Dysbiosis, organ injury, and Systemic Inflammation

About This Grant

Project Summary/Abstract: Our long-term goal is to elucidate the cellular and molecular mechanisms by which dysbiosis, organ injury, and the host systemic response lead to multiple organ dysfunction syndrome (MODS) in critical illness, ultimately identifying therapeutic targets. Trauma, burns, and surgery often cause microbiome imbalances (dysbiosis) and increased gut permeability, which are key drivers of systemic infallamtion and MODS in critically ill patients, significantly increasing ICU mortality. Clinical evidence indicates that the microbiota and host immunity function as an integrated system, where intestinal dysbiosis and injury compromise gut defenses and heighten susceptibility to nosocomial infections and systemic inflammation. Indeed, our recent findings suggest that dysbiosis substantially raises the risk of gut injury progressing to systemic inflammation and MODS. Despite this knowledge, the mechanisms linking the host immune response to gut dysbiosis and injury in sepsis and MODS remain poorly understood, and clinically relevant investigations are limited. Dysbiosis is characterized by the loss of commensal bacteria, reduced microbial diversity, and overgrowth of pathobionts. While earlier work mainly addressed adaptive immunity (T, B, and NK cells), critically ill ICU patients with MODS frequently exhibit innate immune dysregulation associated with dysbiosis. Thus, gut innate immunity, as the first line of defense, is essential in orchestrating systemic responses. Over the next five years, our research will (1) validate that dysbiosis, as a critical risk factor, exacerbates organ injury and systemic responses across various models, (2) identify organ-specific mechanisms in dysbiosis-initiated, organ-driven systemic inflammation and MODS, and (3) target dysbiosis-induced metabolic and epigenetic alterations, employing novel techniques to illuminate potential prevention and treatment strategies. Our broader vision unfolds in multiple layers. First, establishing direct evidence that dysbiosis contributes to organ injury severity and systemic responses will have significant implications for clinical care and public health. Second, we will integrate diverse approaches in our research program: clinical assessment systems to track disease progression, multiple injury models, germ-free and genetically modified mice, and advanced technologies such as single-cell RNA-seq, ATAC-seq, 16S rRNA-seq, shotgun metagenomics, metabolite profiling, Seahorse real-time metabolic assays, and ChIP-seq. These complementary methods will deepen our understanding of the complex interactions between microbiome and immunity. Finally, successful completion of these projects will expand our understanding of how intestinal conditions influence systemic host responses, provide deeper mechanistic insights, and guide the development of therapeutic strategies to mitigate the public health burden of critical illnesses.