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Metagenomic-wide association study of gut microbiota in type 2 diabetes

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Type 2 diabetes (T2D)

This is a complex disease that has both an environmental and genetic component. It plauges the American society who don't eat healthy and exercise whom may already have a predisposition to the disease. This is a disease that can be combated with medications and diet and exercise requirements but it remains with no cure. A link to the National Institute's of health page that gives more information on T2D is here

Microbiomibsnormal

Previous Studies

Previous research has found an association between the compsition of the microbiome and an increased risk of various diseases. For example, Turnbaugh et al (2009), Ley et al (2005) and Zhang et al. (2009) all showed that obesity was associated with an increase in the Firmicutes and a decrease in Bacteriodetes. There has been research on Crohn's disease that shows a significant decrease in the microbiota diversity of those with Crohn's (Manichanh et al., 2006). The research leading up to this article includes a study showing the proportion of Firmicutes and Clostridia were significantly reduced in T2D patients but little was known about the genomes of these microbes and how all of them working together achieve a balanced and healthy state within the gut. It would be helpful to be able to tell if someone is predisposed to T2D or other diseases by simply understanding the composition and diversity of their specific gut.


Methods of the metagenome-wide association study

A total of 345 Chinese T2D and control patients' stool samples were used to deep next generation shotgun sequence the gut metagenome. The researchers were able to identify components of the genomes of the microbes in various individuals to see the functional relationships between microbiomes from T2D patients and control individuals.

The first step of analyzing the next gen data was to create a reference metagenome. This sequencing the metagenome of 145 Chinese individuals and de novo assembling each and then comparing the 145 metagenomes to each other to create a consensus. This involved dealing with 3.3 million genes. After the metagenome reference was created, they annotated the updated gene catalogue (MetaHIT).

Informative Nature article

The next step was to identify metagenomic assosciation markers for T2D metagenomes using a two-stage MGWAS. During the first stage, a quatification of the gut microbiota was done that allowed the researchers to identify which major groups of microbes were present. A principal components analysis showed that Bacteriodes, Prevotella, Bifidobacterium and Ruminococcus were the most highly abundant in the gut but showed no association with the T2D disease. After correcting for population stratification, and analyzing using the EIGENSTRAT method the researchers did find an association between the genes being true T2D-associated gut microbial genes.

In part II of their MGWAS an additional 200 Chinese individuals were used to validate the part I results.


Metagenomics Linkage Group

Qin et al. 2012 define the MLG as "a group of genetic material in a metagenome that is probably physically linked as a unit rather than being independently distributed." This concept arises out of the fact that bacteria often undergoe lateral gene transfer (LGT) which allows the microbiome to act essentally as one massive genome through the sharing of genes via LGT. These MLG will give valuable information on the contents of the microbes in the gut even when nothing is known about the species. This will also give researchers important taxonomic information about naming species based on sequence similarity to other known species. Being able to name species and know associations between species more present in T2D patients will give better assemsment of the patients predisposition to the disease.


A LINK TO THE HUMAN MICROBIOME PROJECT for more information on current research in microbiome genomics. The below figure demonstrates the three main subgroups found in the microbiome. The circles represent control individuals and the triangles represent T2D individuals. This figure shows that there are more Bacteroides in T2D individuals loading in PC1 and PC2.

Screen shot 2012-11-28 at 6.10.25 PM


Results


Screen shot 2012-11-28 at 6.17.42 PM

-47 MLGs in the T2D gene markers were found

-A co occurence nework of MLGs was made to see the association between the T2D associated gut bacteria's genes.

Screen Shot 2012-11-17 at 1.05.18 PM

-Many of the T2D associated markers were commonly involved in membrane transport. This matched with previous data on IBS patients.

-Microbial dysbiosis was significant in T2D individuals

-Decrease in universal butyrate-producing bacteria that are involved in cell motility.

-Increase in opportunistic pathogens

-Increase in microbes with functions such as: sulphate reduction and oxidative stress resistance

-3.8% of the gut microbial genes were associated with an T2D individual. This table shows the unknown microbe genomes found and the punative identify based on % similarity in genes.







TO CLARIFY: The above figure is demonstrating the linkage groups associated the in control (non T2d) group that were elevated in comparison to the T2D group. On the right, those are linkage groups within the biome that are found significantly elevated in the T2D group (and thus found significantly lower in the control group).

TAKE HOME MESSAGE

The general conclusions of this study were that the microbiome (microbial composition of the gut) which is traditionally thought of as influenced by the environment is associated with and increased risk of T2D in a Chinese population (group sampled). This finding can lead to better diagnosis of predisposition of T2D before syptoms display and allow the individual to modify their lifestyle to try to cutail the effects of the disease. In addition, this study highlights in importance of the balance in the microbiome and how slight modifications to the balance can lead to diseases such as Crohn's, IBS and T2D.


Literature Cited

Qin et al. (2012) Nature. A metagenome-wide association study of gut microbiota in type 2 diabetes

A primer on metagenomics

Science Daily article on Qin et al. 2012 Nature publication

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