Phenylacetylglutamine exacerbates sepsis-induced cardiac dysfunction and left ventricular remodeling via the ferroptosis and TLR4/NF-κB pathway.

BACKGROUND: Cardiac dysfunction and arrhythmias are serious complications of sepsis-induced cardiomyopathy and are closely associated with increased mortality. The gut microbial metabolite phenylacetylglutamine (PAGln) has been shown to be closely associated with the prognosis of patients with heart failure. However, it remains unclear whether PAGln plays a role in regulating sepsis-induced cardiac dysfunction and ventricular arrhythmias (VAs). OBJECTIVE AND METHODS: The objective of this study is to evaluate the effects of PAGln on ventricular remodeling and VAs in mice with sepsis. In this study, we administered intraperitoneal injections of PAGln to mice for 14 days as a pretreatment, followed by stimulation with lipopolysaccharide (LPS) to establish a sepsis model, which was then evaluated using histopathology, molecular biology, cardiac electrophysiology, and echocardiography. RESULTS: We found that PAGln pretreatment exacerbated LPS-induced cardiac dysfunction and LPS-mediated inflammatory responses. Furthermore, PAGln exacerbated cardiac electrical remodeling and increased susceptibility to VAs in LPS-treated mice. Mechanistically, PAGln may participate in mediating sepsis-induced inflammation, cardiac dysfunction, and susceptibility to VAs by regulating the ferroptosis and TLR4/NF-κB signaling pathway. CONCLUSIONS: This study preliminarily demonstrates that the gut microbial metabolite PAGln exacerbates LPS-induced cardiac dysfunction and inflammation and increases susceptibility to VAs, a mechanism that may be associated with the activation of ferroptosis and the TLR4/NF-κB signaling pathway.