Microbiota-Derived Lactate Controls Hematopoiesis and Erythropoiesis Through Regulating Stem Cell Factor from Leptin Receptor+ Niche Cells in the Bone Marrow

Abstract

Although functional interplay between intestinal microbiota and the distant sites beyond the gut has been identified, it is unclear how microbiota-derived metabolites influence the fate of hematopoietic stem cells (HSCs). In this study, we investigated the role of microbiota-derived lactate in hematopoiesis using G-protein–coupled receptor (Gpr) 81, a known lactate receptor, deficient (Gpr81-/-) mice. We found that the total number of HSCs was significantly reduced in the bone marrow (BM) of Gpr81-/- mice as compared with heterogenic (Gpr81+/-) mice in a steady state. Notably, the expression levels of stem cell factor (SCF), which is required for proliferation of HSCs, were significantly decreased in leptin-receptor expressing (LepR+) mesenchymal stromal cells (MSCs) around the sinusoidal vessels of BM obtained from Gpr81-/- mice as compared with Gpr81+/- mice. Hematopoietic recovery and activation of BM niche cells after irradiation or busulfan treatment required Gpr81 signals. Oral administration of lactic acid-producing bacteria (LAB) activated the secretion of SCF from LepR+ BM MSCs and subsequently accelerated hematopoiesis and erythropoiesis. Most importantly, LAB feeding accelerated the self-renewal of HSCs in germ-free mice. These results suggested that microbiota-derived lactate stimulates SCF secretion by LepR+ BM MSCs and subsequently activates hematopoiesis and erythropoiesis in a Gpr81-dependent manner.