Understanding the Microbiome
It’s one of the hottest topics in science—but could it lead to a diabetes cure?
Don’t look now, but you’re covered in bacteria—inside and out. The human body plays host to thousands of different species of microscopic organisms. All of the bacteria that live inside us are collectively known as the microbiome, and it’s a world as diverse and complicated as any rainforest. These organisms live in and on our hair and skin, and especially in our digestive system. Researchers estimate our bodies contain 100 trillion single-celled bacteria and just 10 trillion human cells.
All of these passengers aren’t just along for the ride. We now know that some of the bacteria inside us perform necessary tasks. “The microbiome breaks down the food you eat and makes essential vitamins,” says Stanford University geneticist Mike Snyder, PhD.
Other bacteria are unpleasant or harmful, producing toxins, eating away at our teeth, or making our armpits stink. Still others may be an evolutionary advantage gone wrong: By helping the body wring more calories out of food, for example, some species of gut bacteria may contribute to obesity and type 2 diabetes.
The idea that the trillions of bacteria inside our bodies could have a dramatic effect on our health is relatively new. In the past decade, research into this world within has become one of the hottest fields in science, driven by new gene sequencing technologies that let researchers quickly and inexpensively catalog and identify the thousands of different species living inside us.
As they learn more about how the microbiome works, some scientists have begun to wonder whether our bacteria are in a state of upheaval. Technological advances such as antibiotics, indoor plumbing, and processed food all have an effect on the bacteria inside us. Such triumphs of civilization have undoubtedly led to an overall improvement in human health: Around the world, people live longer than they did a century ago.
But by altering or upsetting a balance between our bodies, our diets, and the microbes established over millennia, these microbiome-altering factors may be promoting or even causing diseases virtually unknown to our hunter-gatherer ancestors, from type 2 diabetes to asthma, rheumatoid arthritis to irritable bowel syndrome.
“In general, there is an increasing awareness that the microbiome—which is essentially bacteria that live in our bodies—may have a role in the development of multiple diseases in human beings,” says Nicolas Musi, MD, a diabetologist at the University of Texas Health Science Center in San Antonio. “There’s an increasing interest in understanding how the microbiome and the human body interact.”
Unlocking the secrets of the microbiome could contribute to a cure for diabetes. Researchers—including many funded by the American Diabetes Association (ADA)—are investigating the connections between the microbiome and diabetes.
So far, the results are promising: Bacteria living in the digestive tract have been linked to obesity and inflammation, both contributors to type 2 diabetes. The interaction between the microbiome and the body’s immune system might be a factor in triggering type 1 diabetes. Gestational diabetes and obesity during pregnancy may impact the maternal microbiome and the bacteria that mothers pass on to their children during birth and breast-feeding, contributing to obesity in the offspring later in life.
There’s lots more work to be done, particularly in terms of translating discoveries about the microbiome into practical, widely applicable treatments. One major possibility is probiotics, foods and dietary supplements that contain beneficial live bacteria. Scientists are already finding clues as to what doctors and patients might be doing in the future to maximize the microbiome.
For her ADA-funded research into the cellular chemistry of people with type 2 diabetes, University of Wisconsin School of Medicine and Public Health diabetes researcher Michelle Kimple, PhD, uses specially bred mice, genetically altered so that they never feel full. The rodents eat so much they get fat; by the time they’re 10 weeks old, they should develop the equivalent of type 2 diabetes. “They are extremely obese—they look like little marshmallows with legs,” she says.
Not long ago, though, Kimple noticed something strange. The rodents raised in her lab were getting fat right on schedule. But the mice weren’t developing type 2 diabetes. That, in turn, made them useless for the experiments she had planned.
At first, Kimple thought she had been sold a faulty batch of mice. When genetic tests confirmed that the mice were as advertised, she set about looking for other explanations. Soon she focused on the conditions the mice lived in: Mice raised and fed in sterile conditions at a special breeding facility reliably developed type 2 diabetes. Those in her lab, where protective booties and hand-washing are about the only steps taken to prevent contamination from outside, did not.
Her surprising conclusion: Something about the environment of her lab or the food the mice were eating was altering their microbiome, short-circuiting the process that led to diabetes. “Evidence strongly points to the gut microbiome as playing a role in the protection from developing diabetes,” she says. “Something about the building is protecting these mice.”
Kimple is now working with colleagues to investigate the bacteria in the digestive systems of the two groups of mice. She’s already found some major differences, including species of bacteria that are all but missing in the sterile-raised mice. It wasn’t what she expected when she began her work, but she’s excited by the possibility that this lab mouse mystery might be a window into how diabetes and the microbiome are connected. “It’s a surprisingly strong result,” she says. “It’s got the potential to inform on human disease just by trying to figure out what’s going on in these mice.”
