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Not So Black and White
In any kind of census, it’s necessary to group individuals into categories that oversimplify their differences. In a human census, that means checkboxes that reduce people to race, gender, income, and marital status. In the microbiota census occupying scientists’ minds, it means the temptation to group gut bacteria into good and bad, pathogens versus commensals (microbes that don’t cause disease). But this process hardly paints a full picture of what’s going on in our intestines, says Yale’s Medzhitov.
“The difference between commensals and pathogens is not that they are two very different types of microbes,” Medzhitov explains. In fact, microbes considered commensals in one organism’s gut, or in one situation, can act pathogenically in a host with a compromised immune system or in a different organism. “So the distinctions between the two are in many ways arbitrary,” Medzhitov says.
In reality, each bacterium in our gut falls along a spectrum between pathogenic and commensal. Medzhitov thinks that instead of lumping bacteria into these extremes, based on their outcomes (disease or health), scientists should focus on how each bacterium interacts with its host—the human body.
Humans have intricate immune systems exquisitely tuned to identify intruders. Medzhitov studies a class of receptors—called Toll-like receptors—that recognize invading bacteria and signal the immune system to act. His lab has found that Toll-like receptors recognize bacteria that could do harm to the body, and they also help keep the intestinal microbiota balanced by detecting bacteria that are less virulent.
“There’s something about the environment of the gut that controls this interaction so that, under healthy conditions, Toll-like receptors sense commensals and don’t react to them as harmful,” says Medzhitov. Of course, if those same tame bacteria sneak out of the gut into the bloodstream—during surgery, for example—the receptors will respond with fury, leading to dangerous inflammation and sepsis. Medzhitov wants to know what it is about the intestines that keeps Toll-like receptors in check.
And that’s far from the only way the immune system interacts with gut bacteria. HHMI investigator Lora Hooper, at the University of Texas Southwestern, is fascinated by the subtleties of the interaction.
“I’ve been studying this for 15 years and it’s still not clear to me—how can you have a hundred trillion bacteria in your gut and you don’t get sick?” says Hooper.
When she first started studying the microbiota, as a postdoctoral fellow in the lab of Jeffrey I. Gordon at Washington University in St. Louis School of Medicine, Hooper began working with germ-free mice. These mice are raised from birth in sterile environments—they eat sterilized food, live in germ-free bubbles, and interact only with other germ-free mice. These cleaner-than-clean mice allow researchers to study the effects of individual bacteria strains in a simple system.
Hooper and Gordon’s first experiments with germ-free mice gave them a glimpse at some of the jobs of gut bacteria: they stimulated immune responses, helped detoxify compounds the mice ate, stimulated the growth of new blood vessels, allowed proper tissue development, and performed countless metabolic tasks.