Work

Erythropoietin-mediated IL-17 F attenuates sepsis-induced gut microbiota dysbiosis and barrier dysfunction

Year: 2023

Type: article

Abstract: Background: Septic gut damage is critical in the progression of sepsis and multiple organ failure, characterized by gut microbiota dysbiosis and epithelium deficiency in the gut barrier. Recent studies highlight the protective effects of Erythropoietin (EPO) on multiple organs. In this study, we investigated the gut protective effects of EPO in sepsis and its underlying mechanisms.Methods: The LPS-induced septic mice and intestinal epithelial tissue-specific EPOR conditional knockout mice (EporIECCre mice) were utilized to investigate the protective effects of EPO in the intestinal barrier. 16S rRNA gene sequencing and bioinformatics analysis of feces were performed to screen differential intestinal flora. Differentially expressed genes of intestinal epithelium samples from EPO-treated septic EporIECCre and Eporflox/flox mice were screened using RNA sequencing and analysis. The recombinant protein gavage and fecal microbiota transplantation (FMT) were further utilized to clarify the gut protective effects of IL-17F on sepsis.Findings: Our data showed that EPO treatment significantly alleviated the survival rate, suppressed inflammatory responses, and ameliorated intestine damage in mice with sepsis. EPO treatment also reversed sepsis-induced gut microbiota dysbiosis. The protective role of EPO in the gut barrier and microbiota was impaired after EPOR knockout. Notably, we innovatively demonstrated that IL-17F screened by transcriptome sequencing could ameliorate sepsis and septic gut damage including gut microbiota dysbiosis and barrier dysfunction, which was verified by IL-17F-treated FMT as well.Interpretation: Our findings highlight the protection effects of EPO-mediated IL-17F in sepsis-induced gut damage by alleviating gut barrier dysfunction and restoring gut microbiota dysbiosis. EPO and IL-17F may be potential therapeutic targets in septic patients.Funding: This project was supported by the National Key Research and Development Program of China (No.2022YFC2504404); the National Natural Science Foundation of China Joint Fund Project (U22A20273); the National Natural Science Foundation of China (No. 82270098, No.82272451).Declaration of Interest: All authors have declared that no conflict of interest exists.Ethical Approval: We conducted all animal experiments per the Laboratory animal Guideline for ethical review of animal welfare (GB/T 35892-2018, China) and with approval from the Laboratory Animal Ethics Committee of Wenzhou Medical University.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2023.115072