Abstract
Background
Inflammatory bowel disease (IBD) is a chronic, potentially cancerous disease with limited treatment options. Quercetin may be a novel treatment for IBD. However, its efficacy and safety are unknown. Our goal was to conduct a systematic evaluation to summarize the preclinical effects of quercetin, which may help guide future studies.
Methods
The literature was drawn from three English databases (PubMed, Embase, and Web of Science), and the quality of the included literature was assessed using the SYRCLE list (10 items). The meta-analysis was performed using STATA 15.1 software.
Results
A total of 11 animal studies with 199 animals were involved. The current meta-analysis showed that quercetin could reduce histological score (HS), Disease Activity Index (DAI), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), nitric oxide(NO), malondialdehyde (MDA), myeloperoxidase (MPO) activity and increase colon length (CL), weight change degree (WCD), interleukin-10 (IL-10), glutathione (GSH), superoxide dismutase (SOD) activity and catalase (CAT) activity, which may involve anti-inflammatory, anti-oxidative stress, cytoprotective, barrier protection, flora regulation.
Conclusions
In conclusion, preclinical evidence suggests that quercetin is an ideal agent for IBD treatment. However, the validity of the findings may be compromised by the low methodological quality and the small number of studies included. There may be some discrepancies between the results of the current analysis and the real situation. More rigorous experimental designs and more comprehensive studies are needed to test the protection of quercetin against IBD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of data and materials
The raw data used in the study are included in the article and further inquiries can be made by contacting the first author or corresponding author.
Abbreviations
- CAT:
-
Catalase
- CL:
-
Colon length
- DAI:
-
Disease Activity Index
- GSH:
-
Glutathione
- HS:
-
Histological score
- HO-1:
-
Heme oxygenase-1
- IL-1β:
-
Interleukin-1β
- IL-10:
-
Interleukin-10
- MDA:
-
Malondialdehyde
- MPO:
-
Myeloperoxidase
- NO:
-
Nitric oxide
- SOD:
-
Superoxide dismutase
- TNF-α:
-
Tumor necrosis factor-α
- TNBS:
-
Trinitrobenzene sulfonic acid
- WCD:
-
Weight change degree
References
Araki T, Kawamura M, Tanaka K, Okita Y, Fujikawa H, Uchida K et al (2015) FK506-binding protein 5 mRNA levels in ileal mucosa are associated with Pouchitis in patients with ulcerative colitis. Dig Dis Sci 60(6):1617–1623. https://doi.org/10.1007/s10620-015-3528-9
Bonta RK (2020) Dietary phenolic acids and flavonoids as potential anti-cancer agents: current state of the art and future perspectives. Anticancer Agents Med Chem 20(1):29–48. https://doi.org/10.2174/1871520619666191019112712
Calis Z, Mogulkoc R, Baltaci AK (2020) The roles of flavonols/flavonoids in neurodegeneration and neuroinflammation. Mini Rev Med Chem 20(15):1475–1488. https://doi.org/10.2174/1389557519666190617150051
Carvalho ACA, Souza GA, Marqui SV, Guiguer EL, Araujo AC, Rubira CJ et al (2020) Cannabis and canabidinoids on the inflammatory bowel diseases: going beyond misuse. Int J Mol Sci. https://doi.org/10.3390/ijms21082940
Castangia I, Nácher A, Caddeo C, Merino V, Díez-Sales O, Catalán-Latorre A et al (2015) Therapeutic efficacy of quercetin enzyme-responsive nanovesicles for the treatment of experimental colitis in rats. Acta Biomater 13:216–227. https://doi.org/10.1016/j.actbio.2014.11.017
Chen WH, Wang R, Shi YP (2010) Flavonoids in the poisonous plant Oxytropis falcata. J Nat Prod 73(8):1398–1403. https://doi.org/10.1021/np100339u
Cho HS, Reboldi A, Hall JA, Berg LJ (2019) The Tec kinase ITK is essential for ILC2 survival and epithelial integrity in the intestine. Nat Commun 10(1):784. https://doi.org/10.1038/s41467-019-08699-9
Chow JP, Simionescu DT, Warner H, Wang B, Patnaik SS, Liao J et al (2013) Mitigation of diabetes-related complications in implanted collagen and elastin scaffolds using matrix-binding polyphenol. Biomaterials 34(3):685–695. https://doi.org/10.1016/j.biomaterials.2012.09.081
