METABOLOMICS IN GULF WAR ILLNESS: A SYSTEMS BIOLOGY APPROACH TO DISSECTING MECHANISMS OF DISEASE

Background: This application is submitted by Dr. W. Ian Lipkin of the Center for Infection and Immunity (CII) at Columbia University in response to Fiscal Year 2018 Gulf War Illness Research Program New Award Investigator with a Special Interest in Molecular Signatures. Professors Kimberly Sullivan and Nancy Klimas will provide samples to complete the work outlined in Aim 1 and Aim 2, respectively. Lipkin and his team at CII have extensive experience in pathogen and biomarker discovery for acute and chronic diseases including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-treatment Lyme disease (PTLD). Their recent metabolomic studies in ME/CFS have enabled delineation of endophenotypes that differ in body mass index (BMI) and demonstrated the presence of gastrointestinal complaints, cognitive impairment, and differences in fecal microbiota. Lipkin will use the same instruments and protocols for plasma metabolomic analyses in Gulf War Illness (GWI) as employed for studies of ME/CFS and PTLD. GWI, ME/CFS, and PTLD have significant symptom overlap, including gastrointestinal, cognitive, and psychiatric dysfunction as well as fatigue, which suggest studying them in parallel may enable discovery of common triggers for disease in addition to diagnostic and prognostic biomarkers, and insights that can lead to therapeutic interventions.Hypotheses:(1) Illness in Gulf War (GW) Veterans is associated with metabolic disturbances that are reflected in distinctive plasma metabolomic profiles.(2) Metabolomic differences between GWI and control subjects will be enhanced by the stress of an exercise tolerance test (ETT).(3) Machine learning and topological analyses of data obtained through these studies will reveal GWI, ME/CFS, and PTLD group-specific similarities and differences.Specific Aims:Aim 1: Profile metabolites in plasma of 100 GW Veterans with GWI and 100 GW Veteran controls without GWI who are matched 1:1 for age (+/- 5 years), sex, race, and socioeconomic status.Aim 2: Profile metabolites in plasma of 50 GW Veterans with GWI and 50 GW Veteran and civilian controls without GWI at baseline and 24 hours after an ETT.Aim 3: Integrate metabolomic data as well as clinical metadata from Sullivan and Klimas in an effort to identify pathways that can provide insight into the pathogenesis of GWI, ME/CFS, and PTLD as well as targets for intervention in animal models and clinical trials.Study Design:This is a metabolomic discovery project to survey plasma metabolomes of 100 GW Veterans with GWI at rest and 50 GW Veterans with GWI before and after exercise stress. Normal controls will include GW Veterans and civilians without GWI. Metabolomic data will be used comparatively from ME/CFS and PTLD controls. Metabolomic methods will examine primary metabolites, biogenic amines, complex lipids, and bioactive oxylipins. Bioinformatic and biostatistical methods will include machine learning and topological analyses.Impact:Nearly three decades after the 1990-91 Gulf War, approximately 250,000 U.S. Veterans are estimated to be chronically disabled by GWI. Organophosphate pesticides, sarin gas, pyridostigmine bromide, depleted uranium, smoke from burning oil wells, multiple vaccinations, and combinations thereof are attributed, but unconfirmed, to the pathophysiology of GWI, and there are no approved diagnostic biomarkers or treatments. We will build on current work in plasma metabolomics analyses in ME/CFS and PTLD as they overlap in symptoms with GWI. Our goal is to identify biomarkers for diagnosis and determine insights into the pathogenesis of GWI. This project has the potential to translate into tests that will enable diagnosis and management, and inform the development of new animal models that could culminate in strategies for clinical intervention.