Assistant Professor Washington University, St. Louis Saint Louis, Missouri, United States
Disclosure(s):
Umang Jain, PhD: No relevant disclosure to display
Introduction/Rationale: Mucosal repair is compromised in inflammatory bowel diseases (IBD), contributing to ongoing and recurrent inflammation. Bacterial microbiota is known to influence mucosal repair in IBD, however, the role of non-bacterial members of the gut microbiota such as fungi remain largely undefined. We hypothesize that commensal fungi deliver essential regenerative signals that promote mucosal repair following injury.
Methods: Wild type SPF mice depleted of fungal microbiota or germ-free mice colonized with human isolates of commensal fungi were subjected to two distinct murine models of colonic repair. Healing response to commensal fungi was studied using RNA-seq, immunostaining and histological measurements (epithelial restitution and crypt regeneration). Metabolites were quantified via mass spectrometry. Expression of key lipid enzymes and receptors in the mucosa from human IBD patients was evaluated by qPCR and by interrogating published datasets.
Results: Intestinal wounds in mice lacking fungi exhibit impaired crypt regeneration compared to controls, a phenotype that was reversed by re-introduction of select human isolates of commensal fungi. Mechanistically, fungi suppressed colonic expression of N-acylethanolamine acid amidase (NAAA), the enzyme responsible for degrading N-acyl-ethanolamines (NAEs). Diminished NAAA caused an accumulation of the lipid mediator palmitoylethanolamide (PEA), which subsequently augmented crypt regeneration. We further show that PEA signals through PPAR to drive mucosal repair. Finally, analysis of the human IBD cohorts revealed disruption of the NAAA–PEA–PPAR axis within inflamed mucosal lesions, highlighting the clinical relevance of this pathway.
Conclusion: Our findings identify a novel fungal microbiota induced repair paradigm suggesting that fungal/NAAA/PEA axis might be a valuable target to promote healing.
