Match!

Genetic Mouse Models with Intestinal-Specific Tight Junction Deletion Resemble an Ulcerative Colitis Phenotype

Published on Oct 1, 2017in Journal of Crohns & Colitis7.827
· DOI :10.1093/ecco-jcc/jjx075
Wolfgang Stremmel75
Estimated H-index: 75
,
Simone Staffer5
Estimated H-index: 5
+ 8 AuthorsThomas Efferth67
Estimated H-index: 67
Abstract
A key pathogenetic feature of ulcerative colitis [UC] is an intrinsic low mucus phosphatidylcholine[PC] content. Recently, a paracellular transport for PC across tight junctions[TJs] was described, suggesting TJ disturbance as a cause of diminished luminal PC transport. Therefore, we aimed to generate mutant mice with TJ deletion to evaluate whether a UC phenotype developed.CL57BL/6 control wild-type mice were compared to mutant mice with tamoxifen-induced villin-Cre-dependent intestinal deletion of kindlin 1 and 2.Electron microscopy of mucosal biopsies obtained from both mutants before overt inflammation following only 2 days of tamoxifen exposure revealed a defective TJ morphology with extended paracellular space and, by light microscopy, expanded mucosal crypt lumina. PC secretion into mucus was reduced by >65% and the mucus PC content dropped by >50%, causing a >50 % decrease of mucus hydrophobicity in both mutants. Consequently, the microbiota was able to penetrate the submucosa. After 3 days of tamoxifen exposure, intestinal inflammation was present in both mutants, with loose bloody stools as well as macroscopic and histological features of colitis. Oral PC supplementation was able to suppress inflammation. By analogy, colonic biopsies obtained from patients with UC in remission also showed a defective epithelium with widened intercellular clefts, and enlarged crypt luminal diameters with functionally impaired luminal PC secretion.Genetic mouse models with intestinal deletion of kindlin 1 and 2 resulted in TJ deletion and revealed pathophysiological features of impaired PC secretion to the mucus leading to mucosal inflammation compatible with human UC.
  • References (47)
  • Citations (5)
📖 Papers frequently viewed together
14 Citations
201536.22Cell
143 Citations
19 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References47
Newest
#1Agatha Korytowski (Heidelberg University)H-Index: 3
#2Wasim Abuillan (Heidelberg University)H-Index: 6
Last. Motomu Tanaka (Kyoto University)H-Index: 28
view all 9 authors...
Abstract The accumulation of phosphatidylcholine (PC) in the intestinal mucus layer is crucial for the protection of colon epithelia from the bacterial attack. It has been reported that the depletion of PC is a distinct feature of ulcerative colitis. Here we addressed the question how PC interacts with its binding proteins, the mucins, which may establish the hydrophobic barrier against colonic microbiota. In the first step, the interactions of dioleoylphosphatidylcholine (DOPC) with two mucin p...
4 CitationsSource
#1Wolfgang StremmelH-Index: 75
#2Simone StafferH-Index: 5
Last. Daniel HornussH-Index: 1
view all 6 authors...
1 CitationsSource
#1Wolfgang StremmelH-Index: 75
#2Simone StafferH-Index: 5
Last. Annika GaussH-Index: 8
view all 6 authors...
Phosphatidylcholine (PC) is the most abundant phospholipid in intestinal mucus, indicative of a specific transport system across the mucosal epithelium to the intestinal lumen. To elucidate this transport mechanism, we employed a transwell tissue culture system with polarized CaCo2 cells. It was shown that PC could not substantially be internalized by the cells. However, after basal application of increasing PC concentrations, an apical transport of 47.1 ± 6.3 nmol h− 1 mM PC− 1 was observed. Eq...
7 CitationsSource
#1Susan Prattis (AUB: American University of Beirut)H-Index: 1
#2Abdo Jurjus (AUB: American University of Beirut)H-Index: 17
Inflammatory Bowel Disease (IBD) is a multifactorial disorder with many different putative influences mediating disease onset, severity, progression and diminution. Spontaneous natural IBD is classically expressed as Crohn’s Disease (CD) and Ulcerative Colitis (UC) commonly found in primates; lymphoplasmocytic enteritis, eosinophilic gastritis and colitis, and ulcerative colitis with neuronal hyperplasia in dogs; and colitis in horses. Spontaneous inflammatory bowel disease has been noted in a n...
9 CitationsSource
#1Silvia Tietz (University of Bern)H-Index: 3
#2Britta Engelhardt (University of Bern)H-Index: 73
Unique intercellular junctional complexes between the central nervous system (CNS) microvascular endothelial cells and the choroid plexus epithelial cells form the endothelial blood–brain barrier (BBB) and the epithelial blood–cerebrospinal fluid barrier (BCSFB), respectively. These barriers inhibit paracellular diffusion, thereby protecting the CNS from fluctuations in the blood. Studies of brain barrier integrity during development, normal physiology, and disease have focused on BBB and BCSFB ...
128 CitationsSource
#1Declan F. McCole (UCR: University of California, Riverside)H-Index: 7
Technological advances in the large scale analysis of human genetics have generated profound insights into possible genetic contributions to chronic diseases including the inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis. To date, 163 distinct genetic risk loci have been associated with either Crohn’s disease or ulcerative colitis, with a substantial degree of genetic overlap between these 2 conditions. Although many risk variants show a reproducible correlation with di...
47 CitationsSource
OBJECTIVES: Phosphatidylcholine is a key component of the mucosal barrier. Treatment with modified release phosphatidylcholine aims to improve the impaired barrier function. The primary objective is to evaluate the efficacy of LT-02, a newly designed modified release phosphatidylcholine formula, in a multicenter setting. METHODS: This is a double-blinded, randomized, placebo-controlled, superiority study conducted in 24 ambulatory referral centers in Germany, Lithuania, and Romania. A total of 1...
