A little dirt won't hurt

Duke researchers find our immune systems could benefit from a few more germs.
June 1, 2016

This might be hard to hear, but you are not an individual.

Really, you’re more like a very fecund, populous ecosystem—your moist, oxygenated, constant- temperature body is providing climate-controlled habitat for trillions of living creatures from hundreds of different species. These bacteria form a stunningly diverse, interdependent community of organisms, not unlike a rainforest of biodiversity.

Perhaps the creature that depends the most on that connected food web is you. As biologists like to say, we are “commensal” with our microbes, which means we’re literally eating together at the same table.

“You simply can’t imagine life without them,” says John Rawls, an associate professor of molecular genetics and microbiology at Duke who studies how the cells of our gut communicate with—and support—the cells of the gut microbiome. “Every single step in our evolution has been in a world that’s teeming with microbes.”

None of this is really new, of course. Ever since Anton van Leeuwenhoek and Louis Pasteur first twigged (between the seventeenth and nineteenth centuries) that there is a biosphere of these invisibly tiny creatures all around us, we’ve known that bacteria are ubiquitous in our outer and inner environments.

What is new is gene-sequencing technology developed in just the last decade that enables microbiome scientists to put a stool sample or skin swab through a DNA-reading machine and have it count and name hundreds of different microbial species in a matter of hours. The scientists can’t tell yet what all of these bugs are doing, but they can at least put names on many of them. “The science of microbiomes is like a riptide right now, powered by the technology that allows you to do these things,” says Patrick Seed, a pediatric infectious-disease specialist at Duke Health. “But it’s also powered by the idea that people don’t fully understand these things.”

(The School of Medicine has established a Center for the Genomics of Microbial Systems that supports this work, connecting microbiome scientists not only on the medical campus, but also in the marine lab, the Nicholas School of the Environment, and Arts & Sciences. Rawls is the director of the group.)

This sharpened view of the tiny bacterial lives is leading to a dawning awareness that our ancient relationship with our commensal microbes is a lot more important to our well-being than we had appreciated. “There’s evidence that microbes are affecting our risk for many different diseases, the foods we’re able to tolerate, even our behavior,” Rawls says. “Our interaction with microbes is an inextricable part of life. They are like the air we breathe.”

With the miraculous advent of antibiotics and the emergence of industrial chlorine chemistry, post-World War II American society turned its considerable war-fighting ability toward the microbial world. “Germs” became advertising’s bad guys, and the Formula 409 flowed like a mighty river. Hardly a childhood passed without several slurps of that liquid bubble- gum antibiotic, amoxicillin.

But that hyper-sanitized, hot-water-and- Ajax lifestyle is completely at odds with how we lived for the previous 10,000 generations as modern humans, not to mention the millions of years prior to that we spent as upand- coming primates. Even 100 years ago, most Americans were using outhouses, and there wasn’t exactly a bottle of Purell next to the door.

Plumbing, sanitation, and antibiotics have saved lives, but maybe we took things a little too far. The modern maladies of autoimmune disease and allergy in humans can be traced back to the modern assault on the microbial community, according to associate professor of surgery William Parker, whose desk and keyboard in a tiny, windowless research office are reassuringly dusty. He’s an immunologist who thinks the case is pretty solid for what’s called the hygiene hypothesis, but Parker prefers to call it “biome depletion: the loss of species diversity from the ecosystem of the human body.”

Early immunology viewed all germs as bad guys, but our coexistence with the microbiome “is not as simple as an us versus them kind of thing,” says Staci Bilbo, an associate professor of psychology and neuroscience who studies the immune system’s effect on fetal brain development by giving pregnant rats and mice non-fatal “challenge” infections. “Not everything is out to kill us,” and in fact, there are microbes on our skin and in our various orifices that help keep the more dangerous species at bay, says Bilbo. “In immune system terms, you can define self versus other, but when it comes to microbes, it’s really danger versus safe.”

The hygiene hypothesis says that our immune system—shaped by eons of germiness— is out of whack in a sanitized world. “We’re getting diseases where our immune system is starting to do bad things to microbes that aren’t infections—they’re not guilty of any crimes,” Parker says. “But our immune system has identified them as the enemy.” When the danger signals are misapplied, we see allergy, autoimmune diseases, and inflammation. “There are all kinds of danger signals that our own body can produce that the immune system responds to,” says Bilbo.

