Gut bust: Intestinal microbes in peril

By Bruce Goldman

Let’s be clear: Justin and Erica Sonnenburg, both PhD, are not advocating a return en masse to the hunter-gatherer lifestyle that has characterized 95 percent of our species’ evolutionary history.

Modern society is great!

Camille, Claire, Erica and Justin Sonnenburg reap what they sow: a high-fiber diet for a healthy gut. Photo by Timothy Archibald

The benefits of industrial civilization are too numerous to name. Here are just a few: Abundant food supplies. Clean water. Indoor plumbing. Centralized heating. Refrigeration. Public sanitation. Vaccination. Antibiotics. An understanding of the value of hygienic practices such as washing hands and brushing teeth.

They add up to much lower infant mortality rates and three- or fourfold increases in overall life expectancies. The risks of dying from warfare or homicide have diminished in modern times. And when they do occur, we have the mass media and the Internet to trumpet the news to the four corners of the Earth.

But in mastering our environment, we’ve also changed it.

We’ve all heard the arguments that the last few centuries of urbanization and industrialization have disrupted many ecosystems, some irreversibly.

The Sonnenburgs — Justin is a Stanford associate professor of microbiology and immunology and Erica is a senior research scientist in his lab — are concerned about an ecosystem nobody ever really used to pay much attention to, mainly because it was too hard to see. To do that, we need to look deep inside ourselves.

We’re not talking about introspection or meditation. Look lower. Peer deeply into your bowel. Therein lies one of the most crucial of all ecosystems: your intestinal microbiota, a collection of trillions of one-celled creatures, mostly bacteria. Copious studies have implicated the gut micro­biota in training the human immune system, guiding our tissues’ maturation, preventing pathogenic invasions and even manipulating our thought processes.

The Sonnenburgs are concerned that our modern ways — and most particularly our diet — have caused the diversity of our intestinal biota to shrink substantially. Worse, new experiments they’ve conducted suggest that this shrinkage may be handed down over the generations.

In recent years, technological advances pioneered by David Relman, MD, a professor of microbiology and immunology and of medicine at Stanford, have enabled scientists to conduct accurate censuses of our resident microbes. Relman — borrowing a method first put to use by micro-ecologists exploring microbial diversity in soil, bodies of water and so forth — employed rapid gene-sequencing techniques to accurately identify and count microbes from human tissues and fecal samples based on genetic “bar codes” unique to each microbial species. Before that, such censuses were conducted by culturing these microorganisms, but numerous species failed to thrive in culture, resulting in a drastic undercount.

Now we know that hundreds, even thousands, of distinct bacterial species inhabit every healthy individual’s large intestine. Far from being parasitic, this community of microbes, mainly bacteria, gets along with us so well it might be viewed as an additional organ.

If your heart or your lungs or your liver or your pancreas were losing substantial amounts of cells, wouldn’t you be concerned?

That’s what seems to be happening to the gut communities of people who live in industrialized societies, says Justin Sonnenburg. A study performed in his lab and published in Nature in January 2016 suggests that a pervasive lack of fiber in the typical diet in industrialized societies may be to blame, and that this ongoing mass extinction in our guts could be passed along to future generations. (Technically, the term “fiber” denotes any complex carbohydrates we eat but can’t digest. By that definition, sawdust is fiber, for example. But Justin Sonnenburg is chiefly concerned only with the fiber our resident bacteria can digest. Think fruits and vegetables, not sawdust.)

If that suggestion turns out to be true, then once an entire population has experienced the loss of key bacterial species, simply “eating right” may no longer be enough to restore these lost species to the guts of individuals in that population. Those who live in advanced industrial societies may already be heading down that path.

The die-off within us

When it comes to diet and intestinal microbes, we denizens of the industrialized world are the abnormal ones.

Human beings have relied on hunting and gathering for 95 percent of their evolutionary history. A half-dozen studies in recent years have compared the diets and microbiota of hunter-gatherer and rural agrarian populations from Africa, South America and Papua New Guinea with those of citizens of industrialized countries in Europe or North America. These studies have shown that the diversity of bacterial species inhabiting the intestines of individual members of traditional cultures — whose own numbers, ironically, are rapidly declining — greatly exceeds that of individuals living in modern industrialized societies. (One such comparison tallied about 1,800 bacterial species, on average, in the guts of Guahibo Amer­indians of Venezuela, but only 1,200 in those of United States residents.)
Far from being parasitic, this community of microbes, mainly bacteria, gets along with us so well it might be viewed as an additional organ.

