Targeted-Bacterium-Depleted (TBD) Mice Model and its Validation Using <i>Escherichia Coli</i> Phage T7 in a Microbiota-Gut-Brain Axis Study

Abstract

Microbiome colonizing human gut is considered as the last human body organ and enteric end of the Microbiota-Gut-Brain axis (MGB). Animal models including germ-free, antibiotic treatment and gnotobiotic mice, are the most prominent tools to elucidate the functions of gut microbiota in MGB. Here, we propose a new Targeted-Bacterium-Depleted (TBD) model using lytic bacteriophage to selectively deplete targeted bacterium in the gut of healthy animal or other defined animal models. And these phage-treated animals should have near-complete spectrum of gut bacteria with only defined bacterium depleted. Comparing to the existing models, the TBD model offers precision to connect a specific microbe with its diminishing on the host physiology. In particular, the impact can be evaluated via tracing and complementation experiments. To validate this new approach, we employed Escherichia coli specific lytic phage T7 to selectively repress E. coli in the gut of healthy mice and evaluated the impact on animal behaviour, gut microbiome disturbance and organ health. Our results showed that the E. coli-depleted mice exhibited a unique behavioural pattern similar to combined effects of anxiolytics and antidepressants. Interestingly, these behaviours are directly correlated to the status of E. coli itself rather than the global gut microbiota rebalance. Thus, we demonstrated the feasibility of using bacteriophage as a tool to elucidate the impact of a specific bacterial strain on MGB; which is a significant advance for microbiota research to zoom into the gut microbiome community and elucidate the interconnections between a bacterial species and human health.