Dysfunction of intestinal mucosal immunity after clinical and experimental polytrauma

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The gut-blood-barrier (GBB) is composed of mucus, intestinal epithelium and an arsenal of fluid-phase proteins (antimicrobial peptides, complement system) and innate immune cells (leukocytes). However, in polytrauma the GBB represents a main target of remote injury. Our preliminary findings of the GBB as a major driver of multiple-organ dysfunction syndrome (MODS) during systemic inflammation provide the rationale to further investigate the underlying immuno-pathophysiology of posttraumatic GBB failure. Thus, we propose that i) polytrauma leads to dysfunctional innate intestinal mucosal immunity, ii) mainly driven by pancreatic- and complement-derived proteases, which iii) upon blockade result in improved thrombo-inflammation and (multiple) organ performance. In mucus and intestinal tissue, lymph nodes and blood samples obtained from highly standardized pig and murine polytrauma models, we will define changes of the antimicrobial, complement- and pancreatic proteases-driven response. Furthermore, spatial-temporal characterization of the cellular innate immune response in the intestine and blood will include detection and immune-phenotyping of neutrophils, monocytes/macrophages, and dendritic cells. In addition, we will follow the proposed translocation axis of microbes and their associated molecular patterns (MAMPs) including early microbiome shifts. First therapeutic approaches by blockade of proteolytic activity (by tranexamic acid or TriFU as fluid phase inhibitor) will be evaluated. Finally, in a prospective descriptive study we aim to translate the findings within the consortium into the clinical setting after polytrauma and to ultimately offer a mucosal-immunomodulatory approach to improve the patient outcome.