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

Cell Host Microbe. 2018 Dec 12;24(6):833-846.e6. doi: 10.1016/j.chom.2018.11.002.

Abstract

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.

Keywords: Gpr81; gut microbiota; intestinal stem cell; lactate; symbiont.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Goblet Cells / cytology*
  • Goblet Cells / drug effects
  • Goblet Cells / radiation effects
  • HEK293 Cells
  • Humans
  • L-Lactate Dehydrogenase / genetics
  • L-Lactate Dehydrogenase / metabolism
  • Lactic Acid / metabolism*
  • Lactobacillus plantarum / genetics
  • Lactobacillus plantarum / metabolism*
  • Methotrexate / administration & dosage
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Paneth Cells / cytology*
  • Paneth Cells / drug effects
  • Paneth Cells / radiation effects
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*

Substances

  • Hcar1 protein, mouse
  • Lgr5 protein, mouse
  • Receptors, G-Protein-Coupled
  • Lactic Acid
  • L-Lactate Dehydrogenase
  • Methotrexate