Myricetin protects mice against colitis by activating aryl hydrocarbon receptor signaling pathway

Tao Xu; Xinyan Qu; Yue Song; Mengxiong Luo; Yuhan Jia; Jia Li; Qingjun Li

doi:10.29219/fnr.v69.10677

Tao Xu Shandong University of Traditional Chinese Medicine, Jinan, China; and Department of Traditional Chinese Medicine, Taishan District People’s Hospital, Taian, China
Xinyan Qu Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
Yue Song Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
Mengxiong Luo Shandong University of Traditional Chinese Medicine, Jinan, China
Yuhan Jia Shandong University of Traditional Chinese Medicine, Jinan, China
Jia Li Shandong University of Traditional Chinese Medicine, Jinan, China
Qingjun Li Shandong University of Traditional Chinese Medicine, Jinan, China

DOI: https://doi.org/10.29219/fnr.v69.10677

Keywords: myricetin, targeted metabolomics, ulcerative colitis, aryl hydrocarbon receptor, mechanism

Abstract

Objective: Myricetin is a bioactive compound in many edible plants. We have previously demonstrated that myricetin could significantly protect mice against colitis by regulating Treg/Th17 balance, while underlying mechanism remains unclear. The current study aimed to unravel the potential regulating mechanism of myricetin.

Methods: The concentrations of 22 amino acids in colon were determined using HPLC-MS/MS and principal component analysis (PCA) was performed on the data. MetaboAnalyst was used to detect potential biological pathway influenced by myricetin. The results were further verified using qPCR, molecular docking method, and AhR inhibitor.

Results: Studies had found that the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; and histidine metabolism were the most important pathways related to myricetin. Therefore, the aryl hydrocarbon receptor (AhR), which is closely related to the metabolism of tryptophan, phenylalanine, and tyrosine, was postulated to be the underlying signaling pathways. Furthermore, administration of myricet in significantly increased the relative expressions of CYP1A1 and CYP1B1, whereas AhR inhibitor abolished the amelioration of myricetin on DSS-induced colitis. Moreover, AhR inhibitor weakened the regulatory effect of myricetin on Treg/Th17 balance. Furthermore, the results obtained by the molecular docking method speculated that myricetin could bind to AhR as a ligand and activate AhR.

Conclusion: The results suggested that myricetin could exert its protection against dextran sulfate sodium (DSS)-induced colitis by activating AhR signaling pathway.

Downloads

Download data is not yet available.

References

1.
Gajendran M, Loganathan P, Jimenez G, Catinella AP, Ng N, Umapathy C, et al. A comprehensive review and update on ulcerative colitis(UC). Disease-a-month: DM. 2019; 65: 100851. doi: 10.1016/j.disamonth.2019.02.004

2.
Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med 2011; 365: 1713–25. doi: 10.1056/NEJMra1102942

3.
Fernandez-Rojas B, Gutierrez-Venegas G. Flavonoids exert multiple periodontic benefits including anti-inflammatory, periodontal ligament-supporting, and alveolar bone-preserving effects. Life Sci 2018; 209: 435–454. doi: 10.1016/j.lfs.2018.08.029

4.
Peng KY, Gu JF, Su SL, Zhu Y, Guo JM, Qian DW, et al. Salvia miltiorrhiza stems and leaves total phenolic acids combination with tanshinone protect against DSS-induced ulcerative colitis through inhibiting TLR4/PI3K/AKT/mTOR signaling pathway in mice. J Ethnopharmacol 2021; 264: 113052. doi: 10.1016/j.jep.2020.113052

5.
Zhao J, Hong T, Dong M, Meng Y, Mu J. Protective effect of myricetin in dextran sulphate sodium-induced murine ulcerative colitis. Mol Med Rep 2013; 7: 565–70. doi: 10.3892/mmr.2012.1225

6.
Phillips PA, Sangwan V, Borja-Cacho D, Dudeja V, Vickers SM, Saluja AK. Myricetin induces pancreatic cancer cell death via the induction of apoptosis and inhibition of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Cancer Lett 2011; 308: 181–8. doi: 10.1016/j.canlet.2011.05.002

