“The classical view of infectious disease is that a single organism invades and produces an infection,” Seed says. “But then we found that certain diseases, like irritable bowel syndrome, seem to be caused by imbalances in the organisms that communicate with the host. So then people asked, ‘Why is this not the case for many other states of human health?’ ” Preliminary work by other groups, similarly made up of both biomedical researchers and microbial ecologists, suggests that imbalances in the microbiome might also be linked to allergies, diabetes, and obesity.
The partnership between ecologists and biomedical researchers is characteristic of how things work in the relatively new but burgeoning field of microbiome studies. Vanja Klepac-Ceraj, a microbial ecologist by training and an assistant research investigator at the Forsyth Institute in Cambridge, Massachusetts, has helped organize symposia with ecologists and biomedical researchers giving joint talks on the ecology of disease. “Biomedical scientists understand disease, so they know where the problem lies within the body,” she says. “Ecologists understand complex systems and the interaction of many organisms.”
Klepac-Ceraj recently worked with Michigan State University ecologist Brian Maurer on a study of cystic fibrosis that showed the importance of microbial biodiversity in diseased lungs. Cystic fibrosis leads to mucus buildup in the lungs, which creates habitats for microbes and ultimately makes patients prone to lung infections. But their study of 45 cystic fibrosis patients showed that when the respiratory tract contains a more diverse community of microbes, the patient is less likely to harbor Pseudomonas aeruginosa, a key pathogen associated with later stages of cystic fibrosis. “The fuller and more diverse community correlated with a healthier outcome even though that community was not the model of a healthy lung,” Maurer says.
Microbiome studies run directly against the notion in the minds of most people—even many researchers—that microbes are linked to disease, not to health. And of course not all microorganisms are benign. Infants in particular are susceptible to a number of diseases caused by gastrointestinal bacteria, including sepsis, chronic diarrhea, and necrotizing enterocolitis, an infection of the intestinal lining that is one of the leading causes of death in premature babies. Antibiotics have long been the first option in fighting these dangerous microbes, but many researchers are troubled by modern medicine’s heavy reliance on them. After all, many pathogens found within the human microbiome are harmless or even beneficial. “There is Staphylococcus and
E. coli in all of us, but they don’t always cause problems,” Jackson says. “It’s the balance that is important. A more normal population of microbes in the gut can offset the bad players.”
The Preemie Microbiome Project is an important step in understanding how we achieve a healthy, balanced microbiome in the first place. Researchers know that infants acquire about 100 species of microbes in the birth canal, and others come from the mother’s skin after birth. As a child’s contacts increase, some microbes are added from the doctor, the nurses, the proud dad, the doting relatives, and the curious family pets. By the time a baby is 6 months old, he or she has some 700 species of microflora, and by the end of the third year, each child has a microbial community as unique as a fingerprint.
Most of the infants enrolled in the Duke study are delivered by cesarean section, generally because the mother or the child has an infection or because the mother suffers from pregnancy-induced hypertension. Since they do not travel through the birth canal, “these infants come into life with virtually a clean slate, with few or no microbes at all,” Seed says. “It gives us an opportunity to understand how the system works and develops.”
The study also gives the researchers a chance to understand how antibiotics impact the formation of the microbiome. “Most premature infants are given antibiotics right away because of the dangers of disease,” LaTuga says. “But more and more, we are learning antibiotics have multiple risks.”
Heavy use of antibiotics can lead to antibiotic resistance, but researchers now speculate that antibiotics can also upset the balance of the microbial community, allowing disease to take over rather than fighting it. Michael Cotten, another neonatologist on the Duke project, analyzed the duration of antibiotic therapy given to 4,039 premature babies at 19 treatment centers across the country and found that prolonged use of the drugs is associated with increased risk of necrotizing enterocolitis and death. Antibiotics probably also prevent beneficial bacterial communities from forming in infants.
Last year, Stanford microbiologist David Relman published a study that illustrated the potentially devastating impact of antibiotics on the microbiome. He gave three healthy adults a five-day course of the antibiotic Cipro, then another course six months later, and monitored the state of the microbiome after each treatment. The gut flora of all three subjects gradually recovered from the impact of the antibiotic treatment but never returned to their original state—they had different compositions and were less diverse. “We don’t know if these differences matter to health,”
Relman says. “But in general, you’d be concerned about a change.” He had chosen Cipro because it has limited effectiveness against most species of bacteria in the gut, but it still affected one-third to one-half of the microbial flora in the subjects. “Knocking out one organism could have a ripple effect on the lives of others,”
This is especially concerning given that the number of different microbial species in the intestines may be important in countering pathogens. “The greater the diversity, the lower the probability that pathogens can invade and persist,” says Richard Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies in New York. “If all the niches are taken up in the gut, it might be hard for them to get hold.”