Mysteries of the Microbiome
Dr. Alexander Khoruts understands if you hesitate to shake his hand. He does dirty work. But he's saving lives with what the rest of us flush away.
The University of Minnesota associate professor is part of a revolution that's overturning decades of scientific assumptions in acknowledging the critical role of bacteria in managing our health.
Though officially a gastroenterologist/immunologist, in reality Khoruts is more of a microscopic wildlife manager. He attempts to restore the gut-flora system of those wracked with Clostridium difficile, or C. diff, a gastro-intestinal affliction.
C. diff typically strikes those who are hospitalized and given antibiotics. Sufferers get the runs until they literally run out. Death usually occurs from dehydration. With 15,000 to 20,000 deaths per year from C. diff, the disease claims more lives in the U.S. annually than HIV.
Khoruts's treatment involves a simple, straightforward procedure dating back to fourth-century China, but which has only found sporadic acceptance until recently. It's called a fecal transplant.
Healthy donors come to his office and leave a sample of the rich diversity in their gut and colon. Khoruts liquefies, filters, and freezes it for future study or transplant.
Khorut's lifesaving stool transplants are just the first application made possible by our emerging understanding of the microbiome, the 100 trillion or so microorganisms that inhabit the body, particularly the gut. There are 10 times as many microbial as human cells, and their DNA is both more diverse and plentiful than our own by a hundredfold.
These bacteria, viruses, fungi, and other microorganisms that evolved inside of us over the course of millions of years appear to play such an important role in our biology that they've been collectively dubbed "the forgotten organ."
"I was an immunologist, I like to think I still am in some ways," Khoruts says from the office adjoining his old immunology lab on the University of Minnesota campus. "Within my clinical sub-specialty a whole new organ was just accepted. I have to drop whatever I am doing and focus on that because that is never going to happen again."
Not only do our microbiota facilitate digestion, but they've also been linked to mental health, allergies, auto-immune diseases, heart disease, and various cancers. Where genes evolve over generations, our microbial ecosystem responds and adapts much quicker to environmental stressors or changes.
The microbiome appears to work epigenetically (turning genes on or off) and in concert with our immunological system to keep us healthy. While we've long heard about pathogenic bacteria, the great majority of bacteria in our body perform beneficial functions.
Some create enzymes we can't. For example, there are plentiful complex oligosaccharides in breast milk, which humans lack the enzyme to break down. But it's food for some species of beneficial gut bacteria that turn it into nutrients the baby can use. This fuels the growth of good gut bacteria, which squeezes out the pathogens, keeping them isolated.
This is just a small example of how our bodies and bacteria have co-evolved. But Khoruts and other researchers increasingly believe that widespread use of antimicrobial agents and antibiotics — along with our Western diet — are damaging our hard-won gut flora. It may be the key factor in a wide range of recent epidemics including obesity, diabetes, Crohn's disease, and even autism.
"The diversity of our microorganisms is decreasing," Khoruts says, "with possibly deleterious consequences like the emergence of these diseases."
Two years ago Catherine Duff's life was hardly a life at all. She was suffering her seventh bout of C. diff in six years, beset by abdominal pain, fever, loss of appetite, and chronic diarrhea that would strike 20 to 30 times a day.
"My bed is about maybe 15 feet from the toilet in our bathroom," says the 57-year old mother of three who lives in Indianapolis. "I had to have a potty chair beside the bed."
The only time she left the house was to go to the hospital, which she had to do almost every other day. Over the course of 10 to 12 hours, she'd get 12 to 15 bags of saline and bags of enriched plasma to boost her busted immune system.
The line between dehydration and death can be thin, so she had a network of friends who took turns checking in on her while her husband was at work.
"They would come over and I wouldn't be making any sense. They'd say, 'Come on, we have to get some fluids in you.' This was my life for months at a time," Duff recalls. "You literally feel your life draining out of you."
Duff first caught C. diff in 2005 after a diverticulitis attack whose treatment went south to the point where she had to have a temporary colostomy. They removed part of her colon and had to treat her with broad spectrum antibiotics because the wound became infected.
Duff would catch C. diff five more times, in each instance treating it with stronger antibiotics as it became harder and harder to eradicate. Eighty percent of the time you treat C. diff with antibiotics and it goes away. It recurs for 20 percent, and each time it does means the disease is two to three more times likely to return.
