Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response That Drives Goblet Cell Necroptosis and Spontaneous Colitis in MiceSummary
Background & Aims: Patients with ulcerative colitis have low concentrations of the major membrane lipid phosphatidylcholine (PC) in gastrointestinal mucus, suggesting that defects in colonic PC metabolism might be involved in the development of colitis. To determine the precise role that PC...
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Elsevier
2021-01-01
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Series: | Cellular and Molecular Gastroenterology and Hepatology |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X20301855 |
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doaj-13b401fe7615444286f1361c641b7deb |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
John P. Kennelly Stephanie Carlin Tingting Ju Jelske N. van der Veen Randal C. Nelson Jean Buteau Aducio Thiesen Caroline Richard Ben P. Willing René L. Jacobs |
spellingShingle |
John P. Kennelly Stephanie Carlin Tingting Ju Jelske N. van der Veen Randal C. Nelson Jean Buteau Aducio Thiesen Caroline Richard Ben P. Willing René L. Jacobs Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response That Drives Goblet Cell Necroptosis and Spontaneous Colitis in MiceSummary Cellular and Molecular Gastroenterology and Hepatology Phosphatidylcholine Inflammation Colon Mouse Model Lipid |
author_facet |
John P. Kennelly Stephanie Carlin Tingting Ju Jelske N. van der Veen Randal C. Nelson Jean Buteau Aducio Thiesen Caroline Richard Ben P. Willing René L. Jacobs |
author_sort |
John P. Kennelly |
title |
Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response That Drives Goblet Cell Necroptosis and Spontaneous Colitis in MiceSummary |
title_short |
Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response That Drives Goblet Cell Necroptosis and Spontaneous Colitis in MiceSummary |
title_full |
Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response That Drives Goblet Cell Necroptosis and Spontaneous Colitis in MiceSummary |
title_fullStr |
Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response That Drives Goblet Cell Necroptosis and Spontaneous Colitis in MiceSummary |
title_full_unstemmed |
Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response That Drives Goblet Cell Necroptosis and Spontaneous Colitis in MiceSummary |
title_sort |
intestinal phospholipid disequilibrium initiates an er stress response that drives goblet cell necroptosis and spontaneous colitis in micesummary |
publisher |
Elsevier |
series |
Cellular and Molecular Gastroenterology and Hepatology |
issn |
2352-345X |
publishDate |
2021-01-01 |
description |
Background & Aims: Patients with ulcerative colitis have low concentrations of the major membrane lipid phosphatidylcholine (PC) in gastrointestinal mucus, suggesting that defects in colonic PC metabolism might be involved in the development of colitis. To determine the precise role that PC plays in colonic barrier function, we examined mice with intestinal epithelial cell (IEC)-specific deletion of the rate-limiting enzyme in the major pathway for PC synthesis: cytidine triphosphate:phosphocholine cytidylyltransferase-α (CTαIKO mice). Methods: Colonic tissue of CTαIKO mice and control mice was analyzed by histology, immunofluorescence, electron microscopy, quantitative polymerase chain reaction, Western blot, and thin-layer chromatography. Histopathologic colitis scores were assigned by a pathologist blinded to the experimental groupings. Intestinal permeability was assessed by fluorescein isothiocyanate–dextran gavage and fecal microbial composition was analyzed by sequencing 16s ribosomal RNA amplicons. Subsets of CTαIKO mice and control mice were treated with dietary PC supplementation, antibiotics, or 4-phenylbutyrate. Results: Inducible loss of CTα in the intestinal epithelium reduced colonic PC concentrations and resulted in rapid and spontaneous colitis with 100% penetrance in adult mice. Colitis development in CTαIKO mice was traced to a severe and unresolving endoplasmic reticulum stress response in IECs with altered membrane phospholipid composition. This endoplasmic reticulum stress response was linked to the necroptotic death of IECs, leading to excessive loss of goblet cells, formation of a thin mucus barrier, increased intestinal permeability, and infiltration of the epithelium by microbes. Conclusions: Maintaining the PC content of IEC membranes protects against colitis development in mice, showing a crucial role for IEC phospholipid equilibrium in colonic homeostasis. SRA accession number: PRJNA562603. |
