Some of My Best Friends Are Germs (!Excellent Article!)

[Oliver Crangle]

Some of My Best Friends Are Germs

Hannah Whitaker for The New York Times. Prop stylist: Emily Mullin.

By MICHAEL POLLAN
Published: May 15, 2013 114 Comments
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I can tell you the exact date that I began to think of myself in the
first-person plural — as a superorganism, that is, rather than a plain
old individual human being. It happened on March 7. That’s when I
opened my e-mail to find a huge, processor-choking file of charts and
raw data from a laboratory located at the BioFrontiers Institute at
the University of Colorado, Boulder. As part of a new citizen-science
initiative called the American Gut project, the lab sequenced my
microbiome — that is, the genes not of “me,” exactly, but of the
several hundred microbial species with whom I share this body. These
bacteria, which number around 100 trillion, are living (and dying)
right now on the surface of my skin, on my tongue and deep in the
coils of my intestines, where the largest contingent of them will be
found, a pound or two of microbes together forming a vast, largely
uncharted interior wilderness that scientists are just beginning to
map.

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Hannah Whitaker for The New York Times. Prop stylist: Emily Mullin.
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I clicked open a file called Taxa Tables, and a colorful bar chart
popped up on my screen. Each bar represented a sample taken (with a
swab) from my skin, mouth and feces. For purposes of comparison, these
were juxtaposed with bars representing the microbiomes of about 100
“average” Americans previously sequenced.

Here were the names of the hundreds of bacterial species that call me
home. In sheer numbers, these microbes and their genes dwarf us. It
turns out that we are only 10 percent human: for every human cell that
is intrinsic to our body, there are about 10 resident microbes —
including commensals (generally harmless freeloaders) and mutualists
(favor traders) and, in only a tiny number of cases, pathogens. To the
extent that we are bearers of genetic information, more than 99
percent of it is microbial. And it appears increasingly likely that
this “second genome,” as it is sometimes called, exerts an influence
on our health as great and possibly even greater than the genes we
inherit from our parents. But while your inherited genes are more or
less fixed, it may be possible to reshape, even cultivate, your second
genome.

Justin Sonnenburg, a microbiologist at Stanford, suggests that we
would do well to begin regarding the human body as “an elaborate
vessel optimized for the growth and spread of our microbial
inhabitants.” This humbling new way of thinking about the self has
large implications for human and microbial health, which turn out to
be inextricably linked. Disorders in our internal ecosystem — a loss
of diversity, say, or a proliferation of the “wrong” kind of microbes
— may predispose us to obesity and a whole range of chronic diseases,
as well as some infections. “Fecal transplants,” which involve
installing a healthy person’s microbiota into a sick person’s gut,
have been shown to effectively treat an antibiotic-resistant
intestinal pathogen named C. difficile, which kills 14,000 Americans
each year. (Researchers use the word “microbiota” to refer to all the
microbes in a community and “microbiome” to refer to their collective
genes.) We’ve known for a few years that obese mice transplanted with
the intestinal community of lean mice lose weight and vice versa. (We
don’t know why.) A similar experiment was performed recently on humans
by researchers in the Netherlands: when the contents of a lean donor’s
microbiota were transferred to the guts of male patients with
metabolic syndrome, the researchers found striking improvements in the
recipients’ sensitivity to insulin, an important marker for metabolic
health. Somehow, the gut microbes were influencing the patients’
metabolisms.

Our resident microbes also appear to play a critical role in training
and modulating our immune system, helping it to accurately distinguish
between friend and foe and not go nuts on, well, nuts and all sorts of
other potential allergens. Some researchers believe that the alarming
increase in autoimmune diseases in the West may owe to a disruption in
the ancient relationship between our bodies and their “old friends” —
the microbial symbionts with whom we coevolved.

These claims sound extravagant, and in fact many microbiome
researchers are careful not to make the mistake that scientists
working on the human genome did a decade or so ago, when they promised
they were on the trail of cures to many diseases. We’re still waiting.
Yet whether any cures emerge from the exploration of the second
genome, the implications of what has already been learned — for our
sense of self, for our definition of health and for our attitude
toward bacteria in general — are difficult to overstate. Human health
should now “be thought of as a collective property of the human-
associated microbiota,” as one group of researchers recently concluded
in a landmark review article on microbial ecology — that is, as a
function of the community, not the individual.

Such a paradigm shift comes not a moment too soon, because as a
civilization, we’ve just spent the better part of a century doing our
unwitting best to wreck the human-associated microbiota with a
multifronted war on bacteria and a diet notably detrimental to its
well-being. Researchers now speak of an impoverished “Westernized
microbiome” and ask whether the time has come to embark on a project
of “restoration ecology” — not in the rain forest or on the prairie
but right here at home, in the human gut.

