Neurochemical and neuroinflammatory perturbations in two Gulf War Illness models: Modulation by the immunotherapeutic LNFPIII

Assessing the Beneficial Effects of the Immunomodulatory Glycan LNFPIII on Gut Microbiota and Health in a Mouse Model of Gulf War Illness

“…Following the Zakirova [ 18 ] model in both the short- (12 days; N = 24 mice) and long-term (9 months; N = 59) studies, mice were randomly divided into treatment groups and treated daily for 10 days with a combination of PB and PM (0.7 and 200 mg/kg, respectively) or DMSO vehicle (i.p.). In the short-term study, the immunomodulatory treatment, LNFPIII, or dextran vehicle (both 35 µg/mouse; s.c.) were administered concurrently with PB/PM as in [ 19 ]. The treatment groups in the short-term study were as follows: DMSO-Dextran ( n = 6), DMSO-LNFPIII ( n = 6), PB/PM-Dextran ( n = 6), and PB/PM-LNFPIII ( n = 6).…”

“…While clinical reports of peripheral and central inflammation are, respectively, variable and sparse, a consensus for immune disruption has emerged in GWI etiology, as GWI veterans exhibit increases in circulating cytokines and glial (TSPO) activation compared to controls [ 14 , 15 , 16 , 17 ]. Immune alterations are further driven by (neuro) inflammatory increases in multiple laboratory models of GWI; this showcases how interplay between the nervous and immune systems impacts GWI development, specifically regarding the effects of inflammation on neurological and neurobehavioral function [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. However, the relationship between GWI GI symptomology, immune alterations, and behavioral outcomes have not been investigated.…”

“…Immunotherapies may be an advantageous treatment option considering the pathogenic role inflammation and immune dysregulation play in GWI symptomology. Lacto-N-fucopentaose III (LNFPIII), a glycan found in human milk that, to date, has had no documented adverse outcomes and has shown promising immunomodulatory effects by reducing peripheral and central inflammation [ 19 , 39 , 40 , 41 , 42 , 43 ]. When conjugated to a dextran carrier, LNFPIII skews the inflammatory balance of the innate immune system in an anti-inflammatory direction by activating CD14/TLR-4 signaling for extracellular signal-regulated kinase (ERK) dependent production of anti-inflammatory mediators [ 39 , 40 , 41 , 42 , 43 ].…”

“…Thus, within the context of GWI, LNFPIII may be beneficial in absolving GWI-induced gut inflammation and subsequent neuroinflammation through its modified anti-inflammatory TLR-4 signaling [ 10 ]. In fact, our earlier studies demonstrated LNFPIII’s beneficial effects in preventing and reducing brain wide monoaminergic disbalance and inflammation in the hippocampus after acute experimental GWI exposure [ 19 ], as well as restoring long-term behavioral deficits caused by PB/PM exposure, particularly in motor function. Whether LNFPIII modulates gut microbiota and gut health is currently unknown.…”

“…This study examines the effects of exposure to GW-related chemicals on GI microbial ecology in an established model of GWI (PB/PM). Our earlier studies using this established exposure paradigm indicated acute neurological [ 19 ] and long-term neurobehavioral deficits that were largely restored by the immunotherapeutic, LNFPIII. However, while some data exist on the human and animal GI effects of GWI after exposure, the short- and long-term GI effects of this GWI treatment paradigm have not been investigated.…”