A reproducible enteric phage community improves blood glucose 1 regulation in an obesity mouse model

Introduction Recent evidence suggest a link between gut microbiome dysbiosis and metabolic syndrome, including type-2-diabetes, obesity, and non-alcoholic fatty liver disease (NAFLD). Fecal microbiota transplantation (FMT) has been explored as a way to restore a healthy gut microbiome in obese patients but poses safety concerns. The wide use of FMT is limited by safety concerns about transferring the entire fecal microbiome from one individual to another. Fecal virome transplantation (FVT) is a safer alternative that transfers bacteriophages without bacterial transfer, but still carries the risk of eukaryotic virus infection. Therefore, a safer and more effective tool for modulating gut microbiome is needed. Methods We explored the potential of implementing three alternative FVT techniques with increased safety established in a recent study (eukaryotic viruses were either eliminated or inactivated) to ameliorate symptoms associated with a diet-induced obesity mouse model. Male mice were fed with an ad libitum high-fat diet before being euthanized (23 weeks of age) and received the different FVT treatments twice with one week of interval. Body weight was measured, oral glucose tests were performed, feces were sampled frequently, and liver, fat pads, mesenteric lymph node, and blood serum were sampled at termination of study. Results FVT treatments had no effect on weight gain or the amount of epididymal white adipose tissue. Mice given regular untreated FVT (FVT-UnT) had a significant (p < 0.05) drop in the pathological score of their liver tissue when compared to HFD-control mice. Mice treated with a chemostat propagated fecal virome (FVT-ChP, eukaryotic viruses eliminated by dilution) improved their blood glucose regulation significantly (p < 0.05) compared to HFD-control mice. Gut microbiome analysis of both the bacterial and viral component suggested that bacteriophage-mediated modulation of the gut microbiome could be a driving factor for the observed effects. Conclusions These results may lay the ground to develop safer bacteriophage-based therapeutic tools to restore the dysbiotic gut microbiome associated with metabolic syndrome.