Mice fed an obesogenic western diet, administered antibiotics and subjected to a sterile surgical procedure develop lethal septicemia with multi-drug resistant pathobionts.. Mice fed an obesogenic western diet, administered antibiotics and subjected to a sterile surgical procedure develop lethal septicemia with multi-drug resistant pathobionts

Human sepsis is characterized by a major disruption in the community structure and function of the intestinal microbiome owing to both physiologic stress and the unavoidable use of antibiotics. Among the critically ill, collapse of the microbiome is associated with its replacement by multi-drug resistant (MDR) pathobiota which are generally assumed to be acquired from cross transmission and/or the selective pressure of antibiotics. Here we demonstrate that drug resistant bacteria can emerge from among the normal microbiota and cause lethal sepsis when mice are exposed to a high fat/ low fiber Western-like diet (polyunsaturated fatty acid-PUFA), antibiotics and an otherwise completely recoverable surgical injury (30% hepatectomy). The feeding of a PUFA diet alone resulted in a major imbalance of the cecal microbiota characterized by a decrease in diversity, elimination of Bacteroidetes, a bloom in Proteobacteria, and increased antibiotic resistance. When mice were fed a PUFA diet, exposed to antibiotics and then subjected to a 30% hepatecomy, lethal sepsis developed characterized by severe organ damage in the kidneys, lung, liver, and spleen and stem cell apoptosis in the cecal mucosal. Notable was the emergence and systemic dissemination of multi-drug resistant (MDR) pathobionts including carbapenem-resistant ESBL-producing Serratia marcescens, that similar to the antibiotic sensitive strains, demonstrated a virulent and immunosuppressive phenotype. Analysis of the distribution of the exact sequence variants (ESVs) belonging to genus Serratia suggested that these strains originated from the cecal tissues. Taken together, this novel model of endogenous sepsis demonstrates the critical influence a western-like diet has on the development of lethal sepsis in mice with the emergence of virulent multi-drug resistant pathobionts.