7.
Domitrovic R, Rashed K, Cvijanovic O, Vladimir-Knezevic S, Skoda M, Visnic A. Myricitrin exhibits antioxidant, anti-inflammatory and antifibrotic activity in carbon tetrachloride-intoxicated mice. Chem Biol Interact 2015; 230: 21–9. doi: 10.1016/j.cbi.2015.01.030

8.
Qu X, Li Q, Song Y, Xue A, Liu Y, Qi D, et al. Potential of myricetin to restore the immune balance in dextran sulfate sodium-induced acute murine ulcerative colitis. J Pharm Pharmacol. 2020; 72: 92–100. doi: 10.1111/jphp.13197

9.
Zhuang Y, Qin K, Yu B, Liu X, Cai B, Cai H. A metabolomics research based on UHPLC-ESI-Q-TOF-MS coupled with metabolic pathway analysis: treatment effects of stir-frying Xanthii Fructus on allergic rhinitis in mice model. Biomed Chromatogr. 2018; 32: e4352. doi: 10.1002/bmc.4352

10.
Song Y, Chai T, Yin Z, Zhang X, Zhang W, Qian Y, et al. Stereoselective effects of ibuprofen in adult zebrafish (Danio rerio) using UPLC-TOF/MS-based metabolomics. Environ Pollut. 2018; 241: 730–9. doi: 10.1111/jphp.13197

11.
Hu C, Li H, Wu L, Ke J, Yu X, Xiong Y, et al. Metabolic profiling of 19 amino acids in triptolide-induced liver injured rats by gas chromatography-triple quadrupole mass spectrometry. Hum Exp Toxicol 2021; 40: 1685–97. doi: 10.1177/09603271211006167

12.
Zhao Q, Bian X, Shan C, Cheng J, Wang C, Xu Y, et al. Quantitative analysis of nutrients for nucleosides, nucleobases, and amino acids hidden behind five distinct regions-derived Poria cocos using ultra - performance liquid chromatography coupled with triple - quadrupole linear ion - trap tandem mass spectrometry. J Separat Sci 2022; 45: 4039–51. doi: 10.1002/jssc.202200516

13.
Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, et al. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res 2018; 46: W486–94. doi: 10.1093/nar/gky310

14.
Shen J, Yang L, You K, Chen T, Su Z, Cui Z, et al. Indole-3-acetic acid alters intestinal microbiota and alleviates ankylosing spondylitis in mice. Front Immunol 2022; 13: 762580. doi: 10.3389/fimmu.2022.762580

15.
Zhuang H, Ren X, Jiang F, Zhou P. Indole-3-propionic acid alleviates chondrocytes inflammation and osteoarthritis via the AhR/NF-κB axis. Mol Med 2023; 29: 17. doi: 10.1186/s10020-023-00614-9

16.
Ray RM, Johnson LR. Regulation of intestinal mucosal growth by amino acids. Amino Acids 2014; 46: 565–73. doi: 10.1007/s00726-013-1565-2

17.
Liu Y, Wang X, Hu CA. Therapeutic potential of amino acids in inflammatory bowel disease. Nutrients 2017; 9: 920. doi: 10.3390/nu9090920

18.
Bosch S, Struys EA, van Gaal N, Bakkali A, Jansen EW, Diederen K, et al. Fecal amino acid analysis can discriminate de novo treatment-naïve pediatric inflammatory bowel disease from controls. J Pediatr Gastroenterol Nutr 2018; 66: 773–8. doi: 10.1097/mpg.0000000000001812

19.
Wiggins T, Kumar S, Markar SR, Antonowicz S, Hanna GB. Tyrosine, phenylalanine, and tryptophan in gastroesophageal malignancy: a systematic review. Cancer Epidemiol Biomark Prev 2015; 24: 32–8. doi: 10.1158/1055-9965.Epi-14-0980

20.
Stifel FB, Herman RH. Histidine metabolism. Am J Clin Nutr 1971; 24: 207–217. doi: 10.1093/ajcn/24.2.207

21.
Obata T, Inada T. Protective effect of histidine on MPP+-induced hydroxyl radical generation in rat striatum. Brain Res 1999; 817: 206–208. doi: 10.1016/s0006-8993(98)01225-6

22.
Andou A, Hisamatsu T, Okamoto S, Chinen H, Kamada N, Kobayashi T, et al. Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Gastroenterology 2009; 136: 564–574.e562. doi: 10.1053/j.gastro.2008.09.062

