ECCO Pioneer Award Functional assessment of the microbiome in persistent IBD-related psychological symptoms

Abstract

Abstract Background and Aims It is well established that patients with inflammatory bowel disease (IBD) experience psychological comorbidities, and that these symptoms persist upon remission of the IBD in more than 50% of patients. The mechanisms underlying this clinical association are unknown, which hampers to objectify the problem and limits the possibilities to intelligently consider targeted treatments. We recently observed behavioral anomalies and neuroinflammation in a mouse model of extinguished chronic colitis, enabling the fundamental study of psychological symptoms in IBD. Fueled by technical evolutions to characterize translationally active bacteria at the single-cell level, their importance in colitis, and a proof-of-concept stool transplantation experiment, the purpose of this project is to determine if specific bacterial functions drive persistent neuroinflammation upon IBD remission. Methods First, a state-of-the-art flow-cytometry based method will be used to temporally map translationally active bacteria during the course of extinguished chronic colitis. Second, the same functional microbial analysis will be achieved in human fecal samples of IBD patients in remission before and after treatment for fatigue, and results will be compared with persistent bacterial changes found in mouse flora. Finally, causality of associated bacteria to induce neuroinflammation will be tested by transplantation studies of bacterial communities isolated from the previous tasks. Anticipated Impact This research may impact the field in the short-term by creating solid scientific awareness that psychological comorbidities are intrinsically linked with IBD remission, and by more specifically attributing a role for specific bacterial functions in these symptoms. In addition, the technique applied may open novel insights for the IBD microbiome community. In the medium-term, this project aims to shed light on the actual bacterial mechanisms that lead to neuroinflammation and behavioral anomalies, which in the long-term could help identify biomarkers for diagnostic purposes or microbiome-related targets to design rational therapeutics for patients with IBD suffering from psychological comorbidities.