1. NEWS Jiao Tong University’s Shanghai Center for
Systems Biomedicine, Zhao oversees several
My Microbiome and Me clinical studies that look at the role of the
microbiome in diabetes, obesity, and liver
Zhao Liping combines traditional Chinese medicine and studies of gut microbes function. But his work remains grounded in
to understand and fight obesity his personal story—which friends say reflects
a willingness to explore uncharted territory
SHANGHAI, CHINA— In some ways it’s a old with flat-top hair and a square jaw— through raw trial and error. “As a scientist,”
familiar story. In 1987, Zhao Liping mar- has become an unlikely spokesperson for a he says, “you should work on questions for
ried Ji Liuying, a college classmate. Within burgeoning field. In 2010, he presented his which there is very little evidence but that you
2 years, they had a daughter and Zhao fin- weight-loss story at the Human Microbiome believe are important.”
ished his Ph.D. Under new pressure and eat- Project meeting in St. Louis, Missouri, Uncertainty about cause and effect is
ing richly—Ji is a good cook—the micro- at the invitation of George Weinstock of what plagues the field right now. It is difficult
biologist put on weight. By 1990, when he Washington University in St. Louis. Gordon’s to prove, for example, that F. prausnitzii
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started an environmental micro- facilitated Zhao’s slimming and didn’t just
biology lab at Shanxi Academy show up once his gut was healthy. “The list of
of Agricultural Sciences in Tai- the diseases that the microbiome may play a
yuan, China, Zhao had grown role in is just growing and growing,” says Lita
from 60 to 80 kilograms. Later, Proctor, director of the U.S. National Institutes
on a postdoctoral fellowship at of Health’s Human Microbiome Project in
Cornell University, he put on Bethesda, Maryland. “But the problem is that
another 10 kilograms. By the we’re only able to look at associations of the
time he returned to China in microbiome with disease and aren’t yet able
1995, his waist measured a cor- to conduct cause-and-effect studies. What
pulent 110 centimeters and his we’re witnessing is a very young field trying
health was poor. to figure out ‘Okay, what’s the right way to
But in 2004, he read a approach [these] data?’ ”
paper that eventually changed For Zhao, the way involves transferring his
the shape of his career—and weight-loss program to hundreds of human
his body. Jeffrey I. Gordon, a subjects and drawing on animal studies to
microbiologist at Washington decide what metabolic parameters to monitor
University School of Medicine in people. While his ultimate
in St. Louis, Missouri, and goal is to establish a molecular
colleagues showed a link pathway connecting the micro-
between obesity and gut biota to obesity, his e-mail
microbiota in mice (Science, signature reads: “EAT RIGHT,
29 May 2009, p. 1136). Zhao KEEP FIT, LIVE LONG, DIE
was curious whether that link QUICK.”
extended to himself and decided The science of shrinking. Microbiologist
to find out. In 2006, he adopted a Zhao Liping, shown here before and after a Faith in traditional medicine
regimen involving Chinese yam change in diet, thinks he lost 20 kilograms by Zhao grew up in a small farming
and bitter melon—fermented regulating his gut microbiota. town in Shanxi Province. Like
prebiotic foods that are believed most Chinese born on the eve of
to change the growth of bacteria in the research had set off a the Cultural Revolution, he and
digestive system—and monitored not just flurry of new studies, but his two younger brothers had a
his weight loss but also the microbes in his Weinstock says scientists simple upbringing. His father
gut. When he combined these prebiotics had reached something was a high school teacher and
with a diet based on whole grains, he lost of an impasse. The “field his mother worked in a textile
20 kilograms in 2 years. His blood pressure, had been standardized to factory. Both of his parents were
heart rate, and cholesterol level came down. some extent by the early firm believers in traditional rem-
CREDITS: COURTESY OF ZHAO LIPING (2)
Faecalibacterium prausnitzii—a bacterium researchers following the edies. Zhao remembers watching
with anti-inflammatory properties— same path,” Weinstock says, and Zhao’s his father try to fight a hepatitis B infection by
flourished, increasing from an undetectable willingness to dive in and experiment on drinking a pungent, murky herbal concoction
percentage to 14.5% of his total gut bacteria. himself “brought a breath of fresh air.” Even twice a day.
The changes persuaded him to focus on the more refreshing was that Zhao presented his A good student, Zhao earned a Ph.D. in
microbiome’s role in his transformation. He findings in a “detached, agnostic, scientific molecular plant pathology from Nanjing
started with mice but has since expanded his way,” Weinstock adds. “He was not religious Agricultural University. When he returned
research to humans. about it at all.” to Shanxi to start his lab, he focused on using
Zhao—now a slim, soft-spoken 49-year- Now associate director of Shanghai beneficial bacteria to rein in plant pathogens.
