title: Bimodal plasma metabolomics strategy identifies novel inflammatory metabolites in inflammatory bowel diseases.
abstract: BACKGROUND
  Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by variable phenotypes. Metabolites are signatures of biochemical activity that can reveal unknown pathogenic pathways. We employed untargeted mass spectrometry (MS) based metabolomics to identify novel inflammatory mechanisms in IBD and a targeted assay to quantify metabolites of the auto-immunomodulating kynurenine pathway (KP) in IBDs and health.
  
  
  METHODS
  Metabolome analysis of CD, UC, and control plasmas was performed on a Liquid Chromatography (LC)-MS/MS system. KP metabolites quinolinic acid (QA) and picolinic acid (PA) were quantified by gas chromatography/MS.
  
  
  RESULTS
  Nineteen UC, 25 CD, and 9 control plasmas were analyzed: 34 metabolites exhibited abundance profiles associated with CD by global metabolome analysis (P≤0.05, false discovery rate q≤0.01). Notably, inflammatory-implicated metabolites angiotensin IV (P=0.049, q<0.001), diphthamide (P=0.018, q<0.001), and GM3 gangliosides (P<0.001, q<0.001) were increased in CD. By targeted kynurenine metabolites assay, QA (73.53 ng/mL ± 23.40 SD) and combined kynurenine metabolites (CKM) were increased in CD (120.19 ± 39.71) compared to controls (QA 50.14 ± 15.04; P<0.01; CKM 92.73 ± 26.30; P<0.01). CD QA positively correlated with CDAI (r=0.85; P<0.01), CRP (r=0.46; P=0.01), and ESR (r=0.42; P=0.03), while CKMs correlated with CDAI (r=0.615; P<0.01) and CRP (r=0.615; P=0.02).
  
  
  CONCLUSIONS
  Associations of angiotensin IV, diphthamide, and GM3 gangliosides with CD implicate novel pathways in activating a Th1/Th17 inflammatory profile. Increased QA concentrations in CD may indicate a defective auto-immunomodulation mechanism.
authors.affiliation: Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales, Kensington, NSW 2000, Australia and Department of Gastroenterology, Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
authors.forename: Yunki Y
authors.initials: YY
authors.lastname: Yau
authors.affiliation: Department of Gastroenterology, Concord Repatriation General Hospital, Concord, NSW 2139, Australia and the Department of Gastroenterology, Bankstown-Lidcombe Hospital, Bankstown, NSW 2200, Australia.
authors.forename: Rupert W L
authors.initials: RW
authors.lastname: Leong
authors.affiliation: Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales, Kensington, NSW 2000, Australia.
authors.forename: Sean
authors.initials: S
authors.lastname: Shin
authors.affiliation: Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales, Kensington, NSW 2000, Australia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Bustamante
authors.affiliation: Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales, Kensington, NSW 2000, Australia.
authors.forename: Russell
authors.initials: R
authors.lastname: Pickford
authors.affiliation: Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales, Kensington, NSW 2000, Australia.
authors.forename: Leila
authors.initials: L
authors.lastname: Hejazi
authors.affiliation: Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales, Kensington, NSW 2000, Australia.
authors.forename: Beth
authors.initials: B
authors.lastname: Campbell
authors.affiliation: Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales, Kensington, NSW 2000, Australia.
authors.forename: Valerie C
authors.initials: VC
authors.lastname: Wasinger
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000097:blood; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000097:blood / Q000276:immunology; D003424:Crohn Disease / Q000097:blood / Q000276:immunology; D005260:Female; D005679:G(M3) Ganglioside / Q000097:blood; D006639:Histidine / Q000031:analogs & derivatives / Q000097:blood; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D015212:Inflammatory Bowel Diseases / Q000097:blood* / Q000276:immunology; D007737:Kynurenine / Q000097:blood; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D010848:Picolinic Acids / Q000097:blood; D010865:Pilot Projects; D017378:Quinolinic Acid / Q000097:blood; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D005679:G(M3) Ganglioside; D018836:Inflammation Mediators; D010848:Picolinic Acids; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D007737:Kynurenine; D006639:Histidine; C027527:diphthamide; D017378:Quinolinic Acid; C030614:picolinic acid