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Change your microbiome, Change yourself

Single-celled bacteria living in and on our bodies outnumber human cells by at least 3 to 1 — and perhaps as much as 10 to 1. The latest estimates from the American Academy of Microbiology put our bodies at 37 trillion human cells and our microbiomes — as those bugs are collectively called — at 100 trillion. Yes, that’s right, our skin and guts, mouths and noses, along with every other body surface, are home to 100,000,000,000,000 microscopic bugs. The typical human microbiome is said to represent about 1,000 different species, with wide variation from one person to the next in exactly which species. If it’s still hard to fathom just how big a single microbiome is, consider this: That same report says those microbes, each vanishingly small and seemingly weightless on its own, add up to something like 2.5 pounds.from Genome Magazine see article here

If these statistics have you reaching for the hand sanitizer, slow down. The vast majority of these bugs are no threat at all. Quite the opposite, in fact. Many of them are our best friends and allies in myriad surprising ways that scientists are only now beginning to sort out. And to think that with all of those antibiotics and disinfectants we’ve been waging an all-out war. We really haven’t known microbes (or ourselves, for that matter) at all.

“We’ve had this perception of microbes as germs, as pathogens, as disease-bearing organisms,” says Lita Proctor, a scientist at the National Human Genome Research Institute and program director of the Human Microbiome Project. “Much of the scientific literature for decades and decades has been completely focused on pathogens, and that has also framed our point of view about microbes. But it has become clear that the vast majority of microbes we come in contact with on a daily basis are not pathogenic. They are either benign and couldn’t care less that there is a human nearby or they actually provide a benefit.”

Bacteria play essential roles in the development of our immune systems as newborn babies are colonized at birth and subsequently by microbes from mom and the environment. Once established, those microbes, and particularly those that fit our cells like a lock and key, provide us with energy sources and vitamins humans can’t make on their own. They produce ingredients that act as anti-inflammatories and send signals to our brain. “Good” microbes help us fend off the “bad” ones. We really can’t live without them.

The Other Human Genome

“Instead of declaring war, we need to think in the context of ecosystems that make up our bodies. Figuring out how to encourage good microbes while eliminating the bad will be of increasing importance.”

Despite their importance and value, all of these microbes had gone mostly unrecognized, especially in the biomedical field. That began to change substantially in 2007 when the National Institutes of Health launched the Human Microbiome Project, an effort to catalog the microorganisms living in and on healthy human bodies. It was in some ways a follow-up to the Human Genome Project. Scientists would apply rapidly improving DNA sequencing technologies to define what some like to consider the “other human genome” — the human microbiome — via samples taken from hundreds of healthy people and many parts of their bodies: behind the ear, the inner elbow, the lower intestine, and the mouth. The object of study was literally right under our noses, but it was still so foreign that NIH Director Francis Collins has likened the researchers who carried out the work to “15th-century explorers describing the outline of a new continent.”

The result is the first comprehensive picture of what a normal human microbiome looks like, at least in these modern times. “We have defined the boundaries of normal microbial variation in humans,” said James Anderson, director of the NIH Division of Program Coordination, Planning, and Strategic Initiatives, in the release issued by the NIH as the first big batch of Human Microbiome Project studies were published last year. “Now we have a very good idea of what is normal for a healthy Western population and are beginning to learn how changes in the microbiome correlate with physiology and disease.”

A Veritable Explosion

Since then, there has been an avalanche of new studies connecting the microbiome to health on the one hand and disease on the other. A disrupted microbiome, driven perhaps by the overuse of antibiotics combined with an overprocessed food supply, is now a suspected contributor to the obesity epidemic. Those disruptions often arise from the very first days of life as babies delivered by C-section miss their first inoculation with healthy bacteria found in their mothers’ vaginas. Formula-fed babies also show significant differences in their microbiomes compared to those who are breastfed.

Changes in the microbiome have been linked to obesity, inflammatory bowel diseases, allergies, and asthma, which means the key to treating such disorders could be right under our noses.

A study reported in Science found that differences in the microbiome might help to explain instances in which one individual in a pair of twins is obese while the other is not. Microbiome samples taken from obese twins and delivered to mice led the animals to gain weight in a way that the microbiomes of their leaner siblings simply did not. And a comparable study of mice and twins from Malawi showed that differences in the microbial composition of the gut could explain how two children in the same family sometimes differ so markedly when it comes to malnutrition, too.

