Microbiota-derived lactate promotes hematopoiesis and erythropoiesis by inducing stem cell factor production from leptin receptor+ niche cells

Abstract

Although functional interplay between intestinal microbiota and distant sites beyond the gut has been identified, the influence of microbiota-derived metabolites on hematopoietic stem cells (HSCs) remains unclear. This study investigated the role of microbiota-derived lactate in hematopoiesis using mice deficient in G-protein-coupled receptor (Gpr) 81 (Gpr81^-^/-), an established lactate receptor. We detected significant depletion of total HSCs in the bone marrow (BM) of Gpr81^-/- mice compared with heterogenic (Gpr81^+/-) mice in a steady state. Notably, the expression levels of stem cell factor (SCF), which is required for the proliferation of HSCs, decreased significantly in leptin receptor-expressing (LepR⁺) mesenchymal stromal cells (MSCs) around the sinusoidal vessels of the BM from Gpr81^-/- mice compared with Gpr81^+/- mice. Hematopoietic recovery and activation of BM niche cells after irradiation or busulfan treatment also required Gpr81 signals. Oral administration of lactic acid-producing bacteria (LAB) activated SCF secretion 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 suggest that microbiota-derived lactate stimulates SCF secretion by LepR⁺ BM MSCs and subsequently activates hematopoiesis and erythropoiesis in a Gpr81-dependent manner.