“The immune system is like a bored teenager,” Parker adds. “If you don’t give it something to do, it will find something stupid to do.”

So what can we do to make things right with our microbial support team?

“It’s very difficult to read the literature and not eat more fiber,” says Lawrence David, an assistant professor of molecular genetics and microbiology who studies the ebb and flow of bacterial populations in the human gut over time and with changes in diet. As a graduate student at MIT, David volunteered to help his thesis adviser on a study by collecting samples of his own feces daily for a year. That year included extended stays abroad, during which David’s diet changed, but the sampling continued, leading to a very interesting discussion about the contents of his backpack when he came through U.S. Customs on the way home.

A sizable portion of a healthy gut microbiome, 30 to 40 trillion organisms from 500 different families, is devoted to bugs that digest the things we can’t— roughage, your grandmother used to call it. To earn their livings, these microbes break apart various molecules in your food, producing what are politely termed “bacterial products.” They poop and fart so that you can, too.

In so doing, bacteria liberate things from your diet that would otherwise not be available to you, including some vitamins and other essential micronutrients. “Our bodies expect the output of those bacteria to be around,” David says over a chicken gyro outside Twinnie’s Café on West Campus. “We’ve evolved such that those kinds of bacterial products are expected to be present. If we don’t provide the bacteria with the input to create those products, our intestine won’t function optimally. That’s the model. It’s still being fully tested, but I think most signs point to that.”

You wouldn’t exactly starve without your microbes, but mice that don’t have them need to eat about a third more food or take a lot of dietary supplements.

“When it comes to the gut, the diet is the main thing,” Parker agrees. “This is a cool thing: Your bacteria need that stuff that you can’t digest. That’s what they live on. And that’s what gives your bacteria that rich complexity that helps us out. If you just ate McDonald’s hamburgers all the time— white flour, beef, not much else—your body can digest almost all of that and you leave nothing over for your bacteria. It’s sad to be a bacterium in that situation.”

David discovered that the teeming ecosystem of inner space is in fact incredibly robust. “I went into it thinking if you eat sushi today, Taco Bell tomorrow, Lebanese the third day, there would be a signature of each of those and you could somehow see it reflective of all these small dietary decisions. But, for better or worse, this thing can take care of itself. We could detect some signals, like some components of food—fiber was the one that jumped out.”

The contents of your gut are more microbe than food: 60 to 80 percent of human feces is bacteria. “There are mass extinctions every time you have a bowel movement,” Parker says. “But my own gut cells turn over every few days as well, so I can’t really feel too bad for my microbiome.”

David’s continuing time-series studies of gut microbes—he’s no longer the subject—is also showing that the species found in this massive community don’t change a whole lot. “You’re kind of stuck with what you’ve got,” he says. “It didn’t look like being in Thailand shifted what was present, it just changed the relative abundance.” David, whose lab receives some research funding from a probiotic company, is interested in how you get new species to colonize the gut. “That’s an important question for probiotic research, and there’s a lot we don’t understand.”

There’s a long-held belief that the only part of our lives when we aren’t absolutely swimming in bacteria is inside the womb. The placenta connecting mother and fetus is viewed as a stern barrier to the outside world, like the blood-brain barrier.

While the mammalian womb is indeed relatively sterile, it doesn’t ring quite true to Duke pediatrician Patrick Seed that the womb would be completely so. “It doesn’t make sense that we’re this sterile being born into a germ-filled world,” Seed says. Fighting a cold, he keeps a bottle of hand sanitizer nearby in his research office in the Jones Building. “How is it that we think we could have this naïve system that we now give all this stuff to?”

Somewhat heretically, Seed’s research group is building evidence in mouse studies that the womb is not completely sterile, nor is breast milk. The mother, he proposes, is providing the developing fetus with a carefully controlled little taste of her bugs well before birth to prepare its immune system for the germy world ahead. He hasn’t quite nailed it down, but Seed suspects mom has a way of packaging microbes and delivering them to the baby in careful doses. The process then continues after birth as mom provides a starter kit of microbes right along with the immune system cells she shares in her milk.

