The Phospholipid Flippase ATP8B1 is Involved in the Pathogenesis of Ulcerative Colitis via Establishment of Intestinal Barrier Function

Patients with mutations in ATP8B1 develop progressive familial intrahepatic cholestasis type 1 [PFIC1], a severe liver disease that requires life-saving liver transplantation. PFIC1 patients also present with gastrointestinal problems, including intestinal inflammation and diarrhoea, which are aggra...

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Published in:	Journal of Crohn's and colitis Vol. 18; no. 7; pp. 1134 - 1146
Main Authors:	Koelink, Pim J, Gómez-Mellado, Valentina E, Duijst, Suzanne, van Roest, Manon, Meisner, Sander, Ho-Mok, Kam S, Frank, Sabrina, Appelman, Babette S, Bloemendaal, Lysbeth Ten, Vogel, Georg F, van de Graaf, Stan F J, Bosma, Piter J, Oude Elferink, Ronald P J, Wildenberg, Manon E, Paulusma, Coen C
Format:	Journal Article
Language:	English
Published:	England Oxford University Press 06-08-2024
Subjects:	Adenosine Triphosphatases - genetics Adenosine Triphosphatases - metabolism Animals Caco-2 Cells Cholestasis, Intrahepatic - genetics Cholestasis, Intrahepatic - metabolism Claudin-4 - genetics Claudin-4 - metabolism Colitis, Ulcerative - genetics Colitis, Ulcerative - metabolism Colitis, Ulcerative - pathology Crohn Disease - metabolism Crohn Disease - pathology Dextran Sulfate Disease Models, Animal Female Humans Intestinal Barrier Function - genetics Intestinal Mucosa - metabolism Intestinal Mucosa - pathology Male Mice Mice, Inbred C57BL Mice, Knockout Original Permeability Phospholipid Transfer Proteins - genetics Phospholipid Transfer Proteins - metabolism Tight Junctions - metabolism Intestinal Epithelial Barrier CLDN4 IBD ATP8B1 Ulcerative Colitis
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Summary:	Patients with mutations in ATP8B1 develop progressive familial intrahepatic cholestasis type 1 [PFIC1], a severe liver disease that requires life-saving liver transplantation. PFIC1 patients also present with gastrointestinal problems, including intestinal inflammation and diarrhoea, which are aggravated after liver transplantation. Here we investigate the intestinal function of ATP8B1 in relation to inflammatory bowel diseases. ATP8B1 expression was investigated in intestinal samples of patients with Crohn's disease [CD] or ulcerative colitis [UC] as well as in murine models of intestinal inflammation. Colitis was induced in ATP8B1-deficient mice with dextran sodium sulphate [DSS] and intestinal permeability was investigated. Epithelial barrier function was assessed in ATP8B1 knockdown Caco2-BBE cells. Co-immunoprecipitation experiments were performed in Caco2-BBE cells overexpressing ATP8B1-eGFP. Expression and localization of ATP8B1 and tight junction proteins were investigated in cells and in biopsies of UC and PFIC1 patients. ATP8B1 expression was decreased in UC and DSS-treated mice, and was associated with a decreased tight junctional pathway transcriptional programme. ATP8B1-deficient mice were extremely sensitive to DSS-induced colitis, as evidenced by increased intestinal barrier leakage. ATP8B1 knockdown cells showed delayed barrier establishment that affected Claudin-4 [CLDN4] levels and localization. CLDN4 immunohistochemistry showed a tight junctional staining in control tissue, whereas in UC and intestinal PFIC1 samples, CLDN4 was not properly localized. ATP8B1 is important in the establishment of the intestinal barrier. Downregulation of ATP8B1 levels in UC, and subsequent altered localization of tight junctional proteins, including CLDN4, might therefore be an important mechanism in UC pathophysiology.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Pim J Koelink and Valentina E Gómez-Mellado contributed equally.
ISSN:	1873-9946 1876-4479 1876-4479
DOI:	10.1093/ecco-jcc/jjae024