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Low-temperature electron micrograph of a cluster of E. coli bacteria, magnified 10,000 times. Each individual bacterium is oblong shaped. (Photo credit: Wikipedia)Type 2 diabetes is a serious global epidemic, having grown from 30 million cases to nearly 300 million over the past three decades. Although several recent studies have shown a link between type 2 diabetes and our gut bacteria, we’re still only at the dawn of learning about the microbiome. There’s a great deal we don’t yet know, including what kinds of bacteria live in our gut and how they go about making a living there. In a paper published in the September issue of Nature, a team of scientists from China and Denmark used whole genome sequencing technologies to overcome these gaps in our knowledge and get some more clues about the relationship between our gut bacteria and this disease.

To get around the fact that we still don’t know the identity of most of the bacteria in our gut, let alone know about their biology, the researchers sequenced the “metagenome” of the microbiome; they simply extracted as much DNA as they could and sequenced it all together without worrying about separating individual species. The metagenome was then analysed in a genome-wide association study (GWAS), a technique which uses statistics to identify genes that are linked with a particular trait, such as the gene responsible for blond hair in Melanesian populations. By using a GWAS to compare the microbial metagenome of people with and without type 2 diabetes, the researchers hoped they would be able to find genes linked with the disease without needing to know more about the composition of the microbiome. In order to conduct such a study, the scientists needed a reference metagenome for the microbiome.

The beginnings of a reference metagenome were available from MetaHIT, an EU-funded project to sequence the microorganisms found in the human intestinal tract. MetaHIT produced a catalog of the metagenome containing an incredible 3.3 million genes; by comparison, the human genome has roughly 21,000 genes, meaning that our gut bacteria encode about 150 times more genes than we do! The team used the MetaHIT catalog as a starting point but expanded it to include sequence results from Chinese volunteers. Since MetaHIT was built with data from individuals of European descent, the Chinese samples added over a million genes to the database; this is yet another demonstration of the diversity between populations and the importance of trying to capture and understand this diversity. Using this immense database as the basis for their GWAS, the team came up with a list of roughly 52,000 genes they were confident were associated with type 2 diabetes.

Most genomes, including our own, have far fewer than 52,000 genes. In an attempt to bring some order to this immense list, the team organized them into groups by using statistics to determine which genes were likely to be physically linked. Physically linked genes probably come from the same bacteria; by comparing these “linkage groups” with sequences from known bacteria, the team was able to connect some of them with species which have already been described. The microbiomes of the volunteers with type 2 diabetes had a different distribution of species than those of healthy individuals, with an increase in the amount of opportunistic harmful bacteria and fewer bacteria that produced butyrates, fatty acids that are an important food source for cells lining the colon. Fewer butyrate-producing bacteria are also found in patients with colorectal cancer, so it’s possible that these bacteria may play a protective role against several types of disease. The researchers used their findings to generate a list of 50 diagnostic markers for type 2 diabetes which could help to identify groups of people who may not have symptoms but nevertheless have a higher risk of progressing to clinically defined type 2 diabetes.

Of course, observing these changes in the microbiome doesn’t tell us whether they are the cause or consequence of diabetes. “The big question now is whether the changes in gut bacteria can affect the development of type 2 diabetes or whether the changes simply reflect that the person is suffering from type 2 diabetes,” said Professor Karsten Kristiansen of the University of Copenhagen. One way to resolve this would be to transplant gut bacteria from people with type 2 diabetes into mice to see if they develop diabetes, which is precisely what the researchers plan to do, according to Professor Oluf Pedersen of the University of Copenhagen. While this study is unlikely to lead to any immediate improvements in treatment for diabetics, it nevertheless makes important contributions to our basic understanding of this disease.

Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., Liang, S., Zhang, W., Guan, Y., Shen, D., Peng, Y., Zhang, D., Jie, Z., Wu, W., Qin, Y., Xue, W., Li, J., Han, L., Lu, D., Wu, P., Dai, Y., Sun, X., Li, Z., Tang, A., Zhong, S., Li, X., Chen, W., Xu, R., Wang, M., Feng, Q., Gong, M., Yu, J., Zhang, Y., Zhang, M., Hansen, T., Sanchez, G., Raes, J., Falony, G., Okuda, S., Almeida, M., LeChatelier, E., Renault, P., Pons, N., Batto, J., Zhang, Z., Chen, H., Yang, R., Zheng, W., Li, S., Yang, H., Wang, J., Ehrlich, S., Nielsen, R., Pedersen, O., Kristiansen, K., & Wang, J. (2012). A metagenome-wide association study of gut microbiota in type 2 diabetes Nature, 490 (7418), 55-60 DOI: 10.1038/nature11450

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