The gut-liver axis and the role of bacteria in severe dengue virus infection in mice
- 1School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia
Abstract
Patients with severe dengue virus (DENV) infection can experience hemorrhage, shock and organ damage that coincides with defervescence and declining viremia. In addition to vascular leak, published work has shown that gut barrier permeability and elevated serum lipopolysaccharide (LPS) levels correlate with DENV disease severity. We previously described profound gut pathology in a mouse model of infection. This led to the hypothesis that a loss of gut epithelial barrier integrity and the influx of microbial products contribute to exacerbated inflammation and severe dengue disease. Consistent with this, here we demonstrated that DENV2 infection of AG129 mice compromised the gut epithelial barrier, promoted bacterial translocation, and induced microbial changes indicative of dysbiosis, including a reduced abundance of putatively beneficial microbial taxa and disrupted microbial circadian oscillations. Depleting gut bacteria with antibiotics from 1-day post-infection sharply reduced gut pathology as well as viral RNA in the proximal colon and liver, and the number of infected Kupffer cells in the liver. There was no evidence for systemic suppression of viral replication. We propose that viral infection of intestinal macrophages leads to inflammatory damage and mucosal barrier breakdown, dysbiosis and gut leak, with gut bacteria-dependent products promoting the susceptibility of Kupffer cells to DENV infection. Given the importance of liver damage in severe and fatal dengue disease, therapies that protect the gut barrier may help reduce disease severity.
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BibTeX
@misc{pliegozamora2026gutliver,
title = {{The gut-liver axis and the role of bacteria in severe dengue virus infection in mice}},
author = {A. Pliego-Zamora and J. Kim and N. Modhiran and K. Takizawa and E. Gollasch-Miller and R. Wang and P. R. Young and D. Watterson and S. Z. Hasnain and P. Vajjhala and Y. Sekiguchi and H. Bielefeldt-Ohmann and D. M. Tourlousse and K. J. Stacey},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.749971},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.749971v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - The gut-liver axis and the role of bacteria in severe dengue virus infection in mice
AU - A. Pliego-Zamora
AU - J. Kim
AU - N. Modhiran
AU - K. Takizawa
AU - E. Gollasch-Miller
AU - R. Wang
AU - P. R. Young
AU - D. Watterson
AU - S. Z. Hasnain
AU - P. Vajjhala
AU - Y. Sekiguchi
AU - H. Bielefeldt-Ohmann
AU - D. M. Tourlousse
AU - K. J. Stacey
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.749971
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.749971v1
AB - Patients with severe dengue virus (DENV) infection can experience hemorrhage, shock and organ damage that coincides with defervescence and declining viremia. In addition to vascular leak, published work has shown that gut barrier permeability and elevated serum lipopolysaccharide (LPS) levels correlate with DENV disease severity. We previously described profound gut pathology in a mouse model of infection. This led to the hypothesis that a loss of gut epithelial barrier integrity and the influx of microbial products contribute to exacerbated inflammation and severe dengue disease. Consistent with this, here we demonstrated that DENV2 infection of AG129 mice compromised the gut epithelial barrier, promoted bacterial translocation, and induced microbial changes indicative of dysbiosis, including a reduced abundance of putatively beneficial microbial taxa and disrupted microbial circadian oscillations. Depleting gut bacteria with antibiotics from 1-day post-infection sharply reduced gut pathology as well as viral RNA in the proximal colon and liver, and the number of infected Kupffer cells in the liver. There was no evidence for systemic suppression of viral replication. We propose that viral infection of intestinal macrophages leads to inflammatory damage and mucosal barrier breakdown, dysbiosis and gut leak, with gut bacteria-dependent products promoting the susceptibility of Kupffer cells to DENV infection. Given the importance of liver damage in severe and fatal dengue disease, therapies that protect the gut barrier may help reduce disease severity.
ER -