The Human Microbiome

The sequencing of the human genome was heralded as the key to understanding human health, promising to drive progress in research efforts aimed at understanding complex diseases and providing a path to the development of safe and effective therapies to treat these disorders.

Certainly, the successful completion of Human Genome Project will go down in the annals of history as one of the most important medical achievements of all time.  But our DNA, that which makes us uniquely who we are, is only part of how we get to be who we are.

Each of us is host to a great diversity of microbial fauna referred to collectively as the human microbiome.  These microorganisms can be found everywhere from the tops of our heads to the bottom of our toes.  They colonize our skin, nose, lungs, urogenital tracts and, of course, our entire gastrointestinal (GI) system.  These organisms are quite numerous, approximating something like 100 trillion cells.  That’s about 10 microorganisms for every cell in the human body, with a composite mass of over half a kilogram!  While we have been aware of these cohabitants for some time, we have just recently come to realize that they play very important roles in human health and disease.

The interplay between the microorganisms that we host and the normal physiology of the sites they inhabit is quite complex.  For example, the bacterial populations in our lower GI tracts are important sources of vitamins (e.g., vitamin K) and assist with the breakdown of nutrients.  We are, however, just beginning to understand that the types and balance of specific strains of commensal bacteria can play a major role in disease induction.

Central to this discussion is an appreciation for the role of diet and diet induced obesity in this process.  When we are born, our GI tracts are free of bacteria.  Soon after birth, bacteria begin to colonize the gut so that we end up with about 100 species and 200 strains of bacteria.  The balance of these organisms can have profound effects on human health and disease. 
 
We are now discovering that diets rich in various nutrients can alter the balance of the gut microflora, with significant implications.  For example, feeding mice a diet rich in milk fat increases a strain of bacteria called bilophila, or bile-loving.  The milk fat feeding causes an increase in the production of a bile salt called taurocholate.  The bilophila happen to love taurocholate.  These organisms have been isolated from a number of disease states, but most importantly, seem to play a role in colitis and Crohn’s disease. ¹

Another example of obesity-induced changes in gut bacteria relate to obesity-associated liver cancer.  A recent study by the Japanese Foundation for Cancer Research² has defined a link between obesity, changes in the intestinal microflora, and the increased production of deoxycholate, another bile salt.  Deoxycholate is transported to certain liver cells where it seems to induce senescence of those cells, resulting in the release of inflammatory mediators that can promote malignant transformation.

In yet another study³, researchers at the Cleveland Clinic have demonstrated that people who consume diets rich in meat harbor a species of bacteria that can transform carnitine into trimethylamine-N-oxide; a chemical that has been shown to produce atherosclerosis in animals.

This area of research has garnered so much attention that the NIH is sponsoring an initiative called the Human Microbiome Project, with a stated goal of understanding the relationships between our microbiota and human physiology and disease.  For those interested in understanding a bit more about her or his particular microbiota, the American Gut Project will sequence the organisms that reside in and on your body for a paltry fee of $99 and present you with a distribution map of your cohabitants as compared to the population at large!

These findings are just some examples of the importance of comprehending the contribution of the microbiome in health and disease.  The continuous monitoring of the Charles River vivarium conditions and the sentinel animal program help to define the commensal gut flora of our SPF animals.  Serology and microbiology testing by Charles River’s Research Animal Diagnostic Services group, the largest laboratory of its kind in the world, provides testing services for investigators across the globe for the purposes of conducting research animal health surveillance, and environmental monitoring of water, feed, bedding and surfaces for sources of contamination.  Finally, the Discovery Research Services group is mindful of the impact that the changing microbiome has on pathophysiology and is examining the impact of a consistent gut flora on various disease models.
 

References

1. Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB.  Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice.  Nature. 2012 Jul 5;487(7405):104-8. doi: 10.1038/nature11225.
2. Shin Yoshimoto, Tze Mun Loo, Koji Atarashi, Hiroaki Kanda, Seidai Sato, Seiichi Oyadomari, Yoichiro Iwakura, Kenshiro Oshima, Hidetoshi Morita, Masahisa Hattori, Kenyaonda,Yuichi Ishikawa, Eiji Hara & Naoko Ohtani.  Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.  Nature 499, 97–101 (04 July 2013) doi:10.1038/nature12347.
3. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL.  Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.  Nat Med. 2013 May;19(5):576-85. doi: 10.1038/nm.3145.

Joe Cornicelli, Ph.D., F.A.H.A., is the Director of Inflammation and Cardiovascular Pharmacology Services for Charles River, and has over 22 years of experience in drug discovery and development. Trained at the University of Cincinnati, Dr. Cornicelli completed post-doctoral fellowships at the Mayo Clinic Foundation and Columbia University, where he was part of the research faculty in the Department of Medicine. He joined Warner-Lambert in 1985 where he served as a Research Fellow in the inflammation and cardiovascular therapeutic areas. In 2007, Dr. Cornicelli joined MIR Preclinical Services at Charles River where he is responsible for directing discovery efforts for the assessment of potential therapeutics for inflammatory and cardiovascular disorders. Dr. Cornicelli is a Fellow of the American Heart Association.