Microbiota-Derived Lactate Accelerates Intestinal Stem-Cell-Mediated Epithelial Development

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. [Display omitted] •Symbiont-generated lactate is critical for Lgr5+ ISC-mediated epithelial development•Lactate signals through the G-protein-coupled receptor Gpr81 to elicit ISC proliferation•Lactobacillus plantarum lacking lactate dehydrogenase fails to induce ISC regeneration•Pre-feeding of lactate protects mice from chemotherapy- and radiation-induced gut damage Lee et al. reveal how lactic-acid-producing bacteria, including Bifidobacterium and Lactobacillus spp., support intestinal epithelial cell regeneration. Symbiont-derived lactate is sensed by G-protein-coupled receptor 81 on Paneth and stromal cells to promote regeneration in a Wnt3/ β-catenin-dependent manner. Lactate pre-administration protects mice exposed to radiation- and chemotherapy-induced intestinal damage.