“It’s really well-contained. Things aren’t growing out of control,” Seed says. “We do know that there are uterine environments in which something breaks and some organisms grow out of control, and that’s one of the reasons why you have preterm birth. It’s actually that process of an infection out of control.”

Preterm birth is what put Seed on this scientific path in the first place. He regularly attends to premature infants in Duke’s neonatal ICU who are fighting infections of all sorts. Born ten or fifteen weeks early, they haven’t had all the bacterial priming the mother might provide.

And try as they might to shield the vulnerable babies, “a neonatal ICU has seventy or eighty nurses who work in there, never mind all the respiratory therapists, and that’s a lot of people who carry a lot of organisms in and out,” Seed says. Blankets placed into the isolette crib with a preemie are meticulously cleaned beforehand to kill bugs, but Seed has begun to wonder if that’s wise. “Should we be sending the blankets home with parents to sleep with first?”

There’s growing evidence that the process of birth itself is another inoculation. Babies born vaginally have significantly different bacterial populations on their skin and in their guts than those born surgically by caesarian section, so much so that one research team at New York University is experimenting with smearing some of mom’s vaginal secretions on caesarian babies at birth.

“When my own kids were born and I hear of other people’s kids being born, the thought definitely crosses my mind that it’s not just the day they’re born, it’s the day they’re colonized,” Rawls says. “It’s not just a birthday, it’s a colonization day.”

Nobody knows yet whether altering the colonization of a newborn makes a difference in a person’s life over the long-term, but say it’s only a 5 percent difference in microbial populations at birth. Seed argues that if you think of the life course as a trajectory, that initially small difference in the path of one’s microbial populations could become a dramatic difference by age eighty.

Duke’s microbiome scientists are pretty much of one mind on these recommendations: Eat more fiber and fermented foods. Go easy on the chlorine cleaning products. Try a few of the probiotic supplements to see if they make any difference. Avoid antibiotics that would purge a bunch of your normal microbes just to make your cough go away.

“I get very upset by the thought that I might have to take antibiotics,” Bilbo says. “Unless I’m really sick, I’m not going to take them. They are a miracle drug, but make sure you need them.”

Make no mistake: Antibiotics have changed the course of natural history by saving more lives than anyone could count. But physicians, public-health officials, and parents are coming around to the idea that these drugs have been overused, taking away a large measure of their magic and leading to hardened strains of bad bugs for which we have fewer countermeasures.

Seed marvels at how much this growing awareness has changed his medical practice. “I have families whose kid is in ICU with a bloodstream infection and we know for darn certain they need an antibiotic— there’s just no survival otherwise. I can say outright to them, ‘Your child will die without this antibiotic,’ and they’re asking, ‘Do we really need an antibiotic?’ because they’re thinking about protecting the microbiome.”

Seed has been thinking about protecting the microbiomes of his children, now fifteen and ten, for a long time. “Between the two of them, one has had one course of antibiotics in their entire life and she was about three.” He recalls the anxiety among pediatricians as they moved from treating almost all ear infectious with an antibiotic to waiting it out a day when a young patient shows up with what could be an ear infection. They provide pain relief, but not antibiotics, and more than half the time, the kid is better in a day or two.

David and his wife have two preschool children who frolic barefoot with the backyard chickens and eat the beans and lentils the adults are eating. “There had been literature that kids exposed to livestock have fewer allergies. So I throw the kids into the coop now and tell them to get the eggs and make sure they cover themselves in as much chicken droppings as possible!” David says, only half-joking.

To increase his exposure to healthy bugs, Seed makes yogurt from his own carefully curated bacterial cultures. “A lot of the live yogurts have mixtures of organisms in them. I’m geeky enough to say that I cultured some of those organisms to see if it was bunk because there are a lot of bogus probiotics out there that don’t even have live cultures in them.”

As is his wont, Parker has taken the probiotic movement a step further. “I use Mother Dirt’s product,” he declares. The product, rightly called AO+ Mist, is a probiotic spray made with ammonia-oxidizing soil bacteria. It’s forty-nine dollars for three and a half ounces, and he has to keep it in the fridge because it’s a live culture. After a shower, “if you decide to use soap,” you spritz some of the clear spray on your “sweat-prone areas.” As a result, Parker, who doesn’t smell unpleasant at all, doesn’t use deodorant. “We’ve lost our contact with the dirt, but we can just buy the product to make up for it now!”