In fact, these studies indicate the complete absence, throughout industrialized populations, of numerous bacterial species that are shared among many of the hunter-gatherer and rural agrarian populations surveyed, despite those latter groups being separated from one another by vast geographic expanses for tens of millennia.

But hunter-gatherers’ life spans are a lot shorter than those in industrialized societies, so what’s the big deal? Actually, that’s largely due to high infant mortality rates caused by infectious disease. Once hunter-gatherers get to be 30 to 40 years old, though, they do pretty well. They don’t die so much from things that kill off so many of the rest of us in old age: heart disease, cancer, diabetes, autoimmunity.

“There are very few ecosystems where low species diversity is a good thing, and there’s no reason to think our gut is any exception,” says Erica Sonnenburg, the lead author of the Nature study and the co-author with her husband of the book The Good Gut, which details what’s been going wrong inside of us and do-it-yourself methods to perhaps fix it.

“What has caused this loss of microbial diversity in the industrial Western world?” asks Erica Sonnenburg. “We decided to look at diet. Traditional fiber intake massively eclipses ours. We wondered, might this be the cause of our microbial species loss?”

Wonder Bread nation

Virtually all health experts agree that low-fiber diets are suboptimal, says Justin Sonnenburg. Probably the chief reason is that fiber, which by definition can’t be digested by human enzymes, is the main food source for the commensal bacteria that colonize our colons.

“In essence, our microbiota is like an organ for degrading plant polysaccharides,” he says. “Fiber is more than a bulking agent.” It’s also fuel for microbes. They’ve got all kinds of enzymes we don’t have, which allows them to chop up complex carbohydrates we can’t digest on our own. Humans have genes for about a dozen enzymes that help snap apart complex carbohydrates by chewing up chemical links between different combinations of constituent sugar subunits. Our microbiota collectively boasts at least 10,000 such genes.

Our beneficial gut bacteria feast on the fiber found in vegetables.

Our beneficial gut bacteria feast on the fiber found in vegetables. Photo by Timothy Archibald
We don’t get much fiber in our diet anymore.

The proliferation of nearly fiber-free, processed convenience foods since the mid-20th century has resulted in average per capita fiber consumption in industrialized societies of about 15 grams per day. That’s as little as one-tenth of the intake among the world’s dwindling hunter-gatherer and rural agrarian populations, whose living conditions and dietary intake presumably most closely resemble those of our common human ancestors.

The first Hostess CupCake was sold on May 11, 1919. In 1950, its component cake mix and icing were souped up and the signature squiggle added to the top to flag the cupcake’s update. By 2011, sales of the cupcake, with its single gram of fiber, were exceeding 600 million a year.

Wonder Bread, a company birthed in 1921, was in 1930 the first to start shipping pre-sliced bread nationwide, spawning the phrase “the greatest thing since sliced bread.” During the late ’50s and early ’60s, Americans gobbled an average of a pound and a half of white bread per person weekly, deriving 25 to 30 percent of their daily calories from the cloudlike clumps of starch (1 gram of fiber per slice).

The 1950s saw phenomenal growth in sales of processed convenience foods with names like Tang, PopTarts, Velveeta and Kraft Dinner. There were Campbell’s condensed soups, and there were Swanson’s frozen TV dinners.

Let’s not talk about Jell-O.

Trans-generational curse

There is now some troubling evidence that our dietary decisions can dramatically alter the microbiome we bequeath to our offspring. We pass on not only our genes but our microbes to our children. While we pick up these microscopic passengers in the course of routine exposures throughout our lifetimes, one of the most significant sources of our intestinal bacterial populations is our immediate family, especially our mothers during childbirth and infancy.

In the womb, the gut is largely sterile. Kids pick up mom’s microbes in the birth canal, then from close contact such as when breastfeeding, and secondarily from family members, pets and household surfaces.

The January 2016 study spearheaded by the Sonnenburgs showed, in mice, that low-fiber diets not only deplete the complex microbial ecosystems residing in the gut, but can cause an irreversible loss of diversity within those ecosystems in as few as three or four generations.

“Factors including widespread antibiotic use, more-frequent cesarean sections and less-frequent breastfeeding have been proposed for why we see this depletion in industrialized populations,” says Erica Sonnenburg. “We asked ourselves whether the huge difference in dietary fiber intake between traditional and modern populations could, alone, account for it.”

