The Gut as a Target to Improve Outcomes in Sepsis

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Sepsis is the leading cause of death among critically ill patients in the United States, and costs of sepsis for Medicare beneficiaries exceed $62 billion annually. Outside of antibiotics, treatment for sepsis is non-specific, and there are no approved therapeutics available once antibiotics and supportive therapy fail. Patients with cancer are nearly ten times more likely to develop sepsis than the general population, and cancer represents the most common co-morbidity in septic patients. Moreover, cancer is the co-morbidity associated with the highest risk of death in sepsis, and the increased mortality is seen disproportionately in younger adult patients. The gut has long been characterized as the motor of multiple organ dysfunction syndrome. All major elements of gut integrity are altered in sepsis, with dysregulation in the epithelium (permeability, apoptosis, proliferation, migration), the microbiome and the mucosal immune system. Further, both immunity and gut integrity are disproportionately impacted in cancer/sepsis hosts compared to previously healthy/sepsis hosts. This program seeks to understand mechanisms underlying dysregulated gut integrity in sepsis. The first approach will be to examine what happens within the epithelium, the mucosal immune system and the microbiome, to elucidate mechanisms of sepsis-induced intestinal alterations within individual processes in isolation. The next approach will be to examine crosstalk between the three broad components of the gut since each element directly impacts each other, leading to further alterations in all. The final approach will be to examine how the gut leads to extra-intestinal effects on distant organs, where gut-derived changes lead to subcellular, cellular and organ dysfunction, resulting in worsened morbidity and mortality. Additionally, the program seeks to understand why outcomes are different in cancer/sepsis, by examining differences seen in both the adaptive immune system and gut integrity. A “one size fits all” approach to an inherently heterogeneous syndrome is likely a key reason why more progress has not been made in decreasing mortality from sepsis clinically, and the goal of understanding mechanisms of how a chronic co-morbidity leads to different outcomes at the bedside is to move towards precision medicine in septic patients. The program will use human samples (gut, blood and stool) paired when feasible with clinical data and outcomes. Mechanistic questions will then be approached using a bedside to bench paradigm whereby insights obtained examining human samples will then be evaluated using a variety of in vivo and in vitro techniques when experiments cannot be performed in patients. Since the gut plays a major role in both initiating and propagating critical illness and co-morbidities play a crucial role in worsening outcomes in septic patients, understanding mechanisms through which gut integrity is dysregulated in sepsis especially in hosts with cancer has significant public health implications in a disease that is common, very costly, and highly lethal.