title: Intestinal microbiota-derived metabolomic blood plasma markers for prior radiation injury.
abstract: OBJECTIVE
  Assessing whole-body radiation injury and absorbed dose is essential for remediation efforts following accidental or deliberate exposure in medical, industrial, military, or terrorist incidents. We hypothesize that variations in specific metabolite concentrations extracted from blood plasma would correlate with whole-body radiation injury and dose.
  
  
  METHODS
  Groups of C57BL/6 mice (n=12 per group) were exposed to 0, 2, 4, 8, and 10.4 Gy of whole-body gamma radiation. At 24 hours after treatment, all animals were euthanized, and both plasma and liver biopsy samples were obtained, the latter being used to identify a distinct hepatic radiation injury response within plasma. A semiquantitative, untargeted metabolite/lipid profile was developed using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry, which identified 354 biochemical compounds. A second set of C57BL/6 mice (n=6 per group) were used to assess a subset of identified plasma markers beyond 24 hours.
  
  
  RESULTS
  We identified a cohort of 37 biochemical compounds in plasma that yielded the optimal separation of the irradiated sample groups, with the most correlated metabolites associated with pyrimidine (positively correlated) and tryptophan (negatively correlated) metabolism. The latter were predominantly associated with indole compounds, and there was evidence that these were also correlated between liver and plasma. No evidence of saturation as a function of dose was observed, as has been noted for studies involving metabolite analysis of urine.
  
  
  CONCLUSIONS
  Plasma profiling of specific metabolites related to pyrimidine and tryptophan pathways can be used to differentiate whole-body radiation injury and dose response. As the tryptophan-associated indole compounds have their origin in the intestinal microbiome and subsequently the liver, these metabolites particularly represent an attractive marker for radiation injury within blood plasma.
authors: Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York; Department of Mathematical Sciences, Yeshiva University, New York, New York.
authors: Pilib
authors: P
authors: Ó Broin
authors: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York.
authors: Bhavapriya
authors: B
authors: Vaitheesvaran
authors: Department of Radiation Oncology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York.
authors: Subhrajit
authors: S
authors: Saha
authors: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York.
authors: Kirsten
authors: K
authors: Hartil
authors: Department of Pharmacology, Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors: Emily I
authors: EI
authors: Chen
authors: Department of Medicine, Oregon Health and Science University, Portland, Oregon.
authors: Devorah
authors: D
authors: Goldman
authors: Department of Medicine, Oregon Health and Science University, Portland, Oregon.
authors: William Harv
authors: WH
authors: Fleming
authors: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York.
authors: Irwin J
authors: IJ
authors: Kurland
authors: Department of Radiation Oncology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York. Electronic address: cguha@montefiore.org.
authors: Chandan
authors: C
authors: Guha
authors: Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York; Department of Mathematical Sciences, Yeshiva University, New York, New York. Electronic address: aaron.golden@einstein.yu.edu.
authors: Aaron
authors: A
authors: Golden
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D004307:Dose-Response Relationship, Radiation; D007422:Intestines / Q000382:microbiology* / Q000528:radiation effects; D008055:Lipids / Q000097:blood*; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D020543:Proteome / Q000032:analysis*; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000097:blood* / Q000382:microbiology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014916:Whole-Body Irradiation / Q000009:adverse effects*
chemical_list: D001426:Bacterial Proteins; D015415:Biomarkers; D008055:Lipids; D020543:Proteome
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