title: Phosphorylated dihydroceramides from common human bacteria are recovered in human tissues.
abstract: Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 (TLR2) including promotion of IL-6 secretion from dendritic cells and inhibition of osteoblast differentiation and function in vitro and in vivo. The PE DHC lipids also enhance (TLR2)-dependent murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The unique non-mammalian structures of these lipids allows for their specific quantification in bacteria and human tissues using multiple reaction monitoring (MRM)-mass spectrometry (MS). Synthesis of these lipids by other common human bacteria and the presence of these lipids in human tissues have not yet been determined. We now report that synthesis of these lipids can be attributed to a small number of intestinal and oral organisms within the Bacteroides, Parabacteroides, Prevotella, Tannerella and Porphyromonas genera. Additionally, the PDHCs are not only present in gingival tissues, but are also present in human blood, vasculature tissues and brain. Finally, the distribution of these TLR2-activating lipids in human tissues varies with both the tissue site and disease status of the tissue suggesting a role for PDHCs in human disease.
authors.affiliation: Department of Oral Health and Diagnostic Sciences, University of Connecticut School of Dental Medicine, Farmington, Connecticut, United States of America. nichols@nso.uchc
authors.forename: Frank C
authors.initials: FC
authors.lastname: Nichols
authors.forename: Xudong
authors.initials: X
authors.lastname: Yao
authors.forename: Bekim
authors.initials: B
authors.lastname: Bajrami
authors.forename: Julia
authors.initials: J
authors.lastname: Downes
authors.forename: Sydney M
authors.initials: SM
authors.lastname: Finegold
authors.forename: Erica
authors.initials: E
authors.lastname: Knee
authors.forename: James J
authors.initials: JJ
authors.lastname: Gallagher
authors.forename: William J
authors.initials: WJ
authors.lastname: Housley
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clark
mesh_terms: D001158:Arteries / Q000382:microbiology; D001419:Bacteria / Q000378:metabolism*; D001921:Brain / Q000382:microbiology; D002518:Ceramides / Q000302:isolation & purification* / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000382:microbiology; D009928:Organ Specificity; D010519:Periodontium / Q000382:microbiology; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000382:microbiology; D010949:Plasma / Q000382:microbiology; D051195:Toll-Like Receptor 2 / Q000378:metabolism
chemical_list: D002518:Ceramides; D051195:Toll-Like Receptor 2; C109343:dihydroceramide