Journal of Ginseng Research

  • 제46권6호
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  • Pages.780-789
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  • 2022
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  • 1226-8453(pISSN)
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  • 2093-4947(eISSN)
고려인삼학회 (The Korean Society of Ginseng)
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Compound K attenuates hyperglycemia by enhancing glucagon-like peptide-1 secretion through activating TGR5 via the remodeling of gut microbiota and bile acid metabolism

  • Tian, Fengyuan (First School of Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Huang, Shuo (First School of Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Xu, Wangda (First School of Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Chen, Lan (First School of Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Su, Jianming (Department of Emergency, First Affiliated Hospital of Zhejiang Chinese Medical University) ;
  • Ni, Haixiang (Department of Endocrinology, First Affiliated Hospital of Zhejiang Chinese Medicine University) ;
  • Feng, Xiaohong (Department of Endocrinology, First Affiliated Hospital of Zhejiang Chinese Medicine University) ;
  • Chen, Jie (Department of Endocrinology, First Affiliated Hospital of Zhejiang Chinese Medicine University) ;
  • Wang, Xi (Central Laboratory, First Affiliated Hospital of Zhejiang Chinese Medical University) ;
  • Huang, Qi (Department of Endocrinology, First Affiliated Hospital of Zhejiang Chinese Medicine University)
  • 투고 : 2021.12.13
  • 심사 : 2022.03.29
  • 발행 : 2022.11.01
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초록

Background: Incretin impairment, characterized by insufficient secretion of L-cell-derived glucagon-like peptide-1 (GLP-1), is a defining step of type 2 diabetes mellitus (T2DM). Ginsenoside compound K (CK) can stimulate GLP-1 secretion; however, the potential mechanism underlying this effect has not been established. Methods: CK (40 mg/kg) was administered orally to male db/db mice for 4 weeks. The body weight, oral glucose tolerance, GLP-1 secretion, gut microbiota sequencing, bile acid (BA) profiles, and BA synthesis markers of each subject were then analyzed. Moreover, TGR5 expression was evaluated by immunoblotting and immunofluorescence, and L-cell lineage markers involved in L-cell abundance were analyzed. Results: CK ameliorated obesity and impaired glucose tolerance in db/db mice by altering the gut microbiota, especially Ruminococcaceae family, and this changed microbe was positively correlated with secondary BA synthesis. Additionally, CK treatment resulted in the up-regulation of CYP7B1 and CYP27A1 and the down-regulation of CYP8B1, thereby shifting BA biosynthesis from the classical pathway to the alternative pathway. CK altered the BA pool by mainly increasing LCA and DCA. Furthermore, CK induced L-cell number expansion leading to enhanced GLP-1 release through TGR5 activation. These increases were supported by the upregulation of genes governing GLP-1 secretion and L-cell differentiation. Conclusions: The results indicate that CK improves glucose homeostasis by increasing L-cell numbers, which enhances GLP-1 release through a mechanism partially mediated by the gut microbiota-BA-TGR5 pathway. Therefore, that therapeutic attempts with CK might be useful for patients with T2DM.

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과제정보

This work was supported by the National Key Research and Development Program of China (2018YFC2000200), The National Natural Science Foundation of China (82174131), Zhejiang Provincial Natural Science Foundation of China (LY21H030002), and the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (2019RC229).

