Brain-Body Pathways Contributing to Gulf War Illness
Abstract
Chronic multi-symptom illness continues to affect 36% of U.S. Veterans deployed to the Persian Gulf War (GW) in 1990-1991. Symptoms reported consistently by Gulf War veterans at excess rates fall into five general domains: neurological/cognition/mood (memory, concentration, anxiety, depression), muscle/joint pain, respiratory, gastrointestinal (GI) and especially chronic fatigue. GW Illness (GWI) has no precise pathogenesis and, therefore, there is no treatment available. GWI may be due to a widespread inflammatory response involving the gut-brain axis; however, more research is needed to confirm this. Ill GW Veterans are two times more likely to report colitis/intestinal inflammation, and their GI symptoms closely resemble inflammatory bowel disease/syndrome. Inflammation in the gut can alter a variety of processes in the brain including functions that control other body organ systems responsible for normal metabolism, energy balance, and stress responses. Bacteria in the gut are an important component of gut-brain signaling since their metabolites can affect brain health, in part, by regulating the release of gut hormones that regulate circadian rhythms, anxiety, and behavior. It is still unclear which factors cause GWI. However, we know that intoxication due to the use of pesticides such as permethrin, which was enforced for use by GW troops, can cause ailments such as vomiting, diarrhea, and cognitive symptoms. Another putative agent causing GWI is the reversible acetylcholinesterase inhibitor pyridostigmine bromide (PB), which was given prophylactically (30 mg/every 8 hours) to protect troops against exposure to the nerve agent soman. Therefore, several animal models have used pesticides in combination with PB and the insect repellant DEET to mimic GW agent exposure and restraint stress to mimic deployment/combat stress in GW Veterans. Using these experimental models, scientists have found close similarity in the symptoms produced in mice and humans including cognitive deficits, anxiety, and GI disturbances. This indicates that rodent models of GWI have close validity to the conditions suffered by GW Veterans. These models offer an opportunity to characterize the etiology and pathophysiology of GWI. Using a mouse model of GWI with exposure paradigms that represent those of deployed GW Soldiers, we will examine the gut-brain interactions that may be responsible for the multiple system symptoms in GWI. There is evidence that gut-brain interactions can lead to brain disease and behavioral deficits including decreased cognition, fatigue, and anxiety. To test whether gut-brain interactions participate in GWI, we will first measure markers of gut, systemic, and brain inflammation. In other experiments, we will test the hypothesis that gut signals during GW agent-induced inflammation are responsible for cognition/mood/neurological disturbances. We will use deafferentation of vagus nerve fibers that carry sensory signals from the gut to the brain and check for reduced or removal of GWI symptoms. In other experiments, we will evaluate the contribution of gut bacteria to gut-brain interactions determined in the aforementioned experiments. We will do this by treating GW agent-exposed mice with oral probiotics that include healthful bacterial strains commonly found in the human gut and that add bacterial diversity needed for normal GI and whole body health. We predict that “leaky gut” and pro-inflammatory systemic signals triggered by GW agent exposure are partly responsible for neurocognitive pathology and that these are, in part, mediated by gut-brain signals traveling in the vagus nerve. In addition, we expect that gut bacteria contribute to this effect. Our findings should help unravel the complex integrative relationships present between the brain and body that are hijacked by exposure to GW agents. This information can help define the pathophysiology of GWI and may lead eventually to the developm
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910802
Entities
People
- Margarita Curras-collazo
Organizations
- United States Army
- University of California, Riverside