Pharma R&D Today
Ideas and Insight supporting all stages of Drug Discovery & Development
Venturing into the Microbiome
Posted on September 28th, 2016 by Jeffrey Paul, PhD in Pharma R&D
The growing library of bacterial genomic material and microorganisms that reside within the human host is termed the microbiome. Microbiota, a less-used term, refers to the community of single cell organisms (i.e. bacteria, fungi, virus, etc.) that inhabit us, the superhost human organism. Prior to genomic sequencing, bacterial identification occurred by laboratory isolation and culturing. There are about 10 times as many microorganisms that inhabit the human host as there are human cells, and now there is exciting new research that regards the inhabiting bacteria as shaping our physiology and response to disease and drugs.
Research sponsored by the Human Microbiome Project (Ref 1) and International Human Microbiome Consortium (Ref 2) is focusing on regional microbiological differences in the various sections of the GI, skin and respiratory/nasal and their relationship to health and disease. Once the bacteria are profiled, the next steps are to fully understand how the community changes with age, diet, disease, immunity, etc. Transcriptomics, proteomics and metabolomics are used to characterize the biological activity and to understand how the microbiome responds to a change in diet or presence of disease. The microbiome may respond with a shift in organisms and/or metabolic activity.
Diet has an important role in maintaining a healthy microbiome, which, again, is neither dormant nor transient. The microbial community in the gut participates in providing essential nutrients, vitamins, immunity for the host and resistance to pathogens. An unhealthy shift of the microbiome is termed dysbiosis and research is finding strong connections to inflammatory bowel disease, diabetes, obesity and other inflammatory-related diseases. A change in diet from a low-fat, vegetable-based diet to a Western, high-fat, high-sugar, high-processed diet has a profound effect on the microbiome and its metabolic activity. Any interindividual differences in our GI flora are masked by the larger effect of diet. The core community of bacteria does not change as much with diet as its metabolic machinery and metabolomic profiles. We are learning that these shifts in metabolism can have a profound influence on health and disease.
Take, for example, the production of short-chained fatty acids (SCFA) by gut bacteria, which is the end product of bacteria breaking down complex carbohydrates. Judith Pluznick (Johns Hopkins University) has found that circulating SCFAs act on the renal afferent vasculature, controlling renin release, thereby influencing blood pressure. Therefore, gut bacteria, modulated by diet, provides a direct link to the kidneys and blood pressure.
Another example: Ted Dinan (University College, Cork) has been reporting on the secretion of the neurotransmitters, serotonin and GABA, by gut bacteria. It is possible that gut bacteria, influenced by diet, can affect mood, such as anxiety, but the connection between brain and gut is not totally understood. He believes that the treatment of certain mood disorders and perhaps some developmental syndromes (i.e. autism) could be treated with certain bacteria. Psychobiotics refers to treating stress disorders by prescribing specific probiotic preparations. The organization MyNewGut (Ref 3) has a focus in better understanding the brain/gut communication via the microbiome.
Inflammatory Bowel Disease (IBD) and microbiome has received much recent attention. Sequencing studies of the genomic sequences collected at various regions of the IBD GI shows dysbiosis and may be critical in the disease pathophysiology and immunity. Furthermore, correcting dysbiosis may provide a future therapeutic opportunity, an intervention directed to modulating the connection between colorectal cancer, IBD and immunity. Perhaps it’s possible to change the relationship or outcome of IBD and colorectal cancer by the microbiome?
The microbiome also affects the host’s response to drugs. For years it has been known that gut bacteria play a role in the toxicity of xenobiotics, primarily by affecting its biotransformation and elimination. Employing the metabolomic platform, Rima Kaddurah-Daouk (Duke University) has termed a new field, pharmacometabolomics, by profiling the metabolic activity of the individual and their microbiome after drug administration. This profile, termed “metabotype”, is the result of environment, genes and the gut microbiome. Her research has shown the influence of gut microflora on the metabotype of various drugs across many disease areas, including acetaminophen, simvastatin, antidepressants, anti-psychotics and irinotecan, to name a few.
The use of prebiotics and probiotics by consumers as dietary supplements is growing. At a recent annual meeting of the American Society of Nutrition, a professor explained to me that a new direction in research is to personalize probiotics, not to just supplement your diet with the usual mix of bacteria. The idea is to provide a precise and personal probiotic regimen that would be a custom fit for your gut. So, just as your prescription drug and dose may be personalized based on your specific needs, so too will your probiotic.
Future research in microbiome will require spanning many disciplines: therapeutic disease specialists, microbiologists, GI biologists and bioinformatics in order to fully understand how the microbiome provides for health, causes disease and is used to optimize therapy.
Ref 3: http://www.mynewgut.eu
All opinions shared in this post are the author’s own.
R&D Solutions for Pharma & Life SciencesWe're happy to discuss your needs and show you how Elsevier's Solution can help.
Jeffrey Paul, PhD
Principal at JPharm Consulting
- Assessing the State of the Genomic Revolution
- Clean food, gut bacteria, and drug effects: Is diet another variable drug development?
- A Bright Future for Bacteria
- Can your Microbiome Make you Fat?