Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness

O’Callaghan, James P.; Michalovicz, Lindsay T.; Miller, Julie V.; Kelly, Kimberly A.

doi:10.1016/j.ebiom.2017.11.021

Cited by 7 publications

(5 citation statements)

References 11 publications

(14 reference statements)

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“…Mice were exposed to Gulf War chemicals based on established rodent models of Gulf War Illness with some modifications (Zakirova et al, 2015; O’Callaghan et al, 2017). The treated wild-type mice group (GW) were dosed tri-weekly for 1 week with PB (2mg/Kg) and Permethrin (200 mg/kg) by oral gavage.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous research reported an altered microbiome in a murine model of GWI with increase in Firmicutes over Bacteriodetes and a decrease in several butyrogenic bacteria. This dysbiosis was accompanied by activation of TLR4, increased inflammation, a leaky gut, endotoxemia with release of damage associated molecular patterns (DAMPS) such as HMGB1 in gulf war chemical treated mice compared to controls (Alhasson et al, 2017; O’Callaghan et al, 2017; Seth et al, 2018). Interestingly, a recent study by Hernandez et al, showed that exposure to pyridostigmine bromide a known gulf war chemical exposure resulted in enteric neuronal and glial reactivity and inflammation (Hernandez et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology

et al. 2019

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About 14% of veterans who suffer from Gulf war illness (GWI) complain of some form of gastrointestinal disorder but with no significant markers of clinical pathology. Our previous studies have shown that exposure to GW chemicals resulted in altered microbiome which was associated with damage associated molecular pattern (DAMP) release followed by neuro and gastrointestinal inflammation with loss of gut barrier integrity. Enteric glial cells (EGC) are emerging as important regulators of the gastrointestinal tract and have been observed to change to a reactive phenotype in several functional gastrointestinal disorders such as IBS and IBD. This study is aimed at investigating the role of dysbiosis associated EGC immune-activation and redox instability in contributing to observed gastrointestinal barrier integrity loss in GWI via altered tight junction protein expression. Using a mouse model of GWI and in vitro studies with cultured EGC and use of antibiotics to ensure gut decontamination we show that exposure to GW chemicals caused dysbiosis associated change in EGCs. EGCs changed to a reactive phenotype characterized by activation of TLR4-S100β/RAGE-iNOS pathway causing release of nitric oxide and activation of NOX2 since gut sterility with antibiotics prevented this change. The resulting peroxynitrite generation led to increased oxidative stress that triggered inflammation as shown by increased NLRP-3 inflammasome activation and increased cell death. Activated EGCs in vivo and in vitro were associated with decrease in tight junction protein occludin and selective water channel aquaporin-3 with a concomitant increase in Claudin-2. The tight junction protein levels were restored following a parallel treatment of GWI mice with a TLR4 inhibitor SsnB and butyric acid that are known to decrease the immunoactivation of EGCs. Our study demonstrates that immune-redox mechanisms in EGC are important players in the pathology in GWI and may be possible therapeutic targets for improving outcomes in GWI symptom persistence.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology

et al. 2019

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“…Our finding of an association between the frequency of hearing chemical alarms sound and cognitive status is in line with animal ( Filliat et al, 2007 ; Joosen et al, 2009 ; Mamczarz et al, 2011 ) and human ( Pereira et al, 2014 ) studies that have reported cognitive deficits after exposure to chemical nerve agents and organophosphate chemicals. Similar to air pollutants, low levels of chemical warfare agents likely produce neurotoxic effects in the brain through neuroinflammation, oxidative stress, and microglia activation ( O’Callaghan et al, 2017 ; Michalovicz et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

The prevalence of mild cognitive impairment in Gulf War veterans: a follow-up study

Chao,

Sullivan,

Krengel

et al. 2024

Front. Neurosci.

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IntroductionGulf War Illness (GWI), also called Chronic Multisymptom Illness (CMI), is a multi-faceted condition that plagues an estimated 250,000 Gulf War (GW) veterans. Symptoms of GWI/CMI include fatigue, pain, and cognitive dysfunction. We previously reported that 12% of a convenience sample of middle aged (median age 52 years) GW veterans met criteria for mild cognitive impairment (MCI), a clinical syndrome most prevalent in older adults (e.g., ≥70 years). The current study sought to replicate and extend this finding.MethodsWe used the actuarial neuropsychological criteria and the Montreal Cognitive Assessment (MoCA) to assess the cognitive status of 952 GW veterans. We also examined regional brain volumes in a subset of GW veterans (n = 368) who had three Tesla magnetic resonance images (MRIs).ResultsWe replicated our previous finding of a greater than 10% rate of MCI in four additional cohorts of GW veterans. In the combined sample of 952 GW veterans (median age 51 years at time of cognitive testing), 17% met criteria for MCI. Veterans classified as MCI were more likely to have CMI, history of depression, and prolonged (≥31 days) deployment-related exposures to smoke from oil well fires and chemical nerve agents compared to veterans with unimpaired and intermediate cognitive status. We also replicated our previous finding of hippocampal atrophy in veterans with MCI, and found significant group differences in lateral ventricle volumes.DiscussionBecause MCI increases the risk for late-life dementia and impacts quality of life, it may be prudent to counsel GW veterans with cognitive dysfunction, CMI, history of depression, and high levels of exposures to deployment-related toxicants to adopt lifestyle habits that have been associated with lowering dementia risk. With the Food and Drug Administration’s recent approval of and the VA’s decision to cover the cost for anti-amyloid β (Aβ) therapies, a logical next step for this research is to determine if GW veterans with MCI have elevated Aβ in their brains.

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“…As described by Dantzer and colleagues [3], sickness behaviors are likely linked to activation of macrophages and microglia, and subsequent neuroinflammation via production of proinflammatory cytokines such as Tnfa, IL1β, and IL6. GWI thus has the features of a neuroimmune disorder [4][5][6][7]; but causes are otherwise poorly understood. The leading suspected causes are chemicals to which the personnel were exposed.…”

Section: Introductionmentioning

confidence: 99%

Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness

Jones

Miller

et al. 2020

Brain Sciences

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Between 25% and 30% of the nearly one million military personnel who participated in the 1991 Persian Gulf War became ill with chronic symptoms ranging from gastrointestinal to nervous system dysfunction. This disorder is now referred to as Gulf War Illness (GWI) and the underlying pathophysiology has been linked to exposure-based neuroinflammation caused by organophosphorous (OP) compounds coupled with high circulating glucocorticoids. In a mouse model of GWI we developed, corticosterone was shown to act synergistically with an OP (diisopropylflurophosphate) to dramatically increase proinflammatory cytokine gene expression in the brain. Because not all Gulf War participants became sick, the question arises as to whether differential genetic constitution might underlie individual differences in susceptibility. To address this question of genetic liability, we tested the impact of OP and glucocorticoid exposure in a genetic reference population of 30 inbred mouse strains. We also studied both sexes. The results showed wide differences among strains and overall that females were less sensitive to the combined treatment than males. Furthermore, we identified one OP-glucocorticoid locus and nominated a candidate gene—Spon1—that may underlie the marked differences in response.

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Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness

Cited by 7 publications

References 11 publications

Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology

Dysbiosis-Associated Enteric Glial Cell Immune-Activation and Redox Imbalance Modulate Tight Junction Protein Expression in Gulf War Illness Pathology

The prevalence of mild cognitive impairment in Gulf War veterans: a follow-up study

Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness

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