In March I traveled to Boulder to see the Illumina HiSeq 2000
sequencing machine that had shed its powerful light on my own
microbiome and to meet the scientists and computer programmers who
were making sense of my data. The lab is headed by Rob Knight, a
rangy, crew-cut 36-year-old biologist who first came to the United
States from his native New Zealand to study invasive species, a
serious problem in his home country. Knight earned his Ph.D. in
ecology and evolutionary biology from Princeton when he was 24 and
then drifted from the study of visible species and communities to
invisible ones. Along the way he discovered he had a knack for
computational biology. Knight is regarded as a brilliant analyst of
sequencing data, skilled at finding patterns in the flood of
information produced by the machines that “batch sequence” all the DNA
in a sample and then tease out the unique genetic signatures of each
microbe. This talent explains why so many of the scientists exploring
the microbiome today send their samples to be sequenced and analyzed
by his lab; it is also why you will find Knight’s name on most of the
important papers in the field.

Over the course of two days in Boulder, I enjoyed several meals with
Knight and his colleagues, postdocs and graduate students, though I
must say I was a little taken aback by the table talk. I don’t think
I’ve ever heard so much discussion of human feces at dinner, but then
one thing these scientists are up to is a radical revaluation of the
contents of the human colon. I learned about Knight’s 16-month-old
daughter, who has had most of the diapers to which she has contributed
sampled and sequenced. Knight said at dinner that he sampled himself
every day; his wife, Amanda Birmingham, who joined us one night, told
me that she was happy to be down to once a week. “Of course I keep a
couple of swabs in my bag at all times,” she said, rolling her eyes,
“because you never know.”

A result of the family’s extensive self-study has been a series of
papers examining family microbial dynamics. The data helped
demonstrate that the microbial communities of couples sharing a house
are similar, suggesting the importance of the environment in shaping
an individual’s microbiome. Knight also found that the presence of a
family dog tended to blend everyone’s skin communities, probably via
licking and petting. One paper, titled “Moving Pictures of the Human
Microbiome,” tracked the day-to-day shifts in the microbial
composition of each body site. Knight produced animations showing how
each community — gut, skin and mouth — hosted a fundamentally
different cast of microbial characters that varied within a fairly
narrow range over time.

Knight’s daily sampling of his daughter’s diapers (along with those of
a colleague’s child) also traced the remarkable process by which a
baby’s gut community, which in utero is sterile and more or less a
blank slate, is colonized. This process begins shortly after birth,
when a distinctive infant community of microbes assembles in the gut.
Then, with the introduction of solid food and then weaning, the types
of microbes gradually shift until, by age 3, the baby’s gut comes to
resemble an adult community much like that of its parents.

The study of babies and their specialized diet has yielded key
insights into how the colonization of the gut unfolds and why it
matters so much to our health. One of the earliest clues to the
complexity of the microbiome came from an unexpected corner: the
effort to solve a mystery about milk. For years, nutrition scientists
were confounded by the presence in human breast milk of certain
complex carbohydrates, called oligosaccharides, which the human infant
lacks the enzymes necessary to digest. Evolutionary theory argues that
every component of mother’s milk should have some value to the
developing baby or natural selection would have long ago discarded it
as a waste of the mother’s precious resources.

It turns out the oligosaccharides are there to nourish not the baby
but one particular gut bacterium called Bifidobacterium infantis,
which is uniquely well-suited to break down and make use of the
specific oligosaccharides present in mother’s milk. When all goes
well, the bifidobacteria proliferate and dominate, helping to keep the
infant healthy by crowding out less savory microbial characters before
they can become established and, perhaps most important, by nurturing
the integrity of the epithelium — the lining of the intestines, which
plays a critical role in protecting us from infection and
inflammation.

“Mother’s milk, being the only mammalian food shaped by natural
selection, is the Rosetta stone for all food,” says Bruce German, a
food scientist at the University of California, Davis, who researches
milk. “And what it’s telling us is that when natural selection creates
a food, it is concerned not just with feeding the child but the
child’s gut bugs too.”

Where do these all-important bifidobacteria come from and what does it
mean if, like me, you were never breast-fed? Mother’s milk is not, as
once was thought, sterile: it is both a “prebiotic” — a food for
microbes — and a “probiotic,” a population of beneficial microbes
introduced into the body. Some of them may find their way from the
mother’s colon to her milk ducts and from there into the baby’s gut
with its first feeding. Because designers of infant formula did not,
at least until recently, take account of these findings, including
neither prebiotic oligosaccharides or probiotic bacteria in their
formula, the guts of bottle-fed babies are not optimally colonized.

Most of the microbes that make up a baby’s gut community are acquired
during birth — a microbially rich and messy process that exposes the
baby to a whole suite of maternal microbes. Babies born by Caesarean,
however, a comparatively sterile procedure, do not acquire their
mother’s vaginal and intestinal microbes at birth. Their initial gut
communities more closely resemble that of their mother’s (and
father’s) skin, which is less than ideal and may account for higher
rates of allergy, asthma and autoimmune problems in C-section babies:
not having been seeded with the optimal assortment of microbes at
birth, their immune systems may fail to develop properly.

