Gut DNA Virome Diversity and Its Association with Host Bacteria Regulate Inflammatory Phenotype and Neuronal Immunotoxicity in Experimental Gulf War Illness

Ratanesh K Seth,Ronnie D Horner,Kimberly Sullivan,Rabia Maqsood,Nancy Klimas,Larinda A Holland,Patricia Janulewicz Lloyd,Ayan Mondal,Saurabh Chatterjee,Dipro Bose,Diana Kimono,Efrem S Lim

doi:10.3390/v11100968

Abstract

Gulf War illness (GWI) is characterized by the persistence of inflammatory bowel disease, chronic fatigue, neuroinflammation, headache, cognitive impairment, and other medically unexplained conditions. Results using a murine model show that enteric viral populations especially bacteriophages were altered in GWI. The increased viral richness and alpha diversity correlated positively with gut bacterial dysbiosis and proinflammatory cytokines. Altered virome signature in GWI mice also had a concomitant weakening of intestinal epithelial tight junctions with a significant increase in Claudin-2 protein expression and decrease in ZO1 and Occludin mRNA expression. The altered virome signature in GWI, decreased tight junction protein level was followed by the presence an activation of innate immune responses such as increased Toll-like receptor (TLR) signaling pathways. The altered virome diversity had a positive correlation with serum IL-6, IL-1β, and IFN-γ, intestinal inflammation (IFN-γ), and decreased Brain-Derived Neurotrophic Factor (BDNF), a neurogenesis marker. The co-exposure of Gulf War chemical and antibiotic (for gut sterility) or Gulf War chemical and Ribavirin, an antiviral compound to suppress virus alteration in the gut showed significant improvement in epithelial tight junction protein, decreased intestinal-, systemic-, and neuroinflammation. These results showed that the observed enteric viral dysbiosis could activate enteric viral particle-induced innate immune response in GWI and could be a novel therapeutic target in GWI.

Highlights

Gulf war illness (GWI) is a chronic multisymptomatic, medically unexplained disorder that affected25%–33% of the veterans returned from the Persian Gulf War in 1990–1991 [1]
We found that the mice exposed with GW Chemicals (GWI group) that had an altered virome diversity compared to controls showed a significant increase in monocyte chemoattractant protein 1 (MCP1) and interleukin 6 (IL6)
The current study investigates a mechanistic analysis of the gut virome-bacteriome mediated GI and neuroinflammation

Summary

Introduction

Gulf war illness (GWI) is a chronic multisymptomatic, medically unexplained disorder that affected25%–33% of the veterans returned from the Persian Gulf War in 1990–1991 [1]. The exact cause of these illnesses is unknown, recent research has found an association between environmental exposures in the Gulf war theatre and symptoms presented by sufferers [4,5]. Mice treated with PB, pesticides, and permethrin (insect repellent) showed cognitive impairment, learning difficulty, fatigue and GI dysfunction [8,9]. Our recent report, we have shown that mice exposed to PB and permethrin along with stress hormone corticosterone causes gut microbiome alteration, endotoxemia and intestinal and neuroinflammation [4,10]. How these gut bacterial communities are regulated in GWI is largely unknown.

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Results

Conclusion