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.

尽管已经确定了肠道微生物群与肠道以外远处部位之间的功能相互作用，但微生物群衍生的代谢物对造血干细胞 (HSC) 的影响仍不清楚。本研究使用缺乏 G 蛋白偶联受体 (Gpr) 81 (Gpr81 ^{− /−} )（一种既定的乳酸受体）的小鼠，研究了微生物群衍生的乳酸在造血作用中的作用。与稳定状态下的异源 (Gpr81 ^+/- ) 小鼠相比，我们检测到 Gpr81 ^-/-小鼠骨髓 (BM) 中总 HSC 的显着耗竭。值得注意的是，HSC 增殖所需的干细胞因子 (SCF) 的表达水平在瘦素受体表达 (LepR ^{+) 与 Gpr81 +/-}小鼠相比，来自 Gpr81 ^-/-小鼠的 BM 窦状血管周围的间充质基质细胞 (MSC) 。辐射或白消安处理后 BM 生态位细胞的造血恢复和激活也需要 Gpr81 信号。口服产生乳酸的细菌 (LAB) 激活 LepR ⁺ BM MSCs 的 SCF 分泌，随后加速造血和红细胞生成。最重要的是，LAB 喂养加速了无菌小鼠 HSC 的自我更新。这些结果表明，微生物群衍生的乳酸刺激 LepR ⁺ BM MSC 分泌 SCF，随后以 Gpr81 依赖性方式激活造血和红细胞生成。