title: Deciphering the role of the presenilins Psen1 and Psen2 in intestinal epithelial homeostasis and inflammation
Creators: name: Erkert, Lena
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 2024

description: Intestinal epithelial cells (IECs) form a protective barrier against harmful pathogens present in the intestinal lumen, while acting as a communication platform between the microbiome in the lumen and adjacent immune cells in the lamina propria. Tight control of IEC differentiation, proliferation and death is therefore essential to ensure intestinal homeostasis. If the balance between these vitally important processes is disturbed, intestinal pathologies such as inflam-matory bowel diseases (IBD) can result. To date, the pathophysiology of IBD is incompletely understood and requires further investigation. However, several factors have been identified that contribute to disease pathology, including genetic and environmental factors, such as al-terations in the microbiome that induce the recruitment of mucosal immune cells to the in-flamed areas, ultimately leading to barrier defects. In this context, different human studies have already identified various risk genes associated with IBD. Preliminary analysis by our group of RNA sequencing data from inflamed tissue of mice with experimentally induced colitis identified, for the first time, deregulation of several molecules involved in the Alzheimer’s Dis-ease pathway, including the presenilin Psen1 and Psen2. Although presenilins are well studied molecules in the brain due to their association with Alzheimer's disease and their important function in the γ-secretase complex, their role in the gut remains largely unknown. Therefore, the aim of this work was to verify the hypothesis that presenilins play an important role during intestinal homeostasis and under inflammatory conditions. To this end, an IEC-specific Psen1 deletion in mice (Psen1ΔIEC) was established. The absence of Psen1 in IECs had no effect on cell differentiation, proliferation or death, which could be explained by a compensatory overex-pression of Psen2. Based on these findings, an inducible Psen1/Psen2 double knockout (Psen2-/- Psen1iΔIEC) mouse line was established. Mice lacking both presenilins in the intestinal epitheli-um rapidly and severely lost weight and developed spontaneous intestinal inflammation. In addition, Psen2-/- Psen1iΔIEC mice showed a breakdown of the intestinal barrier with bacterial translocation into the lamina propria. However, attempts to rescue the observed phenotype by antibiotic treatment to eliminate the microbiota improved the inflammatory signature but not the wasting disease. Most importantly, Psen2-/- Psen1iΔIEC mice showed a disturbance of IEC differentiation, with a significant upregulation of the number of secretory cells and an almost complete loss of absorptive enterocytes. This alteration in cell composition might be responsi-ble for the observed wasting disease, attributed to compromised nutrient uptake. Molecularly, the present thesis was able to demonstrate that the observed phenotype is mainly the result of a complete blockade of Notch signaling. In conclusion, this work has identified the prese-nilins Psen1 and Psen2 as important molecules in the maintenance of intestinal homeostasis. Their absence results in barrier breakdown with subsequent bacterial translocation, goblet cell hyperplasia and, most importantly, absorptive enterocyte hypoplasia and hence malnutrition.