Intestinal Dysbiosis Following Cholestasis is Reduced by Active Immunization with a Detoxified Endotoxin Vaccine

Background: Cholestasis inevitably leads to intestinal barrier loss resulting in endotoxemia and sepsis. Using a cholestatic mouse model, we have previously reported decreased intestinal barrier resistance, increased rates of bacterial translocation, endotoxemia and increased mortality following cholestasis. Furthermore, we found an intestinal dysbiosis, an altered gut microbiota, with increased numbers of virulent bacterial species 2 weeks after cholestatic injury as compared to sham-operated mice. We hypothesize that active immunization with the detoxified endotoxin vaccine, J5dLPS, will prevent the dysbiosis seen following cholestasis. Methods: C57Bl/6J mice were vaccinated with a detoxified endotoxin vaccine, J5dLPS. Saline-injected mice served as controls. Following confirmation of serum antibody titers, mice then underwent either a Common Bile Duct Ligation (CBDL) as a model for cholestatic injury or a sham operation. Both before surgery and one week following surgery, stool specimens were collected for bacterial DNA isolation and sequencing. Results: In this pilot study, J5dLPS vaccination was highly immunogenic and well-tolerated in C57Bl/6J mice. No dysbiosis was seen following active immunization. Moreover, J5dLPS-vaccinated mice which underwent CBDL demonstrated reduced intestinal dysbiosis and a strong trend [p=0.07] toward no dysbiosis compared to the dysbiosis seen in saline-injected mice after CBDL. Conclusions: The detoxified endotoxin vaccine, J5dLPS, does not cause an intestinal dysbiosis in mice which have been actively immunized. This finding provides additional evidence of safety supporting future clinical use of this vaccine. Moreover, this same vaccine greatly reduces the gut dysbiosis seen in mice following cholestatic injury. Future studies are warranted to determine if maintenance of the gut microbiota strengthens the intestinal barrier following cholestasis and prevents gut colonization with opportunistic pathogens.