At dinner, Knight told me that he was sufficiently concerned about
such an eventuality that, when his daughter was born by emergency C-
section, he and his wife took matters into their own hands: using a
sterile cotton swab, they inoculated the newborn infant’s skin with
the mother’s vaginal secretions to insure a proper colonization. A
formal trial of such a procedure is under way in Puerto Rico.

While I was in Boulder, I sat down with Catherine A. Lozupone, a
microbiologist who had just left Knight’s lab to set up her own at the
University of Colorado, Denver, and who spent some time looking at my
microbiome and comparing it with others, including her own. Lozupone
was the lead author on an important 2012 paper in Nature, “Diversity,
Stability and Resilience of the Human Gut Microbiota,” which sought to
approach the gut community as an ecologist might, trying to determine
the “normal” state of the ecosystem and then examining the various
factors that disturb it over time. How does diet affect it?
Antibiotics? Pathogens? What about cultural traditions? So far, the
best way to begin answering such questions may be by comparing the gut
communities of various far-flung populations, and researchers have
been busy collecting samples around the world and shipping them to
sequencing centers for analysis. The American Gut project, which hopes
to eventually sequence the communities of tens of thousands of
Americans, represents the most ambitious such effort to date; it will
help researchers uncover patterns of correlation between people’s
lifestyle, diet, health status and the makeup of their microbial
community.

It is still early days in this research, as Lozupone (and everyone
else I interviewed) underscored; scientists can’t even yet say with
confidence exactly what a “healthy” microbiome should look like. But
some broad, intriguing patterns are emerging. More diversity is
probably better than less, because a diverse ecosystem is generally
more resilient — and diversity in the Western gut is significantly
lower than in other, less-industrialized populations. The gut
microbiota of people in the West looks very different from that of a
variety of other geographically dispersed peoples. So, for example,
the gut community of rural people in West Africa more closely
resembles that of Amerindians in Venezuela than it does an American’s
or a European’s.

These rural populations not only harbor a greater diversity of
microbes but also a different cast of lead characters. American and
European guts contain relatively high levels of bacteroides and
firmicutes and low levels of the prevotella that dominate the guts of
rural Africans and Amerindians. (It is not clear whether high or low
levels of any of these is good or bad.) Why are the microbes
different? It could be the diet, which in both rural populations
features a considerable amount of whole grains (which prevotella
appear to like), plant fiber and very little meat. (Many firmicutes
like amino acids, so they proliferate when the diet contains lots of
protein; bacteroides metabolize carbohydrates.) As for the lower
biodiversity in the West, this could be a result of our profligate use
of antibiotics (in health care as well as the food system), our diet
of processed food (which has generally been cleansed of all bacteria,
the good and the bad), environmental toxins and generally less
“microbial pressure” — i.e., exposure to bacteria — in everyday life.
All of this may help explain why, though these rural populations tend
to have greater exposures to infectious diseases and lower life
expectancies than those in the West, they also have lower rates of
chronic disorders like allergies, asthma, Type 2 diabetes and
cardiovascular disease.

“Rural people spend a lot more time outside and have much more contact
with plants and with soil,” Lozupone says. Another researcher, who has
gathered samples in Malawi, told me, “In some of these cultures,
children are raised communally, passed from one set of hands to
another, so they’re routinely exposed to a greater diversity of
microbes.” The nuclear family may not be conducive to the health of
the microbiome.

As it happens, Lozupone and I had something in common, microbially
speaking: we share unusually high levels of prevotella for Americans.
Our gut communities look more like those of rural Africans or
Amerindians than like those of our neighbors. Lozupone suspects that
the reasons for this might have to do with a plant-based diet; we each
eat lots of whole grains and vegetables and relatively little meat.
(Though neither of us is a vegetarian.) Like me, she was proud of her
prevotella, regarding it as a sign of a healthy non-Western diet, at
least until she began doing research on the microbiota of H.I.V.
patients. It seems that they, too, have lots of prevotella. Further
confusing the story, a recent study linking certain gut microbes
common in meat eaters to high levels of a blood marker for heart
disease suggested that prevotella was one such microbe. Early days,
indeed.

Two other features of my microbiome attracted the attention of the
researchers who examined it. First, the overall biodiversity of my gut
community was significantly higher than that of the typical Westerner,
which I decided to take as a compliment, though the extravagantly
diverse community of microbes on my skin raised some eyebrows. “Where
have your hands been, man?” Jeff Leach of the American Gut project
asked after looking over my results. My skin harbors bacteria
associated with plants, soil and a somewhat alarming variety of animal
guts. I put this down to gardening, composting (I keep worms too) and
also the fact that I was fermenting kimchi and making raw-milk cheese,
“live-culture” foods teeming with microbes.

