Microbiota-derived lactate accelerates intestinal stem cell-mediated epithelial development through the Gpr81

Authors: LEE, YONG-SOO - University Of Ulsan College Of Medicine; KIM, TAE-YOUNG - University Of Ulsan College Of Medicine; KIM, YEJI - University Of Ulsan College Of Medicine; LEE, SU-HYUN - University Of Ulsan College Of Medicine; KIM, SEUNGIL - University Of Ulsan College Of Medicine; KANG, SUNG WAN - University Of Ulsan College Of Medicine; YANG, JIN-YOUNG - University Of Ulsan College Of Medicine; BAEK, IN-JEOUNG - Asan Medical Center; SUNG, YOUNG HOON - Asan Medical Center; PARK, YUN-YONG - Asan Medical Center; HWANG, SUNG WOOK - Asan Medical Center; O, EUNJU - Institute For Basic Science; KIM, KWANG SOON - Institute For Basic Science; Liu, Siqing; KAMADA, NOBUHIKO - University Of Michigan Medical School; GAO, NAN - Rutgers University; KWEON, MI-NA - University Of Ulsan College Of Medicine

Submitted to: Cell Host and Microbe
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/19/2018
Publication Date: 12/12/2018
Citation: Lee, Y., Kim, T., Kim, Y., Lee, S., Kim, S., Kang, S., Yang, J., Baek, I., Sung, Y., Park, Y., Hwang, S., O, E., Kim, K., Liu, S., Kamada, N., Gao, N., Kweon, M. 2018. Microbiota-derived lactate accelerates intestinal stem cell-mediated epithelial development through the Gpr81. Cell Host and Microbe. 24(6):833-846. https://doi.org/10.1016/j.chom.2018.11.002.
DOI: https://doi.org/10.1016/j.chom.2018.11.002

Interpretive Summary: Some species of Lactic acid bacteria (LAB), such as Bifidobacterium and Lactobacillus spp., can be used as health promoting probiotics. This paper reports the short term administration of LAB-type beneficial bacteria significantly increases the growth of some intestinal cells. The lactate producing bacterium can induce immune responses that protect and repair cellular damage. These results will enable further studies on the use of microorganisms to promote host defense systems and prevent gut infections and inflammatory diseases.

Technical Abstract: Symbionts play an indispensable role in gut homeostasis but underlying mechanisms have yet to be described. To clarify the exact role of symbionts on intestinal stem cell (ISCs)-mediated epithelial development, we fed mice for 5 days with human-use symbionts containing lactic acid-producing bacteria (LAB) such as Bifidobacterium and Lactobacillus spp. Here we show that short-term administration of LAB-type symbionts significantly increased the growth of intestinal epithelium including expansion of Lgr5+ ISCs, Paneth cells, and goblet cells. Lactate stimulated ISCs proliferation through Wnt/ß-catenin signals of Paneth cells and intestinal stromal cells. The G-protein–coupled receptor (Gpr) 81, a known lactate receptor, was highly expressed on Paneth and intestinal stromal cells in the steady-state condition and blockade of Gpr81 during gut organoid culture in the presence of lactate significantly reduced epithelial development. Moreover, Lactobacillus plantarum strains lacking lactate dehydrogenase activity (L. plantarum 'ldhD-'ldhL), which are deficient in lactate production, elicited less ISCs 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 ISCs-mediated epithelial development was found in the Gpr81-/- mice in vitro and in vivo. Our results demonstrate that LAB-type symbiont-derived lactate plays a pivotal role in promoting ISCs-mediated epithelial development by stimulating Wnt/ß-catenin signaling of Paneth cells and intestinal stromal cells in a Gpr81-dependent manner.