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

Blood cell formation: Support from gut bacteria 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.