Sepsis and obesity: Weighing the outcomes of two models

Obesity is associated with an increased risk of multiple organ dysfunction, sepsis, and death; the proportion of overweight and obese ICU patients is increasing[1]. There is conflicting data on whether obesity is protective in sepsis and a knowledge gap in how obesity shapes the response to sepsis. Our objective is to describe organ dysfunction in a murine diet-induced obesity model of sepsis. Methods C57Bl/6 mice of both sexes, housed in static cages, were fed a high-fat diet (HFD, 21% butterfat) or low-fat (LFD, 10% butterfat) diet for 16 weeks. Glucose tolerance tests (1 g/kg 50% dextrose) were performed at 15 weeks. Infection was induced by intraperitoneal injection of rat fecal slurry (FIP) using 0.25 mg of fecal slurry per g of mouse (WB) or a set dose (SD) of 6 mg. MQTiPPSS guidelines were followed [2]. Mice received 15 ml/kg Lactated Ringers, 25 mg/kg imipenem and 0.05 mg/kg buprenorphine at 8 h and every 12 h thereafter. Mice were monitored every 4 h for the first 24 h, then every 12 h. Mice were sacrificed at 72 h. Organ damage in the lungs, livers, and kidneys was evaluated by histology. Results Mice received an average of 10.7 mg and 7 mg in the HFD and LFD WB cohorts, respectively. No mortality was observed. HFD had peak glucose of 24.6 ± 4.8 mmol/dL at 30 min. LFD mice peak glucose of 17.4 ± 4.5 mmol/dL at 15 min post-IP glucose injection. During infection, the lowest mean glucose was 5.5 ± 3.6 at 8 h in the LFD-FIP weight-based cohort versus 2.2 ± 0.8 mmol/dL at 12 h in the set-dose. The lowest mean temperature in the LFD-FIP group was 35.2 ± 2.2 °C in the weight-based cohort versus 33.3 ± 1.4 °C in the set-dose. The Mouse Sepsis Score (MSS) was consistently higher in the WB and SD HFD-FIP cohorts compared to the LFD-FIP cohorts. The SD cohorts had higher Mouse Grimace Scores (MGS) than the WB cohorts. Both the MGS and MSS peaked at 4 h in the LFD-FIP WB cohort versus 8 h in the HFD-FIP WB and SD mice. Histological evaluation of the lungs, livers, and kidneys showed minimal organ injury in the SD cohort compared to the WB mice. Lung myeloperoxidase did not differ significantly between cohort nor diet. Conclusion We showed that the dosing method of fecal-induced peritonitis is critical to developing sepsis in a murine obesity model. This study highlights the importance of developing rigorous standardized pre-clinical models that assess organ injury to enhance translational relevance and optimize the potential for successful therapeutics.