Gulf War Veterans' Illness: Symptom Chronicity via Interactions of Diet andLifestyle Risk Factors with the Gut Microbiome

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Principal Investigator: Mariana  Angoa-Perez
Organization: JOHN D DINGELL VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs

Project Summary/Abstract
Gulf War Veterans’ Illnesses (GWVI) presents as a complex constellation of diverse symptoms that have
persisted in Gulf War Veterans more than 25 years after their deployment to the Gulf region. This set of
symptoms is so broad, it baffles diagnostic criteria and as a result, consideration of GWVI as a bona fide illness
has progressed slowly from denial of its existence to the use of such terms as “unexplained illnesses” (used by
the VA) and “multisymptom illness”. The most recent report by the Institute of Medicine Committee on Gulf War
and Health (2016) concludes that GWVI is not a psychosomatic condition and sufficient evidence now exists to
conclude that a causal relationship exists between being deployed to the Gulf War and the health outcomes
associated with this disorder. This august Committee noted that little progress has been made in elucidating
the pathological mechanisms that underlie the complex symptom set associated with GWVI and as a result, “it
does not appear that a single mechanism can explain the multitude of symptoms seen in Gulf War Illness, and
it is unlikely that a single definitive causal agent will be identified this many years after the war” (p. 3 of report).
We agree that a single cause for all elements of GWVI is unlikely, it is possible that a single pathophysiological
mechanism that could influence the diverse symptoms of GWVI, and explain their persistence, and that
mechanism is a dysbiosis in the gut microbiome. The broad objectives of this project are to analyze the effects
of Gulf War agents on the commensal bacteria in the gut and to determine if these interactions result in
changes in the bacterial production of short chain fatty acids (SCFAs) and other bioactive small molecules
produced by gut bacteria. These products of bacterial fermentation and metabolism exert numerous effects
throughout the body to include the CNS. Mice will be treated with a validated mouse model of GWVI
(pyridostigmine bromide plus permethrin) and the gut microbiome will be analyzed via 16S rRNA sequencing
using the MiSeq platform. The effects of these same agents on SCFA production will be determined using
liquid chromatography-mass spectrometry. CNS and GI disorders that are confirmed symptoms of GWVI will
also be assessed. Thereafter, the effects of a high fat diet on the microbiome and SCFA production will be
evaluated. Finally, a new treatment aim is proposed that will test dietary intervention and fecal microbiota
transfer for their ability to restore balance in the GWVI-modified gut microbiome and to diminish the CNS and
GI symptoms of this serious disorder. It is predicted that a high fat diet will magnify the effects of Gulf War
agents on the microbiome and the metabolome and cause a time-dependent worsening of GWVI symptoms.
Together, the application of next generation sequencing and cutting edge mass spectrometry will help fill gaps
in our understanding of how Gulf War agents influence communication along the gut-brain axis. These studies
may also reveal new therapeutic targets for GWVI by restoring balance in the gut microbiome through dietary
and microbiota transfer interventions.

Terms: <16S gene sequencing><16S rRNA amplicon sequencing><16S rRNA gene amplicon sequencing><16S rRNA gene sequencing><16S rRNA genomic profiling><16S rRNA sequencing><16S ribosomal RNA gene sequencing><16S ribosomal RNA sequencing><16S sequencing><Agreement><Animal Model><Animal Models and Related Studies><BBB crossing><Behavior><Blood Serum><Brain><Brain Nervous System><Bromides><Characteristics><Chronic><Communication><Complex><Diet><Dietary Intervention><Disease><Disorder><Disparate><Elements><Encephalon><Equilibrium><Fermentation><GI microbiome><GW veteran><Gulf War><Gulf War Illness><Gulf War Syndrome><Gulf War veteran><Health><High Fat Diet><Institute of Medicine><Institute of Medicine (U.S.)><Intermediary Metabolism><Intervention><Intervention Strategies><LC/MS><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Metabolic Processes><Metabolism><Mice><Mice Mammals><Murine><Mus><NAS/IOM><NGS Method><NGS system><Nutrition Interventions><Nutritional Interventions><Obesity><Operation Desert Shield><Operation Desert Storm><Outcome><Pathologic><Permethrin><Persian Gulf Syndrome><Production><Psychophysiologic Disorders><Psychophysiological Diseases><Psychophysiological Disorders><Psychosomatic Diseases><Psychosomatic Disorders><Public Health><Reporting><Risk Factors><Serum><Short-Chain Fatty Acids><Symptoms><Testing><Time><Volatile Fatty Acids><War><adiposity><associated symptom><bacteria in the gut><balance><balance function><blood-brain barrier crossing><bloodbrain barrier crossing><chronic symptom><co-morbid symptom><co-occuring symptom><commensal bacteria><commensal bacterial species><comorbid symptom><concurrent symptom><cooccuring symptom><corpulence><diagnostic criteria><diet intervention><dietary><diets><digestive tract microbiome><dysbacteriosis><dysbiosis><dysbiotic><enteric microbiome><expectation><experiment><experimental research><experimental study><experiments><fecal microbial community><fecal microbiota><gastrointestinal microbiome><gut bacteria><gut microbiome><gut to brain axis><gut-associated microbiome><gut-brain axis><gut-brain communication><gut-brain interactions><gut-brain relationship><gut-brain signaling><high-fat/low-fiber diet><interventional strategy><intestinal biome><intestinal microbiome><liquid chromatography mass spectrometry><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><microbial consortia><microbial flora><microbial imbalance><microbiome><microbiota><microflora><model of animal><mouse model><multispecies consortia><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next gen sequencing><next generation sequencing><nextgen sequencing><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><persistent symptom><psychosomatic><pyridostigmine><small molecule><symptom association><symptom comorbidity><western diet><western-style diet><western-type diet>