Cinnamtannin D1 ameliorates DSS-induced colitis by preventing Th17/Treg imbalance through activation of the AMPK/mTOR pathway
Main Article Content
Keywords
AMPK pathway, cinnamtannin D1, inflammatory bowel disease, Th17–Treg imbalance
Abstract
Background: Inflammatory bowel disease (IBD) is a chronic idiopathic gastrointestinal disease, including ulcerative colitis (UC) and Crohn’s disease (CD), which is typically characterized by chronicity and relapse. Cinnamtannin D1 (CTD1), extracted from Cinnamomum tamala, has been found to exert good immunosuppressive activity. However, the role of CTD1 in IBD is unclear.
Methods: The colitis mice model was established by dextran sulfate sodium (DSS) treatment. Protein levels (p-STAT3/STAT3, ROR-γt, p-STAT5/STAT5, FOXP3, p-AMPK/AMPK, and p-mTOR/mTOR) were examined using Western blotting analysis. Changes in histopathology were detected through hematoxylin and eosin staining. The proportion of T helper 17 (Th17) cells and regulatory T (Treg) cells was measured by flow cytometry analysis.
Results: CTD1 improved body weight and colon length, and alleviated inflammation and histological damage in DSS-induced colitis mice model. DSS treatment also demonstrated a negative effect on Th17–Treg cells balance whereas CTD1 restored the balance of Th17– Treg cells in DSS-induced colitis mice model. Regulatory factors (such as STAT3, ROR-γt, STAT5, and FOXP3) that closely related to the balance of Th17–Treg cells were regulated by CTD1. In addition, AMPK phosphorylation was increased and mTOR phosphorylation was inhibited by CTD1 in DSS-induced colitis mice model.
Conclusion: These findings established that CTD1 improved DSS-induced colitis by suppressing Th17–Treg cells balance by activating the AMPK/mTOR pathway. This study provided a new strategy for developing novel treatments for patients with IBD.
References
2. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142(1):46–54, e42; quiz e30. 10.1053/j.gastro.2011.10.001.
3. Axelrad JE, Lichtiger S, Yajnik V. Inflammatory bowel disease and cancer: The role of inflammation, immunosuppression, and cancer treatment. World J Gastroenterol. 2016;22(20):4794–801. 10.3748/wjg.v22.i20.4794.
4. Uranga JA, Lopez-Miranda V, Lombo F, Abalo R. Food, nutrients and nutraceuticals affecting the course of inflammatory bowel disease. Pharmacol Rep. 2016;68(4):816–26. 10.1016/j.pharep.2016.05.002.
5. Chou SC, Krishna V, Chou CH. Hydrophobic metabolites from Rhododendron formosanum and their allelopathic activities. Nat Prod Commun. 2009;4(9):1189–92.
6. Krishna V, Chang CI, Chou CH. Two isomeric epoxysitosterols from Rhododendron formosanum: 1H and 13C NMR chemical shift assignments. Magn Reson Chem. 2006;44(8):817–9. 10.1002/mrc.1844.
7. Wang CM, Li TC, Jhan YL, Weng JH, Chou CH. The impact of microbial biotransformation of catechin in enhancing the allelopathic effects of Rhododendron formosanum. PLoS One. 2013; 8(12):e85162. 10.1371/journal.pone.0085162.
8. Chen L, Sun P, Wang T, Chen K, Jia Q, Wang H, et al. Diverse mechanisms of antidiabetic effects of the different procyanidin oligomer types of two different cinnamon species on db/db mice. J Agric Food Chem. 2012;60(36):9144–50. 10.1021/jf3024535.
9. Chakraborty A, Sankaran V, Murugan R, Chellappan DR. Comparative spasmolytic effect between Cinnamomum tamala and Cinnamomum verum leaf essential oils and eugenol through in vitro and in silico approaches. Z Naturforsch C J Biosci. 2021;76(9–10):383–91. 10.1515/znc-2020-0153.
10. Chen L, Yang Y, Yuan P, Chen K, Jia Q, Li Y. Immunosuppressive effects of A-type procyanidin oligomers from Cinnamomum tamala. Evid Based Complement Alternat Med. 2014; 2014:365258. 10.1155/2014/365258.