Compared to a rain forest or a prairie, the interior ecosystem is not
well understood, but the core principles of ecology — which along with
powerful new sequencing machines have opened this invisible frontier
to science — are beginning to yield some preliminary answers and a
great many more intriguing hypotheses. Your microbial community seems
to stabilize by age 3, by which time most of the various niches in the
gut ecosystem are occupied. That doesn’t mean it can’t change after
that; it can, but not as readily. A change of diet or a course of
antibiotics, for example, may bring shifts in the relative population
of the various resident species, helping some kinds of bacteria to
thrive and others to languish. Can new species be introduced? Yes, but
probably only when a niche is opened after a significant disturbance,
like an antibiotic storm. Just like any other mature ecosystem, the
one in our gut tends to resist invasion by newcomers.

You acquire most of the initial microbes in your gut community from
your parents, but others are picked up from the environment. “The
world is covered in a fine patina of feces,” as the Stanford
microbiologist Stanley Falkow tells students. The new sequencing tools
have confirmed his hunch: Did you know that house dust can contain
significant amounts of fecal particles? Or that, whenever a toilet is
flushed, some of its contents are aerosolized? Knight’s lab has
sequenced the bacteria on toothbrushes. This news came during
breakfast, so I didn’t ask for details, but got them anyway: “You want
to keep your toothbrush a minimum of six feet away from a toilet,” one
of Knight’s colleagues told me.

Some scientists in the field borrow the term “ecosystem services” from
ecology to catalog all the things that the microbial community does
for us as its host or habitat, and the services rendered are
remarkably varied and impressive. “Invasion resistance” is one. Our
resident microbes work to keep pathogens from gaining a toehold by
occupying potential niches or otherwise rendering the environment
inhospitable to foreigners. The robustness of an individual’s gut
community might explain why some people fall victim to food poisoning
while others can blithely eat the same meal with no ill effects.

Our gut bacteria also play a role in the manufacture of substances
like neurotransmitters (including serotonin); enzymes and vitamins
(notably Bs and K) and other essential nutrients (including important
amino acid and short-chain fatty acids); and a suite of other
signaling molecules that talk to, and influence, the immune and the
metabolic systems. Some of these compounds may play a role in
regulating our stress levels and even temperament: when gut microbes
from easygoing, adventurous mice are transplanted into the guts of
anxious and timid mice, they become more adventurous. The expression
“thinking with your gut” may contain a larger kernel of truth than we
thought.

The gut microbes are looking after their own interests, chief among
them getting enough to eat and regulating the passage of food through
their environment. The bacteria themselves appear to help manage these
functions by producing signaling chemicals that regulate our appetite,
satiety and digestion. Much of what we’re learning about the
microbiome’s role in human metabolism has come from studying
“gnotobiotic mice” — mice raised in labs like Jeffrey I. Gordon’s at
Washington University, in St. Louis, to be microbially sterile, or
germ-free. Recently, Gordon’s lab transplanted the gut microbes of
Malawian children with kwashiorkor — an acute form of malnutrition —
into germ-free mice. The lab found those mice with kwashiorkor who
were fed the children’s typical diet could not readily metabolize
nutrients, indicating that it may take more than calories to remedy
malnutrition. Repairing a patient’s disordered metabolism may require
reshaping the community of species in his or her gut.

Keeping the immune system productively engaged with microbes — exposed
to lots of them in our bodies, our diet and our environment — is
another important ecosystem service and one that might turn out to be
critical to our health. “We used to think the immune system had this
fairly straightforward job,” Michael Fischbach, a biochemist at the
University of California, San Francisco, says. “All bacteria were
clearly ‘nonself’ so simply had to be recognized and dealt with. But
the job of the immune system now appears to be far more nuanced and
complex. It has to learn to consider our mutualists” — e.g., resident
bacteria — “as self too. In the future we won’t even call it the
immune system, but the microbial interaction system.” The absence of
constructive engagement between microbes and immune system
(particularly during certain windows of development) could be behind
the increase in autoimmune conditions in the West.

So why haven’t we evolved our own systems to perform these most
critical functions of life? Why have we outsourced all this work to a
bunch of microbes? One theory is that, because microbes evolve so much
faster than we do (in some cases a new generation every 20 minutes),
they can respond to changes in the environment — to threats as well as
opportunities — with much greater speed and agility than “we” can.
Exquisitely reactive and adaptive, bacteria can swap genes and pieces
of DNA among themselves. This versatility is especially handy when a
new toxin or food source appears in the environment. The microbiota
can swiftly come up with precisely the right gene needed to fight it —
or eat it. In one recent study, researchers found that a common gut
microbe in Japanese people has acquired a gene from a marine bacterium
that allows the Japanese to digest seaweed, something the rest of us
can’t do as well.

This plasticity serves to extend our comparatively rigid genome,
giving us access to a tremendous bag of biochemical tricks we did not
need to evolve ourselves. “The bacteria in your gut are continually
reading the environment and responding,” says Joel Kimmons, a
nutrition scientist and epidemiologist at the Centers for Disease
Control and Prevention in Atlanta. “They’re a microbial mirror of the
changing world. And because they can evolve so quickly, they help our
bodies respond to changes in our environment.”

