Heart failure (HF) is a leading cause of death worldwide. We have shown that pressure overload (PO)-induced inflammatory cell recruitment leads to heart failure in IL-10 knockout (KO) mice. However, it is unclear whether PO-induced inflammatory cells also target the gut mucosa, causing gut dysbiosis and leakage. We hypothesized that transverse aortic constriction (TAC) exacerbates immune cell homing to the gut (small intestine and colon), promoting dysbiosis and gut leakage in IL-10 KO mice. HF was induced in 8- to 10-wk-old C57BL/6J wild-type (WT) and B6.129P2-Il10tm1Cgn/J mutant (IL-10 KO) male and female mice by TAC and cardiac function was measured using visual sonics VEVO 3100. Fourteen days post-TAC, levels of monocytes, macrophages, neutrophils, and proinflammatory cytokines were measured in blood and gut. Gut dysbiosis was assessed via 16S rRNA sequencing in feces at 56 days post-TAC. IL-10 KO mice showed worsened cardiac dysfunction post-TAC. TAC worsened monocytes, and neutrophils infiltration in systemic circulation and facilitated their homing to the gut in IL-10 KO mice. Intriguingly, proinflammatory cytokines level was increased in blood, and gut of IL-10 KO mice following TAC. Furthermore, IL-10 expression was reduced in the colon of WT mice post-TAC. Moreover, TAC exacerbated gut dysbiosis in IL-10 KO mice. Finally, an impaired intestinal permeability was noted in IL-10 KO mice post-TAC. In conclusion, TAC-induced systemic inflammation leads to gut dysbiosis and impaired gut permeability in IL-10 KO mice, indicating IL-10's potential role in regulating intestinal integrity and microbiota balance during heart failure.