Establishment and evaluation of a new type of animal model of persistent inflammation, immunosuppression, and catabolism syndrome based on gut microbiota dysbiosis and bacterial translocation

Abstract Background Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) refers to the chronic critical illness phase of severe immunosuppression with persistent inflammatory response and repeated nosocomial infections, protein hypercatabolism, poor nutritional status, and persistent multiple organ injury in critical patients. These patients are difficult to treat and have a poor prognosis. Here, we established a new type of mouse PICS model to investigate its underlying pathophysiological mechanisms and its potential treatment. Methods We divided C57BL/6 male mice at 8-10 weeks into SHAM-operated group, DEXA group, CLP group and CLP + DEXA group. Each group had 10 mice. Sepsis was induced using a modified cecal ligation and perforation (CLP) model on day 1 (cecal ligation site to 30% away from the end of the cecal), and the inflammatory response was maintained by injection of dexamethasone (DEXA) at a dose of 2 mg/kg/day on day 3. Then ELISA, flow cytometry, western blotting and Q-PCR were used to detect inflammation, immunosuppression and catabolic indicators in mice. Results We found that at day 14, the levels of IL-6, TNF-α, and IL-1β in the CLP + DEXA group increased by approximately 3000%, 400%, and 300%, respectively, compared to the CLP group. The proportions of MDSCs and CD4 + T cells in the CLP + DEXA group were about 31.2% and 5.7%, while the proportions in the CLP group were 22.97% and 8.03%. This result also suggests a severe immunosuppressive state in the CLP + DEXA group. Compared with the CLP group, the body weight and muscle mass of the CLP + DEXA group were reduced by about 3.6 g and 135 mg, respectively, and the expression of muscle atrophy related genes such as Atrogin-1 and MuRF-1 was also increased by more than 500%. By examining intestinal tight junction proteins such as ZO-1 and Occludin, we found that the intestinal barrier of CLP + DEXA mice was severely disrupted. The 16srRNA and blood coated plates also confirmed the presence of the gut microbiota dysbiosis and translocation in the CLP + DEXA mice, which was similar to those in critically ill patients. Conclusions Collectively, our work developed a new type of mouse PICS model and elucidated that bacterial translocation plays a critical role in PICS. It also sheds light on tryptophan derivatives as potential therapeutic targeting of PICS.