Ellagic acid alleviates sepsis-induced intestinal injury by modulating gut microbiota and NF-κB-mediated MLCK/MLC signaling pathway

Abstract

Sepsis is a systemic inflammatory response syndrome triggered by infection. Severe sepsis is associated with dysbiosis of the intestinal flora and impaired intestinal function. Ellagic acid (EA) is a natural compound known for its ability to inhibit bacteria and viruses, thereby preventing infections. However, it remains unclear whether EA mitigates intestinal barrier dysfunction. In this work, BALB/c mice were administered doses of EA via gavage, followed by an injection of lipopolysaccharide (LPS) to induce sepsis. Fecal samples, serum, and ileum tissues were collected for molecular or pathological analysis. The intestinal contents underwent 16S rRNA sequencing and targeted metabolomics for short-chain fatty acids (SCFAs) detection. Additionally, an in vitro injury model was established using IEC6 cells treated with LPS; subsequent changes in inflammation and oxidative stress were assessed following EA treatment. The results indicated that EA reduced inflammation and oxidative stress as well as ameliorated intestinal lesions and enhanced intestinal barrier function in both mouse and cell models. Moreover, EA inhibited the signaling of nuclear factor kappa-light-chain-enhancer of activated B cells/myosin light chain kinase/myosin light chain (NF-κB/MLCK/MLC) pathway. Besides, EA also rectified genomic and metabolomic disturbances within the gut microbiota caused by sepsis. In conclusion, EA mitigates sepsis-induced intestinal injury through modulation of gut microbiota composition and inhibition of NF-κB-mediated MLCK/MLC signaling pathway. Thus, EA might represent a promising therapeutic agent for addressing intestinal injuries associated with sepsis.