A New Normal
Early research on microbiota focused largely on the commensal bacteria that reside in the human gut. Commensal gut bacteria supply nutrients, help metabolize indigestible compounds, and defend against colonization by nonnative opportunistic pathogens.
But the distinction between "good" microbes that aid health and "bad" pathogenic microbes that cause disease has become blurred in recent years. Researchers have shown that under certain conditions, some types of normal gut bacteria can trigger disease. Sarkis Mazmanian, a microbiologist at the California Institute of Technology, dubbed these elements "pathobionts"; the term "pathogens," in contrast, refers to opportunistic microbes that are not normally part of the gut microbial community.
Disturbances to the microbial equilibrium of the gut may mean that some microbes become overrepresented while others are diminished. "It's like a garden—you're less likely to have weeds growing if you have lush vegetation, but without this vegetation the weeds can potentially take over," Mazmanian says. When the gut moves toward a state of microbial imbalance, normally benign gut microbes may begin to induce inflammation and trigger disease throughout the body, even in the nervous system.
Researchers have long postulated that gut bacteria influence brain function. A century ago, Russian embryologist Elie Metchnikoff surmised that a healthy colonic microbial community could help combat senility and that the friendly bacterial strains found in sour milk and yogurt would increase a person's longevity.[6,7]
In 2011 Mazmanian and colleagues reported that changes in gut microbial composition might have far-ranging effects that extend to the brain. They worked with germ-free ("gnotobiotic") mice, which are born in sterile environments and are not naturally colonized with microbiota.
The researchers found the mice were highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, after immunization with central nervous system antigens. These substances stimulate an immune response and normally induce EAE. However, when some of the mice were intestinally colonized with segmented filamentous bacteria—common commensal inhabitants of the mouse gut—they developed the disease upon being immunized with the central nervous system antigens.
Although the study suggested that gut bacteria could affect neurologic inflammation, how that might happen remains unclear. For the most part, Mazmanian says, the microorganisms that colonize the human gut don't leave the intestine, but the immune cells that contact them do. He explains that, although 70% of the immune cells in the body at any one time can be found in the intestine, they circulate throughout the body, and the microbiota of the gut environment help determine how immune cells will behave elsewhere. He gives an example: "If T-cells, while in the gut, are programmed by the microbiota to have anti-inflammatory properties, then they may suppress inflammation even after they leave the gut."
Proteins, carbohydrates, and other molecules shed by microbes also leave the gut and may play a role in signaling disease. Studies have shown these bacterial metabolites are pervasive throughout the body—in the lungs, amniotic fluid, and breast milk, all tissues once thought to be free of microbial communities.
Other researchers have suggested a link between the gut–brain axis and neuropsychiatric disorders such as autism, depression, and eating disorders. The gut contains microorganisms that share a structural similarity with the neuropeptides involved in regulating behavior, mood, and emotion—a phenomenon known as molecular mimicry. The body can't tell the difference between the structure of these mimics and its own cells, so antibodies could end up attacking both, potentially altering the physiology of the gut–brain axis.
Environ Health Perspect. 2013;121(9):a276-a281. © 2013 National Institute of Environmental Health Sciences