Angiotensin-(1-7) modulates gut-bone marrow axis in diabetes

Diabetes promotes inflammation by compromising colon epithelial barrier integrity and upregulation of myelopoiesis in the bone marrow (BM). Angiotensin-(1-7) (Ang-(1-7)) is a cardiovascular protective peptide in diabetes. This study tested if Ang-(1-7) restores the colon epithelial barrier integrity and myelopoiesis in diabetes via restructuring dysbiotic gut microbiota and the BM-inflammatory landscape. Nondiabetic (ND) or streptozotocin-induced type 1 or db/db type 2 diabetic mice were treated with saline or Ang-(1-7). The intestinal permeability was evaluated by using FITC-dextran. Claudin1, occludin, Lgr5⁺Olfm4⁺ intestinal stem cells (ISCs), Wnt3a and β-catenin were evaluated by immunohistochemistry or western blotting. Fecal microbiome was analyzed by 16S rRNA sequencing. Monocyte-macrophages were characterized by flow cytometry. Plasma trimethylamine N-oxide (TMAO) and lipopolysaccharide-binding protein (LBP) levels or BM-cytokines were quantified. Increased intestinal permeability in both models of diabetes was reversed by Ang-(1-7) (P < 0.001, n = 5). In db/db colons, Wnt3a and the active β-catenin levels were lower compared to the ND, which were restored by Ang-(1-7). Monocytes and pro-inflammatory macrophages were higher diabetic mice that were decreased by Ang-(1-7), which was accompanied by decreased pro-inflammatory factors, IL6, M-CSF, leptin and others, in the db/db BM-supernatants. Ang-(1-7) increased Bacteroidetes over Firmicutes with abundance of Lactobacillaceae and Akkermansiaceae in the db/db gut microbiota, and decreased the plasma levels of TMAO and LBP in the plasma. The study provides compelling evidence for the pharmacological potential of Ang-(1-7) in ameliorating diabetic disruption of colon barrier integrity and inflammation by restoring the regenerative ISCs and by reversing myelopoiesis.