The protective role of kakkalide in sepsis-induced intestinal barrier dysfunction via inhibition of NF-κB pathway activation

Sepsis, a systemic inflammatory response often triggered by infection, can lead to multi-organ failure, with the intestine being one of the most vulnerable organs. The nuclear factor kappa-B (NF-κB) pathway plays a crucial role in immune responses, inflammation, and cell survival, making it central to sepsis-induced intestinal damage. Kakkalide (KA), a bioactive compound known for its anti-inflammatory, cardiovascular, neuroprotective, and anti-diabetic properties, has potential therapeutic effects. However, its impact on sepsis-induced intestinal injury remains unclear. In this study, murine sepsis models were used both <i>in vivo</i> and <i>in vitro</i> to evaluate the protective effects of KA on intestinal histopathology, apoptosis, and inflammation. Results showed that KA significantly reduced intestinal damage and apoptosis, as evidenced by hematoxylin-eosin and TUNEL staining. KA also improved intestinal barrier integrity, as indicated by reduced diamine oxidase activity, d-lactic acid content, and fluorescein isothiocyanate intensity, along with increased expression of zonula occludens-1. Furthermore, KA alleviates inflammation by reducing the levels of tumor necrosis factor-α, interleukin-1β, prostaglandin E2, inducible nitric oxide synthase, and cyclooxygenase-2. Immunofluorescence and Western blot analysis revealed that KA inhibited the sepsis-induced phosphorylation of inhibitor-kappaBα and RelA (P65) and prevented P65's translocation to the nucleus. These findings were confirmed in lipopolysaccharide-induced Caco-2 cells, suggesting that KA protected the intestinal barrier during sepsis by suppressing the NF-κB pathway.