A handful of microbiologists have begun sounding the alarm about our
civilization’s unwitting destruction of the human microbiome and its
consequences. Important microbial species may have already gone
extinct, before we have had a chance to learn who they are or what
they do. What we think of as an interior wilderness may in fact be
nothing of the kind, having long ago been reshaped by unconscious
human actions. Taking the ecological metaphor further, the
“Westernized microbiome” most of us now carry around is in fact an
artifact of civilization, no more a wilderness today than, say, the
New Jersey Meadowlands.

To obtain a clearer sense of what has been lost, María Gloria
Dominguez-Bello, a Venezuelan-born microbiologist at New York
University, has been traveling to remote corners of the Amazon to
collect samples from hunter-gatherers who have had little previous
contact with Westerners or Western medicine. “We want to see how the
human microbiota looks before antibiotics, before processed food,
before modern birth,” she told me. “These samples are really gold.”

Preliminary results indicate that a pristine microbiome — of people
who have had little or no contact with Westerners — features much
greater biodiversity, including a number of species never before
sequenced, and, as mentioned, much higher levels of prevotella than is
typically found in the Western gut. Dominguez-Bello says these
vibrant, diverse and antibiotic-naïve microbiomes may play a role in
Amerindians’ markedly lower rates of allergies, asthma, atopic disease
and chronic conditions like Type 2 diabetes and cardiovascular
disease.

One bacterium commonly found in the non-Western microbiome but nearly
extinct in ours is a corkscrew-shaped inhabitant of the stomach by the
name of Helicobacter pylori. Dominguez-Bello’s husband, Martin Blaser,
a physician and microbiologist at N.Y.U., has been studying H. pylori
since the mid-1980s and is convinced that it is an endangered species,
the extinction of which we may someday rue. According to the “missing
microbiota hypothesis,” we depend on microbes like H. pylori to
regulate various metabolic and immune functions, and their
disappearance is disordering those systems. The loss is cumulative:
“Each generation is passing on fewer of these microbes,” Blaser told
me, with the result that the Western microbiome is being progressively
impoverished.

He calls H. pylori the “poster child” for the missing microbes and
says medicine has actually been trying to exterminate it since 1983,
when Australian scientists proposed that the microbe was responsible
for peptic ulcers; it has since been implicated in stomach cancer as
well. But H. pylori is a most complicated character, the entire
spectrum of microbial good and evil rolled into one bug. Scientists
learned that H. pylori also plays a role in regulating acid in the
stomach. Presumably it does this to render its preferred habitat
inhospitable to competitors, but the effect on its host can be
salutary. People without H. pylori may not get peptic ulcers, but they
frequently do suffer from acid reflux. Untreated, this can lead to
Barrett’s esophagus and, eventually, a certain type of esophageal
cancer, rates of which have soared in the West as H. pylori has gone
missing.

When after a recent bout of acid reflux, my doctor ordered an
endoscopy, I discovered that, like most Americans today, my stomach
has no H. pylori. My gastroenterologist was pleased, but after talking
to Blaser, the news seemed more equivocal, because H. pylori also does
us a lot of good. The microbe engages with the immune system, quieting
the inflammatory response in ways that serve its own interests — to be
left in peace — as well as our own. This calming effect on the immune
system may explain why populations that still harbor H. pylori are
less prone to allergy and asthma. Blaser’s lab has also found evidence
that H. pylori plays an important role in human metabolism by
regulating levels of the appetite hormone ghrelin. “When the stomach
is empty, it produces a lot of ghrelin, the chemical signal to the
brain to eat,” Blaser says. “Then, when it has had enough, the stomach
shuts down ghrelin production, and the host feels satiated.” He says
the disappearance of H. pylori may be contributing to obesity by
muting these signals.

But what about the diseases H. pylori is blamed for? Blaser says these
tend to occur only late in life, and he makes the rather breathtaking
suggestion that this microbe’s evolutionary role might be to help
shuffle us off life’s stage once our childbearing years have passed.
So important does Blaser regard this strange, paradoxical symbiont
that he has proposed not one but two unconventional therapeutic
interventions: inoculate children with H. pylori to give them the
benefit of its services early in life, and then exterminate it with
antibiotics at age 40, when it is liable to begin causing trouble.

These days Blaser is most concerned about the damage that antibiotics,
even in tiny doses, are doing to the microbiome — and particularly to
our immune system and weight. “Farmers have been performing a great
experiment for more than 60 years,” Blaser says, “by giving
subtherapeutic doses of antibiotics to their animals to make them gain
weight.” Scientists aren’t sure exactly why this practice works, but
the drugs may favor bacteria that are more efficient at harvesting
energy from the diet. “Are we doing the same thing to our kids?” he
asks. Children in the West receive, on average, between 10 and 20
courses of antibiotics before they turn 18. And those prescribed drugs
aren’t the only antimicrobials finding their way to the microbiota;
scientists have found antibiotic residues in meat, milk and surface
water as well. Blaser is also concerned about the use of antimicrobial
compounds in our diet and everyday lives — everything from chlorine
washes for lettuce to hand sanitizers. “We’re using these chemicals
precisely because they’re antimicrobial,” Blaser says. “And of course
they do us some good. But we need to ask, what are they doing to our
microbiota?” No one is questioning the value of antibiotics to
civilization — they have helped us to conquer a great many infectious
diseases and increased our life expectancy. But, as in any war, the
war on bacteria appears to have had some unintended consequences.

