Applied Microbiology and Biotechnology

, Volume 103, Issue 17, pp 7141–7149 | Cite as

Regulation of gut microbiota in Alzheimer’s disease mice by silibinin and silymarin and their pharmacological implications

  • Liang Shen
  • Lu Liu
  • Xin-Yu Li
  • Hong-Fang JiEmail author
Applied microbial and cell physiology


The newly reported associations between Alzheimer’s disease (AD) and gut microbiota indicate the potential of gut microbiota regulation–based therapeutic intervention for AD. Silymarin and its main active component, silibinin, are promising natural agents against AD, while their acting mechanisms remain to be explored. The present study investigated the effects of silibinin and silymarin administration on behavioral and histological manifestations, and regulation on the gut microbiota of transgenic APP/PS1 mice. First, silibinin and silymarin administration could alleviate memory deficits and reduce the amyloid plaque burden in the brain of APP/PS1 mice in comparison with controls. Second, silibinin and silymarin administration tended to decrease the microbiota diversity and exhibited regulative effect in abundances on several key bacterial species associated with AD development. This implied that gut microbiota regulation by silibinin and silymarin might be involved in their effects against AD. Further studies are warranted to fully elucidate the molecular mechanisms.


Alzheimer’s disease Silymarin Silibinin Gut microbiota 


Author contributions

HFJ and LS conceived and directed the study and drafted and revised the manuscript. LL, XYL, and LS performed the experiments and analyzed the data.

Funding Information

This work was supported by the Shandong Provincial Natural Science Foundation (Grant No. ZR2018MH010), Shandong Provincial Key Research and Development Program (Grant No. 2018GSF121001), National Science and Technology Major Projects of New Drugs (Grant No. 2015ZX09102015), and Talent Program of Zibo.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


