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.

Dipro Bose,Ronnie Horner,Ratanesh K Seth,Stephen Lasley,Punnag Saha,Saurabh Chatterjee,Ashok K Shetty,Nancy Klimas,Patricia Janulewicz,Rita R Colwell,Kimberly Sullivan,Ayan Mondal,Brian Fanelli

doi:10.3390/nu12092764

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.

Highlights

Persistence of Gulf War illness (GWI) among deployed veterans is a clinical challenge to diagnose and treat
The results suggested that the underlying obesity following Western diet feeding worsened the GWI intestinal inflammation, as shown by increased levels of IL1β and IL6
The results suggested that the underlying obesity following Western diet feeding associated with increased species diversity.asHowever, was alevels negative correlation worsened the intestinal inflammation, shown bythere increased of IL1β and IL6. between

Summary

Introduction

Persistence of Gulf War illness (GWI) among deployed veterans is a clinical challenge to diagnose and treat. Though there is strong epidemiological evidence of an association of Gulf War exposures to chronic fatigue, metabolic syndrome, gastrointestinal (GI) disturbances and obesity, the persistence or worsening of the symptoms even long after the war has ended and our troops have returned home remains a challenge for clinicians in numerous health centers nationwide [1,2,3,4,5]. There was a strong association of post-traumatic stress disorder (PTSD) in GW veterans with metabolic syndrome and obesity [7]. The study implied that advancing age and lifestyle factors (Western diet, physical inactivity) are augmenting the development of obesity, metabolic syndrome, and other chronic diseases. It is interesting to note that PTSD can lead to physical inactivity and may increase this risk in aging veterans to develop age-related diseases [7]

Methods

Results

Conclusion