Obesity Worsens Gulf War Illness Symptom Persistence Pathology by Linking Altered Gut Microbiome Species to Long-Term Gastrointestinal, Hepatic, and Neuronal Inflammation in a Mouse Model

Abstract

Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese phenotype of the deployed GW veterans. The host microbial profile in the Western diet-fed GWI mice showed a significant decrease in butyrogenic and immune health-restoring bacteria. The altered microbiome was associated with increased levels of IL6 in the serum, Claudin-2, IL6, and IL1β in the distal intestine with concurrent inflammatory lesions in the liver and hyperinsulinemia. Microbial dysbiosis was also associated with frontal cortex levels of increased IL6 and IL1β, activated microglia, decreased levels of brain derived neurotrophic factor (BDNF), and higher accumulation of phosphorylated Tau, an indicator of neuroinflammation-led increased risk of cognitive deficiencies. Mechanistically, serum from Western diet-fed mice with GWI significantly increased microglial activation in transformed microglial cells, increased tyrosyl radicals, and secreted IL6. Collectively, the results suggest that an existing obese phenotype in GWI worsens persistent gastrointestinal and neuronal inflammation, which may contribute to poor outcomes in restoring cognitive function and resolving fatigue, leading to the deterioration of quality of life.

Gut resistome presents a unique biome signature in chronic multi-symptom illness patients and links persistent pro-inflammatory phenotype in a mouse model reversible by fecal microbiota transfer

“…To study the association between IL-1β expression and AGF diversity, we performed a correlation analysis. Our previous studies have reported that a decrease in synaptic plasticity marker BDNF played a key role in brain pathology in GW chemical exposed mice [44] Results showed that expression of BDNF significantly decreased (p=<0.00001 between Control vs GWI & GWI vs GWI_FMT) in GWI group when compared to Control and GW_FMT mice groups (Fig 6d). Interestingly, a negative correlation (r=-0.8866, p=0.19 & r=-0.9799, p<0.001) was observed between BDNF and AGFs suggesting that increased AGF-α-diversity may have a strong influence on observed neuroinflammation GWI mice group (Fig 6j)…”

“…The fixed mouse small intestine and frontal cortex tissues were paraffin embedded and 5 µm thick sections were done for immunohistochemistry. Deparaffinization were performed following previous protocol [44]. Antigen retrieval was performed using epitope retrieval solution and steamer (IHC world, Woodstock, MD, USA).…”

Andrographolide Attenuates Gut-Brain-Axis Associated Pathology in Gulf War Illness by Modulating Bacteriome-Virome Associated Inflammation and Microglia-Neuron Proinflammatory Crosstalk

“…Tight junction (TJ) proteins are responsible for maintaining epithelial barrier integrity, which in turn is essential for regulating nutrient absorption, transport of selective content from the lumen, and blockage of pathogen entry [ 38 , 39 ]. In our previous studies, we showed that GW chemical exposure led to an altered expression of TJ proteins, where Claudin-2 expression was increased with a simultaneous decrease in Occludin expression, leading to gut leaching [ 7 , 11 ]. In this study, we wanted to show whether AG was able to revert the altered expression of TJ proteins in GW chemical-exposed mice.…”

“…GW chemicals (PER and PB) were used to expose the mice following well-established acute rodent models of Gulf War illness with some modifications [ 7 , 9 , 11 ]. All mice were randomly divided into 4 groups after 1 week of acclimatization.…”

“…We were the first group to establish a notable connection between the gut microbiome and GWI pathology, where we showed that the administration of Gulf War chemicals (GWC) in a mice model caused an alteration of the gut bacteriome signature, which in turn led to increased intestinal inflammation, gut leaching, endotoxemia, and release of the damage-associated molecular pattern (DAMP) HMGB1 (High motility group box 1) [ 6 , 7 ]. Subsequently, we have shown that GWI-associated dysbiosis in mice resulted in a decrease of the probiotic butyrogenic bacteria [ 7 , 8 ], increased Firmicutes abundance over Bacteroidetes in the phylum level [ 6 , 7 ], and a decrease of the probiotic species Akkermansia muciniphila [ 9 ] and these alterations attributed to increased intestinal inflammation, gut leaching [ 7 , 8 , 10 , 11 ], enteric glial cell activation [ 12 ], hepatic metabolic reprogramming [ 8 , 11 ], neuronal inflammation [ 6 , 7 , 9 , 10 ], the systemic release of HMGB1 [ 7 , 8 ], symptoms all of which fall under GWI pathology domain. We have also shown that administration of oral butyrate and the nutraceutical Sparstolonin B in mice helped to restore normal bacteriome patterns and decreased GWI-associated symptoms as described previously.…”