  1. Abenavoli L, Capasso R, Milic N, Capasso F (2010) Milk thistle in liver diseases: past, present, future. Phytother Res. 24:1423–1432CrossRefGoogle Scholar
  2. Alam MZ, Alam Q, Kamal MA, Abuzenadah AM, Haque A (2014) A possible link of gut microbiota alteration in type 2 diabetes and Alzheimer’s disease pathogenicity: an update. CNS Neurol Disord Drug Targets. 13:383–390CrossRefGoogle Scholar
  3. Borah A, Paul R, Choudhury S, Choudhury A, Bhuyan B, Das Talukdar A, Dutta Choudhury M, Mohanakumar KP (2013) Potential of silymarin against CNS disorders: insight into the pathways and molecular mechanisms of action. CNS Neurosci Ther 19:847–853CrossRefGoogle Scholar
  4. Boursier J, Diehl AM (2015) Implication of gut microbiota in nonalcoholic fatty liver disease. PLoS Pathog. 11:e1004559CrossRefGoogle Scholar
  5. Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158CrossRefGoogle Scholar
  6. D’Aniello A, Vetere A, Fisher GH, Cusano G, Chavez M, Petrucelli L (1992) Presence of D-alanine in proteins of normal and Alzheimer human brain. Brain Res 592:44–48CrossRefGoogle Scholar
  7. Doulberis M, Kotronis G, Gialamprinou D, Kountouras J, Katsinelos P (2017) Non-alcoholic fatty liver disease: an update with special focus on the role of gut microbiota. Metabolism 71:182–197CrossRefGoogle Scholar
  8. Féher J, Lengyel G (2012) Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Curr Pharm Biotechnol 13:210–217CrossRefGoogle Scholar
  9. Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, Neher JJ, Fåk F, Jucker M, Lasser T, Bolmont T (2017) Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep 7:41802CrossRefGoogle Scholar
  10. Jiang HH, Yan FS, Shen L, Ji HF (2016) Silymarin versus silibinin: differential antioxidant and neuroprotective effects against H2O2-induced oxidative stress in PC12 cells. Nat Prod Commun 11:633–636Google Scholar
  11. Jiang C, Li G, Huang P, Liu Z, Zhao B (2017) The gut microbiota and Alzheimer’s disease. J Alzheimer’s Dis 58:1–15CrossRefGoogle Scholar
  12. Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M (2012) KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res 40:109–114CrossRefGoogle Scholar
  13. Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, Nielsen J, Bäckhed F (2013) Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498:99–103CrossRefGoogle Scholar
  14. Kvasnicka F, Bíba B, Sevcík R, Voldrich M, Krátká J (2003) Analysis of the active components of silymarin. J Chromatogr A 990:239–245CrossRefGoogle Scholar
  15. Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, Clemente JC, Burkepile DE, Vega Thurber RL, Knight R, Beiko RG, Huttenhower C (2013) Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 31:814–821CrossRefGoogle Scholar
  16. Lorenz D, Lücker PW, Mennicke WH, Wetzelsberger N (1984) Pharmacokinetic studies with silymarin in human serum and bile. Method Find Exp Clin 6:655–661Google Scholar
  17. Lu P, Mamiya T, Lu LL, Mouri A, Niwa M, Hiramatsu M, Zou LB, Nagai T, Ikejima T, Nabeshima T (2009a) Silibinin attenuates amyloid beta(25-35) peptide-induced memory impairments: implication of inducible nitric-oxide synthase and tumor necrosis factor-alpha in mice. J Pharmacol Exp Ther 331:319–326CrossRefGoogle Scholar
  18. Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T, Hiramatsu M, Ikejima T, Nabeshima T (2009b) Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol 157:1270–1277CrossRefGoogle Scholar
  19. Luper S (1998) A review of plants used in the treatment of liver diseases: part 1. Altern Med Rev 3:410–421Google Scholar
  20. Lynch SV, Pedersen O (2016) The human intestinal microbiome in health and disease. N Engl J Med 375:2369–2379CrossRefGoogle Scholar
  21. Marques FZ, Mackay CR, Kaye DM (2018) Beyond gut feelings: how the gut microbiota regulates blood pressure. Nat Rev Cardiol 15:20–32CrossRefGoogle Scholar
  22. Parks DH, Tyson GW, Hugenholtz P, Beiko RG (2014) STAMP: statistical analysis of taxonomic and functional profiles. Bioinformatics 30:3123–3124CrossRefGoogle Scholar
  23. Poppe L, Petersen M (2016) Variation in the flavonolignan composition of fruits from different Silybum marianum chemotypes and suspension cultures derived therefrom. Phytochemistry 131:68–75CrossRefGoogle Scholar
  24. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344CrossRefGoogle Scholar
  25. Shen L, Ji HF (2016) Intestinal microbiota and metabolic diseases: pharmacological implications. Trends Pharmacol Sci 37:169–171CrossRefGoogle Scholar
  26. Shen L, Liu L, Ji HF (2017) Alzheimer’s disease histological and behavioral manifestations in transgenic mice correlate with specific gut microbiome state. J Alzheimer’s Dis. 56:385–390CrossRefGoogle Scholar
  27. Williamson EM (2011) Synergy and other interactions in phytomedicines. Phytomedicine 8:401–409CrossRefGoogle Scholar
  28. World Alzheimer Report (2015) Available online:
  29. Wu JW, Lin LC, Hung SC, Chi CW, Tsai TH (2007) Analysis of silibinin in rat plasma and bile for hepatobiliary excretion and oral bioavailability application. J Pharm Biomed Anal 45:635–641CrossRefGoogle Scholar
  30. Zhang L, Wang Y, Xiayu X, Shi C, Chen W, Song N, Fu X, Zhou R, Xu YF, Huang L, Zhu H, Han Y, Qin C (2017) Altered gut microbiota in a mouse model of Alzheimer’s disease. J Alzheimer’s Dis 60:1241–1257CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Liang Shen
    • 1
    • 2
  • Lu Liu
    • 1
    • 2
  • Xin-Yu Li
    • 1
    • 2
  • Hong-Fang Ji
    • 1
    • 2
    Email author
  1. 1.Institute of Biomedical ResearchShandong University of TechnologyZiboPeople’s Republic of China
  2. 2.Zibo Key Laboratory of New Drug Development of Neurodegenerative Diseases, Shandong Provincial Research Center for Bioinformatic Engineering and Technique, School of Life SciencesShandong University of TechnologyZiboPeople’s Republic of China

Personalised recommendations