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2. SPECIALSECTION
One day, a veterinary scientist colleague asked But microbiome studies on mice have
for some strains of Bacillus, explaining that their limitations (see sidebar, p. 1250).
the bacteria helped control diarrhea in pigs To establish a link between the human
and chickens. Zhao realized he was sitting on microbiome and obesity, Zhao knew he
bacterial strains that might control infections needed to study people: “The only successful
in humans as well as plants. example was myself,” he recalls.
Throughout the 1990s, Zhao dabbled in
research on the pig microbiome, exploring Testing in people
the idea that bacterial strains might control In 2009, Zhao returned to Taiyuan to start his
infections in pigs, but couldn’t get funding. first clinical trial. By then, potential candi-
Meanwhile, his family’s health was falling dates for therapy abounded. Obesity was sky-
CREDITS: (TOP) SHUTTERSTOCK; © TRAN THE VUONG/ISTOCKPHOTO.COM; (BOTTOM LEF TO RIGHT) PROVIDED BY GUOYUE ZHONG/CHONGQING ACADEMY OF CHINESE MATERIA MEDICA; MALTE/WIKIMEDIA COMMONS
apart. His plump father’s cholesterol levels rocketing in China, particularly among chil-
spiked, and the elder Zhao suffered two dren, and the incidence of diabetes had spiked
strokes. Zhao’s two brothers had become from roughly 1% of Chinese adults in 1980 to
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obese as well. A few years later, Gordon’s nearly 10% today. After visiting several local
paper provided what Zhao calls “the first hospitals, he had 123 clinically obese volun-
evidence that gut microbiota can actually teers, with a body mass index of at least 30.
regulate host genes.” Thus it seemed He put the patients on 9-week tailored
plausible that this was a way the microbiome programs that included prebiotic foods and
could affect health. He began using himself had them come in for regular checkups and
as a guinea pig to try to pin down what monitoring of gut microbiota and metabolic
microbes might be involved in weight gain. parameters. He followed 90 patients for an
Early microbiome research had raised Gut reaction. Prebiotic foods used in Chinese additional 14 weeks after the diet ended. At
more questions than it answered, however, medicine, including Chinese yam (top) and Chinese three points in the study, participants also gave
and figuring out which of the hundreds bitter melon, may promote the growth of helpful stool samples, which Zhao and colleagues
of microbial species living in the average gut bacteria. used to assess the microflora.
human gut might be involved was tricky. The 93 participants who completed the
He dug into Western literature on weight to single out bacteria associated with obesity. trial showed a median weight loss of about
loss, but introducing a low-calorie diet and For a study published online 12 April in 7 kilograms. In their guts, meanwhile, toxin-
strenuous exercise didn’t make sense to him. The ISME Journal, he and colleagues producing bacteria decreased and beneficial
“Nutritionally, your body is under stress,” he switched mice from normal chow to a high-fat bacteria increased. Encouraged by the results,
says. “Then you add to that physical stress. diet and then back to normal chow again while Zhao added trials in three additional Chinese
Maybe you can lose weight, but you might monitoring changes in their gut microbiota cities for a total of more than 1000 patients.
also damage your health.” Zhao thought of at 2-week intervals. They found about Zhao hopes the research will establish
his father’s herbal concoctions and turned 80 bacterial species associated with a change the molecular pathway that underlies shifts
instead to the traditional medicine literature in diet. More promisingly, the shifts in in metabolism. Studies by Patrice D. Cani
for inspiration. microbiota induced by a high-fat diet were of the Catholic University of Louvain in
Obesity and diabetes plagued members of completely reversible. Belgium and others have shown that a clear
China’s imperial court thousands
of years ago, and the diagnoses
of early doctors preserved in
ancient materia medica resonated
with Zhao. Traditional doctors
“don’t have any idea about gut
microbiota,” Zhao says. “But they
think that the gut is the foundation
for human health—and that the
foundation is acquired after birth.”
(The microbiome is acquired after
birth, and there is increasing
evidence that early colonization
by the right bacteria is important
for health later in life.)
Zhao pinned his hopes on
medicinal vegetables commonly
eaten in China, figuring upping his
dose of these mild foods couldn’t
hurt. As his waistline shrank, he Slimming herbs? Rats fed a high-fat diet together with a compound derived from the herbs Coptis chinensis (left) or Berberis
undertook animal studies, trying vulgaris don’t become obese.
