Mucosal Immunology Laboratory, Department of Convergence Medicine, University of Ulsan College of Medicine/Asan Medical Center, Seoul, Republic of Korea.
Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
Cell Host Microbe. 2018 Dec 12;24(6):833-846.e6. doi: 10.1016/j.chom.2018.11.002.
Symbionts play an indispensable role in gut homeostasis, but underlying mechanisms remain elusive. To clarify the role of lactic-acid-producing bacteria (LAB) on intestinal stem-cell (ISC)-mediated epithelial development, we fed mice with LAB-type symbionts such as Bifidobacterium and Lactobacillus spp. Here we show that administration of LAB-type symbionts significantly increased expansion of ISCs, Paneth cells, and goblet cells. Lactate stimulated ISC proliferation through Wnt/β-catenin signals of Paneth cells and intestinal stromal cells. Moreover, Lactobacillus plantarum strains lacking lactate dehydrogenase activity, which are deficient in lactate production, elicited less ISC proliferation. Pre-treatment with LAB-type symbionts or lactate protected mice in response to gut injury provoked by combined treatments with radiation and a chemotherapy drug. Impaired ISC-mediated epithelial development was found in mice deficient of the lactate G-protein-coupled receptor, Gpr81. Our results demonstrate that LAB-type symbiont-derived lactate plays a pivotal role in promoting ISC-mediated epithelial development in a Gpr81-dependent manner.
共生体在肠道稳态中起着不可或缺的作用，但潜在的机制仍难以捉摸。为了阐明产乳酸细菌（LAB）对肠道干细胞（ISC）介导的上皮发育的作用，我们用 LAB 型共生体（如双歧杆菌和乳杆菌属）喂养小鼠。在这里，我们发现 LAB 型共生体的给药显著增加了 ISC、潘氏细胞和杯状细胞的扩张。乳酸通过潘氏细胞和肠道基质细胞的 Wnt/β-catenin 信号刺激 ISC 增殖。此外，缺乏乳酸脱氢酶活性（缺乏乳酸产生能力）的植物乳杆菌菌株引起的 ISC 增殖较少。用 LAB 型共生体或乳酸预处理可保护小鼠免受辐射和化疗药物联合治疗引起的肠道损伤。在缺乏乳酸 G 蛋白偶联受体 Gpr81 的小鼠中发现 ISC 介导的上皮发育受损。我们的研究结果表明，LAB 型共生体衍生的乳酸通过 Gpr81 依赖性方式在促进 ISC 介导的上皮发育中起着关键作用。
