Is the Forest of Bacteria Inside You Your Most Precious Resource?
After decades of antibiotic treatments, Americans have lost many of their native bacteria. Could a damaged microbiome be the real cause of autoimmune diseases like asthma and metabolic conditions like obesity?
Imagine a lush, chaotic ecosystem with thousands of species in every possible niche, eating, breeding, and fighting off invaders. It's not the rainforests of Borneo — it's a patch of skin in the crook of your elbow. It's what's inside your large intestine.
The human body carries trillions of bacteria, viruses, and other tiny microbes — so many that they outnumber human cells 10 to 1. The more than 10,000 species of microbes that humans carry contribute 8 million or so genes, whereas parents pass down a measly 22,000. Thought to be the most important bacterial landscape in the body, the gut has 100 billion bacteria for every 1 gram of intestinal matter.
Scientists call these resident microbes and all of their genes “the human microbiome.”
“The microbiome is the collection of the total microbial cells that colonize us in and on our bodies. It’s on our skin. It’s in our gastrointestinal tract. They’re in the crevasses between our teeth,” said Laurie Cox, Ph.D., a researcher at New York University (NYU).
Some of these microbes can be harmful, but most have lived and evolved with humans for millennia.
Our hangers-on help us digest food and make short-chain fatty acids vital for our cells. They produce vitamins, anti-inflammatories, and even their own brand of antibacterials to fend off foreign germs that could hurt us (and steal resources from them).
Bacteria pull much-needed nutrients from the food we eat and produce essentials like vitamins K and B12, but humans have found ways to “hack” the microbiome to make these organisms do even more.
For example, researchers at Rutgers University have found a way to coax a mutant strain of Escherichia coli (E. coli) to produce beta carotene, which the body converts to vitamin A, and deliver it throughout the bodies of mouse hosts. Vitamin A deficiency is a serious public health problem, especially in Africa and Southeast Asia, where poor families may not get enough of the vitamin in their diets.
Though scientists still don’t know what some 30 to 40 percent of our native bacteria do, they believe we could be on the verge of an entirely new understanding of human health and how to achieve it.
Ironically, like the Amazon basin and the Florida Everglades, just as we find the technology to take a full account of what’s there, we realize that the vibrant habitat is already under threat.
Is There Such a Thing as a ‘Normal’ Microbiome?
The Human Microbiome Project (HMP), an offshoot of the Human Genome Project of the early 2000s, is an 8-year, nearly $200 million effort by the U.S. National Institutes of Health. Its aim is to sequence the genes of all our microbes and to answer the deceptively simple question, “What are they all doing?” The project is set to conclude in 2015.
As dozens of HMP researchers at labs across the country began to sequence the bacterial DNA of 300 healthy American adults, they were surprised to find many differences among the microbiomes, even for volunteers living in the same city.
“When we started the HMP, there was this implicit assumption that … we’d get at some kind of characteristic or core microbiome that’s only found in healthy people and another kind of microbiome that’s found in people with various kinds of diseases,” said Lita Proctor, Ph.D., Director of the HMP. “What we found is that there’s quite a bit of variability in the makeup of each of our microbiomes.”
Proctor explained that, of the 10,000 or so species of bacteria that commonly live in healthy humans, each of us plays host to only about 1,000. Which 1,000 species depends on the individual.
It isn’t so much which bacteria you carry that’s important, but the specific jobs they do. For example, it doesn’t matter if you host the same bacterium that can control inflammation as your neighbor, as long as it does that duty.
However, the HMP data don’t paint a complete picture. The scientists only studied microbes found in Americans. What about people from other backgrounds?
José Clemente, Ph.D., an assistant professor at the Icahn School of Medicine at Mount Sinai, set out to study the microbiomes of villagers in remote, rural parts of Venezuela and Malawi.
“If you want to treat people with interventions for the microbiome, the first thing you have to understand is variability across populations,” Clemente told Healthline.
Scientists can figure out which microbes the human body should ideally carry by comparing different body sites and diverse groups of humans.