참고문헌

  1. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-705. https://doi.org/10.1016/S0140-6736(06)69705-5
  2. Basak O, Beumer J, Wiebrands K, Seno H, van Oudenaarden A, Clevers H. Induced quiescence of Lgr5+ stem cells in intestinal organoids enables differentiation of hormone-producing enteroendocrine cells. Cell Stem Cell 2017;20:177-190 e4. https://doi.org/10.1016/j.stem.2016.11.001
  3. Petersen N, Frimurer TM, Terndrup Pedersen M, Egerod KL, Wewer Albrechtsen NJ, Holst JJ, Grapin-Botton A, Jensen KB, Schwartz TW. Inhibiting RHOA signaling in mice increases glucose tolerance and numbers of enteroendocrine and other secretory cells in the intestine. Gastroenterology 2018;155:1164-11676 e2. https://doi.org/10.1053/j.gastro.2018.06.039
  4. Gehart H, Clevers H. Tales from the crypt: new insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol 2019;16:19-34. https://doi.org/10.1038/s41575-018-0081-y
  5. Clevers H. The intestinal crypt, a prototype stem cell compartment. Cell 2013;154:274-84. https://doi.org/10.1016/j.cell.2013.07.004
  6. Gradwohl G, Dierich A, LeMeur M, Guillemot F. neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci U S A 2000;97:1607-11. https://doi.org/10.1073/pnas.97.4.1607
  7. Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, Tsai MJ. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev 1997;11:2323-34. https://doi.org/10.1101/gad.11.18.2323
  8. Ye DZ, Kaestner KH. Foxa1 and Foxa2 control the differentiation of goblet and enteroendocrine L- and D-cells in mice. Gastroenterology 2009;137:2052-62. https://doi.org/10.1053/j.gastro.2009.08.059
  9. Morimoto K, Watanabe M, Sugizaki T, Irie J, Itoh H. Intestinal bile acid composition modulates prohormone convertase 1/3 (PC1/3) expression and consequent GLP-1 production in male mice. Endocrinology 2016;157: 1071-81. https://doi.org/10.1210/en.2015-1551
  10. Sato T, Clevers H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 2013;340:1190-4. https://doi.org/10.1126/science.1234852
  11. Komaroff AL. The microbiome and risk for obesity and diabetes. JAMA 2017;317:355-6. https://doi.org/10.1001/jama.2016.20099
  12. Wahlstrom A, Sayin SI, Marschall HU, Backhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metabol 2016;24:41-50. https://doi.org/10.1016/j.cmet.2016.05.005
  13. Jadhav K, Xu Y, Xu Y, Li Y, Xu J, Zhu Y, Adorini L, Lee YK, Kasumov T, Yin L, et al. Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR. Mol Metabol 2018;9:131-40. https://doi.org/10.1016/j.molmet.2018.01.005
  14. Deutschmann K, Reich M, Klindt C, Droge C, Spomer L, Haussinger D, Keitel V. Bile acid receptors in the biliary tree: TGR5 in physiology and disease. Biochim Biophys Acta (BBA) - Mol Basis Dis 2018;1864:1319-25. https://doi.org/10.1016/j.bbadis.2017.08.021
  15. Lund ML, Sorrentino G, Egerod KL, Kroone C, Mortensen B, Knop FK, Reimann F, Gribble FM, Drucker DJ, de Koning EJP, et al. L-cell differentiation is induced by bile acids through GPBAR1 and paracrine GLP-1 and serotonin signaling. Diabetes 2020;69:614-23. https://doi.org/10.2337/db19-0764
  16. Kim DH. Gut microbiota-mediated pharmacokinetics of ginseng saponins. J Ginseng Res 2018;42:255-63. https://doi.org/10.1016/j.jgr.2017.04.011
