The role of AI-2-mediated quorum sensing in gut microbiome-immune dysbiosis

Abstract

Microbes colonize the gastrointestinal tract, forming microbiomes essential for gut function, immune responses, and other host systems¹. Patients requiring life-support treatment develop profound gut microbiome ecology alterations, characterized by a loss of beneficial commensals and overgrowth of potential pathogens (pathobionts), including Enterobacteriaceae and Enterococcaceae families^2,3. This increases patients’ risk of adverse outcomes, including nosocomial infections, by driving systemic immune dysregulation^4,5. Prior research suggests that inter-microbe molecular communication (quorum sensing) contributes to pathobiont overgrowth in ICU patients' guts^6,7. The quorum-sensing molecule AI-2 contributes to gut microbiome dysbiosis, yet its role in critical illness is poorly understood^8,9. This project aims to understand the contribution of altered Enterobacteriaceae AI-2 signalling towards gut microbiome dysbiosis and host immune dysfunction in critical illness. We will screen a library of ICU-patient-derived Enterobacteriaceae isolates and bioreactor-cultured fecal microbiomes against healthy human-derived samples to assess AI-2 concentration and activity. Next, we will utilize AI-2-deficient mutant bacteria and over-expressing controls to test whether AI-2 enables pathobiont overgrowth in germ-free and gnotobiotic mice. Lastly, we will use patient isolates and mutants to determine the impact of AI-2 on the host immune response to ICU gut microbiome dysbiosis in gnotobiotic mice. Through this, the effects of AI-2 signalling on pathogenic gut bacteria colonization resistance, inflammation, and patient outcomes will be defined. Our results will provide a mechanistic understanding of the role of gut dysbiosis in adverse outcomes in ICU patients and inform the development of targeted treatments or biomarkers for this patient population.