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

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. Lactic acid produced by microbes in the gut has been implicated in supporting the production of blood cells, suggesting oral administration of lactic acid-producing bacteria might be useful for treating blood disorders, including anemia. Researchers in South Korea and China, led by Mi-Na Kweon at the University of Ulsan in Seoul, explored the significance of lactic acid using mice deficient in the gene for a protein receptor that allows lactic acid to influence various cellular processes. Without the benefit of this receptor the levels of blood cell-forming stem cells in bone marrow were reduced. The normal effect of lactic acid was linked to production of a protein called stem cell factor in specific cells. Oral administration of lactic acid-producing bacteria restored blood cell formation, indicating its therapeutic potential.