A murine model of diarrhea, growth impairment and metabolic disturbances with<i>Shigella flexneri</i>infection and the role of zinc deficiency

Abstract

<i>Shigella</i> is one of the major enteric pathogens worldwide. We present a murine model of <i>S. flexneri</i> infection and investigate the role of zinc deficiency (ZD). C57BL/6 mice fed either standard chow (HC) or ZD diets were pretreated with an antibiotic cocktail and received <i>S. flexneri</i> strain 2457T orally. Antibiotic pre-treated ZD mice showed higher <i>S. flexneri</i> colonization than non-treated mice. ZD mice showed persistent colonization for at least 50 days post-infection (pi). <i>S. flexneri</i>-infected mice showed significant weight loss, diarrhea and increased levels of fecal MPO and LCN in both HC and ZD fed mice. <i>S. flexneri</i> preferentially colonized the colon, caused epithelial disruption and inflammatory cell infiltrate, and promoted cytokine production which correlated with weight loss and histopathological changes. Infection with <i>S. flexneri ΔmxiG</i> (critical for type 3 secretion system) did not cause weight loss or diarrhea, and had decreased stool shedding duration and tissue burden. Several biochemical changes related to energy, inflammation and gut-microbial metabolism were observed. Zinc supplementation increased weight gains and reduced intestinal inflammation and stool shedding in ZD infected mice. In conclusion, young antibiotic-treated mice provide a new model of oral <i>S. flexneri</i> infection, with ZD promoting prolonged infection outcomes.