  17. Chen W, Wang J, Luo Y, Wang T, Li X, Li A, Li J, Liu K, Liu B. Ginsenoside Rb1 and compound K improve insulin signaling and inhibit ER stress-associated NLRP3 inflammasome activation in adipose tissue. J Ginseng Res 2016;40: 351-8. https://doi.org/10.1016/j.jgr.2015.11.002
  18. Kim K, Park M, Lee YM, Rhyu MR, Kim HY. Ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells via bile acid receptor activation. Arch Pharm Res (Seoul) 2014;37:1193-200. https://doi.org/10.1007/s12272-014-0362-0
  19. Tian F, Wang X, Ni H, Feng X, Yuan X, Huang Q. The ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells by regulating the RhoA/ROCKs/YAP signaling pathway and cytoskeleton formation. J Pharmacol Sci 2021;145:88-96. https://doi.org/10.1016/j.jphs.2020.11.005
  20. Song W, Wei L, Du Y, Wang Y, Jiang S. Protective effect of ginsenoside metabolite compound K against diabetic nephropathy by inhibiting NLRP3 inflammasome activation and NF-kappaB/p38 signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. Int Immunopharm 2018;63: 227-38. https://doi.org/10.1016/j.intimp.2018.07.027
  21. Yang L, Xiong A, He Y, Wang Z, Wang C, Wang Z, Li W, Yang L, Hu Z. Bile acids metabonomic study on the CCl4- and alpha-naphthylisothiocyanate-induced animal models: quantitative analysis of 22 bile acids by ultraperformance liquid chromatography-mass spectrometry. Chem Res Toxicol 2008;21: 2280-8. https://doi.org/10.1021/tx800225q
  22. Sun L, Pang Y, Wang X, Wu Q, Liu H, Liu B, Liu G, Ye M, Kong W, Jiang C. Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters. Acta Pharm Sin B 2019;9:702-10. https://doi.org/10.1016/j.apsb.2019.02.004
  23. Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, Angelin B, Hyotylainen T, Oresic M, Backhed F. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metabol 2013;17:225-35. https://doi.org/10.1016/j.cmet.2013.01.003
  24. Vital M, Rud T, Rath S, Pieper DH, Schluter D. Diversity of bacteria exhibiting bile acid-inducible 7alpha-dehydroxylation genes in the human gut. Comput Struct Biotechnol J 2019;17:1016-9. https://doi.org/10.1016/j.csbj.2019.07.012
  25. Kuhre RE, Wewer Albrechtsen NJ, Larsen O, Jepsen SL, Balk-Moller E, Andersen DB, Deacon CF, Schoonjans K, Reimann F, Gribble FM, et al. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metabol 2018;11:84-95. https://doi.org/10.1016/j.molmet.2018.03.007
  26. Dong S, Zhu M, Wang K, Zhao X, Hu L, Jing W, Lu H, Wang S. Dihydromyricetin improves DSS-induced colitis in mice via modulation of fecal-bacteria-related bile acid metabolism. Pharmacol Res 2021;171:105767. https://doi.org/10.1016/j.phrs.2021.105767
  27. Lu S, Luo Y, Zhou P, Yang K, Sun G, Sun X. Ginsenoside compound K protects human umbilical vein endothelial cells against oxidized low-density lipoprotein-induced injury via inhibition of nuclear factor-kappaB, p38, and JNK MAPK pathways. J Ginseng Res 2019;43:95-104. https://doi.org/10.1016/j.jgr.2017.09.004
  28. Hwang YC, Oh DH, Choi MC, Lee SY, Ahn KJ, Chung HY, Lim SJ, Chung SH, Jeong IK. Compound K attenuates glucose intolerance and hepatic steatosis through AMPK-dependent pathways in type 2 diabetic OLETF rats. Korean J Intern Med 2018;33:347-55. https://doi.org/10.3904/kjim.2015.208
  29. Cao H, Li C, Lei L, Wang X, Liu S, Liu Q, Huan Y, Sun S, Shen Z. Stachyose improves the effects of berberine on glucose metabolism by regulating intestinal microbiota and short-chain fatty acids in spontaneous type 2 diabetic KKAy mice. Front Pharmacol 2020;11:578943. https://doi.org/10.3389/fphar.2020.578943