One of the more striking results from the sequencing of my microbiome
was the impact of a single course of antibiotics on my gut community.
My dentist had put me on a course of Amoxicillin as a precaution
before oral surgery. (Without prophylactic antibiotics, of course,
surgery would be considerably more dangerous.) Within a week, my
impressively non-Western “alpha diversity” — a measure of the
microbial diversity in my gut — had plummeted and come to look very
much like the American average. My (possibly) healthy levels of
prevotella had also disappeared, to be replaced by a spike in
bacteroides (much more common in the West) and an alarming bloom of
proteobacteria, a phylum that includes a great many weedy and
pathogenic characters, including E. coli and salmonella. What had
appeared to be a pretty healthy, diversified gut was now raising
expressions of concern among the microbiologists who looked at my
data.

“Your E. coli bloom is creepy,” Ruth Ley, a Cornell University
microbiologist who studies the microbiome’s role in obesity, told me.
“If we put that sample in germ-free mice, I bet they’d get inflamed.”
Great. Just when I was beginning to think of myself as a promising
donor for a fecal transplant, now I had a gut that would make mice
sick. I was relieved to learn that my gut community would eventually
bounce back to something resembling its former state. Yet one recent
study found that when subjects were given a second course of
antibiotics, the recovery of their interior ecosystem was less
complete than after the first.

Few of the scientists I interviewed had much doubt that the Western
diet was altering our gut microbiome in troubling ways. Some, like
Blaser, are concerned about the antimicrobials we’re ingesting with
our meals; others with the sterility of processed food. Most agreed
that the lack of fiber in the Western diet was deleterious to the
microbiome, and still others voiced concerns about the additives in
processed foods, few of which have ever been studied for their
specific effects on the microbiota. According to a recent article in
Nature by the Stanford microbiologist Justin Sonnenburg, “Consumption
of hyperhygienic, mass-produced, highly processed and calorie-dense
foods is testing how rapidly the microbiota of individuals in
industrialized countries can adapt.” As our microbiome evolves to cope
with the Western diet, Sonnenburg says he worries that various genes
are becoming harder to find as the microbiome’s inherent biodiversity
declines along with our everyday exposure to bacteria.

Catherine Lozupone in Boulder and Andrew Gewirtz, an immunologist at
Georgia State University, directed my attention to the emulsifiers
commonly used in many processed foods — ingredients with names like
lecithin, Datem, CMC and polysorbate 80. Gewirtz’s lab has done
studies in mice indicating that some of these detergentlike compounds
may damage the mucosa — the protective lining of the gut wall —
potentially leading to leakage and inflammation.

A growing number of medical researchers are coming around to the idea
that the common denominator of many, if not most, of the chronic
diseases from which we suffer today may be inflammation — a heightened
and persistent immune response by the body to a real or perceived
threat. Various markers for inflammation are common in people with
metabolic syndrome, the complex of abnormalities that predisposes
people to illnesses like cardiovascular disease, obesity, Type 2
diabetes and perhaps cancer. While health organizations differ on the
exact definition of metabolic syndrome, a 2009 report from the Centers
for Disease Control and Prevention found that 34 percent of American
adults are afflicted with the condition. But is inflammation yet
another symptom of metabolic syndrome, or is it perhaps the cause of
it? And if it is the cause, what is its origin?

One theory is that the problem begins in the gut, with a disorder of
the microbiota, specifically of the all-important epithelium that
lines our digestive tract. This internal skin — the surface area of
which is large enough to cover a tennis court — mediates our
relationship to the world outside our bodies; more than 50 tons of
food pass through it in a lifetime. The microbiota play a critical
role in maintaining the health of the epithelium: some bacteria, like
the bifidobacteria and Lactobacillus plantarum (common in fermented
vegetables), seem to directly enhance its function. These and other
gut bacteria also contribute to its welfare by feeding it. Unlike most
tissues, which take their nourishment from the bloodstream, epithelial
cells in the colon obtain much of theirs from the short-chain fatty
acids that gut bacteria produce as a byproduct of their fermentation
of plant fiber in the large intestine.

But if the epithelial barrier isn’t properly nourished, it can become
more permeable, allowing it to be breached. Bacteria, endotoxins —
which are the toxic byproducts of certain bacteria — and proteins can
slip into the blood stream, thereby causing the body’s immune system
to mount a response. This resulting low-grade inflammation, which
affects the entire body, may lead over time to metabolic syndrome and
a number of the chronic diseases that have been linked to it.

