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.
"We live in a world predominated by microbes," explains Jeffrey I. Gordon, M.D. "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, who led the study, is the Alumni Professor and Head of the Department of Molecular Biology and Pharmacology at Washington University School of Medicine in St. Louis. The first author is Lora V. Hooper, Ph.D., an instructor in molecular biology and pharmacology and a recipient of a career development award from the Burroughs Welcome 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 our 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 world-wide 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. "We did not have a preconceived notion of how many intestinal functions are influenced by gut microbes," notes Hooper. "Gene chips allowed us to survey, in a relatively unbiased way, the effects of a common gut microbe on more than 20,000 mouse genes."
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 post-natal period.
"We were amazed at the breadth of normal intestinal functions affected by a single microbe," says Hooper.
Gordon's group wanted to understand which intestinal cells were responsible for these results. They used another relatively new technique called 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," says Gordon.
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," explains Gordon. "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." According to Gordon, answering this question 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.
"Shortly after birth, resident microbes begin to educate the gut's immune system, signaling that they are safe, normal partners that do not merit an immune response," says Gordon. "As well as preventing adverse responses to normal bacteria, this educational process might help ensure that we don't react poorly to certain antigens we ingest.
When the alliance between microbe and host is upset, there may be serious consequences to human health. In the future, the team hopes to learn more about how normal bacteria develop an effective working relationship with humans. They would like to exploit the strategies developed by our microbes over the course of several million years to help identify new therapies for promoting health and for treating diseases that occur inside, or even outside, our gastrointestinal tract.
Hooper LV, Wong MH, Thelin A, Hansson L, Falk PG, Gordon JI. Molecular analysis of commensal host-microbial relationships in the intestine. Science, Feb. 2, 2001.
Funding from the National Institutes of Health and AstraZeneca Pharmaceuticals supported this research.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.