red recently by Gordon's group. One of the intestinal genes triggered in germfree mice by B. thetaiotaomicron encodes a protein called angiogenin 4 or Ang4. Cancer researchers are particularly interested in this protein, because they have evidence that it nourishes tumors by creating new blood vessels. Gordon's team suspected that Ang4 plays a role in the intestinal blood vessel maturation that they had documented earlier. Indeed, it turned out that Paneth cells make Ang4 and secrete it when they detect bacteria.
While the suspicion that Ang4 makes intestinal blood vessels has not yet been proven, it looks like the protein has a more certain role. It can kill several bacteria and fungi that cause diseases in mammals, Gordon, Hooper, and their colleagues report in the March Nature Immunology. In contrast, B. thetaiotaomicron and other common residents of the mouse intestines are largely resistant to Ang4.
"One interpretation of the interaction between host defense and the resident flora is that the resident bacteria that are resistant to Paneth-cell secretions stimulate these host-defense mechanisms to prevent competition by nonresident bacteria. The host in turn benefits by decreasing its exposure to potential pathogens," says Tomas Ganz of the University of California, Los Angeles in a commentary accompanying the March report.
Hooper agrees that the normal inhabitants of the gut may use Paneth cells and Ang4 to raise what she calls an "electric fence" to keep out competing microbes. Beyond fending off foreign pathogens, such fences may also keep typical intestinal microbes within the gut. "Anything can become a pathogen if it crosses the fence," she says.
Scientists have estimated that the hundreds of bacterial species within the human gut may together possess as many unique genes as a person does, and perhaps far more. "How much of our biology is dependent on metabolic traits encoded in the collective genomes of our microbial partners?" asks Gordon.
Investigators have begun to address that question. For example, Schell recently worked with scientists at the Nestlé Research Center in Lausanne, Switzerland, to unravel some of the genetic secrets of B. longum. This microbe typically colonizes the intestines of a newborn mammal, thrives during the breast-feeding period, and then subsides after weaning, when B. thetaiotaomicron and other bacteria take hold. Nestlé incorporates B. longum into some of its products, such as infant formulas and yogurts, to promote gastrointestinal health.
In the Oct. 29, 2002 Proceedings of the National Academy of Sciences, Schell and his colleagues unveiled the entire DNA sequence of B. longum and identified a large roster of genes for enzymes that break apart sugars and other edible substances. Some of these enzymes may degrade complex sugars found in breast milk, speculates Schell. Others, such as ones that apparently break down plant gums, may help the bacterium survive later in its host's life when B. longum is in the minority in the intestines.
The bacterium appears to break down substances that B. thetaiotaomicron and other Bacteriodes can't handle. "It seems to be more specialized for the leftovers of metabolism," says Schell. In a strategy similar to Gordon's, investigators at Nestlé are now using germfree mice to evaluate B. longum's impact on intestinal genes.
Gordon's team is drawing its own insights from the group's recent deciphering of B. thetaiotaomicron's genome. Among that microbe's nearly 4,800 genes, several hundred encode proteins that bind carbohydrates, enzymes that degrade bonds between sugars, or enzymes that create new sugars, the investigators reported in the March 28 Science. And the activity of many of these genes appears to be regulated by genes encoding molecules related to known environmental sensors, suggesting that the microbe can monitor the contents of the intestines and quickly deploy the molecular machinery needed for it to digest nutrients.
"This organism has a sweet tooth. It knows how to process carbohydrates," says Gordon.
Over the next 5 to 10 years, p