PMID- 29029005
OWN - NLM
STAT- MEDLINE
DCOM- 20180905
LR  - 20190410
IS  - 1876-4479 (Electronic)
IS  - 1873-9946 (Linking)
VI  - 12
IP  - 2
DP  - 2018 Jan 24
TI  - Biopsy-derived Intestinal Epithelial Cell Cultures for Pathway-based
      Stratification of Patients With Inflammatory Bowel Disease.
PG  - 178-187
LID - 10.1093/ecco-jcc/jjx122 [doi]
AB  - Background: Endoplasmic reticulum [ER] stress was shown to be pivotal in the
      pathogenesis of inflammatory bowel disease. Despite progress in inflammatory
      bowel disease [IBD] drug development, not more than one-third of patients achieve
      steroid-free remission and mucosal healing with current therapies. Furthermore,
      patient stratification tools for therapy selection are lacking. We aimed to
      identify and quantify epithelial ER stress in a patient-specific manner in an
      attempt towards personalised therapy. Methods: A biopsy-derived intestinal
      epithelial cell culture system was developed and characterised. ER stress was
      induced by thapsigargin and quantified with a BiP enzyme-linked immunosorbent
      assay [ELISA] of cell lysates from 35 patients with known genotypes, who were
      grouped based on the number of IBD-associated ER stress and autophagy risk
      alleles. Results: The epithelial character of the cells was confirmed by
      E-cadherin, ZO-1, and MUC2 staining and CK-18, CK-20, and LGR5 gene expression.
      Patients with three risk alleles had higher median epithelial BiP-induction [vs
      untreated] levels compared with patients with one or two risk alleles [p = 0.026 
      and 0.043, respectively]. When autophagy risk alleles were included and patients 
      were stratified in genetic risk quartiles, patients in Q2, Q3, and Q4 had
      significantly higher ER stress [BiP] when compared with Q1 [p = 0.034, 0.040, and
      0.034, respectively]. Conclusions: We developed and validated an ex vivo
      intestinal epithelial cell culture system and showed that patients with more ER
      stress and autophagy risk alleles have augmented epithelial ER stress responses. 
      We thus presented a personalised approach whereby patient-specific defects can be
      identified, which in turn could help in selecting tailored therapies.
CI  - Copyright (c) 2017 European Crohn's and Colitis Organisation (ECCO). Published by
      Oxford University Press. All rights reserved. For permissions, please email:
      journals.permissions@oup.com
FAU - Vanhove, Wiebe
AU  - Vanhove W
AD  - Translational Research in Gastrointestinal Disorders [TARGID], Department of
      Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
FAU - Nys, Kris
AU  - Nys K
AD  - Translational Research in Gastrointestinal Disorders [TARGID], Department of
      Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
FAU - Arijs, Ingrid
AU  - Arijs I
AD  - Translational Research in Gastrointestinal Disorders [TARGID], Department of
      Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
AD  - Faculty of Medicine and Life Sciences, Hasselt University, Hasselt, Belgium;
      Jessa Hospital, Hasselt, Belgium.
FAU - Cleynen, Isabelle
AU  - Cleynen I
AD  - Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Leuven,
      Belgium.
FAU - Noben, Manuel
AU  - Noben M
AD  - Translational Research in Gastrointestinal Disorders [TARGID], Department of
      Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
AD  - Department of Development and Regeneration, Stem Cell Institute Leuven, KU
      Leuven, Leuven, Belgium.
FAU - De Schepper, Sebastiaan
AU  - De Schepper S
AD  - Translational Research in Gastrointestinal Disorders [TARGID], Department of
      Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
FAU - Van Assche, Gert
AU  - Van Assche G
AD  - Translational Research in Gastrointestinal Disorders [TARGID], Department of
      Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
AD  - Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU
      Leuven, Leuven, Belgium.
FAU - Ferrante, Marc
AU  - Ferrante M
AD  - Translational Research in Gastrointestinal Disorders [TARGID], Department of
      Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
AD  - Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU
      Leuven, Leuven, Belgium.
FAU - Vermeire, Severine
AU  - Vermeire S
AD  - Translational Research in Gastrointestinal Disorders [TARGID], Department of
      Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
AD  - Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU
      Leuven, Leuven, Belgium.
LA  - eng
GR  - 694679/European Research Council/International
PT  - Journal Article
PT  - Validation Studies
PL  - England
TA  - J Crohns Colitis
JT  - Journal of Crohn's & colitis
JID - 101318676
RN  - 0 (ATG16L1 protein, human)
RN  - 0 (Autophagy-Related Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Keratin-18)
RN  - 0 (Keratin-20)
RN  - 0 (LGR5 protein, human)
RN  - 0 (Membrane Proteins)
RN  - 0 (ORMDL3 protein, human)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (X-Box Binding Protein 1)
RN  - 0 (XBP1 protein, human)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog)
RN  - EC 2.7.11.1 (LRRK2 protein, human)
RN  - EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2)
RN  - EC 2.7.11.1 (ULK1 protein, human)
RN  - EC 3.1.3.48 (MTMR3 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - EC 3.6.1.- (IRGM protein, human)
RN  - YCYIS6GADR (molecular chaperone GRP78)
SB  - IM
MH  - Adult
MH  - Alleles
MH  - Autophagy/*genetics
MH  - Autophagy-Related Protein-1 Homolog/genetics
MH  - Autophagy-Related Proteins/genetics
MH  - Biopsy
MH  - Cells, Cultured
MH  - Endoplasmic Reticulum Stress/drug effects/*genetics
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial Cells/metabolism/*physiology
MH  - Female
MH  - GTP-Binding Proteins/genetics
MH  - Genotype
MH  - Heat-Shock Proteins/genetics
MH  - Humans
MH  - Inflammatory Bowel Diseases/*genetics/*pathology
MH  - Intestinal Mucosa/*pathology
MH  - Intracellular Signaling Peptides and Proteins/genetics
MH  - Keratin-18/genetics
MH  - Keratin-20/genetics
MH  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics
MH  - Male
MH  - Membrane Proteins/genetics
MH  - Middle Aged
MH  - Patient Selection
MH  - Precision Medicine
MH  - Protein Tyrosine Phosphatases, Non-Receptor/genetics
MH  - RNA, Messenger/metabolism
MH  - Receptors, G-Protein-Coupled/genetics
MH  - Thapsigargin/pharmacology
MH  - X-Box Binding Protein 1/genetics
PMC - PMC6443034
MID - EMS77484
OTO - NOTNLM
OT  - ER stress
OT  - IBD
OT  - epithelial cell culture
EDAT- 2017/10/14 06:00
MHDA- 2018/09/06 06:00
CRDT- 2017/10/14 06:00
PHST- 2017/03/24 00:00 [received]
PHST- 2017/09/19 00:00 [accepted]
PHST- 2017/10/14 06:00 [pubmed]
PHST- 2018/09/06 06:00 [medline]
PHST- 2017/10/14 06:00 [entrez]
AID - 4210679 [pii]
AID - 10.1093/ecco-jcc/jjx122 [doi]
PST - ppublish
SO  - J Crohns Colitis. 2018 Jan 24;12(2):178-187. doi: 10.1093/ecco-jcc/jjx122.