Angiotensin-(1-7) alleviates intestinal barrier dysfunction and dysbiosis in mice with polymicrobial sepsis.

Abstract

BACKGROUND AND PURPOSE: The intestine plays a key role in the initiation of sepsis. The gut barrier impedes the translocation of commensal bacteria to the liver in sepsis. Previous studies have reported that angiotensin-(1-7) [Ang-(1-7)] attenuated sepsis-induced organ injury and mortality. However, its role in sepsis-induced intestinal barrier dysfunction remains unclear. Here we have investigated therapeutic effects of Ang-(1-7) on the intestinal barrier dysfunction and dysbiosis in a murine model of sepsis. EXPERIMENTAL APPROACH: We used a model of sepsis in C57BL/6 mice with caecal ligation and puncture (CLP), to assess mortality and histological and biochemical changes in the gut and liver tissues. Faecal microbiota transplantation (FMT) was used to assess the role of the gut microbiome. 16-s rDNA and metabolomics analyses were performed to characterize differences in the gut microbiome signatures and metabolic profiles. KEY RESULTS: Plasma Ang-(1-7) was decreased in patients with sepsis. In CLP mice, exogenous Ang-(1-7) attenuated intestinal barrier dysfunction and liver damage. FMT experiments showed that the protective effects of Ang-(1-7) on the gut depended on the gut microbiota. Furthermore, 16-s ribosomal DNA analysis revealed that Ang-(1-7) treatment increased the abundance of Lactobacillus gasseri (L. gasseri) among commensal bacteria. Mechanistically, L. gasseri regulated the production of antimicrobial peptides in intestinal epithelia by activating NLRP6 inflammation. CONCLUSION AND IMPLICATIONS: Ang-(1-7) protected against sepsis-induced intestine barrier dysfunction and liver injury in mice by modulating gut homeostasis and NLRP6 inflammasome. Ang-(1-7) is a promising candidate drug for protecting intestinal homeostasis in sepsis, offering new insights for clinical treatment.