C. diff exists in both spore and bacteria state. Antibiotics will kill the bacteria but leave the spores, which turn back into bacteria and re-infect the host. This is why antibiotics can have a hard time killing it.
Our gut flora, and possibly the biofilm that protects it, gets worn away with repeated antibiotic treatments until there's no good bacteria left. Here C. diff thrives, and the victims wind up like Catherine Duff.
"In 2009, I had a patient that was quite desperate," Khoruts says, explaining the case that got him written up in the New York Times a year later, helping bridge the way to wider acceptance. "She arguably was more desperate than Catherine."
Khoruts spent seven months treating her with antibiotics, to no avail. So the 49-year-old doctor went back almost a quarter-century to something he heard about back in his first year of med school — fecal microbiota transplantation (FMT). It has been done throughout history and was first attempted in the U.S. in 1958. But perhaps unsurprisingly considering its negative associations, FMT didn't come into widespread practice.
FMT remains an experimental treatment, and Khoruts had to fill out an FDA application that took at least six months to complete and in the end weighed 22 pounds. Khoruts took a stool donation from the woman's husband and had all the microbiota in it sequenced and judged safe before he reseeded her lower intestine, using the same device one would for a colonoscopy.
Not only did the procedure cure her, but subsequent testing proved that her husband's microbiota had successfully inhabited her damaged gut and driven out the C. diff. It was the first documented case in history, mainly because DNA sequencing technology has become affordable only in the last half-dozen years.
Recently a doctor in Canada revealed he'd successfully treated 27 people with poop pills. The pills are simply donor feces encased in gelatin, so it survives your digestive tract. The patient needs to swallow two to three dozen of them.
"Pill or as a colonoscopy, those are little questions and kind of technical challenges," says Khoruts.
In Europe, where colonscopy is rare, this treatment is typically accomplished through nasogastric tubes passed from the nostril to the stomach, another option he considered.
"I went through the mental checklist how am I going to do this," Khoruts says. "My nightmarish image was we infuse this in her stomach and she vomits and aspirates. Then I'm telling how it happened in a courtroom somewhere."
Despite Khoruts's well-publicized operation a year earlier, Duff had great difficulty finding a doctor in her area willing to perform the procedure.
Naturally there's a substantial ick factor, but on the other hand, there's never been a reported complication, and from a medical standpoint, it's mind-bogglingly cheap. The average colonscopy costs less than $1,200, not counting the cost of sequencing the donation material. Preparation requires little more than a disposable blender. Meanwhile, Duff calculated that her insurance paid $275,000 a year for her Vancomycin (antiobiotics).
"Finally, my husband — who is a retired submarine commander and has spent four months at a time under water in a metal tube with 180 guys and is grossed out by nothing — said, 'Let's do it at home,'" Duff recalls.
Her gastroenterologist at least obliged to test her husband's contribution (it was fine), then gave them some enema bags and wished them luck.
The cure took little time to work its magic.
"Literally the next day for the first time in months I got up, took a shower, got dressed, and went downstairs," Duff says.
A Dutch study comparing antibiotics to FMT in treating severe C. diff had to be stopped because the antibiotics patients were faring so poorly. The study, published in Nature, suggested that FMT has a success rate of over 90 percent compared with under 30 percent for antibiotics.
Only in the last year has the practice become widespread enough that scam artists have stepped in. They're charging as much as $20,000 for the procedure, taking advantage of people's desperation and the paucity of doctors willing to do it.
After some initial hesitation and scrutiny of the burgeoning field, this summer the FDA cleared doctors to undertake the procedure without filing the aforementioned 22-pound Investigational New Drug application with the FDA. However, FMT is still considered an experimental procedure, and some insurance companies won't cover it (those that do bill it as a colonoscopy).
Meanwhile, Khoruts and the University of Minnesota have streamlined the process. They've developed a pool of well-screened, healthy donors and own a vault full of filtered, frozen, odorless samples for future use both in transplants and studies.
"The real solution is to move this thing forward and standardize it," says Khoruts. "Make it like anything else in medicine that you can feel comfortable about."
Ellen Bolte was the first to postulate a link between autism and gut bacteria, in 1996. Bolte is a self-taught computer programmer in Chicago with a year of community college education. She delved into medicine only when her youngest child, Andrew, developed autism.
