Beneficial role of a bacterial quorum sensing molecule in gut barrier integrity and inflammation during inflammatory bowel disease – QUOBII

Inflammatory bowel disease (IBD) is a multifactorial pathology characterized by impairment of the intestinal barrier and an excessive immune response to gut microbiota. The intestinal microbiota produces numerous metabolites and small molecules that are considered to be key players in microbiota-host interactions in health and disease. Quorum sensing (QS) is a density-dependent cell-cell communication system used by bacteria to orchestrate collective behaviors and whose impact on host cells has been little studied to date in the gut. Our team was pioneer in the identification of QS molecules belonging to the N-acyl-homoserine lactone (AHL) family in the healthy human gut ecosystem. Among them, we found that the most abundant one, 3-oxo-C12:2-HSL, an AHL never been described so far, was decreased in the gut of patients with IBD compared to healthy subjects, suggesting beneficial effects.
The QUOBII project aims to explore the role of 3-oxo-C12:2-HSL in the host-microbiota dialogue, and its potential therapeutic interest in IBD. Having demonstrated anti-inflammatory effects of 3-oxo-C12:2-HSL in immune cells and shown that it alleviates tight junction disruption in epithelial cells under inflammatory conditions, we hypothesize that 3-oxo-C12:2-HSL could protect the gut barrier integrity through a combined action on epithelial and immune cells. The specific objectives of the QUOBII project are 1) to identify the molecular mechanisms through which the 3-oxo-C12:2-HSL exerts direct effects on intestinal epithelial cells subjected to inflammatory cytokines and to characterize the anti-inflammatory properties of this AHL in immune cells from healthy subjects and IBD patients; 2) to study 3-oxo-C12:2-HSL beneficial effects in an integrated model of human colon inflammation using organ-on-chip technology with human colonic organoids, primary endothelial cells and immune cells from healthy and IBD patients; 3) to validate our observations in vivo in an enterocolitis model in zebrafish, allowing the assessment in real time of several parameters of the intestinal barrier, including oxidative stress and immune cell recruitment.
The project is based on a consortium of three partners who are already actively collaborating. Partner 1 (coordinator of the project) was pioneer in the characterization of human gut AHLs and their protective effects on host cells, including epithelial barrier function and cytokine production by immune cells. Partner 2 has extensive expertise in gut-on-chip models, and has already developed and used them successfully in host-pathogen studies. Partner 3 is specialized in oxidative stress and perfectly masters zebrafish models, which are emerging as a model of choice for real-time in vivo studies of intestinal inflammation. QUOBII project will expand our knowledge of the epithelial-immune dialogue in the intestine and its modulation by microbiota-derived metabolites and will contribute to the discovery of therapeutic strategies to limit gut barrier alterations in IBD.