Accumulation of phosphatidylcholine on gut mucosal surface is not dominated by electrostatic interactions

Korytowski, Agatha; Abuillan, Wasim; Amadei, Federico; Makky, Ali; Gumiero, A.; Sinning, Irmgard; Gauss, Annika; Stremmel, Wolfgang; Tanaka, Motomu

doi:10.1016/j.bbamem.2017.02.008

Cited by 24 publications

(23 citation statements)

References 28 publications

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“…PC appears to be the most abundant component of cellular membranes, comprising 40–50% of all cell phospholipids and found mainly in the outer leaflet of the plasma membrane [ 50 ]. Intestinal PC derives from the diet or from biosynthesis in the liver and enterocytes, followed by secretion into the intestinal lumen [ 50 , 102 ]. In mammals, the major means of PC biosynthesis are CDP-choline and the (phosphatidylethanolamine N-methyltransferase) PEMT pathways [ 50 , 103 ].…”

Section: Major Iecs’ Phospholipids Their Metabolism the Role In Ibd And Therapeutic Potentialmentioning

confidence: 99%

Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases

Boldyreva

Морозова

Saydakova³

et al. 2021

IJMS

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Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic inflammation within the gastrointestinal (GI) tract. Despite the significant progress in understanding the etiology and development of treatment strategies, IBD remain incurable for thousands of patients. Metabolic deregulation is indicative of IBD, including substantial shifts in lipid metabolism. Recent data showed that changes in some phospholipids are very common in IBD patients. For instance, phosphatidylcholine (PC)/phosphatidylethanolamine (PE) and lysophosphatidylcholine (LPC)/PC ratios are associated with the severity of the inflammatory process. Composition of phospholipids also changes upon IBD towards an increase in arachidonic acid and a decrease in linoleic and a-linolenic acid levels. Moreover, an increase in certain phospholipid metabolites, such as lysophosphatidylcholine, sphingosine-1-phosphate and ceramide, can result in enhanced intestinal inflammation, malignancy, apoptosis or necroptosis. Because some phospholipids are associated with pathogenesis of IBD, they may provide a basis for new strategies to treat IBD. Current attempts are aimed at controlling phospholipid and fatty acid levels through the diet or via pharmacological manipulation of lipid metabolism.

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Section: Major Iecs’ Phospholipids Their Metabolism the Role In Ibd And Therapeutic Potentialmentioning

confidence: 99%

Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases

Boldyreva

Морозова

Saydakova³

et al. 2021

IJMS

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“… 6 After translocation across the TJ complex, PC is first bound to membrane-associated mucin 3, from where it is handled to secretory mucin 2. 6 , 7 The PC–mucin 2 complex is capable of moving within the mucus distally along the colonic wall to the rectum. During this transport to the rectum, mucus PC can be broken down by ectophospholipases of the commensal bacterial flora similarly as was shown for Helicobacter pylori in the gastric mucosa.…”

Section: Introductionmentioning

confidence: 99%

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

Stremmel

Staffer

Schneider³

et al. 2017

Journal of Crohn's and Colitis

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Background and AimsA 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.MethodsCL57BL/6 control wild-type mice were compared to mutant mice with tamoxifen-induced villin-Cre-dependent intestinal deletion of kindlin 1 and 2.ResultsElectron 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.ConclusionsGenetic 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.

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“…It was shown that PC is translocated from systemic sources across tight junctions (TJ) to the luminal side of mucosal cells driven by a negative electrochemical gradient generated by the cystic fibrosis transmembrane conductance regulator (CFTR) [7]. After TJ translocation, PC is bound to membrane-associated mucin 3, from where it is handled to secretory mucin 2 [5,8]. The PC-mucin 2 complex moves within the upper mucus layer along the intestinal wall distally to the colon and rectum to provide sufficient hydrophobic protection against colonic microbiota.…”

Section: Introductionmentioning

confidence: 99%

Phospholipase A<sub>2</sub> of Microbiota as Pathogenetic Determinant to Induce Inflammatory States in Ulcerative Colitis: Therapeutic Implications of Phospholipase A<sub>2</sub> Inhibitors

Stremmel¹,

Staffer²,

Stuhrmann³

et al. 2017

Inflamm Intest Dis

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Background: Attack by commensal microbiota is one component of induction of inflammatory episodes in ulcerative colitis (UC). In UC, the mucus layer is intrinsically devoid of phosphatidylcholine (PC) resulting in low hydrophobicity which facilitates bacterial invasion. Colonic ectophospholipase-carrying bacterial strains are likely candidates to further thinning the PC mucus barrier and to precipitate inflammatory episodes. Objective: To evaluate the effect of phospholipase A₂ (PLA₂) inhibitors on inflammation in a genetic UC mouse model. Methods: As PLA₂ inhibitor, we applied the bile acid-phospholipid conjugate ursodeoxycholate-lysophosphatidylethanolamide (UDCA-LPE) or as control 5% Tween 80 by oral gavage to intestine-specific kindlin 2 knockout mice. Results: Luminal UDCA-LPE reduced the PLA₂ activity in stool by 36 ± 8%. Concomitantly no inflammatory phenotype was observed when compared to kindlin 2^(–/–) mice not treated with UDCA-LPE. The improvement was documented in regard to stool consistency, calprotectin levels in stool, and macroscopic/endoscopic as well as histologic features of the mucosa. The pattern of colonic microbiota distribution obtained in the UC phenotype mice was reversed by UDCA-LPE to the control mice pattern. Conclusion: The inhibition of the bacterial ectophospholipase A₂ activity improves mucosal inflammation in a genetic mouse model of UC. It is assumed that the remaining mucus PC shield is better preserved when luminal PLA₂ is suppressed.

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Accumulation of phosphatidylcholine on gut mucosal surface is not dominated by electrostatic interactions

Cited by 24 publications

References 28 publications

Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases

Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases

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

Phospholipase A<sub>2</sub> of Microbiota as Pathogenetic Determinant to Induce Inflammatory States in Ulcerative Colitis: Therapeutic Implications of Phospholipase A<sub>2</sub> Inhibitors

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