Abstract
The 1991 Persian Gulf War veterans presented a myriad of symptoms that ranged from chronic pain, fatigue, gastrointestinal disturbances, and cognitive deficits. Currently, no therapeutic regimen exists to treat the plethora of chronic symptoms though newer pharmacological targets such as microbiome have been identified recently. Toll-like receptor 4 (TLR4) antagonism in systemic inflammatory diseases have been tried before with limited success, but strategies with broad-spectrum TLR4 antagonists and their ability to modulate the host-microbiome have been elusive. Using a mouse model of Gulf War Illness, we show that a nutraceutical, derived from a Chinese herb Sparstolonin B (SsnB) presented a unique microbiome signature with an increased abundance of butyrogenic bacteria. SsnB administration restored a normal tight junction protein profile with an increase in Occludin and a parallel decrease in Claudin 2 and inflammatory mediators high mobility group box 1 (HMGB1), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the distal intestine. SsnB also decreased neuronal inflammation by decreasing IL-1β and HMGB1, while increasing brain-derived neurotrophic factor (BDNF), with a parallel decrease in astrocyte activation in vitro. Mechanistically, SsnB inhibited the binding of HMGB1 and myeloid differentiation primary response protein (MyD88) to TLR4 in the intestine, thus attenuating TLR4 downstream signaling. Studies also showed that SsnB was effective in suppressing TLR4-induced nod-like receptor protein 3 (NLRP3) inflammasome activation, a prominent inflammatory disease pathway. SsnB significantly decreased astrocyte activation by decreasing colocalization of glial fibrillary acid protein (GFAP) and S100 calcium-binding protein B (S100B), a crucial event in neuronal inflammation. Inactivation of SsnB by treating the parent molecule by acetate reversed the deactivation of NLRP3 inflammasome and astrocytes in vitro, suggesting that SsnB molecular motifs may be responsible for its anti-inflammatory activity.
Highlights
Gulf War Illness (GWI) is a chronic, multi-symptomatic disease condition that is known to affect nearly one-third of the veterans who were deployed in the Persian Gulf War of 1990–1991 [1,2].The symptoms include chronic fatigue, musculoskeletal pain, cognitive deficiencies, respiratory and gastrointestinal disturbances [3]
We found that the abundance of beneficial microbes belonging to the Firmicutes phyla were increased in the GWI + Sparstolonin B (SsnB)
Our results showed that SsnB administration, a known Toll-like receptor 4 (TLR4) antagonist in mice that were pre-exposed to GW chemicals, presented a unique microbiome signature when compared to GW
Summary
Gulf War Illness (GWI) is a chronic, multi-symptomatic disease condition that is known to affect nearly one-third of the veterans who were deployed in the Persian Gulf War of 1990–1991 [1,2].The symptoms include chronic fatigue, musculoskeletal pain, cognitive deficiencies, respiratory and gastrointestinal disturbances [3]. Exposure to a wide array of toxic chemicals individually or in combination, in the war theatre, was attributed to being the main reason for GWI [3]. Studies show that administration of pyridostigmine bromide (PB) and permethrin (Per) led to gastrointestinal and neurological disturbances in GWI mouse models [4,5]. Our group was the first to report that the GWI mouse model exhibited significant alteration of the gut microbiome, leading to gut leaching, increased endotoxemia, and Toll-like receptor 4 (TLR4) activation which established a mechanistic connection between gastrointestinal and neuroinflammation [6]. We have further confirmed that the administration of the Gulf War (GW) chemicals in mice led to the activation of enteric glial cells through the Toll-like receptor (TLR) pathway [7]. Though there has been extensive research on the underlying pathobiology of GWI over the past decade, yet there are few reported therapeutic approaches specific for GWI that target the Toll-like receptors [8,9,10,11]
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