Bobbie Finocchio learned the hard way about the human microbiome.
Ten years ago, the elementary school principal’s life was turned upside down by a group of noxious bacteria called Clostridium difficile, which can sometimes overpopulate the intestines when antibiotics disrupt the normal balance of microbes. Despite many rounds of treatment, Bobbie was plagued by abdominal pain and sudden diarrhea. Her life became a search for the nearest restroom.
“I was afraid to drive for more than 10 minutes,” she recalls.
Then, earlier this year, she was referred to Hamed Khalili, MD, MPH, a gastroenterologist at Massachusetts General Hospital. He treated her with a newly designed “stool transplant” pill teeming with living bacteria and other microbes from a healthy donor.
Bobbie explains her treatment this way: “You take stool from a person with healthy bacteria and you give it to a person who is sick with unhealthy bacteria. Then the good bacteria battle with the bad until the good guys win.”
Milepost of a New Era
The transplant pills developed at Mass General are an early milepost in a new era of medicine. Scientists now understand that the microbes inside us play a crucial role in human health as they live, work and interact with our own cells. Known as the human microbiome, this community of microbes is the focus of a rapidly expanding area of research that holds great promise for human health.
High-powered genetic technologies have thrown open the door to such research at Mass General and around the globe. These new technologies can rapidly identify and sequence millions of human and microbial genes and help scientists learn about their functions. The Human Microbiome Project 1, funded by the National Institutes of Health (NIH), has already identified an estimated 10,000 species of microbes that live in us and on us.
The surprise is that our microbes extend their influence far beyond where they live in our gastrointestinal and urogenital tracts and on our skin. These bacteria and other microbes give off substances called metabolites that, in turn, can enter the blood stream and travel to other organs, bringing messages to the cells — even to the brain.
Investigating the Microbiome
“But it’s a two way street,” says Lee Kaplan MD, PhD, director of Mass General’s Obesity, Metabolism and Nutrition Institute. “The human body has enormous capacity to influence these bugs (microbes) and they, in turn, influence human function.”
Across Mass General, clinicians and scientists are investigating the human microbiome in search of new targeted therapies and preventive strategies to treat some of the world’s most challenging diseases. Those maladies include cancer, diabetes, obesity, inflammatory bowel diseases, asthma, autism and others.
As the nation’s largest hospital-based research enterprise, Mass General is well positioned for leadership on this fast-moving research front. Mass General doctors have access to the cutting-edge discoveries pursued by its scientists and the new Research Institute is designed to capitalize on this unique partnership.
“Mass General researchers are making important discoveries in this quest to understand the microbiome,” says Peter L. Slavin, MD, Mass General’s president. “This research involves some of the very basic elements of human development and we are excited about the opportunities that may lie ahead to advance medicine for patients around the world.”
Friends or Enemies?
Doctors have known for decades that humans host a large and diverse community of microbes, but they were largely viewed as harmful invaders.
That view has changed. Researchers now believe microbes work together, almost like another human organ, and closely cooperate with our own human cells to carry out many important functions like digesting food, fighting infection, and breaking down toxins. “It’s a community, an ecosystem that lives in balance,” Dr. Kaplan explains.
But when the microbiome gets out of balance, trouble can ensue.
Finding the Right Balance
Ramnik Xavier, MD, PhD, chief of Gastroenterology, wants to understand the relationship between microbes living in the gut and human genes and the immune response. “We’re doing experiments to try to help us understand how the microbes contribute to health and how the microbes contribute to disease,” says Dr. Xavier, who is also co-director for the MIT Center for the Microbiome and co-directs the Infectious Disease and Microbiome Initiative at the Broad Institute.
Dr. Xavier, a principal investigator for the Human Microbiome Project 2, and colleagues made headlines in 2014 with the news that Crohn’s disease, a debilitating form of inflammatory bowel disease, is linked to an imbalance of microbes in the gut. These findings raised the possibility that altering the microbes in the gut could change the course of the disease.
In 2016, they published a landmark series of papers that followed the development of the microbiome in infants and children. They found evidence that microbes influence or “educate” the development of the human immune system early in life. They followed the development of the microbiome in children at high risk for Type 1 diabetes — an autoimmune disease—in northern Europe. Over time, they found that children who developed diabetes had fewer different kinds of microbes but more of the type that cause inflammation — evidence that microbes play a role in educating the developing human immune system.
Related studies support the “hygiene hypothesis,” which holds that exposure to greater microbial diversity early in life is good for human health. For example, Dr. Xavier and colleagues found that children living in more hygienic, modern communities in northern Europe were less exposed to a diversity of microbes. Those children developed fewer protective substances that stimulate the immune system than those who lived in regions where children are exposed to more microbes early in life. Similar studies are currently under way to understand how the gut microbiome contributes to the risk of food allergies in children.
