Host-Pathogen-Gut Microbiota Interactions: The Role of Diet, Microbiota Metabolites, and the Aryl Hydrocarbon Receptor in Survival from Sepsis and Surgical Injury

Host-microbiota-pathogen interactions play a key role in determining survival from lethal bacterial infection leading to sepsis. Here we demonstrate that western diet, high in fat and low in fiber, increases the risk for pathogen colonization in the gut and results in gut-derived sepsis when mice are exposed to antibiotics, starvation, and a recoverable, surgical injury. The risk of postoperative sepsis is mitigated through dietary prehabilitation with a diet low in fat and high in fiber. Dietary prehab provides protection following functional recovery of the gut microbiota resulting in increased butyrate. Pathogen colonization can be mitigated with a diet high in fiber which increases microbiota through the quorum sensing molecule AI-2 which stabilizes Firmicutes in the face of antibiotic exposure. The western diet alterations not only destabilize metabolite production of the gut microbiota, but also increases the presence of antibiotic resistance genes. Independent of antibiotic exposure, western diet increases the presence of antibiotic resistance genes to macrolides, fluoroquinolones, and cephalosporins. The production of indole metabolites by the gut microbiota was found to drive a recovery directed immune response to lethal bacterial peritonitis. During lethal infection, indole metabolites enhanced survival by activating AhR on peritoneal macrophages which increased bacterial clearance and induced early resolution of inflammation. Oral supplementation with tryptophan or direct injection of indole metabolites improved survival. To further implicate the importance of indole activation of AhR in the setting of lethal peritonitis, bacterial pathogens actively inhibited indole activation of AhR through the secretion of small molecules such as enterobactin. Finally, indole metabolites in the gut of septic patients correlated with survival. In conclusion, the structure and function of the gut microbiota is influenced by diet and has major downstream implications on pathogen colonization, virulence, and survival from lethal bacterial infection.