Alamandine/MrgD pathway modulates gut–bone marrow axis in ageing

Abstract Background and Purpose Ageing is associated with colon epithelial barrier disruption and up‐regulation of myelopoiesis in the bone marrow (BM). Alamandine (Ala) and MrgD are novel members of the renin angiotensin system (RAS). This study tested the hypothesis that Ala restores the colon epithelial barrier integrity in ageing via modulating gut–BM axis. Experimental Approach Mice, 2–3 (Young) or 22–24 months (Old), were treated with saline or Ala by using Osmotic pumps. The intestinal permeability was evaluated using FITC‐dextran. Lgr5 + Olfm4 + intestinal stem cells (ISCs), Wnt3a and β ‐catenin were evaluated by immunohistochemistry or western blotting. Faecal microbiome was analysed by 16S rRNA sequencing. Monocyte‐macrophages were characterized by flow cytometry. Caecal or serum bacterial metabolites were analysed and the caecal supernatants (CS) were tested for myelopoietic potential. Key Results MrgD was expressed in ISCs, which was decreased in the Old. Increased intestinal permeability in ageing was reversed by Ala. In the colon organoids, Ala increased Wnt3a levels and this was antagonized by NF449, SQ22536 or 666‐15. Ala restored phospho‐CREB and active β ‐catenin levels that were decreased in the Old colon‐organoids. Ala increased the richness and β ‐diversity of the microbiota with decreased Bacillota / Bacteroidota in ageing. Ala decreased the CD80 + and increased CX3CR + macrophages in the Old colons. Old‐CS induced myelopoiesis in BM cells with higher number of pro‐inflammatory macrophages, which was prevented by Ala treatment. Conclusions and Implications Targeting Ala/MrgD pathway is a promising approach for ameliorating the inflammatory stress in ageing by restoring homeostasis in the gut–BM inter‐organ communication.