Humanized Mouse Model of Gulf War Veterans' Illness
Project Number1I21BX005850-01A2
Former Number1I21BX005850-01A1
Contact PI/Project LeaderKUHN, DONALD M
Awardee OrganizationJOHN D DINGELL VA MEDICAL CENTER
Description
Abstract Text
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.
Public Health Relevance Statement
This project is highly relevant to the health of Gulf War Veterans because it will establish a humanized mouse
model of Gulf War Veteran's Illness. This will be achieved by fecal microbiota transplantation from stool
samples donated by Gulf War Veterans with this condition into mice. This approach will incorporate the exact
toxicant exposure conditions to which gulf War Veterans were exposed because they are imprinted into at least
the gut microbiome. This innovative model will more closely portray the symptoms of Gulf War Veteran's
Illness and fill gaps in our understanding of how altered communication along the gut–brain axis contributes to
this chronic health condition.
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