Lora Hooper, 2000 Career Award in Biomedical Science and Karen Guillemin, 2001 Career Award in Biomedical Science
2005 - In an era when antimicrobial soaps are popular and frequent use of antibiotics is the norm, scientists are beginning to discover that our zeal to wipe out germs actually may be backfiring on us. Although much of the research on microbes focuses on how to avoid being infected by bacteria, a small cadre of scientists, including several recipients of BWF Career Awards in the Biomedical Sciences, is focusing on the microbes that make the human digestive system their permanent home. Their research is revealing that these microbes are indispensable: they actually help shape our intestines early in life and keep harmful bacteria from setting up shop in our gut.
“It is becoming clear that there is a tremendous amount of cross-talk between the bacterial microflora, which educate and shape the immune system of the gut, and the intestinal cells,” says Lora Hooper, a 2000 recipient of a BWF Career Award and assistant professor of immunology at the University of Texas Southwestern Medical Center-Dallas. Karen Guillemin, a 2001 recipient of a BWF Career Award and assistant professor of biology at the University of Oregon, also is studying the role of intestinal microflora during human development and gut maturation, which occurs in the first two years of life.
Their research records details of a molecular negotiation between microbes and their host that apparently works to the benefit of both. The resident gut microbes receive a steady supply of nutrients and a place to live, and the microbes in turn alert the human immune system to potential pathogens, as well as assist in digestion of food. It’s a partnership that likely evolved during a billion years of coexistence, Dr. Hooper says.
“The idea that ecology and development interact and help shape each other is an emerging field called eco-devo that is gaining a lot of interest right now,” she says. What makes eco-devo so exciting, she adds, is that it integrates environmental and genetic influences on development and examines how the changes in the environment can alter how two organisms with identical genes turn out.
Dr. Hooper became aware of this new way of thinking about the role of bacteria in development as a postdoctoral fellow in Jeffrey Gordon’s lab at Washington University. Dr. Gordon had adapted an experimental system in which mice are raised in a sterile environment so that the developing animals never encounter the bacteria that normally colonize the gut. What the scientists found was astounding. In the absence of bacteria, gut development is arrested and certain features of normally developed digestive systems, such as blood vessel networks that move nutrients into the body, are stunted.
Taking the observation further, Dr. Hooper began experiments with Paneth cells, specialized cells found at the base of tubelike depressions in the lining of the small intestine. “Paneth cells help to create an electric fence that discourages certain bacteria from invading intestinal tissues,” she says. The cells are packed with protein antibiotics that are released in response to bacterial signals and create that “fence” between intestinal surfaces and gut bacteria.
Now in her own laboratory, Dr. Hooper and her colleagues are continuing work on an antibiotic protein, discovered by Hooper as a post-doc in Gordon’s lab, called angiogenin-4, that is made by Paneth cells and can kill disease-causing bacteria and fungi. What’s more, they found that Bacteroides thetaiotaomicron, a normal resident of the gut in mice and humans, turns on production of angiogenin-4. The finding offers one of the first hints that the resident microbes of the gut actively help fend off bacterial intruders. “This result,” she says, “shows how the normal gut bacteria contribute to the rapid-fire response that protects the surfaces of the gut from invading bacteria.”
Dr. Hooper’s lab has subsequently shown that these same bacteria help regulate production of a number of antimicrobial proteins that Paneth cells produce. They are now exploring how the cross-talk between bacteria and Paneth cells takes place. “We are trying to understand how the cross-talk shaped the gut through evolution,” she says.
Dr. Guillemin is using zebrafish, a common aquarium species, to study microbe-gut interactions. She chose the zebrafish because it is easy to raise in a laboratory—it develops from an egg to a free-swimming fish in only five days. Also, zebrafish are transparent, making it easy to follow developmental changes. Dr. Guillemin has followed the lead of Drs. Hooper and Gordon by rearing the fish in a sterile environment to see how it affects their development.
By tagging bacteria with a fluorescent molecule to observe how and when they take up residence in the developing fish, Dr. Guillemin has discovered that bacteria colonize the immature gut soon after the egg hatches and before the animal is fully mature. In a sterile environment, the gut simply doesn’t develop fully and the animals have trouble absorbing nutrients. Further investigation showed that the pattern of sugars that normally coat the intestinal cells also becomes arrested in an immature state that can be reversed if bacteria are introduced.
These results suggest that the normal bacterial community of the gut is communicating with the developmental program of the fish, and that when such communication is interrupted, growth and development are arrested. “We want to understand what genes are regulated by the presence of bacteria,” she says. “What host genes are required and can we isolate mutants that compensate for the developmental arrest?”
Such questions would have been impossible to answer even 10 years ago. But scientists such as Drs. Guillemin and Hooper have embraced a host of new tools, including variations of polymerase chain reaction to amplify traces of genetic material and microarray analysis, which enable them to simultaneously study the activity of thousands of genes. These tools are crucial, says Dr. Hooper, because so many of the bacteria that live in our gut cannot be cultured in the lab. The sheer variety of microbes present makes it difficult to sort out the effect of one from the other without using the newly developed tools. With microarray analysis, however, scientists can study the combined effect of whole populations of microorganisms that colonize the gut.
Such studies are not just of academic interest. Normal bacterial colonization in humans occurs early in life, between birth and weaning, a time when many children undergo repeated rounds of antibiotic treatment for common ear infections that can wipe out intestinal microbes as well. Listening in on the conversation between the protective bacteria of the gut and the developing immune system could keep our own protective bacterial fence intact.