Contributions of the gut microbiota to Gulf War Illness susceptibility: Findings from a mouse model

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In light of the evidence supporting a significant role of the gut microbiome in Gulf War Illness (GWI) pathology, we sought to examine its contribution to GWI susceptibility in a mouse model. We also aimed to identify bacterial taxa and microbially-derived metabolites associated with disease susceptibility. Male mice receiving pyridostigmine bromide (PB) orally, and controls were evaluated for symptoms of GWI at 8 weeks post-treatment. The Kansas criteria were adapted to assess behaviors associated with the following domains: gastrointestinal alterations, pain, mood, cognitive function, skin and respiratory disturbances. PB-treated subjects were classified into susceptible (GWI-S) or resilient (GWI-R). The status of the gut microbiome was assessed via analyses of the 16S rRNA gene and microbial-derived metabolites were evaluated with metabolomics tools. Our results indicate that application of the Kansas criteria to behavioral outcomes in PB-treated mice resulted in a GWI susceptibility rate of ~35 %, similar to the one reported in humans. The composition and structure of the gut microbiome was different in GWI-S subjects compared to both control and GWI-R mice at 8 weeks but differences in microbial community structure were observed prior to PB treatment between GWI-R and GWI-S mice. GWI-S subjects exhibited a pattern of differentially abundant bacterial taxa and microbial metabolites. To our knowledge, this is the first preclinical report in which a stratification by susceptibility to GWI and its association with the gut microbiome is described. In light of the research conundrum that vulnerability to GWI represents, the use of tools that could provide further insight into this complex factor should be considered. • Oral administration of pyridostigmine bromide (PB) in mice induced symptoms associated with GWI as seen in humans. • Application of the Kansas criteria to behavioral outcomes in PB-treated mice resulted in a susceptibility rate of ~35%. • GWI susceptibility was associated with chronic alterations in the composition and structure of the gut microbiome. • Bacterial metabolic shifts in fatty acids, amino acids, bile acids, energy, and vitamins were linked to GWI susceptibility.

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