The Stanford researchers employed several dozen young laboratory mice that had been specially bred and raised in aseptic environments so that, unlike ordinary mice (and ordinary humans), their intestines were devoid of any microbial inhabitants. These “gnotobiotic mice” are a forte of Justin Sonnenburg’s lab. He’s able to perform seminal experiments by adding defined combinations of germ species to their guts and then watching how the behavior of one species affects that of the other.

After populating the mice’s guts with microbes from a human donor, the scientists divided them into two groups. They fed one group a diet rich in plant-derived fiber. The other group’s diet, equivalent to the first with respect to protein, fat and calories, was practically devoid of fiber content.

During the experimentation that followed, the researchers analyzed fecal samples from the animals. The two groups’ gut-bacteria profiles were initially indistinguishable but soon diverged. “Within a couple of weeks, we saw a massive change,” says Justin Sonnenburg. “The low-fiber-intake mice harbored fewer bacterial species in their gut.” More than half of these bacterial species’ populations had dropped by over 75 percent, and many species seemed to have disappeared altogether.

After seven weeks, the mice that had consumed a low-fiber diet were switched back to a high-fiber diet for four weeks. The mice’s gut-bacteria profiles partly recovered — probably due to an uptick in abundance of some bacteria whose ranks had declined to undetectable levels during the low-fiber-intake period. Still, this restoration was only partial: One-third of the original species never fully recovered despite the mice’s return to a high-fiber diet.

No such changes were seen in the control mice consistently fed a high-fiber diet.

The real surprise came after mice had been bred and maintained on low-fiber diets for a few generations. In their experimental confines, these mice were exposed to microbes only through contact with their parents. Each successive generation’s gut-bacterial ecosystem declined in diversity. By generation four, the depletion had reached a point where nearly three-quarters of the bacterial species resident in their great-grandparents’ guts appeared absent in their own. Even after these mice were put back on a high-fiber diet, about two-thirds of the bacterial species identified in the guts of their first-generation ancestors never came back.

On the other hand, a somewhat more aggressive measure — fecal transplantation — did enable these lost species to make a comeback. Introducing fecal contents of fourth-generation high-fiber-diet mice into the intestines of fourth-generation low-fiber mice, together with putting them on the high-fiber diet for two weeks, fully restored their bacterial profiles.

Within 10 days of the procedure, the composition and diversity of the bacteria in the intestines of this group were indistinguishable from those of control mice.

What is to be done?

This was a mouse study. Might differences in human versus murine gut environments — say, the sheer length of our digestive tracts compared with theirs — make us less susceptible to the species losses described in the Sonnenburgs’ study?

“There’s no way to perform this generational test on humans,” says Justin Sonnenburg — unless, he jokes, there are families that have the odd tradition of archiving their stool.

“We haven’t found those families yet,” remarks Erica Sonnenburg.

The Sonnenburgs pack their kids' lunches, rather than rely on low-fiber fare.

“Mice aren’t people,” says Martin Blaser, MD, the director of the Human Microbiome Program at New York University in New York City, who did not participate in the study but is familiar with its contents. “But these results are very, very clear,” he notes. “There’s a lot of internal consistency. That’s one of the markers of scientific rigor.”

About 15 years ago, Blaser began advancing a theory he calls the “disappearing microbe hypothesis.” Autism, allergies, asthma, obesity, type-2 diabetes and other chronic diseases have become endemic in industrialized societies over the past 50 years — pretty much the same time frame during which low-fiber diets, births by cesarean section, antibiotics and other practices have been decimating our resident microbial populations. At the time, Blaser suggested that this is more than mere coincidence.

Since then, studies looking at these chronic conditions have indicated almost without exception that the diseased state is associated with less gut-bacterial diversity than the healthy state.

In a 2009 review Blaser co-wrote with Stanford microbiologist Stanley Falkow, PhD, whom Blaser describes as “the most important scientist in our generation in connection with studying bacteria,” the pair expanded that hypothesis, postulating that this microbiota depletion’s health effects might accumulate through generations. Blaser, whose lay-oriented book Missing Microbes was published in 2014, says he views the Sonnenburgs’ new study as confirming that hypothesis.

Once a society has lost a big chunk of its ancestral gut-microbe diversity, how do its members regain it?

Simple tweaks in cultural practices — for example, not washing hands after gardening or petting the dog — could be a step in the right direction, and steering away from overuse of antibiotics certainly is, Justin Sonnenburg says.

But the ultimate need is to create an environment within ourselves where the kinds of bugs that have grown accustomed to our gut over hundreds of thousands (maybe millions) of years will feel at home. “It’s now evident that everybody should be eating more dietary fiber,” Justin Sonnenburg offers.