Evidence in support of this theory is beginning to accumulate, some of
the most intriguing coming from the lab of Patrice Cani at the
Université Catholique de Louvain in Brussels. When Cani fed a high-
fat, “junk food” diet to mice, the community of microbes in their guts
changed much as it does in humans on a fast-food diet. But Cani also
found the junk-food diet made the animals’ gut barriers notably more
permeable, allowing endotoxins to leak into the bloodstream. This
produced a low-grade inflammation that eventually led to metabolic
syndrome. Cani concludes that, at least in mice, “gut bacteria can
initiate the inflammatory processes associated with obesity and
insulin resistance” by increasing gut permeability.

These and other experiments suggest that inflammation in the gut may
be the cause of metabolic syndrome, not its result, and that changes
in the microbial community and lining of the gut wall may produce this
inflammation. If Cani is correct — and there is now some evidence
indicating that the same mechanism is at work in humans — then medical
science may be on the trail of a Grand Unified Theory of Chronic
Disease, at the very heart of which we will find the gut microbiome.

My first reaction to learning all this was to want to do something
about it immediately, something to nurture the health of my
microbiome. But most of the scientists I interviewed were reluctant to
make practical recommendations; it’s too soon, they told me, we don’t
know enough yet. Some of this hesitance reflects an understandable
abundance of caution. The microbiome researchers don’t want to make
the mistake of overpromising, as the genome researchers did. They are
also concerned about feeding a gigantic bloom of prebiotic and
probiotic quackery and rightly so: probiotics are already being hyped
as the new panacea, even though it isn’t at all clear what these
supposedly beneficial bacteria do for us or how they do what they do.
There is some research suggesting that some probiotics may be
effective in a number of ways: modulating the immune system; reducing
allergic response; shortening the length and severity of colds in
children; relieving diarrhea and irritable bowel symptoms; and
improving the function of the epithelium. The problem is that, because
the probiotic marketplace is largely unregulated, it’s impossible to
know what, if anything, you’re getting when you buy a “probiotic”
product. One study tested 14 commercial probiotics and found that only
one contained the exact species stated on the label.

But some of the scientists’ reluctance to make recommendations surely
flows from the institutional bias of science and medicine: that the
future of microbiome management should remain firmly in the hands of
science and medicine. Down this path — which holds real promise — lie
improved probiotics and prebiotics, fecal transplants (with better
names) and related therapies. Jeffrey Gordon, one of those scientists
who peers far over the horizon, looks forward to a time when disorders
of the microbiome will be treated with “synbiotics” — suites of
targeted, next-generation probiotic microbes administered along with
the appropriate prebiotic nutrients to nourish them. The fecal
transplant will give way to something far more targeted: a purified
and cultured assemblage of a dozen or so microbial species that, along
with new therapeutic foods, will be introduced to the gut community to
repair “lesions” — important missing species or functions. Yet,
assuming it all works as advertised, such an approach will also allow
Big Pharma and Big Food to stake out and colonize the human microbiome
for profit.

When I asked Gordon about do-it-yourself microbiome management, he
said he looked forward to a day “when people can cultivate this
wonderful garden that is so influential in our health and well-being”
— but that day awaits a lot more science. So he declined to offer any
gardening tips or dietary advice. “We have to manage expectations,” he
said.

Alas, I am impatient. So I gave up asking scientists for
recommendations and began asking them instead how, in light of what
they’ve learned about the microbiome, they have changed their own
diets and lifestyles. Most of them have made changes. They were slower
to take, or give their children, antibiotics. (I should emphasize that
in no way is this an argument for the rejection of antibiotics when
they are medically called for.) Some spoke of relaxing the sanitary
regime in their homes, encouraging their children to play outside in
the dirt and with animals — deliberately increasing their exposure to
the great patina. Many researchers told me they had eliminated or cut
back on processed foods, either because of its lack of fiber or out of
concern about additives. In general they seemed to place less faith in
probiotics (which few of them used) than in prebiotics — foods likely
to encourage the growth of “good bacteria” already present. Several,
including Justin Sonnenburg, said they had added fermented foods to
their diet: yogurt, kimchi, sauerkraut. These foods can contain large
numbers of probiotic bacteria, like L. plantarum and bifidobacteria,
and while most probiotic bacteria don’t appear to take up permanent
residence in the gut, there is evidence that they might leave their
mark on the community, sometimes by changing the gene expression of
the permanent residents — in effect turning on or off metabolic
pathways within the cell — and sometimes by stimulating or calming the
immune response.

What about increasing our exposure to bacteria? “There’s a case for
dirtying up your diet,” Sonnenburg told me. Yet advising people not to
thoroughly wash their produce is probably unwise in a world of
pesticide residues. “I view it as a cost-benefit analysis,” Sonnenburg
wrote in an e-mail. “Increased exposure to environmental microbes
likely decreases chance of many Western diseases, but increases
pathogen exposure. Certainly the costs go up as scary antibiotic-
resistant bacteria become more prevalent.” So wash your hands in
situations when pathogens or toxic chemicals are likely present, but
maybe not after petting your dog. “In terms of food, I think eating
fermented foods is the answer — as opposed to not washing food, unless
it is from your garden,” he said.

