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My microbiome and me

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  • 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 Downloaded from www.sciencemag.org on September 25, 2012 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.1248 8 JUNE 2012 VOL 336 SCIENCE www.sciencemag.org Published by AAAS
  • 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 Downloaded from www.sciencemag.org on September 25, 2012 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. www.sciencemag.org SCIENCE VOL 336 8 JUNE 2012 1249 Published by AAAS
  • 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.’ Downloaded from www.sciencemag.org on September 25, 2012 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 HVISTENDAHL1250 8 JUNE 2012 VOL 336 SCIENCE www.sciencemag.org Published by AAAS

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