If changes to our microbiomes might be a cause of obesity, perhaps they can be a cure for it, too. The gut microbiome apparently undergoes drastic change after gastric bypass surgery, and it gets better: Overweight mice given a “post-surgery” microbiome (but no surgery) lose weight, too.

There are other observations that may seem even less obvious. Changes in the intestinal bacteria may explain why HIV patients — even those who do well with treatment — sometimes still suffer from chronic and ultimately life-threatening diseases. Less diverse gut microbiomes have been linked to the risk of some cancers. Signals produced by the gut microbiome influence blood pressure. The microbiome plays a role in the way our bodies metabolize and respond to some prescription drugs.

In December, a study in mice added to evidence that the microbiome can influence the brain. Animals susceptible to autism-like symptoms as a result of infections suffered by their mothers during pregnancy also showed changes in their microbiomes. When researchers at the California Institute of Technology treated the mice with healthy gut bacteria, some of the animals’ abnormal behaviors and anxiety went away.

Even our family dogs are in on it. Another study just found that the dust in dog-friendly homes protects against allergies and asthma through changes (you guessed it) in the gut microbiome. Young mice fed on doggy dust didn’t react much to cockroach allergen compared with animals fed pet-free dust or none at all. While much of the attention is on the gut, similar things are happening on our skin.

The Modern Age

There is reason to think that the Western microbiome has changed in the last century and not necessarily for the better. A study led by researchers at the University of Oklahoma of microbiome samples taken from ancient people — including Otzi the Iceman and a soldier frozen for decades on a glacier — show that our guts used to look more like those of other primates and rural people in less developed countries. These relatively recent microbiome changes might help to explain the rise in certain kinds of diseases even as modern medicine has enabled us to overcome so many others.

“If you look at a lot of the disease issues of the 20th and 21st century, a lot of them have to do with nutrition and autoimmune processes,” says David Suskind, a pediatrician and gastroenterologist at Seattle Children’s Hospital. “We don’t have a definitive cause yet, but as we look at the new science being done, we see a lot of connections to the microbiome and dysbiosis,” meaning microbial imbalances.

Suskind rattles off a list including arthritis, gum disease, obesity, and cardiovascular disease. His primary interest, though, is inflammatory bowel diseases (IBD) — Crohn’s disease and ulcerative colitis — and their symptoms, including persistent and painful diarrhea. IBD has been considered an autoimmune disease and treated as such with immunosuppressant drugs. But there are reasons to suspect there’s more to it than that.

“IBD is considered an autoimmune process attacking the gastrointestinal tract and other organs,” Suskind says. “But humans have been around for millennia, and IBD is a relatively new disorder.”

Doctors started to notice IBD symptoms about 40 to 50 years ago, he says. Since then, the incidence has only risen. There is evidence to connect IBD to immunity-related genes, but what’s the trigger? Suskind says the evidence is pointing to the microbiome. What would happen if, instead of crippling their immune systems, you gave patients with IBD a new and improved set of bugs?

Powerful Poop

It turns out there is a relatively simple if slightly unappetizing way to do that. The method is called a fecal transplant, and it’s exactly what it sounds like. Doctors infuse patients with slurries of fecal matter taken from healthy people, delivered either to the intestine by enema or the stomach through a nasogastric tube. It’s the quickest and easiest way to replace a microbiome, even if the bacteria and other ingredients going in aren’t entirely clear.

In an example that remains the poster child for the power of the microbiome (and of poop), researchers in the Netherlands published a report early last year in the New England Journal of Medicine showing that an infusion of donor feces can be a miracle cure for patients with recurrent and miserable Clostridium difficile infections, whose symptoms include diarrhea and severe abdominal pain. The results were so clear, in fact, that the study had to be stopped early after an interim analysis showed 81 percent resolution of symptoms in patients after a single infusion of stool. By comparison, patients given standard antibiotic treatment had little more than a 30 percent chance of recovery.

