2012 - FIBRE PREVENTS HIGH SALT DIET-INDUCED GUT PERMEABILITY, HAEMATOPOIETIC STEM CELL MOBILISATION AND ATHEROSCLEROSIS

Abstract

A high salt diet (HSD) is a key risk factor for atherosclerotic-cardiovascular disease (CVD). We show that a HSD (3.6% NaCl) promotes the maturation of pathogenic TH17 cells in the bone marrow (BM) and promotes the breakdown of the BM niche, by reducing leptin receptor mesenchymal cells (LepR+MSCs) and increasing the number of osteoclasts in atherosclerotic-prone Apoe-/- mice. This led to the egress of haematopoietic stem and progenitor cells (HSPCs) into the spleen, inducing monocytosis via extramedullary myelopoiesis which plays a causal role in atherosclerosis. Administering anti-IL17A antibody and zoledronic acid restored LepR+MSCs and osteoclast levels in the BM back to control (NSD; 1% NaCl) while preventing HSPC egress and atherogenesis. Recently, a HSD has been found to alter the microbiome, promoting intestinal permeability and TH17 maturation. Thus, we supplemented HSD-mice with fibre (400mg/kg), to restore the microbiome and prevent gut permeability. Fibre prevented HSD-induced intestinal permeability and TH17 maturation. Fibre also reduced BM TH17 cells and restored the levels of HSD-induced LepR+MSCs and osteoclasts back to control levels, preventing HSPC egress to the spleen. This reduced the number of inflammatory monocytes entering into the atherosclerotic lesion, inhibiting atherogenesis. These findings demonstrate that fibre supplementation can prevent HSD-driven inflammatory effects in the gut and the breakdown of the BM niche, to prevent atherogenesis.