51 CitationsSource
#1Wolfgang Stremmel (University Hospital Heidelberg)H-Index: 75
#2Simone Staffer (University Hospital Heidelberg)H-Index: 1
Last. Walee Chamulitrat (University Hospital Heidelberg)H-Index: 20
view all 5 authors...
Excess hepatic fat accumulation leads to nonalcoholic steatohepatitis (NASH), a serious threat to health for which no effective treatment is available. However, the mechanism responsible for fatty acid uptake by hepatocytes remains unclear. Using the human hepatocyte-derived tumor cell line HepG2, we found that fatty acid influx is mediated by a heterotetrameric plasma membrane protein complex consisting of plasma membrane fatty acid-binding protein, caveolin-1, CD36, and calcium-independent mem...
17 CitationsSource
#1Emanuel Rognoni (MPG: Max Planck Society)H-Index: 15
#2Moritz Widmaier (MPG: Max Planck Society)H-Index: 5
Last. Reinhard Fässler (MPG: Max Planck Society)H-Index: 99
view all 11 authors...
Mutations in Kindlin-1 result in Kindler syndrome, which is marked by skin blistering, premature skin aging and increased risk for skin cancer. Reinhard Fassler and his colleagues have developed a new mouse model of the condition, revealing new cellular and molecular mechanistic insight into the pathology of the syndrome.
65 CitationsSource
#1Bertha C. EliasH-Index: 9
#2Sijo MathewH-Index: 13
Last. Roy ZentH-Index: 43
view all 11 authors...
Epithelial cells lining the gastrointestinal tract and kidney have different abilities to facilitate paracellular and transcellular transport of water and solutes. In the kidney, the proximal tubule allows both transcellular and paracellular transport, while the collecting duct primarily facilitates transcellular transport. The claudins and E-cadherin are major structural and functional components regulating paracellular transport. In this study we present the novel finding that the transmembran...
27 CitationsSource
Cited By5
Newest
#1Yulin Huang (NU: Nanjing University)H-Index: 2
#2Chenchen Wang (NU: Nanjing University)H-Index: 2
Last. Zhengliang Ma (NU: Nanjing University)H-Index: 11
view all 8 authors...
Impaired intestinal mucosal integrity during colitis involves the peroxisome proliferator-activated receptor-γ (PPARγ), an important anti-inflammatory factor in intestinal mucosa homoeostasis, which is a potential target in colitis. Recurrent chronic pain is a vital pathogenetic feature of colitis. Nevertheless, potential functions of PPARγ in the colitis-associated hyperalgesia remain unclear. This study aimed to investigate biological roles of pioglitazone in relieving colitis-associated pain ...
Source
Phosphatidylcholine (PC) translocation into mucus of the intestine was shown to occur via a paracellular transport across the apical/lateral tight junction (TJ) barrier. In case this could also be operative in biliary epithelial cells, this may have implication for the pathogenesis of primary sclerosing cholangitis (PSC). We here evaluated the transport of PC across polarized cholangiocytes. Therefore, the biliary tumor cell line Mz-ChA-1 was grown to confluency. In transwell culture systems the...
Source
RESUME Les champignons microscopiques ou micromycetes representent une fraction peu abondante du microbiote, identifiee comme le « mycobiote », et estimee a moins de 0.1 % de la biosphere microbienne de l’intestin. Des travaux recents suggerent que des modifications de la composition du mycobiote jouent un role dans la physiopathologie de nombreuses affections dont les maladies inflammatoires de l’intestin. Beaucoup de ces travaux mettent en avant une augmentation de la frequence de colonisation...
Source
#1Zhiqiang Li (SUNY Downstate Medical Center)H-Index: 20
#2Inamul Kabir (SUNY Downstate Medical Center)H-Index: 3
Last. Xian-Cheng Jiang (SUNY Downstate Medical Center)H-Index: 50
view all 7 authors...
Serine palmitoyltransferase (SPT) is the rate-limiting enzyme for sphingolipid biosynthesis. SPT has two major subunits, SPTLC1 and SPTLC2. We previously found that liver Sptlc2 deficiency in early life impairs the development of adherens junctions. Here, we investigated the role of Sptlc2 deficiency in intestine. We treated Sptlc2-Flox/villin-Cre-ERT2 mice with tamoxifen (days 1, 2, and 3) to ablate Sptlc2 specifically in the intestine. At day 6 after tamoxifen treatment, Sptlc2-deficient mice ...
4 CitationsSource
#1Nour Eissa (UM: University of Manitoba)H-Index: 11
#2Hayam Hussein (OSU: Ohio State University)H-Index: 6
Last. Jean-Eric GhiaH-Index: 24
view all 7 authors...
Ulcerative colitis (UC) is characterized by a functional dysregulation of alternatively activated macrophage (AAM) and intestinal epithelial cells (IECs) homeostasis. Chromogranin-A (CHGA) secreted by neuroendocrine cells is implicated in intestinal inflammation and immune dysregulation. CHGA undergoes proteolytic processing to generate CHGA-derived peptides. Chromofungin (CHR: CHGA47-66) is a short CHGA-derived peptide encoded by CHGA Exon-IV and is involved in innate immune regulation, but the...
12 CitationsSource
#1Wolfgang StremmelH-Index: 75
#2Simone StafferH-Index: 5
Last. Daniel HornussH-Index: 1
view all 7 authors...
Background: Attack by commensal microbiota is one component of induction of inflammatory episodes in ulcerative colitis (UC). In UC, the mucus layer is intrinsica
1 CitationsSource