IL-10, crucial for systemic inflammation regulation and gut mucosal homeostasis, was investigated using IL-10 knockout (KO) mice. Exacerbated gut inflammation was observed post-transverse aortic constriction (TAC) in IL-10-depleted mice, whereas wild-type (WT) mice showed reduced IL-10 gene expression in colon and ileum. TAC induced gut dysbiosis and leakage in IL-10 KO mice, suggesting a link between enhanced inflammatory signaling in heart failure and multi-organ damage via gut dysbiosis and leakage.