At least 100 trillion bacteria live in the mammalian gut. How can we carry all those organisms and not get sick?
At least 100 trillion bacteria live in the mammalian gut and are crucial helpers for food digestion and energy production. But this poses a paradox: How can we carry all those organisms and not get sick?
As it turns out, bacteria are physically separated from the intestinal lining, which prevents them from activating their host's immune system. According to a new study of the mouse small intestine, a molecule called MyD88 signals the presence of the bacteria, activating production of an antibacterial protein that kills any bacteria within a 50-micrometer radius—about the size of a speck of dust. The loss of this protective barrier—what the researchers cheekily call the 'demilitarized zone,' or DMZ—could be involved in inflammatory bowel disease or other diseases characterized by an inflamed intestine, the researchers say.
"Good fences make good neighbors," says HHMI investigator Lora V. Hooper, quoting poet Robert Frost. Hooper led the new study, published October 14, 2011 in Science. "Trillions of friendly bacteria inhabit our guts, and we want them there, but they have to be kept at arm's length."
Trillions of friendly bacteria inhabit our guts, and we want them there, but they have to be kept at arm's length.
Lora V. Hooper
Hooper has been investigating the relationship between the bacteria that live on or in other organisms—known collectively as the microbiota—and host tissue since 1996. Her interest in the DMZ dates to 2008, when she read a study describing this barrier in the mouse colon, or large intestine.
"We started to wonder whether there were components of the immune system that were responsible for patrolling that barrier," Hooper says.
Working with her colleagues at the University of Texas Southwestern Medical Center at Dallas, Hooper looked at mice lacking MyD88, a gene that encodes a signaling molecule that functions downstream of toll-like receptors. These receptors can sense bacteria and turn on the body's innate immune system. This year’s Nobel Prize in Physiology or Medicine was given partly in recognition of the discovery of toll-like receptors and their role in innate immunity.
Mice missing MyD88 show 100 times more bacteria on the intestinal lining than do normal controls, the study found. The researchers saw the same thing in mice missing MyD88 only in epithelial cells, which line the surface of the intestine.
Hooper knew from previous work that MyD88 can turn on production of antibacterial proteins. To test if that was happening here, she looked at whether the presence of the DMZ correlated with the expression of MyD88 and an antibacterial protein called RegIIIγ She found that the DMZ stays intact only when both MyD88 and RegIIIγ are fully expressed.
The findings suggest that toll-like receptors sense the presence of the bacteria and then use MyD88 to alert the rest of the cell. MyD88 then spurs the production of RegIIIγ which kills the invading bacteria.
"It's like a burglar alarm that senses your home is being invaded and radios the police," Hooper says. "The toll-like receptor is the alarm and RegIIIγ is the police."
It's likely that the gut has lots of alarm bells that work against different types of bacteria. RegIIIγ only kills Gram-positive bacteria—those that turn blue or purple when exposed to a Gram stain. About half of the bacteria in the gut are Gram-negative.
"How do we keep our intestinal surfaces clear of Gram-negative bacteria?" Hooper asks. "One might predict that there are antibacterial proteins that can kill Gram-negatives that are also regulated in a similar manner. And so we’re searching for those."
RegIIIγ is part of the innate immune response, but she also predicts that adaptive immune mechanisms also help keep gut bacteria at bay.
Hooper is not only interested in how the microbiota interacts with its host, but how it interacts with viruses, such as polio, that live in the gut. In the same issue of Science, Hooper and senior author Julie Pfeiffer reported that mice treated with antibiotics are less susceptible to infection by poliovirus than are animals whose microbiota are left intact. Their collaborative work suggests that these viruses have evolved to exploit their bacterial neighbors to become more powerful.