Sphingolipids as Mediators in the Crosstalk between Microbiota and Intestinal Cells: Implications for Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) describes different illnesses characterized by chronic inflammation of the gastrointestinal tract. Although the pathogenic mechanisms leading to IBD are poorly understood, immune system disturbances likely underlie its development. Sphingolipids (SLs) have been identified as important players and promising therapeutic targets to control inflammation in IBD. Interestingly, it seems that microorganisms of the normal gut microbiota and probiotics are involved in sphingolipid function. However, there is a great need to investigate the role of SLs as intermediates in the crosstalk between intestinal immunity and microorganisms. This review focuses on recent investigations that describe some mechanisms involved in the regulation of cytokine profiles by SLs. We also describe the importance of gut microbiota in providing signaling molecules that favor the communication between resident bacteria and intestinal cells. This, in turn, modulates the immune response in the bowel and likely in other peripheral organs. The potential of SLs and gut microbiota as targets or therapeutic agents for IBD is also discussed.

Figure 1

(a) Structure of the main bioactive sphingolipids: sphingosine (Sph), sphingosine-1-phosphate (S1P), ceramide (Cer), ceramide-1-phosphate (C1P), sphingomyelin (SM), and glucosylceramide (GluCer). (b) Schematic representation of the central role of ceramide in sphingolipid metabolism.

Figure 2

Known effects of pathogenic bacteria, microbiota members, and probiotics on SL signaling in IBD. Probiotics increase SMase activity and diminish intestinal inflammation reducing mucosal damage in both humans and a mouse model. Bacteroides fragilis, a known microbiota member, induces inflammation by stimulating epithelial production of IDENs containing high levels of S1P and mediating Th17 recruitment. Conversely, the pathogen Shigella flexneri can avoid the inflammatory response by decreasing S1P levels, downregulating SK2 expression and increasing SPL and S1PPs expression. SM: sphingomyelin, LPCs: lysophosphatidylcholines, GPCs: glycerophosphatidylcholines, IL-6: interleukin-6, ILPMC: intestinal lamina propria mononuclear cells, IDENs: intestinal derived exosome like nanoparticles, S1P: sphingosine 1 phosphate, SK2: sphingosine 1 phosphate kinase 2, SPL: sphingosine 1 phosphate lyase, and S1PPs: sphingosine 1 phosphate phosphatases.

Figure 3

Bacterial α-galactosylceramide as iNTK regulator in colon cancer. Treatment with azoxymethane followed by DSS reduces the number of iNTK cells and augments CD25⁺ CD4⁺ T cells, NKT1.1⁺ T cells, and IL-13⁺ CD3⁺ cells, as well as IL-13 release. All this contributes to form a greater number of tumors of a larger size. Probiotic bacteria can produce compounds similar to α-galactosylceramide, which prevents inflammation and reduces the number and size of tumors. B. fragilis produces α-galactosylceramide which stimulates iNKT cells binding to CD1d, increasing production of IFN-γ and proliferation of CD3⁺ Vα24⁺ cells. DSS: dextran sulphate sodium, iNKT: invariant natural killer, NKT: natural killer T cell, and PT: serine palmitoyltransferase.