Organ-on-Chip (OoC) systems have become a promising tool for personalized medicine and drug development with advantages over conventional animal models and cell assays. However, the utility of OoCs in industrial...

Background and Aims Pain is a cardinal symptom in inflammatory bowel disease (IBD). An important structure in the transduction of pain signalling is the myenteric plexus (MP). Nevertheless, IBD-associated infiltration of the MP by immune cells lacks in-depth characterization. Herein we decipher intra- and periganglionic immune cell infiltrations in Crohn´s disease (CD) and ulcerative colitis (UC) and provide a comparison with murine models of colitis. Methods Full wall specimens of surgical colon resections served to examine immune cell populations by either conventional immunohistochemistry or immunofluorescence followed by either bright field or confocal microscopy. Results were compared to equivalent examinations in various murine models of intestinal inflammation. Results While the MP morphology was not significantly altered in IBD, we identified intraganglionic IBD-specific B-cell and monocyte-dominant cell infiltrations in CD. In contrast, UC-MPs were infiltrated by CD8 + T-cells and revealed a higher extent of ganglionic cell apoptosis. With regard to the murine models of intestinal inflammation, the chronic DSS-induced colitis model reflected CD (and to a lesser extent UC) best as it also showed increased monocytic infiltration as well as a modest B-cell and CD8 + T-cell infiltration. Conclusions In CD, MP was infiltrated by B cells and monocytes, while in UC mostly CD8 + cytotoxic T-cells were found. The chronic DSS-induced colitis is the mouse model reflecting best the MP-immune cell infiltrations representative for IBD.

ObjectivePsen1 was previously characterised as a crucial factor in the pathogenesis of neurodegeneration in patients with Alzheimer’s disease. Little, if any, is known about its function in the gut. Here, we uncovered an unexpected functional role of Psen1 in gut epithelial cells during intestinal tumourigenesis.DesignHuman colorectal cancer (CRC) and control samples were investigated for PSEN1 and proteins of theγ-secretase complex. Tumour formation was analysed in the AOM-DSS andApcmin/+mouse models using newly generated epithelial-specificPsen1deficient mice. Psen1 deficient human CRC cells were studied in a xenograft tumour model. Tumour-derived organoids were analysed for growth and RNA-Seq was performed to identify Psen1-regulated pathways. Tumouroids were generated to study EGFR activation and evaluation of the influence of prostanoids.ResultsPSEN1 is expressed in the intestinal epithelium and its level is increased in human CRC.Psen1-deficient mice developed only small tumours and human cancer cell lines deficient in Psen1 had a reduced tumourigenicity. Tumouroids derived fromPsen1-deficientApcmin/+mice exhibited stunted growth and reduced cell proliferation. On a molecular level, PSEN1 potentiated tumour cell proliferation via enhanced EGFR signalling and COX-2 production. Exogenous administration of PGE2reversed the slow growth of PSEN1 deficient tumour cells via PGE2receptor 4 (EP4) receptor signalling.ConclusionsPsen1 drives tumour development by increasing EGFR signalling via NOTCH1 processing, and by activating the COX-2-PGE2pathway. PSEN1 inhibition could be a useful strategy in treatment of CRC.