11. Wang T, Sun P, Chen L, Huang Q, Chen K, Jia Q, et al. Cinnamtannin D-1 protects pancreatic beta-cells from palmitic acid-induced apoptosis by attenuating oxidative stress. J Agric Food Chem. 2014;62(22):5038–45. 10.1021/jf500387d.
12. Maynard CL, Weaver CT. Intestinal effector T cells in health and disease. Immunity. 2009;31(3):389–400. 10.1016/j.immuni.2009.08.012.
13. Peng L, Gao X, Nie L, Xie J, Dai T, Shi C, et al. Astragalin attenuates dextran sulfate sodium (DSS)-induced acute experimental colitis by alleviating gut microbiota dysbiosis and inhibiting NF-kappaB activation in mice. Front Immunol. 2020;11:2058. 10.3389/fimmu.2020.02058.
14. Wu X, Pan S, Luo W, Shen Z, Meng X, Xiao M, et al. Roseburia intestinal is derived flagellin ameliorates colitis by targeting miR2233p mediated activation of NLRP3 inflammasome and pyroptosis. Mol Med Rep. 2020;22(4):2695–704. 10.3892/mmr.2020.11351.
15. Wirtz S, Popp V, Kindermann M, Gerlach K, Weigmann B, Fichtner-Feigl S, et al. Chemically induced mouse models of acute and chronic intestinal inflammation. Nat Protoc. 2017;12(7):1295–309. 10.1038/nprot.2017.044.
16. Peng Y, Yan Y, Wan P, Chen D, Ding Y, Ran L, et al. Gut microbiota modulation and anti-inflammatory properties of anthocyanins from the fruits of Lycium ruthenicum Murray in dextran sodium sulfate-induced colitis in mice. Free Radic Biol Med. 2019;136:96–108. 10.1016/j.freeradbiomed.2019.04.005.
17. Shin HS, Satsu H, Bae MJ, Zhao Z, Ogiwara H, Totsuka M, et al. Anti-inflammatory effect of chlorogenic acid on the IL-8 production in Caco-2 cells and the dextran sulphate sodium-induced colitis symptoms in C57BL/6 mice. Food Chem. 2015;168:167–75. 10.1016/j.foodchem.2014.06.100.
18. Wang XY, Zhu BR, Jia Q, Li YM, Wang T, Wang HY. Cinnamtannin D1 protects pancreatic beta-cells from glucolipotoxicity-induced apoptosis by enhancement of autophagy in vitro and in vivo. J Agric Food Chem. 2020;68(45):12617–30. 10.1021/acs.jafc.0c04898.
19. Yan JB, Luo MM, Chen ZY, He BH. The function and role of the Th17/treg cell balance in inflammatory bowel disease. J Immunol Res. 2020;2020:8813558. 10.1155/2020/8813558.
20. Chang Y, Zhai L, Peng J, Wu H, Bian Z, Xiao H. Phytochemicals as regulators of Th17/treg balance in inflammatory bowel diseases. Biomed Pharmacother. 2021;141:111931. 10.1016/j.biopha.2021.111931.
21. Daniels MA, Teixeiro E. TCR signaling in T cell memory. Front Immunol. 2015;6:617. 10.3389/fimmu.2015.00617.
22. Galvez J. Role of Th17 cells in the pathogenesis of human IBD. ISRN Inflamm. 2014;2014:928461. 10.1155/2014/928461.
23. Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL, Cooper AM, et al. IL-12 and IL-23 cytokines: From discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med. 2015;21(7):719–29. 10.1038/nm.3895.
24. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12R beta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002;168(11):5699–708. 10.4049/jimmunol.168.11.5699.
25. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13–25. 10.1016/j.immuni.2013.01.004.
26. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146(5):772–84. 10.1016/j.cell.2011.07.033.
27. Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007; 282(13):9358–63. 10.1074/jbc.C600321200.
28. Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol. 2007;178(1):280–90. 10.4049/jimmunol.178.1.280.
29. Ren W, Yin J, Duan J, Liu G, Tan B, Yang G, et al. mTORC1 signaling and IL-17 expression: Defining pathways and possible therapeutic targets. Eur J Immunol. 2016;46(2):291–9. 10.1002/eji.201545886.
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.