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The Microbiome in Drug Discovery: Metabolic Disease

In the Age of the Microbiome blog post which initiated this series we introduced the spectacular potential that the microbiome offers for drug discovery. Over the remainder of this series we will look more closely at the role of the microbiome in each of the three areas that drug discoverers primarily target: Metabolic disease, Inflammatory disease and Cancer. Again, Dr Andrew Johnson of the University of California gave us his thoughts on the potential for drug discovery in this exciting research area.

Metabolic disease encompasses various conditions where the body’s fundamental physiology is compromised, such as obesity. Obesity is particularly dangerous because it can act as a potent risk factor predisposing the individual to multiple other diseases, such as diabetes and cardiovascular disease. Indeed, so strong is the link between diabetes and obesity (>80% of diabetics are considered to be overweight or obese) that they are often referred to as “twin” epidemics and now form the fastest growing health risk in the western world. The observation that obese mice and people have notable changes in the bacteria living in their gut was amongst the first few sparks of microbiome research which ignited the field.1 At the time this involved the pioneering development of high-throughput DNA sequencing tools to profile the microbial community based on variation within the 16s rRNA gene and the development of bioinformatics tools to analyze this “big” data. Now, however, next generation sequencing and bioinformatics analysis are readily available, and can be applied specifically to the microbiome.

Using a system where the microbiome from different humans is transferred into recipient mice, researchers have been able to show that the microbiome can contribute to the development of obesity,2 and also to the weight loss observed after procedures such as gastric bypass.3 However, the precise mechanisms by which the microbiome does this remains unclear. One thing that we do know is that the microbiome generates numerous bioactive metabolites, such as short chain fatty acids or bile acid derivatives, which then enter our bodies and potentially change the behavior of target tissues. It is these bioactive molecules which hold the real potential as novel drug targets to treat metabolic disease. The process of uncovering these molecules falls under the heading “metabolomics” where biological samples are screened for both known and unknown molecules of interest. Metabolomics is a highly specialized science in its own right and is commonly contracted out to metabolomics experts. The applications of both microbiomics and metabolomics is in its infancy, but has already been successfully utilized in mice to show how a bioactive product, called 4-EPS, produced by an altered microbiome can cause a behavioral change similar to that observed in autism.4 The challenge is now on to utilize the great power of these two technologies to make the leap from showing how the microbiome can cause metabolic disease to helping us prevent metabolic disease. In our next blog post of “The Microbiome in Drug Discovery” series we will be looking at Inflammatory Disease, a group of conditions which everyone reading this is likely to have contact with in their lifetime.

  1. Ley, Ruth, Turnbaugh, P.J., et al (2006), “Microbial Ecology: Human Gut Microbes Associated With Obesity”, Nature 444: 1022-1023.
  2. Ridaura et al., (2013) “Gut Microbiota From Twins Discordant For Obesity Modulate Metabolism In Mice”, Science 341 (6150):1241214
  3. Liou, Alice, P., Paziuk, Melissa, et al., (2013) “Conserved Shifts in the Gut Microbiota Due to Gastric Bypass Reduce Host Weight and Adiposity”, Science Translational Medicine, 5 (178):178ra41
  4. Hsiao, Elaine Y., Sara W. McBride, et al. (2013). “Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders.” Cell 155 (7): 1451-1463.