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Atrial natriuretic peptide (ANP) activity deficiency contributes to salt-sensitive hypertension in humans and mice. However, the role of ileal microbiota in salt sensitivity in ANP deficiency-related cardiac injury has not been investigated yet. This study used ANP^−/− mice to analyze the role of the salt-sensitive ileal microbiome on cardiac injury. ANP^−/− mice showed an increase in blood pressure (BP), the heart weight/body weight (HW/BW) ratio, and cardiac hypertrophy compared with wild-type (WT) mice. ANP deficiency did not impact the histological structure but reduced occludin expression in the ileum. Antibiotics significantly relieved BP and cardiac hypertrophy in ANP^−/− mice. A high-salt diet (HSD) increased BP, the HW/BW ratio, and cardiac hypertrophy/fibrosis in WT and ANP^−/− mice, and an HSD treatment in ANP^−/− mice exacerbated these cardiac parameters. The HSD markedly decreased muscularis layer thickening, villus length, and numbers of Paneth and goblet cells in the ileum of WT and ANP^−/− mice. Furthermore, the HSD increased the level of TLR4 and IL-1β in ANP^−/− mice ileum compared with WT mice. Antibiotics reduced the HW/BW ratio, cardiac hypertrophy/fibrosis, and the level of TLR4 and IL-1β in the ileum, and rescued the muscularis layer thickening, villus length, and numbers of Paneth and goblet cells in the ileum of HSD-ANP^−/− mice. Importantly, ANP deficiency induced the colonization of <i>Burkholderiales bacterium YL45</i>, <i>Lactobacillus johnsonii</i>, and <i>Lactobacillus reuteri</i> in the ileum on the NSD diet, which was only observed in HSD-induced WT mice but not in WT mice on the NSD. Besides, the HSD significantly enhanced the sum of the percentage of the colonization of <i>Burkholderiales bacterium YL45</i>, <i>Lactobacillus johnsonii</i>, and <i>Lactobacillus reuteri</i> in the ileum of ANP^−/− mice. Ileal microbiota transfer (IMT) from ANP^−/− mice to healthy C57BL/6J mice drove <i>Lactobacillus johnsonii</i> and <i>Lactobacillus reuteri</i> colonization in the ileum, which manifested an increase in BP, the HW/BW ratio, cardiac hypertrophy, and ileal pathology compared with IMT from WT mice. The HSD in C57BL/6J mice with IMT from ANP^−/− mice drove the colonization of <i>Burkholderiales bacterium YL45</i>, <i>Lactobacillus johnsonii</i>, and <i>Lactobacillus reuteri</i> in the ileum and further exacerbated the cardiac and ileal pathology. Our results suggest that salt-sensitive ileal microbiota is probably related to ANP deficiency-induced cardiac injury.