“If you were to name animals that live in the ocean versus animals that live in a forest, you would really be able to tell if something was out of place. Similarly, there are microbes that are known to be dominant on the skin, which are separate from some of the microbes that are dominant in the mouth, which could be separate from the microbes that live in the gut,” Cox told Healthline. “For example, the arctic and the forest both have birds, but a penguin is different from a sparrow.”
We need both penguins and sparrows (and hawks and seagulls and many other types of organisms) in our internal environments. Experts agree that bacterial diversity is one of the keys to a healthy microbiome. Westerners tend to fall behind non-Westerners in this regard, and the Venezuelans and Malawians Clemente’s team studied are much better off microbially than modern Americans.
“Populations in non-Western countries tend to have higher diversity. They have a lot of bacteria that I think we have lost through modern lifestyle,” Clemente said. “That is perhaps linked to protection against certain diseases that we are seeing increased rates of in Western countries — things like Crohn’s disease.”
“The prevalence of Crohn’s disease has increased dramatically in 50 years. So that is telling you it can’t be genetics only,” he added. “These diseases we don’t see in non-Western countries, so we believe that perhaps the changes in the microbiome we have suffered in the last 40 to 50 years could be related to this increase in certain diseases.”
How did the microbiomes of Westerners end up so depleted compared to our cousins in developing countries? And if we now know bacteria can do us so much good, why are we more determined than ever to wipe them out?
The War on Bugs
Germ phobia in the Western world makes sense if you consider that just five generations ago, in the early 1900s, the Industrial Revolution lead to the growth of densely packed, unsanitary cities where germs could easily spread. Twenty percent of children did not live to see age five. Tens of thousands of Americans died every year from bacterial diseases, including typhoid fever and tuberculosis.
With the rise of antibiotics in the late 1930s, child mortality rates dropped rapidly, with few noticeable side effects. However, most antibiotics are broad spectrum, meaning they’re designed to kill as many types of bacteria as possible. This is similar to clear-cutting a grove of trees. It’s helpful if doctors don’t know what type of infection a patient has, but it can be disastrous for the patient’s microbiome.
In 2010, American doctors prescribed 258 million courses of antibiotics. That’s enough to dose 83 percent of people in the United States. By the age of two, the average American child has taken about three courses of antibiotics.
“There are diseases that kids used to die from two or three generations ago that they’re totally impervious to now, and that’s because of vaccines and antibiotics. So you’ll never hear the scientific community say that we shouldn’t be doing vaccines and we shouldn’t be doing antibiotics. But there are, especially with antibiotics, unintended consequences,” Proctor told Healthline.
“Kids get a lot of fevers, and parents get really frightened and go to their pediatricians and request antibiotics. But antibiotics only work on bacteria. Most of those fevers are viral in origin,” Proctor added. “If you give the child a lot of antibiotics, it won’t have any effect on the fever, but what it can do unintentionally is knock back that child’s developing microbiome.”
Besides damaging the microbiome, over-prescribing antibiotics can lead to the growth of antibiotic-resistant bacteria. The more often bacteria are exposed to these drugs, the more chances they have to evolve new defenses and pass them on to their fellow microbes. Infections caused by antibiotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus, or MRSA, sicken 2 million Americans every year and kill 23,000.
Crop-dusting our microbiomes with antibiotics has led to the near-extinction of several kinds of bacteria we know of, and likely more we don’t. One of the best studied is Helicobacter pylori.
Like many of our microbes, H. pylori appears to be something of a double agent, doing good much of the time, but occasionally making us sick. In the 1980s and ’90s, two scientists discovered that H. pylori causes stomach ulcers. They later won the Nobel Prize for their work. It was also shown that the bacterium leads to stomach cancer. Doctors prescribed antibiotics to wipe it out, and by 1995, fewer than 6 percent of American children had H. pylori in their stomachs.