At the time, autism was believed to be a genetic disease. Bolte suspected otherwise, because up until her son was 15 months old, he was happy and healthy. That was when Bolte's pediatrician moved out of state. Around the same time, Bolte switched Andrew from soy milk (the pediatrician's preference) to cow's milk.
When Bolte took Andrew to the new pediatrician for a check-up, the doctor noticed fluid in the child's ears and concluded they were infected. The doctor prescribed an antibiotic to clear them up.
Bolte had three older children; she knew what a child's ear infection was like, and questioned the doctor. Andrew had no fever, and had expressed no discomfort.
"I said, 'What are we treating?' and he said, 'If you value your son's hearing you'll give him these antibiotics,'" Bolte recalls.
Despite repeated treatments with different antibiotics, the doctor saw no improvement in Andrew's ears. After four ten-day treatments over a two-month period, Andrew broke out in a facial rash. The pediatrician switched him to Sulfanomide antibiotics, and after a 10-day treatment, issued a 30-day maintenance dose. About a week into the maintenance dose, Bolte and her husband noticed a change in Andrew's behavior.
"He almost looked like a drunk toddler," Bolte says. "He was so happy and giddy, flinging himself around. As the days went by, the behavior was, well, disturbing in the sense he was laughing like a hyena."
It only got worse from there.
"After about a week of that he started to become real quiet and withdrawn," she continues. "He stopped interacting. Then it got to be he not only didn't want to be interacted with, but if you tried to interact, he screamed. At a certain point he started screaming all day long, a high-pitched siren scream."
Around the same time his behavior changed, Bolte noticed Andrew was also suffering from a host of gastrointenstinal issues. He had chronic diarrhea, and even though he was losing weight, his belly grew swollen and bloated.
Now he really was sick. So what did the pediatrician do? Prescribe more antibiotics. But Bolte wasn't satisfied, so she took Andrew to an ear, nose, and throat specialist, who quickly (and correctly) diagnosed the fluid in the ear as an allergic reaction to cow's milk.
Unfortunately, this was the least of Andrew's problems. Now 20 months old, Andrew was a holy terror. He couldn't be left alone — he'd eat the drywall or injure himself. In March 1994, he was diagnosed with severe autism.
The doctors told Bolte that she just must've missed the early signs — but she knew Andrew was okay until he was 15 months old. He'd begun to use language and had actually regressed.
One doctor broke down in tears telling Bolte that Andrew's affliction was so severe they should simply institutionalize him. A deeply religious person, Bolte refused to accept that.
"They kept telling me autism is incurable," she says. "First of all, I wasn't convinced he had autism. I could see where he met the autism criteria, but he wasn't born with it. So if you don't know what caused it, how can you say you can't fix it?"
Bolte began seeking her own truth. She read the popular press stories, then moved on to medical journals after a sympathetic doctor told her how to get a Medline account. She bought a medical dictionary and pored over articles for hours. She developed theories, which she'd take to skeptical doctors who batted them away like mosquitoes. That only sharpened her resolve.
Bolte ultimately decided the likely cause was a bacteria in the Clostridium family, home to C. diff, botulism, and tetanus, among others. Because they can exist as spores, they're able to survive antibiotics. They also create neurotoxins, which could explain Andrew's loss of language and social functioning. Bolte believes kids with regressive autism represent a different, non-genetic strain of the disease.
"It's hard to think of autism being caused by different things because the symptoms are always the same, but if you think of a fever — that's a symptom," Bolte explains. "There is nothing biochemical you can look at yet that says, 'This kid has autism, I can see it in their blood.'"
Bolte believes the carpet-bombing of Andrew's gut at a crucial stage in development permanently damaged him, and notes that anecdotal cases of miracle "cures" typically feature families who honed in on the gut early in treatment. Bolte points to a 2011 article entitled "It Takes Guts to Grow a Brain," which studied mice born without microbiota and found that certain epigenetic switches for brain development weren't thrown if the mouse wasn't exposed to a microbiome by a certain age.
Khoruts concurs that there may be something to this theory.