23.
Yousef M, Pichyangkura R, Soodvilai S, Chatsudthipong V, Muanprasat C. Chitosan oligosaccharide as potential therapy of inflammatory bowel disease: therapeutic efficacy and possible mechanisms of action. Pharmacol Res 2012; 66: 66–79 doi: 10.1016/j.phrs.2012.03.013

24.
Coëffier M, Marion-Letellier R, Déchelotte P. Potential for amino acids supplementation during inflammatory bowel diseases. Inflamm Bowel Dis. 2010; 16: 518–24. doi: 10.1002/ibd.21017

25.
Minsavage GD, Park SK, Gasiewicz TA. The aryl hydrocarbon receptor (AhR) tyrosine 9, a residue that is essential for AhR DNA binding activity, is not a phosphoresidue but augments AhR phosphorylation. J Biol Chem 2004; 279: 20582–20593. doi: 10.1074/jbc.M312977200

26.
Minsavage GD, Vorojeikina DP, Gasiewicz TA. Mutational analysis of the mouse aryl hydrocarbon receptor tyrosine residues necessary for recognition of dioxin response elements. Arch Biochem Biophys 2003; 412: 95–105. doi: 10.1016/s0003-9861(03)00033-x

27.
Park H, Jin UH, Karki K, Jayaraman A, Allred CH, Michelhaugh SK, et al. Dopamine is an aryl hydrocarbon receptor agonist. Biochem J 2020; 477(19): 3899–910. doi: 10.1042/bcj20200440

28.
Tkachenko A, Bermudez M, Irmer-Stooff S, Genkinger D, Henkler-Stephani F, Wolber G, et al. Nuclear transport of the human aryl hydrocarbon receptor and subsequent gene induction relies on its residue histidine 291. Arch Toxicol 2018; 92: 1151–1160. doi: 10.1007/s00204-017-2129-0

29.
Masuda K, Kimura A, Hanieh H, Nguyen NT, Nakahama T, Chinen I, et al. Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages. Int Immunol 2011; 23: 637–645. doi: 10.1093/intimm/dxr072

30.
Sun M, Ma N, He T, Johnston LJ, Ma X. Tryptophan (Trp) modulates gut homeostasis via aryl hydrocarbon receptor (AhR). Crit Rev Food Science Nutr 2020; 60: 1760–1768. doi: 10.1080/10408398.2019.1598334

31.
Bock KW. Aryl hydrocarbon receptor (AHR)-mediated inflammation and resolution: non-genomic and genomic signaling. Biochem Pharmacol 2020; 182: 114220. doi: 10.1016/j.bcp.2020.114220

32.
Metidji A, Omenetti S, Crotta S, Li Y, Nye E, Ross E, et al. The environmental sensor AHR protects from inflammatory damage by maintaining intestinal stem cell homeostasis and barrier integrity. Immunity 2018; 49: 353–62.e355. doi: 10.1016/j.immuni.2018.07.010

33.
Pernomian L, Duarte-Silva M, de Barros Cardoso CR. The Aryl Hydrocarbon Receptor (AHR) as a potential target for the control of intestinal inflammation: insights from an Immune and Bacteria Sensor Receptor. Clin Rev Allergy Immunol 2020; 49(2): 353–62. doi: 10.1007/s12016-020-08789-3

34.
Yan X, Lin TJ, Zhu QY, Zhang YS, Song ZM, Pan XT. Naringenin protects against acute pancreatitis-associated intestinal injury by inhibiting NLRP3 inflammasome activation via AhR signaling. Front Pharmacol. 2023; 14: 12. doi: 10.3389/fphar.2023.1090261

35.
Singh NP, Singh UP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS. Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS One. 2011; 6: e23522. doi: 10.1371/journal.pone.0023522

36.
Cui XF, Ye ZP, Wang D, Yang Y, Jiao CH, Ma JJ, et al. Aryl hydrocarbon receptor activation ameliorates experimental colitis by modulating the tolerogenic dendritic and regulatory T cell formation. Cell Biosci. 2022; 12: 13. doi: 10.1186/s13578-022-00780-z

37.
Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol. 2019; 19: 184–97. doi: 10.1038/s41577-019-0125-8