  30. Harrison CA, Laubitz D, Ohland CL, Midura-Kiela MT, Patil K, Besselsen DG, Jamwal DR, Jobin C, Ghishan FK, Kiela PR. Microbial dysbiosis associated with impaired intestinal Na(+)/H(+) exchange accelerates and exacerbates colitis in ex-germ free mice. Mucosal Immunol 2018;11:1329-41. https://doi.org/10.1038/s41385-018-0035-2
  31. Ojo BA, O'Hara C, Wu L, El-Rassi GD, Ritchey JW, Chowanadisai W, Lin D, Smith BJ, Lucas EA. Wheat germ supplementation increases Lactobacillaceae and promotes an anti-inflammatory gut milieu in C57bl/6 mice fed a high-fat, high-sucrose diet. J Nutr 2019;149:1107-15. https://doi.org/10.1093/jn/nxz061
  32. Bloom SM, Bijanki VN, Nava GM, Sun L, Malvin NP, Donermeyer DL, Dunne Jr WM, Allen PM, Stappenbeck TS. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe 2011;9:390-403. https://doi.org/10.1016/j.chom.2011.04.009
  33. Fuchs CD, Paumgartner G, Mlitz V, Kunczer V, Halilbasic E, Leditznig N, Wahlstrom A, Stahlman M, Thuringer A, Kashofer K, et al. Colesevelam attenuates cholestatic liver and bile duct injury in Mdr2(-/-) mice by modulating composition, signalling and excretion of faecal bile acids. Gut 2018;67: 1683-91. https://doi.org/10.1136/gutjnl-2017-314553
  34. Kaur A, Patankar JV, de Haan W, Ruddle P, Wijesekara N, Groen AK, Verchere CB, Singaraja RR, Hayden MR. Loss of Cyp8b1 improves glucose homeostasis by increasing GLP-1. Diabetes 2015;64:1168-79. https://doi.org/10.2337/db14-0716
  35. Wu Q, Liang X, Wang K, Lin J, Wang X, Wang P, Zhang Y, Nie Q, Liu H, Zhang Z, et al. Intestinal hypoxia-inducible factor 2alpha regulates lactate levels to shape the gut microbiome and alter thermogenesis. Cell Metabol 2021;10: 1988-2003.
  36. Burcelin R. Gut microbiota and immune crosstalk in metabolic disease. Mol Metabol 2016;5:771-81. https://doi.org/10.1016/j.molmet.2016.05.016
  37. Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The effects of type 2 diabetes mellitus on organ metabolism and the immune system. Front Immunol 2020;11:1582. https://doi.org/10.3389/fimmu.2020.01582
  38. Ward JBJ, Lajczak NK, Kelly OB, O'Dwyer AM, Giddam AK, Ni Gabhann J, Franco P, Tambuwala MM, Jefferies CA, Keely S, et al. Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon. Am J Physiol Gastrointest Liver Physiol 2017;312:G550-8. https://doi.org/10.1152/ajpgi.00256.2016
  39. Sinha SR, Haileselassie Y, Nguyen LP, Tropini C, Wang M, Becker LS, Sim D, Jarr K, Spear ET, Singh G, et al. Dysbiosis-induced secondary bile acid deficiency promotes intestinal inflammation. Cell Host Microbe 2020;27: 659-670 e5. https://doi.org/10.1016/j.chom.2020.01.021
  40. Sorrentino G, Perino A, Yildiz E, El Alam G, Bou Sleiman M, Gioiello A, Pellicciari R, Schoonjans K. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration. Gastroenterology 2020;159:956-968 e8. https://doi.org/10.1053/j.gastro.2020.05.067
  41. Petersen N, Reimann F, van Es JH, van den Berg BM, Kroone C, Pais R, Jansen E, Clevers H, Gribble FM, de Koning EJ. Targeting development of incretinproducing cells increases insulin secretion. J Clin Invest 2015;125:379-85. https://doi.org/10.1172/JCI75838
  42. Chen YS, Liu HM, Lee TY. Ursodeoxycholic acid regulates hepatic energy homeostasis and white adipose tissue macrophages polarization in leptindeficiency obese mice. Cells 2019;8.