peptides, transforming mucus into an active bactericidal agent. To investigate the properties of mucus, we previously developed mucosoid culture models that mimic the healthy human stomach epithelium. Similar to organoids, mucosoids are stem cell-driven cultures; however, the cells are cultivated on transwells at air–liquid interface. The epithelial cells of mucosoids form a polarized monolayer, allowing differentiation into all stomach lineages, including mucus-secreting cells. This setup facilitates the secretion and accumulation of mucus on the apical side of the mucosoids, enabling analysis of its bactericidal effects and protein composition, including antimicrobial peptides. Our findings show that TNFα, IL1β, and IFNγ induce the secretion of antimicrobials such as lactotransferrin, lipocalin2, complement component 3, and CXCL9 into the mucus. This antimicrobial-enriched mucus can partially eliminate Helicobacter pylori, a key stomach pathogen. The bactericidal activity depends on the concentration of each antimicrobial and their gene expression is higher in patients with inflammation and H.pylori-associated chronic gastritis. However, we also find that H. pylori infection can reduce the expression of antimicrobial encoding genes promoted by inflammation. These findings suggest that controlling antimicrobial secretion in the mucus is a critical component of epithelial immunity. However, pathogens like H. pylori can overcome these defenses and survive in the mucosa.
