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Introduction: Recent evidence suggests a role of the gut microbiome in modulating the secondary injury seen after an ischemic stroke. In a novel model of thrombotic stroke in mice, the collagen model, we hypothesized that (a) stroke induces changes in the composition of the microbiome, and (b) depletion of the gut flora with cefoxitin is associated with a reduced infarct size.Methods: C57BL/6 male mice were assigned to one of 4 groups (n=8/group): Control, Stroke (anesthesia, ICA cannulation, collagen injection into the MCA), Sham (same as Stroke without collagen injection), and Stroke+Antibiotic. Cefoxitin was administered in drinking water for 7 days, before stroke induction. Stool pellets were collected before surgery and on the day of euthanasia for taxonomic analysis via 16S rRNA sequencing. Brains were retrieved for infarct volume measurement 2 days after surgery.Results: We observed a significant decrease in Lactobacillus and relative increases in Bacteroides, Streptococcus and Clostridium taxa after surgery in both Sham and Stroke groups (Fig 1). Antibiotic treatment was associated with a significant reduction in infarct volume in cortex and striatum (respectively 36.9% and 17.8% reductions, p<0.05) (Fig 2).Conclusions: Thrombotic stroke in mice is associated with significant changes in the relative preponderance of several bacterial taxa in the gut. Intriguingly, a similar pattern was observed in sham animals, indicating effects on the microbiome not mediated by stroke, possibly by exposure to anesthetic drugs or surgery itself. Cefoxitin administered prior to stroke dramatically altered the gut microbiome and led to a significant reduction in infarct size.