Targeting the Gut–Heart Axis: Dextran from Gut-Derived <i>Weissella cibaria</i> Alleviates Doxorubicin-Induced Cardiotoxicity by Attenuating Low-Grade Endotoxemia

The clinical utility of doxorubicin (Dox) is limited by severe dose-dependent cardiotoxicity. The disruption of the gut microbiota and mucosal barrier by Dox elevates the levels of circulating lipopolysaccharides (LPS), indicative of low-grade endotoxemia, and contributes to Dox-induced cardiotoxicity (DIC). Exopolysaccharides (EPS) are known to function as postbiotics that can regulate both gut microbiota and mucosal barrier function. However, their ability to mitigate DIC and the underlying mechanisms remain unknown. Hence, this study investigated whether a purified, structurally defined dextran EPS-2, derived from <i>Weissella cibaria</i>, alleviated DIC by restoring intestinal barrier integrity and correcting gut microbiota dysbiosis. Specifically, EPS-2 reduced low-grade endotoxemia by decreasing Dox-elevated <i>Escherichia-Shigella</i> (a major LPS producer positively correlated with cardiac damage), likely by directly inhibiting the proliferation of bacteria belonging to <i>Escherichia-Shigella</i>. Consequently, EPS-2 weakened the dysregulation of cardiac inflammation and oxidative stress. The findings demonstrate that modulating the gut microenvironment with bacterial EPS to reduce low-grade endotoxemia is a promising strategy for preventing chemotherapy-induced cardiotoxicity.