P095 The genetic risk in ER stress and autophagy translates into quantifiable epithelial ER stress levels in IBD patients
Vanhove W.*1, Nys K.1, Arijs I.1,2, Cleynen I.3, de Bruyn M.1,4, Korf H.1,5, Ferrante M.1,6, Van Assche G.1,6, Vermeire S.1,6
1KU Leuven, Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, Leuven, Belgium 2Hasselt University, Faculty of Medicine and Life Sciences, Hasselt, Belgium 3KU Leuven, Laboratory for Complex Genetics, Department of Human Genetics, Leuven, Belgium 4KU Leuven, Laboratory of Immunobiology, Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium 5KU Leuven, Hepatology, Department of Clinical and Experimental Medicine, Leuven, Belgium 6University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
The crucial role of the intestinal epithelium in IBD is underscored by association of epithelial homeostasis pathways such as bacterial sensing, autophagy and ER stress signaling. Reducing ER stress has therefore gained attention as a novel therapeutic approach. Nevertheless, molecular tools for patient stratification and therapeutic decision making are lacking.
Therefore, we wanted to study whether ER stress profiles could be quantified in patient-derived (
IBD patients (n=35) undergoing endoscopic evaluation were selected based on the number of IBD-associated ER stress risk alleles in
Median [IQR] Tg-mediated BiP-induction (vs. untreated) read-outs were 2.67 [1.01–6.07], 1.87 [1.50–3.16], 1.70 [1.32–2.41] and 4.48 [3.76–4.64] in IECs from patients carrying 0 (n=4), 1 (n=17), 2 (n=11) or 3 (n=3) ER stress risk alleles, respectively. Patients with 3 ER-stress-related risk alleles had significantly more epithelial ER stress (BiP) induction rates when compared to patients with 1 or 2 risk alleles (p=0.026 and 0.043, respectively). When risk alleles in autophagy genes were added, median [IQR] Tg-mediated BiP-induction read-outs were 1.34 [1.08–1.91], 2.16 [1.68–4.05], 3.60 [1.39–4.48] and 2.41 [1.61–3.27] in IECs from patients belonging to Q1 to Q4, respectively. Patients in Q2 (n=10), Q3 (n=7) and Q4 (n=10) had significantly higher ER stress induction rates when compared to Q1 (n=8) (p=0.034, 0.040 and 0.034, respectively).
IBD patients with an increased genetic risk for ER stress and autophagy have more ER stress as measured in patient-derived IECs. These patients would benefit most from ER stress reducing therapies such as tauroursodeoxycholic acid (TUDCA), which has already shown to reduce inflammation in murine IBD models. We thus present a novel tool for molecular characterization of IBD patients for which pilot studies should be considered.