Type 1 Trigger
To understand how the microbiome might trigger type 1 diabetes, researchers are looking at the Nordic nation of Finland. One in 100 Finns have type 1. That’s three times higher than the frequency in the United States (about 1 in 300 Americans have type 1) and nearly seven times higher than Finland’s neighbor to the east, Russia.
University of Helsinki researcher Mikael Knip, MD, PhD, thinks the microbiome may be part of the explanation. To test the idea, Knip and colleagues collected a wide range of samples—from mothers’ milk to stool and blood—from infants and toddlers in Finland, Russia, and Estonia and compared them.
The goal was to spot differences that could explain why Finnish kids are more likely to develop type 1 diabetes than their counterparts in Estonia and Russia. They found that children in Russia and Estonia were typically exposed to more bacteria earlier in life, via everything from infections to fermented food and breast milk, than children in Finland.
Ramnik Xavier, MD, a gastroenterologist and researcher at the Broad Institute of Harvard and MIT, had a more specific question. “We took 33 kids from Finland and asked … could we identify microbial signals in kids who stayed healthy and kids who developed type 1 diabetes?” He used some of the Finnish stool samples Knip collected to look at the bacteria in the kids’ digestive systems.
In a paper published in the journal Cell Host & Microbe in February, Xavier showed that the gut microbiome was indeed different in kids who went on to develop type 1. The changes showed up long before their symptoms: “A year before they developed diabetes, the complexity of their gut microbiome dropped,” Xavier says. “We know more bacteria are good for you. The more diverse your microbiome, the less likely you are to have type 1.”
Here’s how it might work: In type 1, the body’s immune system mistakes the cells that produce insulin for invaders and wipes them out. Perhaps, Finnish researcher Knip suggests, kids in Finland are too clean and healthy early in life. “With less early infection, the immune system has too little to do, so it starts looking for other targets,” Knip says. “If you have a decreased microbial load, the immune system doesn’t get the exposure it needs to develop healthy responses.”
The next step is identifying what exactly is missing in the microbiome of kids who develop type 1. “If you can find the triggers of disease, you can shift, reprogram, or reset the microbiome,” Xavier says, suggesting probiotic use might be one way to do so. That may stop the type 1 autoimmunity chain reaction before it ever starts.
Little Bacteria, Big Data
In people whose genes put them at risk for type 2 diabetes, disturbances in the microbiome might be the factor that puts them over the edge, triggering the failure of pancreatic beta cells that produce insulin.
Snyder should know. In 2010, he was in the middle of a study that tracked thousands of different molecules in his blood, many of them products of his microbiome. Genetic testing had already shown he was at an increased risk for diabetes, but Snyder—a trim and muscular 50-something who showed up to an interview in July on a battered road bike, drenched in sweat—didn’t take it too seriously.
Nearly a year into the study, though, he caught a cold from one of his sons. “My blood glucose shot through the roof after I got this infection,” he says.
In the weeks that followed, Snyder and his team watched—almost in real time—as he developed type 2 diabetes. “My genome has me predisposed, and a virus triggered the disease,” he theorizes. To bring his diabetes under control, Snyder changed his diet, started running, and doubled his biking. But he’s had flare-ups following viral infections in the three years since the study was published.
The remarkable results led to an ongoing, multimillion-dollar study that applies the same scrutiny to the cells and microbiomes of 100 volunteers without diabetes, focusing on how infections affect what’s going on in their bodies.
To illustrate, Snyder calls up a series of pie charts on his computer screen. The charts represent different species of gut bacteria living in his intestines before and after a cold. “Here’s my stool—healthy, sick, 2½ days later,” Snyder says, pointing to the computer. “When I got sick, you can see the whole microbiome changes. It had a system-wide effect.”
Snyder’s theory is that viral infections and other illnesses may upset the microbial balance inside us. “Whether it’s overfeeding or a viral infection, the microbiome gets disturbed,” he says. That, in turn, could trigger chemical changes that may tip the balance in people already prone to type 2 diabetes or other diseases.
The exhaustive look Snyder’s lab takes at genes and molecules in their volunteers will probably never be practical for the average patient. But Snyder hopes the study’s deep dive into patients’ microbiomes can narrow down the possibilities for future research. “Once we find out which pathways to look for, we can switch to a lighter version,” he says. In the future, doctors might have a new way to identify people at risk for type 2 diabetes and manage their microbiome using probiotics or dietary changes to prevent it from kicking in.