“That was the reason we had to stop,” says Josbert Keller of the University of Amsterdam, who led the trial. “We could not continue randomizing patients with very low a priori chance they would be cured by vancomycin. It was not ethical to prescribe the standard therapy anymore.”

That’s not to say that antibiotics are never the answer for C. difficileinfection. In most patients, vancomycin will do. But once a patient suffers repeated bouts of the infection, Keller says, they really deserve a fecal transplant.

“If we can change the microbiome, we may be able to improve symptoms and lab response. It has the potential to really shift the paradigm of treatment. It’s preliminary and it’s not a cure-all, but I truly do think this will have a real impact on IBD therapy.”

Suskind and his colleagues have recently completed an FDA-approved pilot study in kids with Crohn’s disease or ulcerative colitis as a first step to finding out if the same might hold true in IBD. They treated kids with fecal samples delivered by nasogastric tube, a measure to ensure the microbial cells would reach the whole of the GI tract. While the results have yet to be submitted for publication, Suskind says they have evidence, in Crohn’s at least, that a fecal transplant may put patients into remission.

It’s worth noting that fecal transplants aren’t for everyone, and they don’t come without risk either. After all, they include undefined microbes and viruses, and experts emphasize the importance of careful screening. For those who really do stand to benefit from a borrowed microbiome, eventually there are likely to be simpler ways to obtain fecal samples and receive them in more standardized and appealing manners. A nonprofit called OpenBiome recently launched in the United States as a source for screened fecal samples, with the goal of making the transplants faster and easier for patients and their doctors, and a Toronto hospital reportedly opened the first fecal self-banking system. In even better news, researchers in Canada have some evidence that a fecal transplant pill can knock out C. difficile infections, too.

“If the pills work, that’s the way we should do it,” Keller says. When scientists know more, it might be possible to fill those pills with precise bacterial mixtures in place of poop. There is plenty of promise in probiotics, even if the FDA doesn’t know quite how to regulate and test them just yet. Still, for now, no one really knows what distinguishes a good microbiome from a bad one.

Go With Your Gut

What is clear is that most microbes aren’t out to get you.

“I think we are coming around to the view that most microbes are indeed beneficial,” says Rob Knight of the University of Colorado Boulder. “Instead of declaring war, we need to think in the context of ecosystems that make up our bodies. Figuring out how to encourage good microbes while eliminating the bad will be of increasing importance.”

Knight is one of the leaders of a crowdfunded and crowdsourced study called American Gut, which aims to move the science of the human microbiome ahead by allowing anyone to submit his or her sample for analysis at a $99 fee. They’ll take samples from family members, too, dogs and cats included. (In case you were wondering, they don’t recommend pet alligator samples. “It’s just hard to get the fecal sample safely.”)

Knight says it’s still very early in terms of what people can learn beyond curiosity by participating in American Gut, and they are certainly not providing a medical test. “The main aim is really to democratize the technology and make it accessible for the first time to a wide audience,” he says.

It’s clearly working. They’ve received more than 8,000 samples and raised almost $340,000 on Indiegogo. Eventually, as the data come in and become integrated with other clinical findings, it may become possible to learn much more about what your unique microbial makeup might mean for health and disease — and perhaps also how to change it.

Right now what American Gut offers is a way for people to take a peek at their personal microbiome and to see how they fit with their larger human community. Knight says they will soon add a new “challenge feature” based on the recent findings of Harvard scientists that sudden and extreme dietary shifts — to either a vegetarian or wholly meat-based diet — can alter the microbiome in a matter of days.

Down and Dirty

It’s likely the microbiome is responsible in part for many things we already know about healthy living: why it’s good to eat leafy greens and best to leave the french fries alone, for instance. Other lessons might be harder to swallow, depending on your attitudes about hygiene.

Knight lets his toddler daughter eat off the floor, get dirty outside, and interact with livestock — all things that support a diversity of microbes and perhaps lower risk of infection and autoimmune disease. (Full disclosure: These practices also come as good news for me.) As for the NIH’s Proctor, her best advice for now is to stay tuned and lay off the antibiotics, which she likens to sledgehammers.

“They kill off not only germs but also the microbiome, leaving you vulnerable to invasion by other microbes,” she says. “The microbiome is actually our first line of defense. When you kill it off with antibiotics, you really are doing your own system a disservice.”

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