Genome Of A Major Member Of Gut Bacteria Sequenced; Clues To Beneficial Relationships Between Humans And Microorganisms

"Now that the draft sequence of the human genome is complete, it's critical that we study the environmental forces that regulate our gene expression," says principal investigator Jeffrey I. Gordon, M.D., the Dr. Robert J. Glaser Distinguished University Professor and head of the Department of Molecular Biology and Pharmacology. "Humans enjoy mutually beneficial relationships with billions of bacteria that live in our gut. Discovering how these microbes manipulate our biology to benefit themselves and us should provide new insights about the foundations of our health and new therapeutic strategies for preventing or treating various diseases."

According to Gordon, in order to develop a comprehensive view of humans as a lifeform, we need to consider the fact that the human body is home to diverse communities of microorganisms from birth to death. It is estimated that adults are composed of 10 times more microbial cells than human cells.

The intestine harbors our largest collection of microbes. Although the true extent of biodiversity is not known, it appears that the gut contains at least 1,000 different species of bacteria, and that their collective genomes ('the microbiome') contains 100-fold more genes than the human genome. These bacteria provide certain metabolic capabilities that humans lack, including the ability to process nutrients that human genes cannot break down.

Gordon's team analyzed Bacteroides thetaiotaomicron as a representative of this microbial community because it is such a prominent member.

"This bacterium becomes prominent beginning at a key developmental transition that takes place when infants are weaned from their mother's milk and begin eating a diet rich in polysaccharides," Gordon says.

By decoding the bacterium's genome, he and his students, including Jian Xu and Magnus Bjursell, members of the Biochemistry and Computational Biology Programs in the Division of Biology and Biomedical Sciences, identified some of the strategies it employs to forge a beneficial alliance with its host.

For example, over 100 of its 4,800 genes appear to be dedicated to retrieving dietary polysaccharides from the intestinal cavity. More than 170 enzymes are available to break down these key components of the human diet into simple sugars that can then be fermented and absorbed.

The team also discovered that Bacteroides thetaiotaomicron contains a very elaborate and novel apparatus for sensing its environment so that the correct combination of enzymes that grab and degrade carbohydrates can be expressed when nutrients are available. In addition, the organism has a rich repository of genes that allow it to manufacture carbohydrates on its own cell surface. By changing the features of this carbohydrate mask, the organism may be able to camouflage itself from the host's immune system.

The bacterium also appears to be well equipped to refashion its own genome over time. This capacity may be key to understanding the evolutionary processes that establish and sustain beneficial symbiotic relationships between bacteria and their hosts.

"By peering into ourselves and studying the genomes of our co-evolved bacterial partners, we have an opportunity to address fundamental questions about ecology and evolution and about determinants of our own physiology," Gordon offers. The gut microbiome represents one of the next frontiers to be explored. Not only does it have potential to help us more fully define the complete complement of genes associated with our bodies, but it also represents a fertile field to prospect for natural products that may become tomorrow's wonder drugs."

Xu J, Bjursell MK, Himrod J, Deng S, Carmichael LK, Chiang HC, Hooper LV, Gordon JI. A genomic view of the human-Bacteroides thetaiotaomicron symbiosis. Science, March 28, 2003.

Funding from NIH and AstraZeneca supported this research.