Graphical Abstract Highlights d Symbiont-generated lactate is critical for Lgr5 + ISC-mediated epithelial development d Lactate signals through the G-protein-coupled receptor Gpr81 to elicit ISC proliferation d Lactobacillus plantarum lacking lactate dehydrogenase fails to induce ISC regeneration d Pre-feeding of lactate protects mice from chemotherapy-and radiation-induced gut damage In Brief Lee et al. reveal how lactic-acidproducing 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/ b-catenindependent manner. Lactate preadministration protects mice exposed to radiation-and chemotherapy-induced intestinal damage. SUMMARY 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/b-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-proteincoupled 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.
The regulatory properties of pyruvate kinase M2 isoform (PKM2), the key glycolytic enzyme, influence altered energy metabolism including glycolysis in cancer. In this study, we found that PKM2 was highly expressed in patients with ulcerative colitis or colorectal cancer (CRC). We then investigated the effectiveness of conditionally ablating PKM2 in Lgr5 + intestinal stem cells (ISC) using a mouse model of colitis-associated CRC (AOM plus DSS). Tamoxifen-inducible Lgr5-driven deletion of PKM2 in ISC (PKM2 ΔLgr5 -Tx) significantly promoted tumor incidence and size in the colon and lower body weight compared with findings in vehicle-treated mice (PKM2 ΔLgr5 -Veh). Histopathologic analysis revealed considerable high-grade dysplasia and adenocarcinoma in the colon of PKM2 ΔLgr5 -Tx mice while PKM2 ΔLgr5 -Veh mice had low- and high-grade dysplasia. Loss of PKM2 was associated with dominant expression of PKM1 in Lgr5 + ISC and their progeny cells. Further, the organoid-forming efficiency of whole cancer cells or Lgr5 + cells obtained from colon polyps of PKM2 ΔLgr5 -Tx mice was significantly increased when compared with PKM2 ΔLgr5 -Veh mice. Cancer organoids from PKM2 ΔLgr5 -Tx mice exhibited increased mitochondrial oxygen consumption and a shift of metabolites involved in energy metabolism. These findings suggest that loss of PKM2 function in ISC promotes colitis-associated CRC.
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