t it's a friendly visitor and not a danger, says Gordon.
Among the intestinal genes activated by B. thetaiotaomicron is one suspected to stimulate the growth of new blood vessels. The finding spurred Gordon's group to investigate the microbe's control over the system of blood vessels that runs through the GI tract. These blood vessels are crucial to a body's absorption of nutrients.
The researchers discovered that their germfree mice have a poorly formed network of the capillaries that normally supply the inner intestinal surface with its blood supply. This could partly explain the difficulty that germfree animals have absorbing nutrients.
The team also found that it could stimulate germfree mice to grow a normal network of intestinal capillaries by exposing the animals to either a full complement of microflora or just B. thetaiotaomicron. The investigators reported the finding in the Nov. 26, 2002 Proceedings of the National Academy of Sciences.
This is a vivid illustration that the physical development of the gut can depend on the microbes that normally inhabit animals, says Gordon. The researchers also found cells in the mouse gut that seems to work with the microbes to spur vessel growth.
In the small intestine, so-called Paneth cells normally secrete antimicrobial compounds (SN: 8/26/00, p. 135: Available to subscribers at http://www.sciencenews.org/20000826/fob8.asp). This keeps the intestine healthy by protecting other cells that continually replenish the gut lining. Gordon's team created germfree versions of mutant mice that lack Paneth cells and found that B. thetaiotaomicron couldn't trigger the maturation of blood vessels in such rodents. While most investigators have regarded Paneth cells simply as defenders against invading bacteria, it makes sense that these cells mediate interactions between a host and its natural microflora, says Gordon. "What better cell to respond to the presence or absence of a microbe?" he remarks.
The Paneth cell is at the heart of another microbe-intestine interaction uncovered 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