Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study

Abstract

Goal The aim of this study was to investigate gene expression levels of proteins involved in sphingosine-1-phosphate (S1P) metabolism and signaling in a pediatric inflammatory bowel disease (IBD) patient population. Background IBD is a debilitating disease affecting 0.4% of the US population. The incidence of IBD in childhood is rising. Identifying effective targeted therapies that can be used safely in young patients and developing tools for selecting specific candidates for targeted therapies are important goals. Clinical IBD trials now underway target S1PR1, a receptor for the pro-inflammatory sphingolipid S1P. However, circulating and tissue sphingolipid levels and S1P-related gene expression have not been characterized in pediatric IBD. Methods Pediatric IBD patients and controls were recruited in a four-site study. Patients received a clinical score using PUCAI or PCDAI evaluation. Colon biopsies were collected during endoscopy. Gene expression was measured by qRT-PCR. Plasma and gut tissue sphingolipids were measured by LC-MS/MS. Results Genes of S1P synthesis (SPHK1, SPHK2), degradation (SGPL1), and signaling (S1PR1, S1PR2, and S1PR4) were significantly upregulated in colon biopsies of IBD patients with moderate/severe symptoms compared with controls or patients in remission. Tissue ceramide, dihydroceramide, and ceramide-1-phosphate (C1P) levels were significantly elevated in IBD patients compared with controls. Conclusions A signature of elevated S1P-related gene expression in colon tissues of pediatric IBD patients correlates with active disease and normalizes in remission. Biopsied gut tissue from symptomatic IBD patients contains high levels of pro-apoptotic and pro-inflammatory sphingolipids. A combined analysis of gut tissue sphingolipid profiles with this S1P-related gene signature may be useful for monitoring response to conventional therapy.

Serum Metabolomics Identifies Altered Bioenergetics, Signaling Cascades in Parallel with Exposome Markers in Crohn’s Disease

“…Downregulated S1P (d16:1) might indicate a shortage of S1P. The result is consistent with a recently published case-control pilot study [43], which determined the whole sphingolipid profiles and S1P-related gene expression in the colon tissues of IBD patients. The results identified an association between elevated transcriptomic signatures and active IBD status, which were normalized in remission cases.…”

The role of sphingosine kinase 2 in alcoholic liver disease

“…The critical findings of this study showed an upregulation of S1P synthetic genes (SphK1, SphK2), signaling (S1PR1, S1PR2, S1PR4) and degradation (SGPL1) in colon biopsies of IBD patients with moderate to severe symptoms compared to control or patients in remission. Ceramide and ceramide 1-phosphate (C1P) levels were significantly elevated in IBD patients compared to control [232].…”

CD40 Enhances Sphingolipids in Orbital Fibroblasts: Potential Role of Sphingosine-1-Phosphate in Inflammatory T-Cell Migration in Graves' Orbitopathy

“…S1P is involved in several diseases like cancer, 31 inflammatory bowel disease, 32 chronic kidney diseases, and multiple sclerosis. 33 Recently, it has been shown that S1P also plays a role in GO by promoting inflammation, 28 adipogenesis, 26 and fibrosis.…”