What’s in your gut, analyzing your gut microbiome

The gut microbiome [the totality of microbes, their genetic elements (genomes), and environmental interactions in a defined environment.] has been a huge blind spot in human health and longevity. We firmly believe that achieving the optimal microbial balance will extend life. But first, we need to  understand better what constitutes a healthy gut. The first step is to be able to analyze the gut microbes. That a tall order – 10 trillion or so microbes must be analyzed!

Our next featured expert on the special Thursday night (Jan. 17) teleconference will be Dr. Rob Knight. He will have a lot to say about that. Just look at the far-reaching introduction to his lab:

Genomics, molecular evolution and the microbiome

“Advances in high-throughput sequencing and in computational techniques allow us to address large-scale questions about evolution that have never before been accessible. Our research combines computational and experimental techniques to ask questions about the evolution of the composition of biomolecules, genomes, and communities.

Community composition and the Human Microbiome: We are developing new methods to test factors that make environments more or less similar in terms of the phylogenetic [of or relating to the evolutionary development of organisms] diversity of the organisms they contain. For example, in hot springs in Yellowstone, the driving factors might be temperature, pH, hydrogen sulfide, or any of a number of other physical and chemical factors. In our own human bodies, the microbial symbionts we carry with us outnumber our so-called human cells by as much as an order of magnitude, and these microbial communities have profound implications for health and disease. The Human Microbiome Project [1] seeks to understand these communities.

We recently developed UniFrac [2], a clustering metric that uses a phylogenetic tree to measure the biological distance between each pair of environments represented in the tree. We can then use clustering methods, such as hierarchical clustering, and ordination methods, such as PCA [Principal component analysis], to identify environments that are more similar or different, and to correlate these differences with physical and biological properties of the environment.

We found that microbial diversity in the mouse gut is primarily inherited by parent-offspring contact, but that the relative abundance of different taxa [taxonomic groups of any rank, such as a species, family, or class]  depends on the host genotype [the genetic makeup of the organism with reference to a single trait, set of traits, or an entire complex
of traits] [3].
UniFrac allows all the information in a phylogeny to be brought to bear
on the clustering problem, allowing new insights into the factors that
govern community assembly.

For example, we have used UniFrac to discover

  • that salinity is the main driving factor in a broad range of distinct physical habitats [4],
  • that mammalian gut communities cluster primarily by diet [5],
  • that the gut is a much more distinct habitat from different physical habitats than they are from each other (e.g. the difference between the gut and the mouth communities can be larger than the differences in the communities living in a hot spring and on an ice cap).

We expect UniFrac to have a wide impact in a range of environmental and medical applications.

A key advance we have made is barcoded pyrosequencing [a technique used to sequence {determine the order of nucleotides in DNA} DNA using chemiluminescent enzymatic reactions.] [6-7], especially the use of formal error-correcting codes to allow us to use 454 pyrosequencing to simultaneously study hundreds of microbial communities. Barcoded pyrosequencing opens up whole new vistas of unexplored microbial diversity. For example, we have used this technology to study water quality and samples from cystic fibrosis patients’ lungs [6], to show that, if you’re typical of our study population, your left and right hand probably share only about 18% of their species [8], and that systematic shifts in the gut community occur with obesity [9].

Remarkably, this latter paper shows that radically different species assemblages can maintain a core at the level of gene functions, paralleling trends in macroecology where e.g. grasslands on different continents may share none of their species but may look extremely similar in physical and chemical conditions when compared to, e.g., rainforests. We have also been exploring the biogeography of the human body [10].”

Read more about Dr. Knight’s lab.

The American Gut Health Project

We strongly recommend that you sign up for the American Gut Health project – a first step towards analyzing your gut microbiome. Analyzing the gut microbiome will be a foundational assessment in the new DNA Healthy Aging and Calorie Restriction (DNA HACR) project that we will soon launch. Getting your gut microbiome analyzed now will give you a head start. You can sign up for the American Gut Health project until February 2, and then it will be closed to new entries.We signed up last week.

 

References from Dr. Knight’s Lab

[1] Turnbaugh, P.J, Hamady, M., Ley, R., Fraser, C., Knight, R., and Gordon, J.I. (2007) “The human microbiome project: exploring the microbial side of ourselves“. Nature 449:804.

[2] Lozupone, C.A. and Knight, R. (2005). “Unifrac: A New Phylogenetic Method For Comparing Microbial Communities.” Appl Envrionm Microbiol 71:8228-35.

[3] Ley, R.E., Backhed, F., Turnbaugh, P., Lozupone, C.A., Knight, R.D., and Gordon, J.I. (2005) “Obesity alters gut microbial ecology.” Proceedings of the National Academy of Sciences. 102:11070-11075.

[4] Lozupone, C.A., and Knight, R. (2007) “Global patterns in bacterial diversity.” PNAS 104:11436-40.

[5] Ley, R.E., Hamady, M., Lozupone, C., Turnbaugh, P.J., Ramey, R.R., Bircher, J.S., Schlegel, M.L., Tucker, T.A., Schrenzel, M.D., Knight, R., and Gordon, J.I. (2008) “Evolution of Mammals and their Gut Microbes.” Science 320:1647-51.

[6] Hamady, M., Walker, J.J., Harris, J.K., Gold, N., and Knight, R. (2008) “Error-correcting barcoded primers for pyrosequencing hundreds of samples in multiplex“. Nature Methods 5:235-7.

[7] McKenna, P., Hoffman, C., Aye, P.P., Lackner. A., Liu, Z., Lozupone, C.A., Hamady, M., Knight, R., and Bushman, F.D. (2008) “The Macaque Gut Microbiome in Health, Lentiviral Infection and Inflammatory Bowel Disease.” PLoS Pathogens 4:e20

[8] Fierer, N., Hamady, M., Lauber, C., and Knight, R. (2008) “The influence of sex, handedness, and washing on the diversity of hand surface bacteria.” PNAS 105:17994

[9] Turnbaugh, P.J., Hamady, M., Yatsunenko, T., Cantarel, B.L., Duncan, A., Ley, R.E., Sogin, M.L., Jones, W.J., Roe, B.A., Affourtit, J.P., Egholm, M., Henrissat, B., Heath, A.C., Knight, R., and Gordon, J.I. (2009) “A core gut microbiome in obese and lean twins.” Nature 457:480-4.

[10] Lozupone, C.A., Hamady, M., Cantarel, B.L., Coutinho, P.M., Henrissat, B., Gordon, J.I., and Knight, R. (2008). “The convergence of carbohydrate active gene repertoires in human gut microbes.” PNAS 105:15076.

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