"I worry there is a developmental window, probably very early in life, where there is all of this critical interaction of microbes with the development of the immune system, nervous system, and the metabolism," he theorizes. "We know now microbiota take three years to become adult-like. That could be our window and, of course, our kids being bombarded with antibiotics for ear infections factor in that window. All of our effort should be focused on that population — our kids. It may be too late for the rest of us."
A seven-month old child crawls through the dirt, pressing his mouth against everything he sees — stones, old bones, charred wood from the fire the night before. The scene is contemporaneous, but could stand in for any of our ancestors. That's why Jeff Leach is in Tanzania with the Hadza bushmen.
He's looking to go back in time to a place where the human diet has been unchanged for millions of years. Part of the problem is modern norms that put a premium on baby hygiene — ironically putting kids at greater microbial risk down the line.
"We've started to isolate these kids, and in the process, reduced a lot of the bacteria that they may have taken up," says Leach, skyping from Tanzania via a satellite dish connected to his Land Cruiser's battery. "Kids in the western world — by the time they're 8 to 12 years old, they have a diversity of bacteria that looks very adult-like, but they acquire it very slowly. We think hunter-gatherer groups acquire diversity much faster. So maybe one of the problems with our youth and all these allergies and auto-immune diseases may have to do with delayed acquisition of diversity."
An anthropologist by background before becoming interested in the microbiome, Leach is the founder of the Human Food Project. His group is attempting to crowdsource an idea about what the major bacterial configurations are in our bodies. It's an offspring of the Human Microbiome Project (HMP), which used a $115 million National Institute of Health grant to explore what a healthy microbiome might look like.
The Human Food Project's effort, called the American Gut Project, is soliciting samples from everyone and anyone willing to donate $99 to help defray the cost of analysis. They've already received 7,000 samples, and though they've processed only a third, patterns are already starting to emerge.
"We're still finding new types of configurations, although the rate of discovery of these new configurations is starting to level out," says Rob Knight, a fast-talking New Zealander from the University of Colorado whose computer algorithms have helped this revolution in knowledge. "It's interesting because we're all 99.9 percent the same in terms of our human DNA, but if you take two people, their microbial communities can be 80 to 90 percent different."
Though advances in genetic sequencing have led the way, microbiologists were left with massive piles of genetic data. Knight developed computer algorithms to sort the data into phylogenic trees based on the DNA's relationship to a particular RNA molecule.
These family trees offer insight into a bacteria's modus operandi. Recent research also indicates that once one kind of bacteria occupies a niche, it's very hard for a similar family member to dislodge it.
Leach notes how strange our ancestral neighbors would seem to us today. The Hadza breastfeed for two or three years and start eating solid food much later than us. Much of the mother's gut bacteria finds its way into the children through her breast milk.
Because the Hadza have more bacterial variety and less inflammation/auto-immune disease, researchers suspect that their environment or lifestyle may be conferring a bacterial benefit. Children raised on farms have been shown to have more diverse gut bacteria than those from the city.
So Leach is going native. After returning to the states for the holidays, he'll return to Tanzania and start living like a Hadza for four months.
"The question is: If I eat their food, dig their roots, live in their dirt, and drink their water, can I get my bacteria to look like theirs, and how long does it take, if it happens at all?" he asks.
One of Leach's collaborators is Maria G. Dominguez-Bello, who has also examined the gut bacteria of isolated Amazonian tribes. Besides working with the tribes, Dominguez-Bello is looking at the gut bacteria of children born by caesarean section.
Babies born by the traditional method emerge covered with their mother's microbiome after passing through the birth canal. Research has linked C-section to asthma, allergies, obesity, diabetes, and eczema. Dominguez-Bello is looking into whether it's possible to seed C-section babies with their mother's microbiome right after birth.
Between infant formula, C-sections, antimicrobial soap, and widespread and reckless application of antibiotics, we've waged war on ourselves without even knowing it.
"I think how we define self is possibly a bigger idea today than Darwin's idea of natural selection," Leach says. "And it's staring us right in the face."
Whatever useful treatments come out of our discovery of the microbiome, for the moment it's hard not to revel in this strange idea that our bacteria may be as much a part of what makes us human as our heart or brain.
"We are not just human beings. We are an ecosystem. We're not solely a function of our genes, the human genome, but also all those genes provided by bacteria of which we know very little," says Dominguez-Bello. "In order to be healthy we need them. They have co-evolved with us, and if we eliminate them we may pay the consequences."
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