Airway infection with murine γ-herpesvirus 68 triggers gut-to-liver bacterial translocation via increased intestinal permeability

Primary infection by Epstein-Barr virus (EBV) often causes infectious mononucleosis (IM), which is frequently accompanied by acute hepatitis despite the absence of direct EBV infection of hepatocytes. Our previous studies using murine γ-herpesvirus 68 (MHV68), a murine model of EBV, demonstrated that intestinal bacteria contribute to hepatitis induced by MHV68 airway infection, although the underlying mechanism remains unclear. In the present study, we investigated the effect of MHV68 airway infection on intestinal barrier function. C57BL/6 mice were intratracheally inoculated with MHV68. Intestinal permeability was assessed by the FITC-dextran permeability assay. Total fecal IgA and mucin levels were assessed as intestinal barrier-associated parameters. Bacterial translocation to the liver was evaluated by recovering intrarectally administered GFP-expressing Escherichia coli from the liver. The effect of neomycin on bacterial translocation was also examined. Infected mice exhibited increased FITC-dextran permeability and reduced total fecal IgA and mucin levels, consistent with a leaky gut phenotype. Both GFP-expressing E. coli and endogenous bacteria were recovered from the liver, demonstrating bacterial translocation, albeit transiently, to the liver. Oral administration of neomycin reduced bacterial translocation and attenuated hepatic inflammation. To gain insight into a possible mechanism underlying intestinal barrier dysfunction, we also evaluated circulating cytokine responses during MHV68 infection. Collectively, we found intestinal barrier dysfunction upon MHV68 airway infection, possibly through systemic cytokine responses and resulting in transient intestinal bacterial translocation to the liver. This process likely contributes to MHV68-induced hepatitis and further supports that targeting intestinal bacteria represents a potential therapeutic strategy for IM-associated hepatitis. (250/250 words).