Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability

Abstract

Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long‐chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very‐long acyl chain ceramides with concomitant increase of long chain bases and C16‐ceramides, were more susceptible to dextran sodium sulphate‐induced colitis, and their survival rate was markedly decreased compared with that of wild‐type littermates. Using mixed bone‐marrow chimeric mice, we showed that the host environment is primarily responsible for intestinal barrier dysfunction and increased intestinal permeability. In the colon of CerS2 null mice, the expression of junctional adhesion molecule‐A was markedly decreased and the phosphorylation of myosin light chain 2 was increased. In vitro experiments using Caco‐2 cells also confirmed an important role of CerS2 in maintaining epithelial barrier function; CerS2‐knockdown via CRISPR‐Cas9 technology impaired barrier function. In vivo myriocin administration, which normalized long‐chain bases and C16‐ceramides of the colon of CerS2 null mice, increased intestinal permeability as measured by serum FITC‐dextran levels, indicating that altered SLs including deficiency of very‐long‐chain ceramides are critical for epithelial barrier function. In conclusion, deficiency of CerS2 influences intestinal barrier function and the severity of experimental colitis and may represent a potential mechanism for inflammatory bowel disease pathogenesis.

Effect of N‐palmitoylethanolamine‐oxazoline on comorbid neuropsychiatric disturbance associated with inflammatory bowel disease

“…with comorbidities is the loss of intestinal permeability barrier triggered by an alteration in TJ expression such as ZO-1 and occludin. 30,[53][54][55][56] The maintenance of the intestinal epithelial barrier mainly depends on the dynamic F I G U R E 1 1 Effect of PEAOXA on neuronal activation and neurotrophic factor after colitis. Immunofluorescence of NeuN in Sham (A), DSS (B), and PEAOXA (C).…”

“…(mol mass 4.4 and 40 kDa; Sigma) administered by gavage (0.6 g/kg bodyweight in 0.1 mL in PBS) as described previously. 30…”

Knockout of Ceramide Kinase Aggravates Pathological and Lethal Responses in Mice with Experimental Colitis

“…46) Previous studies revealed that sphingolipids are involved in IBD including UC. The depletion of SphK-1, 7,25) S1P phosphatase-2 mainly expressed in gut tissues, 9) and sphingomyelin synthase-2 10) prevented DSS-induced colitis in mice, whereas colitis was enhanced in gut-specific conditional S1P lyase knockout mice. 47) The loss of S1P phosphatase-1, 9) ceramide synthase-2, 11) alkaline ceramidase-3, 26) and neutral ceramidase 48) exacerbated DSSinduced colitis in mice.…”

“…30) A treatment with DSS changed immune cell homeostasis and inflammation-related gene expression in tissues and individuals, and these changes were different in mice showing modified sphingolipid metabolism. 7,10,12,14,25,44) C1P and/or C1P-regulated cytokines modify the migration of various cells. 14) Changes in immune cell homeostasis, the cytokine balance, and cell migration in DSStreated CerK (−/−) mice need to be examined in more detail in future studies.…”

“…8,9) Thus, the SphK-1/S1P/S1P receptor pathway appears to enhance the severity of colitis. In contrast, the deletion of S1P phosphatase-2 9) and sphingomyelin synthase-2 10) suppressed dextran sodium sulfate (DSS)-induced colitis in mice. A ceramide synthase-2 deficiency was shown to exacerbate DSSinduced colitis.…”