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

Viruses. 2019 Oct 21;11(10):968. doi: 10.3390/v11100968.


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.

Keywords: Gulf war illness; IL6; Ribavirin; Virome; intestinal inflammation; microbiome; neuroinflammation; next-generation sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage
  • Bacteria / virology*
  • Cytokines / immunology
  • DNA
  • Disease Models, Animal
  • Dysbiosis / virology*
  • Gastrointestinal Microbiome*
  • Immunity, Innate
  • Inflammation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / immunology
  • Neurons / pathology*
  • Permethrin / administration & dosage
  • Persian Gulf Syndrome* / chemically induced
  • Persian Gulf Syndrome* / microbiology
  • Persian Gulf Syndrome* / virology
  • Phenotype
  • Pyridostigmine Bromide / administration & dosage
  • Ribavirin / administration & dosage
  • Viruses / classification*


  • Antiviral Agents
  • Cytokines
  • Ribavirin
  • Permethrin
  • DNA
  • Pyridostigmine Bromide