In their everyday life, the Sonnenburgs walk the walk. They eat tons of fiber-rich vegetables grown in their own backyard. They eschew carbonated soda in favor of fiber-filled smoothies whipped up in a blender that’s always easily accessible. They bake their own sourdough, which is leavened with a starter — a fermented flour mixture that picks up wild yeast and bacteria from the environment. They pack their kids’ lunches rather than rely on the standard low-fiber fare most children will pull off the counters in school cafeterias. They brew their own beer, still brimming with the live yeast cultures whose fermentation skills turned its constituent sugars into alcohol, as well as their own kefir: milk soured by (and teeming with) dozens of species of microbes. They got a family dog, Louis (named after Pasteur), whom they encourage to lick their kids’ faces. They’ve rolled out the red carpet for single-celled soldiers of fortune and the complex carbohydrates that fuel them. As a result, their own gut-microbial diversity has increased significantly.

‘Within a few weeks we saw a massive change. The low-fiber-intake mice harbored fewer bacterial species in their gut.’

For those of us who don’t happen to have all the instruments and reagents required to do our own microbe counts, members of the Sonnenburg lab are working on another “homebrew” product: a device for collecting, suspending and analyzing people’s quotidian stool samples and communicating the results to an iPhone app that would interpret the results. This project is in its early stages, but their hope is to develop a prototype of the microbiota monitor that will eventually reside in household toilets, or be deployed for field trials in developing regions of the world.

We can all take at least a few steps in that direction without too much intestinal discomfort, and some of us will be able to tolerate more acute shifts in our dietary trajectories. But what happens if that’s not enough to restore the full palette of beneficial bug buddies? More extreme measures such as mass fecal transplants — which on an individual basis have proven very successful for eradicating life-threatening, colitis-inducing intestinal invasions by pathogens such as C. difficile — would require large-scale testing to make sure they are both advisable and safe. (After all, who knows how those hunter-gatherer bacteria might react to a diet of Twinkies and Velveeta?) In any case, fecal transplants from ... whom? How do you re-expose yourself to essential friendly bacteria if nobody around you is carrying them, either?

“As our modern ways spread around the globe, these traditional peoples are being squeezed into smaller and smaller spaces and rapidly transculturating,” says Erica Sonnenburg. “Our chance to learn from studying them is not going to last forever.”

Blaser and Justin Sonnenburg have embarked on a collaborative effort with a half-dozen other investigators to study the Hadza, a remnant of a Tanzanian hunter-gatherer society with a population of perhaps 300, to better understand the microbiota of people from traditional cultures.

The field researcher who collected the stool samples has also performed, in a personal experiment, a fecal transplant on his apparently perfectly healthy self using material from a Hadza donor. Perhaps it will make sense at some point to harvest and expand libraries of microbial populations from hunter-gatherers for distribution to moderns with recalcitrant germ deficits. But, Erica Sonnenburg says, even if you were to get a fecal transplant from a hunter-gatherer, it’s not clear that those good, rare microbes would stick around if you don’t eat right.

In the future, the Sonnenburgs hope to run a mouse trial in which the initially germ-free mice receive gut microbes from a Hadza donor, to see what kind of diet is necessary to maintain a healthy gut microbiota.

Justin Sonnenburg and David Relman have been named co-directors of Stanford’s Institute of Immunity, Transplantation and Infection’s newly launched Center for Human Microbiome Studies. Among the projects being planned within the new center is a collaboration between Justin Sonnenburg and Christopher Gardner, PhD, a professor of medicine who has focused on diet. Sonnenburg and Gardner intend to initiate a large-scale, long-term, human-diet trial in which people will be fed different diets — for example, high-fiber, plant-rich diets versus more standard Western diets in combination with fiber supplementation — to see if improving the diversity of their microbiota translates to improved health outcomes.

“The hope is to move toward a precision approach to diet: ‘You have microbiota type X, and you are suffering from disease N, so you should eat A and B but not C,’” Justin Sonnenburg says.

Meanwhile, there’s no cause for despair. “The extremely low-fiber intake in industrialized countries has occurred relatively recently,” he notes. Nor is there room for complacency. “We’re about two generations down the road,” says Erica Sonnenburg. “Is it possible we could have a deep descent if we keep it up?”

About the Author
Bruce Goldman is a science writer for the medical school’s Office of Communication & Public Affairs. Email him at goldmanb@stanford.edu.

This article was first published at Stanford Medicine.

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