Exploring the impact of gut microbiota-derived octadecanoids on mucosal healing

forthcoming

The microbiota-host crosstalk is crucial for several processes in the gut and its dysregulation is a hallmark of diseases such as colorectal cancer (CRC) and inflammatory bowel disease (IBD). Despite its key relevance for a holistic understanding of human (patho)physiology, how this crosstalk affects the cellular and molecular programs in the intestine remains is yet to be fully understood, mainly due to a lack of suitable technologies and models. It is known that one of the ways that the gut microbiota interacts with the host is via metabolite production. Among these, octadecanoids, lipid mediators from 18-carbon (18-C) polyunsaturated fatty acids, are poorly studied in the context of the gut despite their high abundance and diversity. Studies on this topic have only focused on inflammation, neglecting the mucosal healing response, highly relevant for IBD outcome and CRC tumorigenesis. In GUTMATES, I will use a new zebrafish model of intestinal damage/regeneration- and organoid-based screening platforms, together with murine colitis models, spatial transcriptomics, metabolomics, metagenomics, and clinical readouts to visualize the effect of microbial octadecanoids in intestinal regeneration. This project will provide the first large-scale exploration of how these metabolites modulate the mucosal healing process in vivo, as well as giving a multi-omic atlas of the impact of selected 18-C compounds in the mouse colon during regeneration. My ultimate aim with GUTMATES is to have a comprehensive view of the mucosal healing landscape given by gut microbial octadecanoids, to eventually find compounds or microbes that can be exploited for regeneration-based therapies in IBD and biomarkers for CRC.