Commensal fungi promote wound repair by modulating host metabolites

Abstract The intestinal epithelium acts as a physical barrier to separate the luminal contents from the underlying tissue compartment of the organ. Typically, any damage caused by medications or environmental toxins is promptly repaired to maintain homeostasis. However, in chronic inflammatory conditions such as inflammatory bowel diseases (IBD), ability to heal wounds is dysregulated perpetuating chronic inflammation. Healthy endogenous microbiota is being increasingly recognized to promote repair, yet the specific mechanisms by which microbes guide repair remains elusive. Moreover, majority of the studies have focussed on bacteria, how nonbacterial members such as fungi modulate wound repair remains unknown. Using murine models of injury and repair and human isolates of fungi, we discovered that endogenous fungi are critical for crypt regeneration post injury. Importantly, the repair promoting effects were specific to the fungal strains that are depleted in IBD. Our preliminary data suggests that endogenous fungi engage epithelial cells to induce Palmitoylethanolamide (PEA), a lipid metabolite, which in turn inhibits inflammatory activation of fibroblasts to promote wound repair. Here we will use conditional knockout mice, single cell RNA sequencing, primary epithelial and fibroblast cultures, and metabolomics to investigate how endogenous fungi alter epithelial transcriptome to induce PEA (Aim 1) and the specific mechanisms by which PEA inhibits inflammatory activation of fibroblasts to promote repair. Successful completion of these aims will give a mechanistic understanding of a previously unappreciated role of endogenous fungi in modulating epithelial cells and fibroblasts to enhance intestinal wound repair. Additionally, it will uncover novel targets for stimulating crypt regeneration in inflammatory conditions of the gastrointestinal tract.