Gut DNA virome diversity and its association with host bacteria regulate inflammatory phenotype and neuronal immunotoxicity in experimental gulf war illness

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

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1 Scopus citations

Abstract

GulfWar 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 GulfWar 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.

Original languageEnglish (US)
Article number968
JournalViruses
Volume11
Issue number10
DOIs
StatePublished - Oct 21 2019

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Keywords

  • Gulf war illness
  • IL6
  • Intestinal inflammation
  • Microbiome
  • Neuroinflammation
  • Next-generation sequencing
  • Ribavirin
  • Virome

ASJC Scopus subject areas

  • Infectious Diseases
  • Virology

Cite this

Seth, R. K., Maqsood, R., Mondal, A., Bose, D., Kimono, D., Holland, L. A., Lloyd, P. J., Klimas, N., Horner, R. D., Sullivan, K., Lim, E. S., & Chatterjee, S. (2019). Gut DNA virome diversity and its association with host bacteria regulate inflammatory phenotype and neuronal immunotoxicity in experimental gulf war illness. Viruses, 11(10), [968]. https://doi.org/10.3390/v11100968