Dave M, Papadakis KA, Faubion WA Jr (2014) Immunology of inflammatory bowel disease and molecular targets for biologics. Gastroenterol Clin North Am 43(3):405–424. https://doi.org/10.1016/j.gtc.2014.05.003
De Cassan C, Fiorino G, Danese S (2012) Second-generation corticosteroids for the treatment of Crohn’s disease and ulcerative colitis: more effective and less side effects? Dig Dis 30(4):368–375. https://doi.org/10.1159/000338128
Diez-Echave P, Ruiz-Malagón AJ, Molina-Tijeras JA, Hidalgo-García L, Vezza T, Cenis-Cifuentes L et al (2021) Silk fibroin nanoparticles enhance quercetin immunomodulatory properties in DSS-induced mouse colitis. Int J Pharm 606:120935. https://doi.org/10.1016/j.ijpharm.2021.120935
Dodda D, Chhajed R, Mishra J (2014a) Protective effect of quercetin against acetic acid induced inflammatory bowel disease (IBD) like symptoms in rats: possible morphological and biochemical alterations. Pharmacol Rep 66(1):169–173. https://doi.org/10.1016/j.pharep.2013.08.013
Dodda D, Chhajed R, Mishra J, Padhy M (2014b) Targeting oxidative stress attenuates trinitrobenzene sulphonic acid induced inflammatory bowel disease like symptoms in rats: role of quercetin. Indian J Pharmacol 46(3):286–291. https://doi.org/10.4103/0253-7613.132160
Dong Y, Lei J, Zhang B (2020b) Dietary quercetin alleviated DSS-induced colitis in Mice through several possible pathways by transcriptome analysis. Curr Pharm Biotechnol 21(15):1666–1673. https://doi.org/10.2174/1389201021666200711152726
Dong Y, Hou Q, Lei J, Wolf PG, Ayansola H, Zhang B (2020a) Quercetin alleviates intestinal oxidative damage induced by H2O2 via modulation of GSH: in vitro screening and in vivo evaluation in a colitis model of Mice. Acs Omega 5(14):8334–8346. https://doi.org/10.1021/acsomega.0c00804
Guazelli CF, Fattori V, Colombo BB, Georgetti SR, Vicentini FT, Casagrande R et al (2013) Quercetin-loaded microcapsules ameliorate experimental colitis in mice by anti-inflammatory and antioxidant mechanisms. J Nat Prod 76(2):200–208. https://doi.org/10.1021/np300670w
Guo C, Wang WJ, Liao YC, Zhao C, Yin Y, Yao MN et al (2022) Effect and mechanisms of quercetin for experimental focal cerebral ischemia: a systematic review and meta-analysis. Oxid Med Cell Longev 2022:9749461. https://doi.org/10.1155/2022/9749461
Helmy AM, Elsabahy M, Abd-Elkareem M, Ibrahim EA, Soliman GM (2020) High-payload chitosan microparticles for the colonic delivery of quercetin: development and in-vivo evaluation in a rabbit colitis model. J Drug Deliv Sci Technol. https://doi.org/10.1016/j.jddst.2020.101832
Hendrickson BA, Gokhale R, Cho JH (2002) Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev 15(1):79–94. https://doi.org/10.1128/CMR.15.1.79-94.2002
Hong Z, Tang P, Liu B, Ran C, Yuan C, Zhang Y et al (2021) Ferroptosis-related genes for overall survival prediction in patients with colorectal cancer can be inhibited by gallic acid. Int J Biol Sci 17(4):942–956. https://doi.org/10.7150/ijbs.57164
Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW (2014) SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 14:43. https://doi.org/10.1186/1471-2288-14-43
Hu X, Adamcakova-Dodd A, Lehmler HJ, Gibson-Corley K, Thorne PS (2015) Toxicity evaluation of exposure to an atmospheric mixture of polychlorinated biphenyls by nose-only and whole-body inhalation regimens. Environ Sci Technol 49(19):11875–11883. https://doi.org/10.1021/acs.est.5b02865
Ju S, Ge Y, Li P, Tian X, Wang H, Zheng X et al (2018) Dietary quercetin ameliorates experimental colitis in mouse by remodeling the function of colonic macrophages via a heme oxygenase-1-dependent pathway. Cell Cycle 17(1):53–63. https://doi.org/10.1080/15384101.2017.1387701
Kamalian A, Sohrabi Asl M, Dolatshahi M, Afshari K, Shamshiri S, Momeni Roudsari N et al (2020) Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways. World J Gastroenterol 26(24):3365–3400. https://doi.org/10.3748/wjg.v26.i24.3365
Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P (2011) Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 106(4):630–642. https://doi.org/10.1038/ajg.2011.64
Kim ER, Chang DK (2014) Colorectal cancer in inflammatory bowel disease: the risk, pathogenesis, prevention and diagnosis. World J Gastroenterol 20(29):9872–9881. https://doi.org/10.3748/wjg.v20.i29.9872
Kolios G, Valatas V, Ward SG (2004) Nitric oxide in inflammatory bowel disease: a universal messenger in an unsolved puzzle. Immunology 113(4):427–437. https://doi.org/10.1111/j.1365-2567.2004.01984.x
Kwon KH, Murakami A, Tanaka T, Ohigashi H (2005) Dietary rutin, but not its aglycone quercetin, ameliorates dextran sulfate sodium-induced experimental colitis in mice: attenuation of pro-inflammatory gene expression. Biochem Pharmacol 69(3):395–406. https://doi.org/10.1016/j.bcp.2004.10.015
Lin R, Piao M, Song Y (2019) Dietary quercetin increases colonic microbial diversity and attenuates colitis severity in Citrobacter rodentium-infected Mice. Front Microbiol 10:1092. https://doi.org/10.3389/fmicb.2019.01092
Mandal P, Park PH, McMullen MR, Pratt BT, Nagy LE (2010) The anti-inflammatory effects of adiponectin are mediated via a heme oxygenase-1-dependent pathway in rat Kupffer cells. Hepatology 51(4):1420–1429. https://doi.org/10.1002/hep.23427
Manolakis AC, Kapsoritakis AN, Tiaka EK, Potamianos SP (2011) Calprotectin, calgranulin C, and other members of the s100 protein family in inflammatory bowel disease. Dig Dis Sci 56(6):1601–1611. https://doi.org/10.1007/s10620-010-1494-9
Mao L, Kitani A, Strober W, Fuss IJ (2018) The role of NLRP3 and IL-1beta in the pathogenesis of inflammatory bowel disease. Front Immunol 9:2566. https://doi.org/10.3389/fimmu.2018.02566
Meister A (1988) Glutathione metabolism and its selective modification. J Biol Chem 263(33):17205–17208
Mi Y, Zhong L, Lu S, Hu P, Pan Y, Ma X et al (2022) Quercetin promotes cutaneous wound healing in mice through Wnt/beta-catenin signaling pathway. J Ethnopharmacol 290:115066. https://doi.org/10.1016/j.jep.2022.115066
Minamoto Y, Otoni CC, Steelman SM, Buyukleblebici O, Steiner JM, Jergens AE et al (2015) Alteration of the fecal microbiota and serum metabolite profiles in dogs with idiopathic inflammatory bowel disease. Gut Microbes 6(1):33–47. https://doi.org/10.1080/19490976.2014.997612
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G et al (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142(1):46–54. https://doi.org/10.1053/j.gastro.2011.10.001
Moon YJ, Wang L, DiCenzo R, Morris ME (2008) Quercetin pharmacokinetics in humans. Biopharm Drug Dispos 29(4):205–217. https://doi.org/10.1002/bdd.605
Nie JP, Qu ZN, Chen Y, Chen JH, Jiang Y, Jin MN et al (2020) Discovery and anti-diabetic effects of novel isoxazole based flavonoid derivatives. Fitoterapia 142:104499. https://doi.org/10.1016/j.fitote.2020.104499
Nikfar S, Rahimi R, Rezaie A, Abdollahi M (2009) A meta-analysis of the efficacy of sulfasalazine in comparison with 5-aminosalicylates in the induction of improvement and maintenance of remission in patients with ulcerative colitis. Dig Dis Sci 54(6):1157–1170. https://doi.org/10.1007/s10620-008-0481-x
Papamichael K, Cheifetz AS, Irving PM (2020) New role for azathioprine in case of switching anti-TNFs in IBD. Gut 69(7):1165–1167. https://doi.org/10.1136/gutjnl-2020-320677
Rahimi R, Nikfar S, Abdollahi M (2007) Do anti-tumor necrosis factors induce response and remission in patients with acute refractory Crohn’s disease? A systematic meta-analysis of controlled clinical trials. Biomed Pharmacother 61(1):75–80. https://doi.org/10.1016/j.biopha.2006.06.022
Ruder B, Atreya R, Becker C (2019) Tumour necrosis factor alpha in intestinal homeostasis and gut related diseases. Int J Mol Sci. https://doi.org/10.3390/ijms20081887
Russo M, Moccia S, Spagnuolo C, Tedesco I, Russo GL (2020) Roles of flavonoids against coronavirus infection. Chem Biol Interact 328:109211. https://doi.org/10.1016/j.cbi.2020.109211