In his best-selling book “Missing Microbes,” Dr. Martin Blaser, director of the Human Microbiome Program at NYU, tells the alternative history of H. pylori. His research has shown that the bacterium helps regulate levels of acid in the stomach. This puts you at risk for ulcers as you age, but can protect you from gastroesophageal reflux disease, or GERD, and esophageal cancer early in life.
“H. pylori was discovered as a pathogen, and now a generation of doctors have been focusing on its role as a pathogen,” Blaser told Healthline. “But we and others have been finding benefits for these last 20 years that are basically being ignored by the medical community.”
Blaser has shown that H. pylori can help protect against asthma and allergies. The immune system sends out T-cells to tamp down inflammation. Blaser’s theory is that the body won’t make enough regulatory T-cells without the stomach inflammation that H. pylori causes. This is the same inflammation that leads to ulcers. Fewer T-cells means more inflammation in general, including in the airways.
In that way, one little microbe can affect the function of a major part of the immune system. And that just may be the key to the castle.
Strong Microbiome, Strong Defenses
Scientists have found that the most crucial period of development for the microbiome is a brief window between birth and age three. The immune system matures during this same period of early life.
“Nature meant for us to have microbes as a way of helping us through life. So there has to be a moment in that child’s lifetime when there’s an opportunity for the good bugs to develop in that child,” Proctor said. “There’s a kind of cross-talk between the developing microbiome and the developing immune system to communicate to the immune system that these microbes are part of ‘self.’”
Around since the 1980s, the “hygiene hypothesis” says that growing up in a sterile environment full of antibiotics and antibacterial soaps means the immune system never learns friend from foe. This causes it to go hyperactive and attack the body by mistake. Blaser’s theory that the root of the problem is a depleted microbiome is not so much a challenge to the hygiene hypothesis as it is an explanation of why it might be true.
“There’s an increasing body of work that our early-life microbes are training our immunity in particular ways. That’s why it’s particularly important that we not perturb those, because we’re changing the training set,” Blaser said. “That’s my hypothesis for one of the factors that’s driving all of the asthma and allergies. These organisms that historically or prehistorically were training our immune system aren’t there anymore.”
The data are striking. Rates of type 1 diabetes in children are now twice as high as they were in the 1980s, and the condition is 10 to 20 times more common than it was a century ago. The incidence of celiac disease (an autoimmune reaction to gluten, a protein in wheat, barley, and rye) has more than quadrupled since 1950. Asthma rates increased from 2001 to 2010, and are now at their highest recorded levels, with more than 25 million American asthma sufferers.
“Even though we’ve been quite good at curing many kinds of infectious diseases because we use antibiotics and vaccines and so on, we’ve also seen this concomitant rise of all kinds of autoimmune diseases and allergies,” Proctor said. “The conversation in the scientific community was, ‘Well, maybe we’re doing something to the microbiome that somehow inadvertently initiated these diseases.’”
Research confirms that a robust microbiome is vital to a healthy immune system.
The gut contains the largest number of immune cells found anywhere in the body. The bacteria that live in the mucous lining of the gut help to destroy any harmful agents we might accidentally eat.
A German research team working with normal and germ-free mice (those raised to have no native bacteria) exposed the mice to common viruses, such as those that cause the flu. The researchers found that mice without native bacteria got much sicker. The problem was that their bodies were not producing cells called type 1 interferons to fight off the virus. Signals from gut bacteria prime the body to make type 1 interferons, allowing it to mount a strong defense.
Disrupted gut bacteria can potentially even be used to diagnose autoimmune conditions. An American team at Harvard University and the Massachusetts Institute of Technology identified a unique pattern of gut bacteria in patients with Crohn’s disease. For one, Crohn’s patients had more harmful bacteria in the same families as Salmonella and E. coli, and fewer beneficial bacteria from the Bifidobacterium group, than people without the disease. Giving the patients antibiotics unbalanced their microbes even further, making their Crohn’s symptoms worse.
Scientists don’t know whether an unbalanced microbiome is the only — or even the main — cause of autoimmune diseases. However, evidence is mounting that we are defenseless without a robust and thorny thicket of microbes.