topic |
Phosphatidylcholine Inflammation Colon Mouse Model Lipid |
url |
http://www.sciencedirect.com/science/article/pii/S2352345X20301855 |
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doaj-13b401fe7615444286f1361c641b7deb2021-03-25T04:30:19ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-011149991021Intestinal Phospholipid Disequilibrium Initiates an ER Stress Response That Drives Goblet Cell Necroptosis and Spontaneous Colitis in MiceSummaryJohn P. Kennelly0Stephanie Carlin1Tingting Ju2Jelske N. van der Veen3Randal C. Nelson4Jean Buteau5Aducio Thiesen6Caroline Richard7Ben P. Willing8René L. Jacobs9Group on the Molecular and Cell Biology of Lipids, Edmonton, Alberta, Canada; Department of Agricultural, Food and Nutritional Science, Edmonton, Alberta, CanadaGroup on the Molecular and Cell Biology of Lipids, Edmonton, Alberta, Canada; Department of Agricultural, Food and Nutritional Science, Edmonton, Alberta, CanadaDepartment of Agricultural, Food and Nutritional Science, Edmonton, Alberta, CanadaGroup on the Molecular and Cell Biology of Lipids, Edmonton, Alberta, Canada; Department of Biochemistry, Edmonton, Alberta, CanadaGroup on the Molecular and Cell Biology of Lipids, Edmonton, Alberta, Canada; Department of Agricultural, Food and Nutritional Science, Edmonton, Alberta, Canada; Department of Biochemistry, Edmonton, Alberta, CanadaDepartment of Agricultural, Food and Nutritional Science, Edmonton, Alberta, CanadaDepartment of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, CanadaGroup on the Molecular and Cell Biology of Lipids, Edmonton, Alberta, Canada; Department of Agricultural, Food and Nutritional Science, Edmonton, Alberta, CanadaDepartment of Agricultural, Food and Nutritional Science, Edmonton, Alberta, CanadaGroup on the Molecular and Cell Biology of Lipids, Edmonton, Alberta, Canada; Department of Agricultural, Food and Nutritional Science, Edmonton, Alberta, Canada; Department of Biochemistry, Edmonton, Alberta, Canada; Correspondence Address correspondence to: René L. Jacobs, PhD, Department of Agricultural, Food and Nutritional Science, 4-002E Li Ka Shing Centre for Health Research and Innovation, University of Alberta, Alberta, T6G2E1 Canada. fax: (780) 492-2343.Background & Aims: Patients with ulcerative colitis have low concentrations of the major membrane lipid phosphatidylcholine (PC) in gastrointestinal mucus, suggesting that defects in colonic PC metabolism might be involved in the development of colitis. To determine the precise role that PC plays in colonic barrier function, we examined mice with intestinal epithelial cell (IEC)-specific deletion of the rate-limiting enzyme in the major pathway for PC synthesis: cytidine triphosphate:phosphocholine cytidylyltransferase-α (CTαIKO mice). Methods: Colonic tissue of CTαIKO mice and control mice was analyzed by histology, immunofluorescence, electron microscopy, quantitative polymerase chain reaction, Western blot, and thin-layer chromatography. Histopathologic colitis scores were assigned by a pathologist blinded to the experimental groupings. Intestinal permeability was assessed by fluorescein isothiocyanate–dextran gavage and fecal microbial composition was analyzed by sequencing 16s ribosomal RNA amplicons. Subsets of CTαIKO mice and control mice were treated with dietary PC supplementation, antibiotics, or 4-phenylbutyrate. Results: Inducible loss of CTα in the intestinal epithelium reduced colonic PC concentrations and resulted in rapid and spontaneous colitis with 100% penetrance in adult mice. Colitis development in CTαIKO mice was traced to a severe and unresolving endoplasmic reticulum stress response in IECs with altered membrane phospholipid composition. This endoplasmic reticulum stress response was linked to the necroptotic death of IECs, leading to excessive loss of goblet cells, formation of a thin mucus barrier, increased intestinal permeability, and infiltration of the epithelium by microbes. Conclusions: Maintaining the PC content of IEC membranes protects against colitis development in mice, showing a crucial role for IEC phospholipid equilibrium in colonic homeostasis. SRA accession number: PRJNA562603.http://www.sciencedirect.com/science/article/pii/S2352345X20301855PhosphatidylcholineInflammationColonMouse ModelLipid |