DOP51 Loss of PTPN23 in the intestinal epithelium results in epithelial hyperproliferation and lethal diarrhea in a microbiota dependent manner
Spalinger, M.(1);Sanchez Alvarez, R.(1);Gottier, C.(1);Montalban-Arques, A.(1);Schwarzfischer, M.(1);Niechcial, A.(1);Scharl, M.(1);
(1)University Hospital Zurich, Department of Gastroenterology and Hepatology, Zurich, Switzerland;
Background
Protein tyrosine phosphtase non-receptor type 23 (PTPN23) plays a critical role in regulating epidermal growth factor (EGF) receptor signaling and its loss has been associated with aberrant cell proliferation and promotes onset of epithelial cancers. However, the role of PTPN23 in the intestinal epithelium has not been investigated yet. Here, we investigated how PTPN23 deletion in intestinal epithelial cells (IEC) affects intestinal homeostasis.
Methods
To study the role of PTPN23 in the intestinal epithelium, we crossed mice with a LoxP flanked PTPN23 gene (PTPN23fl/fl mice) to mice expressing the CreERT construct under the villin promoter (PTPN23-VilCreERT mice). PTPN23 was deleted in IEC in these mice by tamoxifen-injections on five consecutive days. PTPN23 fl/fl mice injected with tamoxifen served as control.
Results
PTPN23 deletion in IEC resulted in drastic loss of weight starting around 10-14days after the first tamoxifen injection, eventually leading to death within 3-5 weeks due to severe wasting disease with severe diarrhea. Histology revealed massive hyper-proliferation of the colonic epithelium accompanied with elevated immune cell infiltration. In line with previous reports on the function of PTPN23, we observed highly elevated levels of EGF receptor, possibly accounting for the massive epithelial hyper-proliferation and aberrant water secretion/defective water resorption in these mice. Furthermore, we observed bacterial translocation to the spleen and the liver, indicating defective anti-bacterial defense in the intestinal epithelium of PTPN23-VilCreERT mice. In line with this, 16S sequencing revealed significant differences in the intestinal microbiome with an overgrowth of bacteria that have been reported to be heavily coated with IgA. PTPN23-VilCreERT mice showed reduced apical presence of the poly Ig receptor, a receptor that transports IgA from the lamina propria through IEC into the gut lumen. Notably, while serum IgA levels were normal, its levels in the stool were reduced, confirming defective transport of IgA into the gut lumen. In addition, autophagy was significantly reduced in PTPN23-VilCreERT mice when compared to their littermates. Of interest, antibiotic treatment was sufficient to prevent epithelial hyper-proliferation, diarrhea and death in PTPN23VilCreERT mice, indicating that this drastic phenotype was microbiota-dependent and likely the result of defects in bacterial handling.
Conclusion
Our results demonstrate that PTPN23 is indispensible for normal IEC function and its loss renders the intestinal epithelium unable to cope with invading bacteria. This uncovers a novel, so far unknown role of PTPN23 for regulating pathways involved in bacterial handling.