The trillions of bacteria in and on us arrive shortly after birth, colonizing our gut, skin, and mouth. Our mothers pass on their bacteria during birth and nourish the fledgling microbiome with special proteins during breast-feeding.
As a result, the first year or two of life have a big influence on what kinds of bacteria we’re stuck with for the rest of our days. “We believe whatever comes first plays a big role in what gets established and has permanence,” says University of Colorado–Denver biologist Jed Friedman, PhD.
That, in turn, means the makeup of the maternal microbiome at the moment of birth is extremely important. Variety is key: Research shows that people with fewer species of bacteria are more likely to be obese and have a higher risk for type 2 diabetes. “With garden-variety obesity, the diversity shrinks and there’s less room for healthy bacteria,” Friedman says.
Yet Friedman’s ADA-funded research shows that just before giving birth, the diversity of the mother’s microbiome plummets. Friedman has experimented with mice, comparing animals given microbes from women in the first trimester of pregnancy to those given transplants of third-trimester microbes. “Mice given the microbiome from women in their third trimester became fatter and more insulin resistant than those given first-trimester microbes,” he says.
In evolutionary terms, this is no coincidence: Mothers tend to give babies the mix of bacteria that maximizes weight gain. “They’re transmitting the microbiome that will allow the infant to extract as much energy as possible from food,” Friedman says. “In theory, it makes sense.” Evolutionarily speaking, you’d want to give babies the best shot at growing big and fast in a world where food might be hard to come by. But in modern times, where calories are overabundant, a fat-maximizing microbiome at birth can set kids up for weight problems later in life.
For babies born to obese mothers or mothers with gestational diabetes, the problem is worse. Gestational diabetes and obesity impact the maternal microbiome even more dramatically. Those differences are passed on to babies. “They’re fatter at birth, and they’re at high risk for extra weight gain,” Friedman says. “What the microbes are doing is telling the body to store more fat.”
The fix, for now, is familiar: Women should aim to reach a healthy weight before getting pregnant or work to healthfully manage weight gain during pregnancy. Women with gestational diabetes should control it as much as they’re able. And, experts say, breast-feeding is recommended for as long as possible after birth.
Not all of the bacteria living inside us are helpful. Some produce a harmful substance known as endotoxin. Normally, it stays in the gut, with a small amount leaking into the bloodstream through the intestinal walls.
When levels of endotoxin in the body rise during an infection, they prompt the immune system to respond. The resulting clash makes us sick. “It’s responsible for the normal signs and symptoms of bacterial infection,” University of Texas researcher Musi says, including fever, chills, a racing heartbeat, and—in large amounts—even organ failure.
Could type 2 diabetes be connected to endotoxins? It would make sense: People with diabetes, as well as people who are obese, often have persistent inflammation in their bodies. It’s as though they’re constantly a little bit sick, with their immune systems working overtime.
Perhaps, Musi says, they’re reacting to unusually high levels of bacterial byproducts in the blood. “People with type 2 diabetes have two to three times the endotoxin level in their bloodstream that a lean, healthy person would have,” he says.
But why? Again, the answer may lie in the microbiome. “One idea is that eating more fat can favor the growth of certain bacteria proven to produce more endotoxin,” he explains. With funding from the ADA, Musi is studying the effects of a fatty diet on gut bacteria—and on the intestinal walls, which could be damaged by fat and allow more endotoxin to leak through.
To test his theory, Musi has healthy volunteers eat a diet with approximately twice the usual fat content (but the same number of calories their previous diet included). After a month, he looks at the levels of endotoxin in their blood. When the study is complete, he should know if diet contributes to higher levels of endotoxins. If so, it would be a clue as to whether the microbiome drives the onset of type 2 diabetes.
It would also provide a simple way to reduce type 2 diabetes risk. “Ideally, nutritional changes would be the best treatment,” Musi says. “Promoting a diet with a lower content of fat is a natural.”
Bacteria are one of the first life forms to have developed on Earth. Single-celled and microscopic, they are also one of the most common and widespread organisms on the planet.
Probiotics are live bacteria, eaten in pill form or in food, in high enough concentrations that, the theory is, the body’s microbiome is affected in a positive way. Yogurt with specially added bacteria is one common example.
Mapping the Course
The American Diabetes Association and the JDRF recently published a paper in the journal Diabetes that summarized expert opinion about specific areas of microbiome research that have the most promise for catalyzing the development of new treatments for diabetes.
Source: Diabetes, published online Sept. 29, 2015