The Microbiome in Drug Discovery: Inflammatory Disease
Having introduced the age of the microbiome in drug discovery and the microbiome in metabolic disease we now turn to the influence of the microbiome in inflammation. Dr. Andrew Johnson of the University of California again gave us his thoughts on this emergent therapeutic area.
There is little need for an introduction into the scale of the problem which inflammatory disease has become as most people reading this will know one or more person suffering from inflammatory bowel disease (IBD), arthritis, asthma, multiple sclerosis… the list goes on and on. Over the past decade or so a series of remarkable experiments in animal models showed that across the board the diseases were less severe or indeed did not develop at all, if the microbiome was absent (e.g. in germ-free mice) or depleted using antibiotics. So the microbiome was shown to be a driver of inflammatory disease.1 Indeed, for IBD antibiotics are also effective in a sizeable proportion of patients and, just like for metabolic disease, changes in the microbiome associate with inflammatory diseases in humans.1 Thus began the search for ways to deplete the microbiome to treat these inflammatory diseases. This has so far focused on using antibiotics to broadly kill groups of bacteria, or using viruses, known as bacteriophage, to target bacteria more specifically.
Ah, but things are never that simple! For, whilst the microbiome overall does drive inflammatory disease, it turns out not all bacteria are created equal. Some bacteria seem to drive more inflammation, but conversely others seem to drive less. In particular some may promote a “regulatory response” whereby by inflammation is actually dampened.2 Thus the search is also on for ways to target the microbiome to boost these anti-inflammatory responses. The ideas so far focus on probiotics (giving live “good” bacteria or bacteria engineered to be “good”), prebiotics (giving particular foods which support growth of “good” bacteria) or synbiotics (a combination of the above). Alternatively, if we can find particular molecules that the bacteria use to influence inflammation perhaps we can use these as targets instead (see the microbiome in metabolic disease for how we might use metabolomics to do this). Indeed, two promising candidates, a sugar called polysaccharide A3 produced by a human microbiome member and a short-chain fatty acid called butyrate4 both seem to enhance regulatory responses in IBD models.
With different components of the microbiome seemingly able to do radically different things in the context of inflammatory disease it has become really important for researchers to precisely know the components of the microbiome in their experiments. Only with this knowledge can we hope to identify key bacteria which might drive disease and others which might be able to prevent it. Fortunately dedicated microbiome service providers have sprung up able to do this for you in a very affordable manner. Then it becomes a challenge for drug discoverers to balance the “good” and the “bad” in the microbiome to keep us all healthy. In the final blog post of this series we will look at the last major therapeutic area targeted by drug discovers: Cancer.
- R. Blumberg, Powrie, F, (2012) “Microbiota, Disease, and Back to Health: A Metastable Journey”, Science Translational Medicine,vol. 4: p137rv7
- W. Strober, (2013), “Impact of the gut microbiome on mucosal inflammation”, Trends In Immunology, 34: pp423-430.
- Mazmanian, SK et al (2008), “A Microbial Symbiosis Factor Prevents Instestinal Inflammatory Disease”, Nature, 452: pp620-625
- Smith, P et al (2013), “The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic TregCell Homeostasis”, Science, 341: pp569-573