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Statins Talk 2009

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  • 1. Investigation of the effects of Simvastatin and other statin drugs on gut Microbiome with regards to clinical obesity
    • Rhonda Garza
    • Akrum Dhaifullah
    • Biochemistry Department
    • Supervisors
    • Dr. Robert Akins, PhD
    • Dr. Jack Sobel, MD (ID DMC)
  • 2. Outline
    • Introduction
    • Hypothesis
    • Methods
    • Results
    • Conclusion
  • 3.
    • Serum cholesterol-lowering statins act by competitive inhibition of the rate-limiting enzyme in cholesterol biosynthesis, hydroxymethylglutaryl-CoA (HMG-CoA) reductase.
    • Hydroxymethylglutaryl-CoA (HMG-CoA) reductase is essential in prokaryotes for biosynthesis of isoprenes, not sterols.
    • Central questions. The main issue to be addressed by this project is to what extent statins inhibit growth of bacteria in vitro.
    Investigation of the effects of Simvastatin and other statin drugs on gut Microbiome with regards to clinical obesity
  • 4. Investigation of the effects of Simvastatin and other statin drugs on gut Microbiome with regards to clinical obesity
    • The human gut is dominated by species in the Fimicutes and Bacteroides phyla.
    • Several studies indicate that the balance of these two groups is surprisingly important in obesity. Obese individuals who enroll in diets and successfully reduce body fat progress from Fimicute dominant to Bacteroides dominate gut species.
    • Obese mice that have disruptions in the obesity gene (ob/ob) show Fimicutes-dominant gut microbiota compared to Bacteroides rich populations in lean mice
  • 5. Hypothesis
    • My hypothesis is that a subset of six commercially used statins will selectively inhibit gut-associated bacteria in the Fimicutes phylum, predominantly Clostridium species.
    • In order to maintain this balance, obese individuals may benefit from specific statins in assisting or maintaining weight loss.
    • The study will have an impact on the choice of statins, if some prove to be superior in bacterial management but equally effective in lowering serum cholesterol.
  • 6. Methods
    • Enterobacteria associated with sepsis, were obtained from a variety of sources and their species was verified by sequencing of their 16S rDNA genes.
    • Statins: Lovastatin, Zocor, Fluvastatin, were dissolved from tablets at 10 mg active ingredient per ml of 15% ethanol, 0.25% NaOH and activated by heating at 60°C for 2 hours. Lipitor and Crestor were dissolved at 10 mg/ml in DMSO, Lovastatin l at 10 mg/ml in ethanol.
  • 7. Results
    • Individual statins varied in the range of species affected
    • Lovastatin, Lipitor, and Zocor all inhibited B. subtilis , none inhibited E. coli , Lipitor and Zocor inhibited P. mirabilis , and only Zocor inhibited S. epidermidis .
    • Effective statins inhibited B. subtilis at 10  g/ml. Fluvastatin inhibited MRSA and MSSA strains of S. aureus , but was not effective against E. coli, K. pneumoniae, E. aerogenes, or S. marcescens
  • 8. R s R S S Fimicute Clostridium sordellii See Fig. 3 and comments. R: Resistant, little or no zone of inhibition; S: susceptible, clear zone of inhibition; s: slightly susceptible, hazy zone of inhibtion S S S S S Fungi Candida albicans R R R R R Enterobacteria E. aerogenes R R R R R Enterobacteria S. marcescens R R s R R Enterobacteria K. pneumoniae R R s s s Fimicute S. epidemidis R R S S S Enterobacteria E. coli R R S S S Fimicute S. aureus (MRSA&MSSA) s S S S S Enterobacteria P. mirabilis R S S S S Fimicute B. subtilis Crestor Lovastatin Lipitor Fluvastatin Zocor Taxonomic group Species Table 1. Variable susceptibilities of bacterial species to individual statins by agar-based assay
  • 9. Bacillus subtilis Zocor Lovastatin Lovastatin (1:10) Zocor (1:10) Fluvastatin Fluvastatin (1:10)
  • 10. Clostridium sordellii Zocor Lovastatin Lovastatin (1:10) Zocor (1:10) Fluvastatin Fluvastatin (1:10)
  • 11. Clostridium sordellii Crestor DMSO Act.Buffer Crestor (1:10) Lipitor Lipitor (1:10)
  • 12.  
  • 13. Future Experiments
    • An in vivo approach was started that will investigate fecal DNA from a donor who was treated with Simvastatin. Samples were taken pre-treatment, during treatment and post-treatment respectively. The GI flora was expected to shift from Fimicutes and Bacteroides flora to Bacteroides-dominant gut microbiota. This is being determined with successful Q-PCR testing. The effectiveness of Simvastain relative to other anti-obesity drugs is currently unclear and will be pursued in future experiments.
  • 14. Conclusion
    • The subset of six commercially used statins did selectively inhibit gut-associated bacteria in the Fimicutes phylum, predominantly Clostridium species.
    • The in vivo approach is suggesting that there is a shift in gut microbiota with the treatment of Simvastatin.
    • A epidemiological study will further enhance the expectation of statins as a drug that targets the Fimicute population in obese patients.