About six months ago, Dr. Barbara Warner got a call in the middle of the night — the kind that she has come to dread.
Warner, a neonatologist, had been caring for a boy born at 26-weeks gestation. Until that night, the baby had been growing gradually stronger. He'd survived the lung problems typical of premature babies that age, was off the ventilator, and was consuming breast milk provided by his mother.
At nearly four weeks, his mother was finally starting to hold her son, was starting to let her guard down. Then the baby suddenly took a bad turn.
When Warner reached the neonatal intensive care unit at St. Louis Children's Hospital, she took one look at his tiny abdomen and knew he was gravely ill with necrotizing enterocolitis, a condition that affects nearly 10 percent of babies born at less than 32 weeks. An X-ray would later confirm what his telltale abdomen already showed.
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"You could bounce a dime off of it," recalls Warner, head of Children Hospital's division of newborn medicine. "You just know it's going to be terrible."
Warner and Dr. Phillip Tarr, a gastroenterologist at Washington University School of Medicine, along with biostatistics expert William Shannon, also of Washington U., have launched a project to study the guts of such premature babies to see whether or how gut bacteria, resident in everyone, affect necrotizing enterocolitis. An early warning might give doctors a chance to intervene.
They're joining a flourishing group of scientists studying the human microbiome, the bacteria that live with us and on us. While it may be unsettling to learn that microbes outnumber other human cells by 10 to one, this arrangement is mostly peaceful and absolutely necessary. The human immune system recognizes the microbiome as friend and leaves them alone. Tarr's team will study stool samples from premature babies by comparing the microbiomes of the preemies who develop necrotizing enterocolitis with those who don't.
A starting place
People are born with few if any microbes. A trip through the birth canal sows the first seeds of the microbiome. Research shows that people acquire their microbiomes during the first year of life. The mother's nutritional status, the quality of breast milk, the type of food each family eats shapes the gut community.
For projects such as Tarr's, the gut is the perfect place to start. There are more bacteria in the gut — the area stretching from the stomach to the anus — than anywhere else it the body. Scientists estimate the number of gut microbes as high as 100 trillion. Bacteria here help shape how the immune system responds to invaders and also provide enzymes to digest food that would be otherwise indigestible.
Scientists view the microbiome as a metabolic organ that acts in unison. To help understand how this organ works, the National Institutes of Health launched the Human Microbiome Project in 2008. Washington U. is one of the centers conducting Human Microbiome Project research. The project aims to discover the dividing line between microbes and human health. Project researchers are taking a census of the microbes from 300 healthy volunteers.
Human Microbiome Project researchers swab about 14 body areas and then figure out which types of bacteria live where. They can tell microbes apart by looking for bacteria's own "barcode." Research from the healthy volunteers shows that microbiomes found in different areas are distinct, from the crook of people's arms to the microbiomes around teeth.
Microbes reflect changing cultural practices, changing lifestyles, where one travels, and what people eat, said Dr. Jeffrey Gordon, a scientist at Washington University School of Medicine. "The marriage of humans and microbes has evolved over time with all participants adapting to one another and helping one another," Gordon said.
Missouri Twins targeted
One of Gordon's ongoing projects studies gut microbes in sets of twins born in Missouri between 1975 and 1985. The twins are lean, obese, or one twin is lean and the other obese. He studies fecal samples from the twins and their mothers to learn what microbes have to say about the mother's nutritional status and the twins' body weight. Gordon's team learned that obese twins have fewer types of bacteria in their guts and a different balance of genes that tell bacteria how to harvest nutrients.
For Gordon's laboratory experiments, his team uses mice raised to be germ-free. The researchers transplant bacteria from the study subjects to the mouse intestines. The team then studies what happens when they alter what the mice eat. Feeding these "humanized" mice a Western, high fat, high sugar diet changes which bacteria flourish and which don't.
In work recently published in the Proceedings of the National Academy of Science, Gordon's team and researcher Andrew Goodman, now at Yale, added human microbes from two healthy volunteers to the germ-free mice. Once the bacteria took hold, the researchers removed the "humanized" mice feces and separated the types of bacteria. Then they chose which bacteria to put back in a new group of mice and those bacteria also took hold in the mouse guts.
Researchers had been trying to grow gut bacteria in the lab for a long time but they never knew that the full diversity of a person's microbes could be captured and then grown in laboratory cultures. Now this research shows that the diversity of lab cultures is very similar to the diversity in the gut the from which the feces came. The work also shows that the whole community of microbes can be split apart.
This project, Gordon said, will help study the gut microbiome of people on three continents with different cultures, work funded through a $5.5 million grant in 2009 from the Bill and Melinda Gates Foundation. He wants to know if microbiomes of people raised in different cultures can change human physiology.
The answers to this and other microbiome research questions will tell scientists whether people walk around with low levels of pathogens all the time, like time bombs waiting to explode, and whether resident microbes that outnumber pathogens hold them in check.
"Of all the bacteria in the world, few are really pathogens, such as tuberculosis and syphilis," said George Weinstock, a geneticist and associate director of Washington University's Genome Institute. Weinstock and his team are searching genes in many human microbiomes, such as the skin and ureter, to understand what bacteria are capable of doing. They want to know which bacteria carry genes that make pathogens dangerous, or carry genes that make bacteria resistant to antibiotics. The next step in the Human Microbiome Project, said Weinstock is to learn how the microbiome changes with age and chronic disease.
"There's hardly a disease I can think of that doesn't have some microbial component," Weinstock said.
That's the hope also of doctors involved in the microbiome project on necrotizing enterocolitis.
'Parents were devastated'
The baby boy whom Warner cared for six months ago was the worst-case scenario, and not all that uncommon, she said. After surgeons operated on him, they found that nothing of his intestines was left to save. All surgeons could do at that point was to close his surgical wound and allow the parents to spend time with him until he died a short time later.
"The parents were devastated," Warner said. "The only consolation, if any, was that baby was participating in our study and they felt as though that they had done everything they can to help prevent another baby from developing this disorder."