Sann H, Erichsen J, Hessmann M, Pahl A, Hoffmeyer A (2013) Efficacy of drugs used in the treatment of IBD and combinations thereof in acute DSS-induced colitis in mice. Life Sci 92(12):708–718. https://doi.org/10.1016/j.lfs.2013.01.028
Shen C, Zhao L, Du X, Tian J, Yuan Y, Jia M et al (2021) Smart responsive quercetin-conjugated glycol chitosan prodrug micelles for treatment of inflammatory bowel diseases. Mol Pharm 18(3):1419–1430. https://doi.org/10.1021/acs.molpharmaceut.0c01245
Siddaway AP, Wood AM, Hedges LV (2019) How to do a systematic review: a best practice guide for conducting and reporting narrative reviews, meta-analyses, and meta-syntheses. Annu Rev Psychol 70:747–770. https://doi.org/10.1146/annurev-psych-010418-102803
Singh A, Rattan S (2021) BDNF rescues aging-associated internal anal sphincter dysfunction. Am J Physiol Gastrointest Liver Physiol 321(1):G87–G97. https://doi.org/10.1152/ajpgi.00090.2021
Singh A, Singh J, Rattan S (2022) Evidence for the presence and release of BDNF in the neuronal and non-neuronal structures of the internal anal sphincter. Neurogastroenterol Motil 34(4):e14099. https://doi.org/10.1111/nmo.14099
Stecher B (2015) The roles of inflammation, nutrient availability and the commensal microbiota in enteric pathogen infection. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.MBP-0008-2014
Tsai PY, Zhang B, He WQ, Zha JM, Odenwald MA, Singh G et al (2017) IL-22 upregulates epithelial claudin-2 to drive diarrhea and enteric pathogen clearance. Cell Host Microbe 21(6):671–681. https://doi.org/10.1016/j.chom.2017.05.009
Yang L, Huang W, Xiong F, Xian Z, Su D, Ren M et al (2017) Silencing of SlPL, which encodes a pectate lyase in tomato, confers enhanced fruit firmness, prolonged shelf-life and reduced susceptibility to grey mould. Plant Biotechnol J 15(12):1544–1555. https://doi.org/10.1111/pbi.12737
Zhang MR, Jiang K, Yang JL, Shi YP (2020) Flavonoids as key bioactive components of Oxytropis falcata bunge, a traditional anti-inflammatory and analgesic Tibetan medicine. Nat Prod Res 34(23):3335–3352. https://doi.org/10.1080/14786419.2019.1574786
Zhen Y, Zhang H (2019) NLRP3 inflammasome and inflammatory bowel disease. Front Immunol. https://doi.org/10.3389/fimmu.2019.00276
Zuo T, Kamm MA, Colombel JF, Ng SC (2018) Urbanization and the gut microbiota in health and inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 15(7):440–452. https://doi.org/10.1038/s41575-018-0003-z
Acknowledgements
The authors thank Chengdu University of Traditional Chinese Medicine for providing a research platform and contributing to this study. Thanks to Yi Zhang and Yi Yang for their assistance in this study.
Funding
This work was supported by the National Natural Science Foundation of China (grant no. 82074397), and the “Hundred Talents Program” of the Hospital of Chengdu University of Traditional Chinese Medicine (grant no. 21-Y17).
Author information
Authors and Affiliations
Contributions
Maoyuan Zhao and Shuangyuan Hu contributed to the manuscript drafting. Pengfei Wei and Wei Li formulated the search strategy and searched the databases. Qingsong Liu and Shuanglan Chen screened the articles and extracted the data. Maoyuan Zhao interpreted the data, and processed the pictures and tables in the manuscript. Xiao Ma, Jinhao Zeng and Jianyuan Tang provided constructive comments and revised the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Ethics approval
As this study was based solely on the summary results of previously published articles, neither ethical approval nor participant consent was required. No individual patient data were obtained or accessed.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Hu, S., Zhao, M., Li, W. et al. Preclinical evidence for quercetin against inflammatory bowel disease: a meta-analysis and systematic review. Inflammopharmacol 30, 2035–2050 (2022). https://doi.org/10.1007/s10787-022-01079-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10787-022-01079-8