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3. sequence of changes occurs in an animal’s Beijing is an outspoken critic of what he looking forward to seeing results from Zhao’s
gut after consuming a high-fat diet. Bad describes as overblown claims surrounding clinical studies when they’re published.
bacteria increase, the gut barrier becomes Chinese medicine, which he dismisses as “Other studies of diet and the microbiome
more permeable, and toxins increase in the “just herbs.” But he says Zhao’s research with fewer participants have yielded valuable
bloodstream. The spike in toxins, in turn, is encouraging. He cites a study in Beijing and statistically significant results,” he says.
triggers inflammation, which prompts a fall in focused on gut microbiota and diabetes in Large clinical studies involving prebiotics
the host’s metabolism. Zhao now hopes to see which Zhao and colleagues are looking for like those Zhao runs may be easier to carry
the reverse in his human subjects as they adopt signature bacterial species connected to out in China. At a bustling vegetarian
healthier diets. “All these markers should diabetes in humans. “He is headed in the restaurant in downtown Shanghai one night,
show expected changes,” he says. right direction,” Zhu says. Zhao feasts on seaweed, ginkgo, bamboo,
Zhu Baoli of the Chinese Academy of Rob Knight, a microbiologist at the Chinese kale, and Chinese yam. Chinese
Sciences’s Institute of Microbiology in University of Colorado, Boulder, says he is volunteers don’t blink when asked to eat such
plants, he says. “They look at the list we give
them and say, ‘Oh, this is food. No problem.’
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Pigs as Stand-Ins for Microbiome Studies ” And because many of the substances are not
yet accepted as food or medicines in
SHANGHAI, CHINA—The Chinese use pigs for Europe and North America, he adds,
just about everything, from processing waste to “it would take years to get permission
enriching the dinner table. Now they are testing to do clinical trials.”
piglets as a new model for human microbiome But Zhao has his sights set beyond
research. The past decade has seen an exponen- Asia, predicting this work will be more
tial rise in interest in how the microbes living fruitful than genome studies in leading
in and on the human body affect health (see to antiobesity drugs. Weinstock agrees
p. 1246). Studies often involve germ-free mice, that the end goal of Zhao’s studies is to
but rodents have a very different physiology and find active ingredients, not prove “that
gut microbiota than humans. Pigs, by contrast, you can only treat people with the
have an anatomy and immune system closer to fungus that grows in the dung of some
those of people—along with an omnivorous beetles.” In Zhao’s lab, he says, “it’s
diet and a similar digestive tract. Western reductionist science meets
For research published in 2007, Shang- traditional Chinese medicine.”
hai Jiao Tong University microbiologist Zhao One promising compound Zhao
Liping led a team that inoculated 28 germ-free and colleagues are looking into is
piglets with the diluted excrement of a healthy berberine, the major pharmacological
10-year-old boy to see whether the boy’s gut component of the Chinese herb Coptis
microbiota would thrive in the piglets’ guts. chinensis, or huanglian. They have
That happened with two groups of bacteria found that when rats were given a
important to a healthy human gut, Bifidobac- high-fat diet together with berberine,
terium and Bacteroides. More importantly, the rodents didn’t develop obesity or
when the researchers analyzed the piglets’ gut insulin resistance—and in their guts,
microbiota 12 days later and compared it with populations of known pathogens
that of the human donor, conventionally raised decreased while those of known
piglets, and unrelated humans, the microbiota Whole hog. Humanized piglets show promise for beneficial bacteria increased. Other
most closely resembled that of the donor— microbiome research. gut species that changed in abundance
suggesting that it is possible to establish a haven’t yet been studied, and it’s not known
human microbiome in piglets while maintaining their health and immunity. whether they are linked to good or bad health.
Piglets with human gut flora have “great potential” for use in microbiome research, Zhao But Zhao is quick to acknowledge that this
says. Sharon Donovan, a pediatric health researcher at the University of Illinois, Urbana- work is not going to produce a panacea. And,
Champaign, agrees: “The piglet is an exceptional model for the human infant in terms of gastro- he adds, “we need to do a lot more work
intestinal, immune, and cognitive development.” to understand how [berberine] will affect
CREDIT: PHOTO PROVIDED BY XIAOYAN PANG
Several obstacles remain. Much less is known about pig genetics, so linking pig genes to the nutrition and metabolism.”
microbiome will be a challenge. Also, piglets are relatively expensive—about $120 apiece in If Zhao does one day prove a link
China—and, like other animals, not always receptive to human microbiota. In another study by between gut microbiota and health, it will
the Shanghai Jiao Tong scientists, seven out of 24 human-flora–associated piglets died because be bittersweet. His father, who suffers from
the bacteria they received from an otherwise healthy human donor’s stool contained a strain of inflammation and lingering effects from his
pneumonia-causing bacteria, which scientists had missed. Nonetheless, says Imperial College strokes, is in his last days, and Zhao has spent
London systems biologist Jeremy Nicholson, pigs inoculated with human microbiota get “closer much of the past few months at his bedside. “I
to an animal model of human overall system behavior” than other animals. Humanized pigs, he wish I had done this research 10 years ago,” he
adds, could be “the best thing you could do for human drug testing.” –M.H. says. “I could have helped him.”
–MARA HVISTENDAHL
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