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Microbiome - I-Screen

Healthy Microbiome is Essential to Optimize Health
TNO develops better research tools that enable the development of Microbiome-Directed Health Products.
Application areas are,

iscreen

Microbiome

Determine microbiota composition in human subjects, and allow for accurate measurement and monitoring of microbiomes in various stages of scientific research to accelerate advancement and discovery. TNO has a wide range of available tools to increase understanding of the impact and interaction of the microbiome on human health. This is key to determining how various diseases change the body, and how various drugs can impact that change.

A movie is created to explain the Expertise and Analytical service, please click right to view

I-Screen; Technology and Application

iscreen TNO developed the I-screen platform for in vitro evaluation of drug metabolism through intestinal microbiota. Human gut microbiota are cultured anaerobically in a multi-well system to mimic the human intestinal in vivo metabolism. This allows for determining the potential of intestinal microbiota to metabolize drug candidates. The starting population of microbiota in the I-screen can be a standardized ex-vivo intestinal microbiota pool collected from either healthy volunteers, or for example obese, or lean adults or even children. This would confer the inherent differences found in each individual’s specific gut microflora. I-screen enables rapid identification of drugs that are susceptible to metabolism by intestinal microbiota. Additionally, it can be used to identify unknown metabolites transformed by intestinal microbiota. Normally, human metabolite profiling and identification data are generated during Phase II and/ or III of clinical trials. Human metabolites can thus be identified in preclinical stages, thereby de-risking and accelerating the drug development process. Each I-screen can be simultaneously exposed to a large number of different conditions, allowing for cost effective screening of interesting candidate drugs.

Example 1: Intestinal microbiota driven metabolism of Sulfasalazine
TNO has successfully applied the I-screen to demonstrate that Sulfasalazine in the I-screen system is metabolized as has been shown in vivo. Sulfasalazine is designed specifically to be metabolized by human intestinal microbiota to the 5-aminosalicylic acid that has therapeutic effect. However, clinical studies demonstrated that sulfasalazine is mainly metabolized to Sulfapyridine by the intestinal bacteria, which give rise to side-effects. In this example, microbiota from healthy adults were exposed to 100 μM sulfasalazine. Samples were taken after 0 and 24 hrs. and were analyzed by HPLC.

Example 2: Intestinal microbiota driven metabolism of Nizatidine, in collaboration with Pfizer Inc.
In a second example, TNO has successfully applied the i-screen in the investigation of Nizatidine, a pharmaceutical compound that is known to be metabolized by human intestinal microbiota. After the incubation period, the analysis of the samples was performed by Pfizer Inc. using high resolution mass spectrometry. The microbiota from healthy adults were exposed to 50 μM nizatidine and samples taken after 0, 6, 24 and 48 hrs, clearly demonstrated the metabolic capacity of gut microbiota.

Technolgies for Analysis
 Microbiome composition
  > 16S or metagenome
  > ITS Fungal composition
  > Anti-biotic resistance
  > Viability
 Microbiome Function
  > Transcriptome
  > Metabolome
    > SCFA analysis
    > Microbiome metabolites
    > Drug metabolites
  > Microscopy (fluorescence)
 Physiology of Host
  > Blood biomarkers
  > Metabolites
  > Host-microbiome
  > Interactions

Publication

Drug Metabolism and Disposition August 29, 2018,
An ex vivo fermentation screening platform to study drug metabolism by human gut microbiota

Evita van de Steeg, Frank H.J. Schuren, R. Scott Obach, Claire van Woudenbergh, Gregory S. Walker, Margreet Heerikhuisen, Irene H.G. Nooijen and Wouter H.J. Vaes

Pharmacol Res. 2012 Dec.
The human gastrointestinal microbiota--an unexplored frontier for pharmaceutical

Roeselers G, Bouwman J, Venema K,Montijn R.

Best Pract Res Clin Gastroenterol. 2013 Feb.
Ex vivo systems to study host-microbiota interactions in the gastrointestinal tract.

Roeselers G, Ponomarenko M, Lukovac S, Wortelboer HM

BMC Med Genomics. 2014 Jun 17
A systems biology approach to understand the pathophysiological mechanisms of cardiac pathological hypertrophy associated with rosiglitazone.

Verschuren L, Radonjic M, Wielinga PY, Kelder T, Kooistra T, van Ommen B, Kleemann R.

PLoS One. 2013
Differential effects of drug interventions and dietary lifestyle in developing type 2 diabetes and complications: a systems biology analysis in LDLr-/- mice.

Radonjic M, Wielinga PY, Wopereis S, Kelder T, Goelela VS, Verschuren L, Toet K, van Duyvenvoorde W, van der Werff van der Vat B, Stroeve JH, Cnubben N, Kooistra T, van Ommen B, Kleemann R.

Pharmacogenet Genomics. 2012 Dec;
Systems biology analysis unravels the complementary action of combined rosuvastatin and ezetimibe therapy

Verschuren L, Radonjic M, Wielinga PY, Kelder T, Kooistra T, van Ommen B, Kleemann R.

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