Lipidomic profiling in Crohn's disease: abnormalities in phosphatidylinositols, with preservation of ceramide, phosphatidylcholine and phosphatidylserine composition.
Crohn's disease is a chronic inflammatory condition largely affecting the terminal ileum and large bowel. A contributing cause is the failure of an adequate acute inflammatory response as a result of impaired secretion of pro-inflammatory cytokines by macrophages. This defective secretion arises from aberrant vesicle trafficking, misdirecting the cytokines to lysosomal degradation. Aberrant intestinal permeability is also well-established in Crohn's disease. Both the disordered vesicle trafficking and increased bowel permeability could result from abnormal lipid composition. We thus measured the sphingo- and phospholipid composition of macrophages, using mass spectrometry and stable isotope labelling approaches. Stimulation of macrophages with heat-killed Escherichia coli resulted in three main changes; a significant reduction in the amount of individual ceramide species, an altered composition of phosphatidylcholine, and an increased rate of phosphatidylcholine synthesis in macrophages. These changes were observed in macrophages from both healthy control individuals and patients with Crohn's disease. The only difference detected between control and Crohn's disease macrophages was a reduced proportion of newly-synthesised phosphatidylinositol 16:0/18:1 over a defined time period. Shotgun lipidomics analysis of macroscopically non-inflamed ileal biopsies showed a significant decrease in this same lipid species with overall preservation of sphingolipid, phospholipid and cholesterol composition.
Division of Medicine, UCL, 5 University Street, London, United Kingdom.
Gavin W
GW
Sewell
Yusuf A
YA
Hannun
Xianlin
X
Han
Grielof
G
Koster
Jacek
J
Bielawski
Victoria
V
Goss
Philip J
PJ
Smith
Farooq Z
FZ
Rahman
Roser
R
Vega
Stuart L
SL
Bloom
Ann P
AP
Walker
Anthony D
AD
Postle
Anthony W
AW
Segal
D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D002518:Ceramides / Q000378:metabolism*; D003424:Crohn Disease / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D003710:Demography; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism*; D013107:Sphingolipids / Q000378:metabolism
D002518:Ceramides; D010713:Phosphatidylcholines; D010716:Phosphatidylinositols; D010718:Phosphatidylserines; D013107:Sphingolipids