Within the human gut lies a bustling community 10,000 times more numerous than the Earth's human population. Four hundred different species of bacteria living in our intestines help us digest food and protect us from marauding pathogens. We, in turn, provide them with a nutrient-rich environment. This relationship is only helpful, however, if the bacteria stay in the gut. If they escape to other parts of the body, the bacteria can wreak havoc.
At the University of Texas Southwestern Medical Center, Lora Hooper is investigating how the lining of the gut, called the epithelium, prevents that escape.
"The epithelium is such an effective barrier," she says. "It's confronted not only with the sheer density of microorganisms in the gut—100 trillion bacteria—but also the staggering complexity of that ecosystem. And yet it's able to corral them. How?"
It's a question she started investigating in 1996 as a postdoctoral researcher in Jeffrey Gordon's lab at Washington University School of Medicine in St. Louis. "At the time we knew absolutely nothing about how these organisms shape human biology," says Hooper. "It was a major hole in our understanding of the human organism." Her studies were among the first to reveal the fundamental influence that intestinal microbes have on epithelial host cells—an impact that was previously thought to be inconsequential.
Hooper's interest in biology came relatively late. At age 10, she was fascinated by physics and astronomy, building a telescope with her father to search the skies over her hometown, Nashville, Tennessee. Physics and the cosmos continued their pull through high school, but a freshman biology class at Rhodes College in Memphis altered Hooper's focus. "I became fascinated with the inner workings of the cell," she says.
After graduate school, which included an HHMI predoctoral fellowship, at Washington University, Hooper moved to Gordon's lab and began picking apart the relationships between microbes and their hosts. One of her first projects confirmed that bacteria could modify carbohydrate molecules involved in cell signaling on the surface of their hosts' cells. Those 1999 findings were the first evidence that "microbes could have a profound influence on specific biochemical pathways in the host cells and thereby influence host physiology," says Hooper.
Hooper is now exploring host-microbe communications in germ-free mice. Mammals acquire the beginnings of their natural microbial community from their mothers during birth; this microbial community evolves over time into the normal adult flora. But with the complexity of bacterial inhabitants in the gut (in addition to viruses, protists, and fungi), teasing out the impact of a single species is impossible.
To home in on the effects of individual species, Hooper became an expert in gnotobiotics, the study of animals raised in a germ-free environment. She established UT Southwestern's gnotobiotic mouse facility when she arrived in 2003; it is one of a handful of such facilities in the country. Her team delivered the original mice for the facility via cesarean section to prevent colonization with the mother's bacteria during birth. The mice and their offspring are raised in sterile plastic bubbles, protected from the microbe-filled outside world, and researchers introduce only one or a few species of microbes at a time into each mouse. By examining what happens to the mice after exposure to the microbes, the investigators can determine how bacteria affect their hosts' physiology.
In 2006, Hooper's research group used gnotobiotic technology to help discover a key member of the gut's antimicrobial arsenal. Her team showed that when a microbe comes into contact with the mucous lining of the epithelium, the epithelial cells produce a protein called RegIIIγ that kills the bacteria, preventing them from crossing the epithelium and invading deeper host tissues.
Hooper is convinced that the epithelium has additional defenses that are still unknown. One of her long-term goals is to better catalog the rich source of protein antibiotics made by the gut epithelium. With so many different species to protect against, "the epithelium needs to be ready for anything," she says. Obtaining a better understanding of how these proteins kill bacteria that threaten the intestine, she hopes, will lead to the development of new treatments for infections in the gut, as well as in other tissues.
She also plans to look at the interactions between host and microbe from the microbes' point of view. "You have all these epithelial cells secreting antimicrobial substances into the gut," she says. "How does that impact the intestine's bacterial communities? Or does it?"
In addition, she wants to "burrow deeper into the gut," she says. Because it has to deal with enormous and complex microbial communities, "the intestinal immune system is radically different from the more familiar immune cells that police invaders in the bloodstream. Although much has been learned over the past several years, it's still a big black box."