Protective Effects of Irisin Against LPS-Induced Intestinal Injury and Its Influence on Gut Microbiota in Septic Mice

Ling Yang,1,2,* Mudi Liu,1,2,* Beilin Hu,1,2,* Kangle Yong,3 Jun Zhou,1,2 Ye Chen2,4 1Department of Anesthesiology, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 3School of Medical Information and Engineering, Southwest Medical University, Luzhou, 646000, People’s Republic of China; 4Department of Traditional Chinese Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Zhou, Email [email protected]; [email protected] Ye Chen, Email [email protected]: Irisin, a novel myokine, has garnered significant attention for its roles in metabolic regulation and anti-inflammatory responses. Sepsis disrupts the intestinal microenvironment, exacerbating its progression and highlighting the need for novel therapeutic approaches. This study aims to investigate whether irisin exerts protective effects against lipopolysaccharide (LPS)-induced intestinal injury in septic conditions and to explore the underlying mechanisms involving the gut microbiota.Methods: To induce sepsis, C57BL/6 mice were injected intraperitoneally with LPS at a dose of 10 mg/kg, and then administered with 1 μg/kg of irisin. The Activity levels and 7-day survival rate were recorded. The intestinal expression of irisin/FNDC5 was assessed using Western blotting and immunofluorescence staining. Inflammatory factors were measured using enzyme-linked immunosorbent assay (ELISA). Peripheral blood bacteria were cultured on blood agar plates. Intestinal histomorphology was analyzed via hematoxylin and eosin (H&E) staining. The expression of occludin and apoptotic-related proteins was determined by Western blot, and apoptotic cells were detected using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. The intestinal microbiota was analyzed through 16S rRNA amplicon sequencing.Results: Irisin improved the survival state and rate of LPS-induced septic mice. It restored endogenous irisin/FNDC5 levels in intestinal tissues, mitigated intestinal barrier injury, and alleviated bacteremia following sepsis treatment. Furthermore, irisin exhibited anti-inflammatory properties by increasing the levels of IL-22 while decreasing those of TNF-α and IL-6, as well as anti-apoptotic effects by increasing levels of pro-caspase-3 and Bcl-2 while decreasing cleaved caspase-3, Bax, and the positive density of apoptotic cells. Additionally, it regulated intestinal microbiota dysfunction.Conclusion: Irisin effectively treats septic acute intestinal injury by reducing apoptosis and inflammation, with the intestinal microbiota likely playing a crucial role. This finding offers a novel approach to clinical management of sepsis.Keywords: irisin/FNDC5, sepsis, anti-inflammation, anti-apoptosis, intestinal microbiota