P039 Suppression of phospholipase A2 of intestinal microbiota by the phospholipid-bile acid conjugate ursodeoxycholate-lysophoshatidylethanolamide ameliorates mucosal inflammation in a genetic mouse model of ulcerative colitis

Stremmel, Wolfgang; Staffer, Simone; Stuhrmann, Nicole; Gauss, Annika; Burger, N.; Hornuß, Daniel

doi:10.1093/ecco-jcc/jjx002.165

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“…This was indeed, shown by oral application of the non-absorbable phospholipase inhibitor UDCA-LPE [a bile acid–phospholipid conjugate 47 ], underlining the proposed concept. 48 A complementary mode of action can be supposed by the data shown in the present study: the luminally applied PC may impact on phospholipase-carrying microbiota, abrogating their pathogenic activity by saturating their aggressiveness towards to the mucus PC shield.…”

Section: Discussionmentioning

confidence: 55%

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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Section: Discussionmentioning

confidence: 55%