BACKGROUND: Previous work suggests that the gut microbiome can be disrupted by antibiotics, anesthetics, opiates, supplemental oxygen, or nutritional deprivation-all of which are common and potentially modifiable perioperative interventions that nearly all patients are exposed to in the setting of surgery. Gut microbial dysbiosis has been postulated to be a risk factor for poor surgical outcomes, but how perioperative care-independent of the surgical intervention-impacts the gut microbiome, and the potential consequences of this impact have not been directly investigated. METHODS: We developed a perioperative exposure model (PEM) in C57Bl/6 mice to emulate the most common elements of perioperative medicine other than surgery, which included 12 hours of nutritional deprivation, 4 hours of volatile general anesthetic, 7 hours of supplemental oxygen, surgical antibiotics (cefazolin), and opioid pain medication (buprenorphine). Gut microbial dynamics and inferred metabolic changes were longitudinally assessed before-and at 3 time points after-PEM by 16S rRNA amplicon sequencing. We then used fecal microbial transplant in secondary abiotic mice to test if, compared to preexposure microbiota, day 3 post-PEM microbial communities affect the clinical response to immune challenge in an endotoxemia model. RESULTS: We observed transient changes in microbiota structure and function after the PEM, including reduced biodiversity, loss of diverse commensals associated with health (including Lactobacillus, Roseburia, and Ruminococcus), and changes in microbiota-mediated amino acid metabolic pathways. Mice engrafted with day 3 post-PEM microbial communities demonstrated markedly reduced survival after endotoxemia compared to those bearing preexposure communities (7-day survival of ~20% vs ~70%, P = .0002). CONCLUSIONS: These findings provide the first clear evidence that the combined effects of common perioperative factors, independent of surgery, cause gut microbial dysbiosis and alter the host response to inflammation in the postoperative period.