Can Your Microbes Make You Fat?
Alongside the rise of autoimmune diseases has come another completely modern scourge: obesity. In 1990, no U.S. state had an obesity rate greater than 15 percent. Today, not a single state has an obesity rate lower than 20 percent, and 18 states have an obesity rate above 30 percent.
Clemente and researchers at Washington University harvested the microbes of sets of identical human twins, one lean and one obese. The scientists put the human microbes into germ-free mice and then fed them the same diets. Those that had received microbes from the lean twin stayed trim, while the mice that had received bacteria from the obese twin gained weight. Housing the mice together allowed them to co-mingle their bacteria (by eating one another’s poop, as mice do). The obese mice shrank back to a healthier size.
“One of the results we thought was striking is that you can transmit this obese phenotype,” Clemente said. “That tells you that the microbiome is actually causing this disease. It does not mean that the microbiome is the only potential cause for obesity, but we demonstrate that if your microbiome is in a certain state, it can induce this obese phenotype.”
Clemente says the main reason modern Americans have gotten bigger is that we eat more protein and fat than our ancestors did. But that’s not the end of the story.
“We keep telling people, ‘You need to eat healthier,’ and it’s not working,” Clemente said. “So one of the things we’re trying to do is understand if modification of the microbiome can help us in controlling — at least to some extent — obesity.”
Laurie Cox, who works alongside Blaser at NYU, conducted a series of experiments to see whether antibiotics are part of what’s standing in the way of curbing the obesity epidemic.
She exposed groups of mice to low doses of penicillin. One group was given antibiotics starting during the last week of growth in the womb and ending after the mouse pups were weaned. A second group received antibiotics starting in the womb and continuing for life. A third group started on antibiotics after weaning and also stayed on them for life. A fourth group received no antibiotics.
The two groups that received antibiotics during the last week in the womb and during nursing were much more likely to gain weight and to have metabolic problems than the mice exposed to antibiotics after weaning or not at all.
“One of the big surprises to us … is we found that the microbiome rebounded about four weeks after we stopped the antibiotics, but the mice got obese about 20 weeks later,” Cox said. “So even though the bacteria got back to normal, there were still lasting changes in body composition.”
When Cox and Blaser looked at the mice’s colons, they found that bacteria living in this part of the gut were taking more of the undigested food that would normally exit the body as feces and creating short-chain fatty acids. Blaser writes that short-chain fatty acids normally make up about 5 to 15 percent of a person’s daily calories, but the microbes in the guts of the antibiotic-treated mice were in overdrive. They were producing more short-chain fatty acids, and therefore many more calories.
The effects of a disturbed microbiome were amplified when Cox put the antibiotic-treated mice on a “human” diet containing high-fat food. The mice packed on a third of their body weight in fat. Scientists think there is a feedback loop between gut microbes and diet. If a person eats a lot of protein and fat, the microbes that dominate their gut are the ones that prefer protein and fat, at the expense of microbes that prefer, say, kale. Those microbes may in turn harvest more energy from these high-fat foods, causing weight gain.
There is also evidence that the microbiome affects metabolism in less direct ways. For example, one Israeli research team found that no-calorie artificial sweeteners actually raise the risk of glucose intolerance and type 2 diabetes by changing the function of some bacteria in the gut.
The science of the microbiome is still in its infancy. Many of the organisms researchers are studying now have yet to be named, let alone fully explored. “It’s a scientific frontier,” Blaser said.
It will take decades for all this research to be translated into the real world. But there are things we do know now, namely that bacterial diversity is important, and that infancy and early childhood are the best times to cultivate it.
Like a national park, our bacterial ecosystems need to be protected, beginning with the judicious use of antibiotics and including thoughtful consideration of what we eat, where we travel, and even how we give birth.
In Part 2 of our series, “The Truth About C-Sections, Probiotics, and the Bacteria in Your Gut,” learn how we can change our microbiomes for the better. Discover practical, expert tips for tending a personal bacterial garden from birth through adulthood.