Rawls says his work has made him neither a germophobe nor a germophile. “I’m just mindful. There’s a level of mindfulness and perspective about our microbial world that I try to carry with me through every day. I’m mindful about the different surfaces in our environment and the different kinds of microbes they’re likely to harbor. I try to be mindful of what I eat and the consequences that will have for my microbes.”

Rawls’ mindfulness about microbes has spread to his family as well. Last holiday season, he persuaded his wife and two children, ten and six, to participate in a most unusual family portrait. “We sequenced everyone’s fecal microbiome,” says Rawls. “The kids were really into it.” He sent the four specimens through the sequencing machines, “and we could see certain bacterial types that we shared, but we were not the same.” His microbiome was the least diverse. “Like any family portrait, we’ll do it again in a few years and see how things have changed. I’m kicking myself for not having done this earlier.”

Between her training and teaching as a yoga instructor, her immunology education, and her research questions, Bilbo acknowledges she thinks about her immune system and microbes pretty much constantly. “But if anything, it’s made me think that the world is not quite as hostile as I once perceived it to be. Not every bug is out to kill us.” 

CARE AND FEEDING of Your Microbiome

In the case of your microbiome, resistance is not only futile, it’s also not a very good idea. There’s a lot of evidence that harboring a struggling or imbalanced microbial ecosystem can make you unwell. So you should embrace your bugs—within limits.

Rest assured, all of the microbiome scientists we spoke with still bathe regularly and wash their hands after using the bathroom. And they admit to using hand sanitizer when traveling through busy airports. But they all said they’ve changed their diets and eased up a bit on the scorched-earth cleaning inside their homes to embrace a somewhat germier lifestyle.

“We have some chlorine for the shower,” neuro-immunologist Staci Bilbo says. “But not for the kitchen; there we only use the hippie kind, the kind you get from Whole Foods. It smells better. “

They suggest getting closer to the dirt in your life—for your own good. Try buying a few bags of composted manure for your garden and get some of it under your fingernails once in a while. Snuggle more with your stinky dog. Introduce your gut to a few new playmates by experimenting with probiotic supplements. Eat live-culture yogurts and some bacterially fermented kimchi or sauerkraut. And fiber—don’t forget the fiber.

Some folks endorse drinking unpasteurized milk for the germs and other supposed health benefits, but there are several very compelling reasons why pasteurization is the law, starting with bloody diarrhea and ending with death. Our societal phobia of germs wasn’t entirely irrational, just a bit overthe- top.

In his new book The Human Super-Organism: How the Microbiome Is Revolutionizing the Pursuit of a Healthy Life (Dutton, July 2016), Cornell professor Rodney Dietert ’74 offers more insight on how to protect your germy inner life.

GERMS MAY EXPLAIN OUR APPENDIX

In 2007, Duke evolutionary theorist and associate professor of surgery William Parker made the bold proposal that the human appendix did have a purpose, despite what Charles Darwin had thought.

“Not only is it useless, but it is sometimes the cause of death,” Darwin wrote in On the Origin of Species.

With all due respect, Parker would like to set the grand theorist of evolution straight: The appendix exists as a lifeboat for your beneficial gut bugs, he says. After a bad-guy bug like salmonella or listeria arrives on some food—and leaves in a gut-wrenching rush that clears out the whole system—the good bugs that have taken shelter in their little cul-de-sac can emerge and repopulate the gut.

But about 6 percent of people in the U.S. have had their appendices surgically removed because of infection or even a rupture. That kind of appendix, as Darwin notes, doesn’t save people, it kills them.

Appendicitis is much less of a problem in the developing world, Parker says, where dysentery is much more common.

The same sanitary practices that put our immune systems out of whack also help protect people who lack an appendix, Parker notes. But these people do seem to run a much greater risk of not being able to get their microbiome to bounce back after high doses of antibiotics and are more likely to experience recurrent infections of the bacteria Clostridium difficile, Parker says. “Of course, that can be resolved by a fecal transplant, but it’s not a fun experience.”

Bates is Duke’s director of research communications.