Cardiovascular disorders (CVDs) are the leading cause of mortality in the world. Yet, the risk of this disease is higher in inflamed bowel conditions. Diets low in fiber or high in saturated fat increase bowel inflammation by causing gut dysbiosis. However, the regular addition of fiber-rich whole foods, including pinto beans (PB) and wheat germ (WG), in the diet is promising in mitigating the adverse effect of high-fat feeding. These studies seek to understand the role of the anti-inflammatory cytokines, interleukin (IL)-10 and -22, in maintaining homeostasis in the gut-cardiovascular axis, as well as the roles of these cytokines in mediating the effect of PB and WG, respectively, in the gut and cardiovascular tissue. WG increased protein expression of aryl hydrocarbon receptor (AhR) and Il22 gene expression in the ileum. More so, supplemental WG repressed the expression of IL22 receptor, alpha 2 (Il22ra2), and reduced the phospho-activation of the signal transducer and activator of transcription (STAT)3 in the ileum. In a similar manner, IL-10 knockout (KO) mice exhibited a significantly lowered serum estrogen (E2), gut bacterial β-glucuronidase activity, and cecal butyrate. More so, KO mice showed reduced S¹¹¹⁹ phosphorylation of NOS3 in the aorta and had higher serum trimethylamine-N-oxide (TMAO), consequently predisposing them to reduced endothelial function and cardiac fibrosis. However, supplementation of a cholesterol-rich atherogenic diet (Ath) to the KO mice increased serum estrogen and jejunum gene expression of the M2 macrophage marker Arg1. Consequently, Ath-treated KO mice had reduced bowel inflammation yet a reduced abundance of the short chain fatty acid-producing taxa Lactobacillus and Roseburia. Correspondingly, Ath-treated mice had low cecal butyrate, higher serum TMAO, cardiac fibrosis and impaired endothelial function. Finally, supplementation of PB in the Ath diet prevented the Ath-mediated reduced diversity of SCFA-producing taxa Lachnospiraceae, Lactobacillus, and Roseburia only in the Wild type (WT) mice strain. Consequently, PB increased cecal butyrate, caused a significant expansion of regulatory T cells (Tregs), and prevented vascular dysfunction only in WT mice. These studies provided mechanistic insights into the anti-inflammatory potential of WG and PB, as well as the central role of IL-22 and IL-10 in maintaining immune homeostasis in the gut.