With his wife, Erica, also a microbiologist, Sonnenburg tends a colony
of gnotobiotic mice at Stanford, examining (among other things) the
effects of the Western diet on their microbiota. (Removing fiber
drives down diversity, but the effect is reversible.) He’s an amateur
baker, and when I visited his lab, we talked about the benefits of
baking with whole grains.

“Fiber is not a single nutrient,” Sonnenburg said, which is why fiber
supplements are no magic bullet. “There are hundreds of different
polysaccharides” — complex carbohydrates, including fiber — “in
plants, and different microbes like to chomp on different ones.” To
boost fiber, the food industry added lots of a polysaccharide called
inulin to hundreds of products, but that’s just one kind (often
derived from the chicory-plant root) and so may only favor a limited
number of microbes. I was hearing instead an argument for a variety of
whole grains and a diverse diet of plants and vegetables as well as
fruits. “The safest way to increase your microbial biodiversity is to
eat a variety of polysaccharides,” he said.

His comment chimed with something a gastroenterologist at the
University of Pittsburgh told me. “The big problem with the Western
diet,” Stephen O’Keefe said, “is that it doesn’t feed the gut, only
the upper G I. All the food has been processed to be readily absorbed,
leaving nothing for the lower G I. But it turns out that one of the
keys to health is fermentation in the large intestine.” And the key to
feeding the fermentation in the large intestine is giving it lots of
plants with their various types of fiber, including resistant starch
(found in bananas, oats, beans); soluble fiber (in onions and other
root vegetables, nuts); and insoluble fiber (in whole grains,
especially bran, and avocados).

With our diet of swiftly absorbed sugars and fats, we’re eating for
one and depriving the trillion of the food they like best: complex
carbohydrates and fermentable plant fibers. The byproduct of
fermentation is the short-chain fatty acids that nourish the gut
barrier and help prevent inflammation. And there are studies
suggesting that simply adding plants to a fast-food diet will mitigate
its inflammatory effect.

The outlines of a diet for the new superorganism were coming clear,
and it didn’t require the ministrations of the food scientists at
Nestlé or General Mills to design it. Big Food and Big Pharma probably
do have a role to play, as will Jeffrey Gordon’s next-generation
synbiotics, in repairing the microbiota of people who can’t or don’t
care to simply change their diets. This is going to be big business.
Yet the components of a microbiota-friendly diet are already on the
supermarket shelves and in farmers’ markets.

Viewed from this perspective, the foods in the markets appear in a new
light, and I began to see how you might begin to shop and cook with
the microbiome in mind, the better to feed the fermentation in our
guts. The less a food is processed, the more of it that gets safely
through the gastrointestinal tract and into the eager clutches of the
microbiota. Al dente pasta, for example, feeds the bugs better than
soft pasta does; steel-cut oats better than rolled; raw or lightly
cooked vegetables offer the bugs more to chomp on than overcooked,
etc. This is at once a very old and a very new way of thinking about
food: it suggests that all calories are not created equal and that the
structure of a food and how it is prepared may matter as much as its
nutrient composition.

It is a striking idea that one of the keys to good health may turn out
to involve managing our internal fermentation. Having recently learned
to manage several external fermentations — of bread and kimchi and
beer — I know a little about the vagaries of that process. You depend
on the microbes, and you do your best to align their interests with
yours, mainly by feeding them the kinds of things they like to eat —
good “substrate.” But absolute control of the process is too much to
hope for. It’s a lot more like gardening than governing.

The successful gardener has always known you don’t need to master the
science of the soil, which is yet another hotbed of microbial
fermentation, in order to nourish and nurture it. You just need to
know what it likes to eat — basically, organic matter — and how, in a
general way, to align your interests with the interests of the
microbes and the plants. The gardener also discovers that, when
pathogens or pests appear, chemical interventions “work,” that is,
solve the immediate problem, but at a cost to the long-term health of
the soil and the whole garden. The drive for absolute control leads to
unanticipated forms of disorder.

This, it seems to me, is pretty much where we stand today with respect
to our microbiomes — our teeming, quasi-wilderness. We don’t know a
lot, but we probably know enough to begin taking better care of it. We
have a pretty good idea of what it likes to eat, and what strong
chemicals do to it. We know all we need to know, in other words, to
begin, with modesty, to tend the unruly garden within.


Michael Pollan is the Knight professor of journalism at the University
of California, Berkeley, and the author, most recently, of “Cooked: A
Natural History of Transformation.”

Editor: Ilena Silverman





http://www.nytimes.com/2013/05/19/magazine/say-hello-to-the-100-trillion-bacteria-that-make-up-your-microbiome.html?pagewanted=all