Going forward, Dr. Xavier and colleagues are tracking women giving birth at Mass General. “If we understand which microbes colonize the infant gut and in what order,” Dr. Xavier says, “we might be able to correct what’s missing in children and decrease their likelihood of developing certain diseases.”
Taking samples of the mothers’ and infants’ microbes from the day of birth through the first two weeks of life, they are observing and recording the actual, real-time development of the human microbiome.
The mother’s microbiome may be key, he says. Also important is anything that perturbs the child’s microbiome, such as exposure to antibiotics.
In a separate line of study, Dr. Xavier is studying how microbes interact with drugs, sometimes limiting their effectiveness or even causing inflammation.
Babies Provide Clues
Doctors already know which genes predispose someone to develop celiac disease, and that gluten, a protein in grains, triggers the disease. But not everyone who has the genes for celiac develops the disease when exposed to gluten and Dr. Fasano and colleagues hope to find out why.
By determining which children develop celiac disease and why, Dr. Fasano hopes to develop customized treatments to replace today’s costly, one-size-fits-all treatments.
One-year-old Jordan Leeds is doing what he can to help. With barely a fuzz of hair atop his head, the plump-cheeked boy may have inherited his father’s gene for celiac disease. But Jordan has not yet developed the disease.
Dr. Fasano and Maureen Leonard, MD, the center’s clinical director, have been monitoring Jordan’s diet and the development of his microbiome since the moment he was born.
Jordan’s parents, Svetlana and Ari Leeds of Stoughton, Mass., send regular samples of Jordan’s stool and blood along with information about family diet, use of antibiotics and the presence of pets in the home, to Mass General to help the doctors learn which of these factors play a role.
Hundreds of other participating families are doing the same.
By determining which children develop celiac disease and why, Dr. Fasano hopes to develop customized treatments to replace today’s costly, one-size-fits-all treatments. “If we really want to provide the best care possible but also be cost efficient,” he says, “we need to customize treatment and, even better, prevent this disease from happening in the first place.”
Obesity and the Microbiome
Dr. Kaplan, director of Mass General’s Obesity, Metabolism and Nutrition Institute, is studying how microbes in the gut influence metabolism — how we store and burn energy. He is also investigating how food is stored as fat and how diseases related to energy metabolism develop. Those diseases include obesity, diabetes and fatty liver disease.
In a landmark 2013 study, Dr. Kaplan and colleagues looked at what happens to the microbiome after gastric bypass surgery — an operation that helps people lose weight. They performed the surgery on mice and found the mice lost weight as expected. But they also found that the balance of microbes in the mice’s stool had changed. There were more of certain bacteria and fewer of others.
Next, they transferred stool from the mice that had the operation into mice that had not. Remarkably, those mice lost weight, too — even without surgery. This suggests the weight loss that follows gastric bypass surgery is at least partially due to microbiome changes. Could we skip the surgery and simply transfer microbes to control weight in humans? Mass General researchers are testing that idea.
Meanwhile, Dr. Kaplan is studying how the microbes exert their influence. Going back and forth — making observations in humans and testing them in mice and vice versa — he is uncovering what microbes are doing that regulate metabolism.
For example, microbes digest the fiber we eat to produce short chain fatty acids which, in turn, circulate in the body and affect energy metabolism. In a different way, microbes also interact with bile acids secreted by the liver into the intestine which have many functions the body. By studying these processes, Dr. Kaplan and colleagues hope to find “targets” for drugs to treat diabetes, obesity and fatty liver disease.
“This is a concept that people have been talking about for years,” says Hamed Khalili, MD, MPH. “Over the past three years or so it has really taken off.”
Success with the Poop Pill
Dr. Khalili, the Mass General gastroenterologist who treated school principal Bobbie Finocchio, says that using healthy microbes to treat a person with an unhealthy microbial balance is a big first step that has broad implications. “This is a concept that people have been talking about for years,” he says. “Over the past three years or so it has really taken off.”
The capsules, sometimes called “poop pills,” were developed at Mass General in the laboratory of Elizabeth Hohmann, MD, an infectious disease specialist. Although a different, commercial version was not successful in a study reported earlier this year, Drs. Khalili and Hohmann have published a study that showed a whopping 92 percent success rate in treating Clostridium difficile with the Mass General capsules.
Last spring, Bobbie Finocchio visited Dr. Khalili’s office at Mass General two days in a row to take a total of 30 capsules while he watched. Since then, recently married, she has returned to work and is thrilled to be getting on with her life.
With the secrets of the microbiome coming rapidly to light through the work of researchers like those at Mass General, the future looks brighter for Bobbie and others with diseases influenced by the microbes within us.
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