Doxycycline for transgene control disrupts gut microbiome diversity without compromising acute neuroinflammatory response

The tetracycline transactivator (tTA) system provides controllable transgene expression through oral administration of the broad-spectrum antibiotic doxycycline. Antibiotic treatment for transgene control in mouse models of disease might have undesirable systemic effects resulting from changes in the gut microbiome. Here we assessed the impact of doxycycline on gut microbiome diversity in a tTA-controlled model of Alzheimer's disease and then examined neuroimmune effects of these microbiome alterations following acute LPS challenge. We show that doxycycline decreased microbiome diversity in both transgenic and wild-type mice and that these changes persisted long after drug withdrawal. Despite the change in microbiome composition, doxycycline treatment had minimal effect on basal transcriptional signatures of inflammation the brain or on the neuroimmune response to LPS challenge. Our findings suggest that central neuroimmune responses may be less affected by doxycycline at doses needed for transgene control than by antibiotic cocktails at doses used for experimental microbiome disruption.Total genomic DNA extracted from 48 stool samples was analyzed, taken from 24 mice at 2 different time points (6 wk and 12 wk of age). 4 experimental groups were compared: Transgenic + 100mg/kg Doxycycline (n=6), Transgenic no treatment (n=7), Wildtype + 100mg/kg Doxycycline (n=6), and Wildtype no treatment (n=5). Dox-treated mice received medicated diet from postnatal day 3 until 6 wk of age, and then were returned to control diet until the final stool sample was collected at 12 wk. Mice without treatment were kept on control diet throughout life.