Article Text
Abstract
Objective Mutations in presenilin genes are the major cause of Alzheimer’s disease. However, little is known about their expression and function in the gut. In this study, we identify the presenilins Psen1 and Psen2 as key molecules that maintain intestinal homoeostasis.
Design Human inflammatory bowel disease (IBD) and control samples were analysed for Psen1 expression. Newly generated intestinal epithelium-specific Psen1-deficient, Psen2-deficient and inducible Psen1/Psen2 double-deficient mice were used to dissect the functional role of presenilins in intestinal homoeostasis.
Results Psen1 expression was regulated in experimental gut inflammation and in patients with IBD. Induced deletion of Psen1 and Psen2 in mice caused rapid weight loss and spontaneous development of intestinal inflammation. Mice exhibited epithelial barrier disruption with bacterial translocation and deregulation of key pathways for nutrient uptake. Wasting disease was independent of gut inflammation and dysbiosis, as depletion of microbiota rescued Psen-deficient animals from spontaneous colitis development but not from weight loss. On a molecular level, intestinal epithelial cells lacking Psen showed impaired Notch signalling and dysregulated epithelial differentiation.
Conclusion Overall, our study provides evidence that Psen1 and Psen2 are important guardians of intestinal homoeostasis and future targets for barrier-promoting therapeutic strategies in IBD.
- GUT INFLAMMATION
- IBD BASIC RESEARCH
- INTESTINAL EPITHELIUM
- EPITHELIAL BARRIER
- MALNUTRITION
Data availability statement
Data are available in a public, open access repository. Data are available on reasonable request. Transcriptomic data of the IBDome cohort will be made available to the scientific community on acceptance of the manuscript. Bulk RNA sequencing data of Psen1 and Psen2 deficient mice have been submitted to ArrayExpress. The publicly available datasets used in this study are published under the accession codes: E-MTAB-9850 and GSE6731.