Die Rolle von GP2-IgA-Mikrobiota Interaktionen für die Darm-Homoöstase und bei Darmerkrankungen
Zusammenfassung der Projektergebnisse
The gut is inhabited by a vast population of symbiotic bacteria - the microbiota. The microbiota is essential to host health, immune system development and maturation. A challenging task for host immunity is to discriminate between beneficial microbiota and disease promoting pathogens. The gut immune system is in constant dialogue with the microbiota and its disruption can lead to the development of inflammatory bowel disease (IBD). A crucial part of this dialogue is the generation of secretory immunoglobulin A (SIgA) – a molecule of the adaptive immune arm which binds gut bacteria and prevents intestinal dysbiosis and inflammation. While the importance of SIgA is well established, the role of innate factors received little attention. In this project we investigated the role of Glycoprotein 2 (GP2), an innate host factor produced by the pancreas and released into the small intestine. However, its role in the gut lumen is poorly characterized. We characterized a “three-part” interaction between GP2, the microbiota and SIgA and examined how this interaction helps to maintain gut homeostasis and how it may change in disease. We found that, in mouse and human intestine, GP2 bound to a large proportion of the microbiota. Interestingly, bacteria that were coated with GP2 also showed SIgA-coating and their levels strongly correlated. In contrast, this pattern was disrupted in IBD patients, suggesting that this “three-part” interaction plays an important role in gut health. In addition, genetically modified mice that lack GP2 showed reduced microbial SIgA-binding, changes in microbial composition and enhanced germinal center B cell responses in inductive compartments. In mice that lack SIgA, GP2 still bound the microbiota, but with altered intensity. Similarly, the microbiota of IgA-deficient humans showed a significant reduction in GP2-binding, indicating that SIgA may be required for optimal GP2-binding. Moreover, fluorescent microscopy and mass spectrometry showed that GP2 and SIgA co-associated on bacterial surfaces. In line with this, we demonstrated that GP2 directly interacts with polymeric antibodies, such as SIgA, suggesting a direct link between innate and adaptive immunity. Functionally, direct GP2 interactions with intestinal antibodies may act as innate scaffolding for enhanced SIgA-mediated agglutination of gut bacteria. Together, our data illustrate how innate and adaptive immune mechanisms act together, increase our understanding of host-microbiota interactions in health and disease and provide a potential new angle for the treatment of dysbiosis-related inflammatory diseases.
