Humanized Mouse Model of Gulf War Veterans' Illness

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Gulf War Veterans' Illnesses (GWVI) is a complex constellation of symptoms that have persisted in Gulf War Veterans (GWV) more than 25 years after their deployment to the Gulf. These symptoms are so diverse, they baffle diagnostic criteria. 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 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 Committee noted that little progress has been made in elucidating the pathological mechanisms that underlie the complex symptoms 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). Another complexity relating to GWVI is establishing the toxicant exposure conditions to which GWVs were exposed. Potential agents include depleted uranium, pyridostigmine bromide (PB), sarin, vaccines, permethrin (PER) and other insecticide repellents, fuels, infectious diseases, stressors, burn pits and blast exposure. These potential toxicants form the basis for numerous animal models of GWVI. It is interesting that 3 of the major symptoms of GWVI- GI disruptions, PTSD/anxiety and chronic fatigue- can be caused individually by a dysbiosis in the gut microbiome, so it is reasonable to hypothesize that imbalances in the gut microbiome might contribute to these major 3 symptoms of GWVI collectively, and others as well. We (and others) have shown recently that PER/PB results in a significant alteration in the diversity and composition of the gut microbiome. Our animal model studies of GWVI-gut microbiome interactions are supported by a BLR&D Merit Award. A significant gap in the understanding of the pathophysiological underpinnings of GWVI arises from the lack of knowledge of the exact toxicant exposures. Self-reporting by GWVs is the basis of what is known about exposures, so it is hard to state with certainty, which agents (single, combinations) and their doses, frequencies and durations led to GWVI. This is an important point because we are learning that outcomes from animal model studies are dependent on the specific agent(s) used. One approach that could remove toxicant exposure conditions from the GWVI equation is the development of a humanized mouse model. In this manner, the GWVs toxicant exposures are already incorporated into the disorder along with its chronic, persistent symptomology. The objective of this Pilot Project is to develop a humanized mouse model via fecal microbiota transplantation (FMT) from stool samples of GWVs with GWVI into healthy mice. It is predicted that the gut microbiome of recipient mice will be colonized with that of the GWVI-donor and rapidly express the symptoms of this disorder. A humanized model of GWVI would incorporate the heterogeneity in symptomology observed in GWVI and maximize homogeneity in the cohorts of recipient mice. Studies of disease mechanisms, sex-based differences in symptomology and the testing of therapies not now possible in humans with GWVI would also become possible. These studies will also provide significant preliminary information to support a full Merit Review Award submission.