Unraveling effects of gut and blood microbial signatures on immune phenotypes and organ dysfunction in sepsis

Duke University, Durham NC

Investigators

Abstract

Project Abstract/Summary Sepsis is among the leading causes of death in the intensive care unit, and therapies that combat the dysregulated host response underlying its high morbidity and mortality remain elusive and urgently needed. Animal studies indicate that the gut microbiota plays a critical role in host immune responses, and modulation of microbiota structure or function may be an effective strategy in the treatment of sepsis. However, development of similar therapies for clinical practice first requires a better understanding of the relationships between the gut microbiota and immune status in septic patients. Due to the increased intestinal permeability associated with sepsis, delineating these host-microbe interactions also requires the consideration of gut- derived microbial products in the blood, and their potentially distinct influences on immune responses. Emerging evidence using modern sequencing techniques demonstrates that microbial products (including lipopolysaccharide) from gut microbes are not universally pro-inflammatory, but rather, transmit species- specific signals to immune cell toll-like receptors (TLRs) that differentially influence nuclear factor-κB activation and cytokine responses. Changes in gut microbial community structure and collateral effects on the composition of blood microbial signatures thus may contribute to the degree of systemic immune activation in sepsis. However, interactions between gut and blood microbial signatures and immune responses have never been simultaneously explored in septic patients. This proposal aims to unravel these relationships, using a meta-systems approach to integrate gut microbial community profiling, metabolomics, measures of intestinal permeability, and blood microbial signatures with immune phenotypes and clinical endpoints in a prospective longitudinal cohort study of ICU patients with sepsis. These investigations will reveal how changes in the microbiota in sepsis – compared to critical illness alone – influence blood microbial signatures and burden, and if specific gut and blood microbial signatures relate to, or are predictive of, immune activation/exhaustion and end-organ dysfunction. Additionally, biochemical, sequencing, and peripheral immune cell assays will be used to investigate if distinct blood microbial signatures identified in septic patients differentially modulate innate immune cell TLR activation and cytokine production. The findings from this study will enhance our understanding of microbiota-immune interactions and have the potential to reveal novel therapeutic approaches that are urgently needed for this lethal disease.