Optimization of a Fresh Fecal Intraperitoneal Injection Sepsis Model and Its Divergent Dynamics from Cecal Ligation and Puncture in Mice

Background Sepsis remains a critical challenge in intensive care, necessitating reliable animal models that accurately mimic human pathophysiological responses. While cecal ligation and puncture (CLP) is widely considered the gold standard, its inherent variability often limits reproducibility. This study aimed to optimize a fecal intraperitoneal injection (FIP) murine model by evaluating the impact of fecal preparation (fresh vs. lyophilized) and dosage (0.5–1.0 g/kg) on model stability. We systematically compared the optimized FIP model with the conventional CLP method in male BALB/c mice to define their respective pathophysiological characteristics and suitability for therapeutic screening. Results Our findings demonstrate that fresh fecal suspensions significantly enhance model reproducibility compared to dried preparations, which showed inconsistent virulence. An optimized FIP dose of 0.7 g/kg induced a hyperacute sepsis phenotype, characterized by rapid systemic bacterial dissemination and significant acute lung and kidney injury within 24 hours. In contrast, the CLP model exhibited a more protracted progression of organ dysfunction, with more pronounced and sustained intestinal mucosal damage and evolving infectious dynamics. Hematological analysis confirmed that while both models induced systemic inflammation, the FIP model provided a more synchronized and predictable onset of multi-organ failure. Conclusions The optimized FIP model, characterized by its procedural simplicity, high controllability, and superior reproducibility, serves as a robust platform for investigating the early, fulminant pathophysiological mechanisms of unmitigated sepsis. Conversely, the CLP model remains the preferred choice for studies focusing on protracted infection and chronic organ dysfunction. These findings provide a methodological framework for selecting appropriate sepsis models based on specific research objectives in experimental medicine.