Abstract
Inflammatory diseases of the gastrointestinal tract are emerging as a global problem with increased evidence and prevalence in numerous countries. A dysregulated sphingolipid metabolism occurs in patients with ulcerative colitis and is discussed to contribute to its pathogenesis. In the present study, we determined the impact of acid sphingomyelinase (Asm), which catalyzes the hydrolysis of sphingomyelin to ceramide, on the course of Citrobacter (C.) rodentium-driven colitis. C. rodentium is an enteric pathogen and induces colonic inflammation very similar to the pathology in patients with ulcerative colitis. We found that mice with Asm deficiency or Asm inhibition were strongly susceptible to C. rodentium infection. These mice showed increased levels of C. rodentium in the feces and were prone to bacterial spreading to the systemic organs. In addition, mice lacking Asm activity showed an uncontrolled inflammatory Th1 and Th17 response, which was accompanied by a stronger colonic pathology compared to infected wild type mice. These findings identified Asm as an essential regulator of mucosal immunity to the enteric pathogen C. rodentium.
Highlights
Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn’s disease, are characterized by chronic, relapsing inflammatory conditions, resulting from a dysregulation of the mucosal immune system in the gastrointestinal tract [1]
The acid sphingomyelinase (Asm) is a relevant enzyme in this context, as it catalyzes the hydrolysis of sphingomyelin to ceramide
To analyze the impact of the sphingolipid metabolism on pathogen-driven intestinal inflammation, C57BL/6 wild type (WT) mice were infected via oral gavage with ∼2 × 109 colony forming units (CFUs) C. rodentium, and the sphingomyelin and ceramide concentrations were determined in the colon at indicated time points post infection by mass spectrometry
Summary
Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn’s disease, are characterized by chronic, relapsing inflammatory conditions, resulting from a dysregulation of the mucosal immune system in the gastrointestinal tract [1]. Sphingolipids are a family of metabolic lipids that are ubiquitous in cellular membranes and include a bioactive subset that regulates various cellular mechanisms and biologic processes such as cell survival, growth, differentiation, and apoptosis [3]. Blockade of Asm bioactivity limited the in vitro differentiation of T helper cells derived from healthy volunteers and patients with Crohn’s disease [14]. These results implicate Asm inhibition as an innovative and effective immunoregulatory strategy for the treatment of IBD [12, 13, 15]
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