Gordon: Study's senior author
By Gila Reckess
February 23, 2001
A paper in the Feb. 2 issue of Science reports the use of new molecular technologies for unraveling the age-old mystery of the relationships between ourselves and the microbes that live in our body.
The study reveals that microorganisms in the gut influence the expression of a number of genes that are important to intestinal development and function.
Gordon: Study's senior author |
"We live in a world predominated by microbes," said Jeffrey I. Gordon, M.D. , who led the study. "These organisms have co-evolved with their mammalian hosts over millions of years. During this time, they have been forced to become master physiologic chemists --they have had to develop strategies for satisfying their own nutritional needs and various needs of their hosts. We wanted to figure out some of the lessons that they have learned about us and how they contribute to our health."
Gordon is the Alumni Professor and head of the Department of Molecular Biology and Pharmacology at the School of Medicine. The first author is Lora V. Hooper, Ph.D., instructor in molecular biology and pharmacology and recipient of a career development award from the Burroughs Wellcome Fund.
The human intestine contains the largest society of friendly microbes in the body. The total number of these microbes may be equal to the total number of cells in the human body. Given its large microbial society, the intestine is the best place to turn when trying to understand how friendly bacteria affect our genes.
These bacteria don't simply sit and wait to be fed by the nutrients we consume. Instead, they actively shape our biology so that they can establish and maintain homes for themselves.
The researchers addressed the general question of how microbes and humans co-exist using mice as a model system. After raising mice in a germ-free environment, they inoculated the animals with Bacteroides thetaiotaomicron, a bacterium normally found in healthy human and mouse intestines. Using two relatively new technologies --DNA microarrays and laser capture microdissection --they examined the bacterium's effect on intestinal functions.
DNA microarrays, or gene chips, are a direct product of the worldwide effort to identify all of the genes in our DNA and in the DNA of other species. These microarrays allow scientists to examine expression of many genes at once.
The team found that B. thetaiotaomicron affected genes involved in a number of critical gut functions. Entry of this microbe into the germ-free intestine activated several mouse genes involved in absorption and metabolism of sugars and fats.
It also activated genes that control the integrity of the cellular barrier that lines the intestine and separates us from dangerous organisms and ingested substances. Other genes affected by the bacterium regulate how potentially toxic compounds are metabolized, how blood vessels are formed and how the gut matures during the postnatal period.
Gordon's group wanted to understand which intestinal cells were responsible for these results. They used laser capture microdissection, originally developed to help cancer researchers define the molecular details of tumor formation. This method allows scientists to carve out a particular cell from a tissue sample and to measure gene expression.
"The combination of a relatively old technique --the use of germ-free mice --and the two newer techniques allowed us, for the first time, to take a detailed look at how particular cells in living animals respond to the addition of a microbe," Gordon said.
For example, the team discovered that certain populations of intestinal lining cells in the mice responded to B. thetaiotaomicron by stepping up their production of three proteins --co-lipase, which helps break down fats; small proline-rich protein 2a (sprr2a), which may help fortify the intestinal barrier; and angiogenin-3, which stimulates blood vessel formation.
Some of these responses (such as the increased expression of sprr2a) were elicited when germ-free mice were colonized with B. thetaiotaomicron but not with some of the other normal resident bacteria of the intestine. This suggests that the composition of our gut's microbial society may help define the nature of our physiology.
"One of our findings is that microbes are able to regulate intestinal genes involved in breaking down foods into simpler units that can be absorbed," Gordon said. "This raises the question of whether there are variations in the types of intestinal microbes between individual humans and how such differences affect our nutritional status, our health and our predisposition to certain diseases."
Answering this question, Gordon said, might shed light on human diseases such as inflammatory bowel disease, irritable bowel syndrome and other disorders. Understanding the regulation of intestinal barrier functions might even reveal how some microbes affect our susceptibilities to food and other allergies.
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