Persistent exercise fatigue and associative learning deficits in combination with transient glucose dyshomeostasis in a mouse model of Gulf War Illness

Induction of distinct neuroinflammatory markers and gut dysbiosis by differential pyridostigmine bromide dosing in a chronic mouse model of GWI showing persistent exercise fatigue and cognitive impairment

“…The analyses were performed 6.6 months after GW exposure in order to increase translational relevance to ill GWVs who continue to suffer from cognitive and chronic fatigue symptoms 30 years after exposure. Here, we show that two exposure regimens, differing in PB dosing (GW1, GW2), induce different underlying neuroinflammatory transcriptional signatures that correspond with dissimilar behavioral profiles described in our adjoining report [ 124 ]. Because recent reports indicate that gut-brain interactions may be implicated in promoting symptoms of GWI [ 24 – 28 ], we also examined GW agent-induced changes in gut microbiome community structure.…”

“…Table 1 shows the summary of GW1 and GW2 biomarkers obtained for gut dysbiosis, systemic endotoxemia, and neuroinflammation from the current study alongside phenotypic characteristics obtained on the same mice and reported in the accompanying manuscript [ 124 ]. The latter were classified according to a subset of the symptom groups included in the Kansas case definition [ 23 ]: neurological/cognitive/mood, fatigue, pain as well as other symptoms such as metabolic (insulin insensitivity, body weight, lean/fat mass), sensorimotor and locomotion ability.…”

“…(GW2). The rationale for the PB dosing was described in the accompanying article [ 124 ]. Both groups received 1.3 mg/kg PER in 100% DMSO (75 μL/30 g b.w.…”

“…The CON/S group also received 5 min restraint stress in perforated 50 mL conicals once daily [ 35 ]. Animals were tested on metabolic, behavioral and exercise parameters as described in the accompanying article [ 124 ]. At 195–202 days post treatment (PT), mice were sacrificed under isoflurane anesthesia and blood and brain collected for analysis.…”

“…However, the pathophysiology underlying the chronic fatigue domain of GWI has been difficult to ascertain since it has been understudied in experimental animals. In an accompanying article in this issue, we characterize enhanced exercise intolerance (fatigue) and GWI phenotypes associated with other symptom domains including cognitive impairment and mood alterations in the same mice after chronic exposure to GW agents [ 124 ]. A comprehensive animal model such as this, displaying the unique multi-symptom presentation of GWI, is critical for unraveling the underlying causes and for testing potential therapeutics [ 23 , 24 ].…”