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Of Guts and Glory

Scientists are mapping the uncharted territory of our body's micro biome....

Even in solitude, our bodies are walking, talking communities of thousands of species of bacteria and other micro-organisms that live in our mouths, on our skin, and in our guts.

The human body is made up of about 10 trillion cells, but these are far outnumbered by the 100 trillion cells belonging to the integral microbes in and on our bodies. Known collectively as the microbiome, these organisms aid digestion and potentially contribute to a startling array of other functions: influencing weight and metabolism, switching allergies on or off, and affecting mental health.

Scientists say an individual’s microbial community is shaped by a host of factors, including genes, diet, medications, even the pets he or she owned as a child. As a result, each person has his or her own blend of resident microorganisms as distinctive as a fingerprint, which researchers predict may one day help solve crimes.

New computational tools mean researchers can process huge volumes of data to measure the number and type of these bacteria more quickly and cheaply. As a result, “the field of microbiota has exploded,” says W. Allan Walker, MD, founder of the division of pediatric gastroenterology and nutrition at Massachusetts General Hospital (MGH) in Boston.

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Weird Science

Few people are as knowledgeable about their own personal microbiomes as Rob Knight, PhD, professor of pediatrics, computer science, and engineering at the University of California, San Diego (UCSD), School of Medicine. A bioinformatics expert, Knight has developed methods to sequence the DNA of microorganisms in the body, allowing researchers to identify and track entire microbial communities. He has also sampled his own gut microbiota—from his palms, forehead, tongue, and toilet paper—daily for the last six years. He has collected regular samples, less frequently, from his wife and toddler. “Other people get sick of the sampling a lot quicker,” he says wryly. Knight began this sampling after collaborating with Jeff Gordon, MD, of Washington University in St. Louis, on a groundbreaking study that linked obesity in mice to the makeup of their gut bacteria. “At the time everyone thought that was completely crazy, or maybe a [fluke] that wouldn’t be reproduced, or something that only applied to the mouse model,” Knight says. But this once-outlandish idea became widely accepted within a relatively short time.

Now, large databases including the National Institutes of Health’s Human Microbiome Project and the American Gut Project provide opportunities for researchers to more closely examine the human gut. How does the microbiome look before the onset of Crohn’s disease? How might a diet rich in leafy greens influence gut flora? Are there similarities in the microbiota of people with autism?

Despite the hope that microbiome research can answer these questions and lead to effective treatments, scientists stress that we are still largely in the dark. Consider the issue of diversity in gut flora: Having fewer species of those organisms “has been associated with a range of adverse conditions, including obesity, inflammatory bowel disease, and colon cancer,” Knight says. “What we don’t know yet is whether that low diversity is the cause of those conditions or a side effect.”

Physicians and scientists are similarly wary of the unregulated probiotic products that line grocery store and pharmacy shelves. Research shows benefits from some specific strains; Bifidobacterium infantis may ease bloating in women, for example. But “for general health, we don’t have any proof,” says Linda A. Lee, MD, clinical director of the division of gastroenterology and hepatology at Johns Hopkins School of Medicine, and director of the Johns Hopkins Integrative Medicine and Digestive Center.

At Johns Hopkins, Dr. Lee performs a stomach-turning procedure known as a fecal transplant, in which patients gravely ill with Clostridium difficile infection are implanted with feces from healthy volunteers in an attempt to reboot their bacterial communities, thus wiping out the infection. As bizarre as it sounds, the treatment is “incredibly effective,” Dr. Lee says. “It works 90 percent of the time in people with recurrent C. diff.” Yet researchers do not fully understand how the transplants work. Dr. Lee herself calls the procedure “crude” and “a shotgun approach,” and she is disturbed by the use of fecal transplants in other countries to treat a range of conditions. “Since we are transplanting whole [microbial] populations, we theoretically could be transplanting a future predisposition to a cancer or a mental health problem,” she says.

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Bacteria from Birth

One important area of research focuses on how healthy bacterial communities are established in the first place. The process appears to begin before we are born. Until recently, researchers believed that babies encounter their first bacteria at birth, when they move from the sterile, bug-free womb out into a contaminated world. But new findings suggest that some bacteria from the pregnant mother’s intestines enter her bloodstream and end up in the amniotic fluid, where the fetus swallows them.

Scientists are just beginning to sort out what role this exposure might play, says MGH’s Dr. Walker. He has spent decades studying how situations such as premature birth and C-sections can disrupt microbiome development and how factors in breast milk build an infant’s defenses. Dr. Walker is particularly interested in ways to prevent necrotizing enterocolitis, a life-threatening intestinal condition that can afflict premature babies soon after birth. His research suggests that preemies—who are frequently born by C-section—have immature intestines that overreact to normally beneficial microorganisms, triggering damaging inflammation. Dr. Walker is planning future studies on Bifidobacterium infantis, a probiotic strain that he believes may prevent this inflammatory response.

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The Way to a Man’s Heart—and Kidney and Brain—is Through the Stomach

Inflammation and autoimmune diseases are strongly linked to digestive health in adults, as well. Several studies have already shown strong associations between gut microorganisms and inflammatory bowel disease (IBD), for instance. Dermot McGovern, MD, PhD, of the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai Medical Center in Los Angeles, says research by his lab and others suggest that genes may predispose a person to mount an immune reaction to his or her own gut flora. He is intrigued by the role of metabolites, the waste products generated by these microorganisms in activating the immune system in people with IBD.

At the Stanford Center for Genomics and Personalized Medicine in Palo Alto, Calif., Michael Snyder, MD, is also curious about the role of metabolites in the development of metabolic disorders like diabetes. His team is following 70 people with metabolic problems for three years, taking blood and urine samples every few months when participants are healthy. “Then when people get a respiratory infection, we sample them more to understand the changes that are occurring,” Dr. Snyder explains. As research on microbiota accelerates, however, scientists are uncovering startling connections between the microbiome and conditions that seem distant from digestive health, with findings that may shift our understanding of these diseases.

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The Heart-Kidney-Gut Tripod

For decades, researchers have been looking for the genetic key to heart disease and have found that only about 10 percent of cases of attributable cardiovascular risks are determined by genetic variants such as DNA. That means the majority of heart-health issues may be spawned from environmental causes, explains Stanley Hazen, MD, PhD, section head of preventive cardiology and rehabilitation at Cleveland Clinic’s main campus in Ohio. And the greatest external input is our diet.

Dr. Hazen and his team initially sought to determine new markers and pathways linked to cardiovascular disease. “We looked at thousands of molecules in blood and asked which had levels that tracked with cardiac risks,” he says. They uncovered the presence of trimethylamine N-oxide (TMAO) in large patient populations and then reverse engineered the strong association between TMAO blood levels and cardiovascular disease risks. Using animal models, they proved the compound played a role in heart disease development. They also learned the compounds in the blood that caused disease and tracked with risks were generated primarily by gut microbes during digestion of dietary nutrients found in red meat, egg yolks, and high-fat dairy products. Red meat and dairy contain carnitine and choline, substances metabolized in the lower GI tract by bacteria. This produces a metabolite called trimethylamine, which then enters the bloodstream and is piped straight to the liver, where it is converted to TMAO, the compound that Dr. Hazen and his team had linked to clogged arteries. In his study published in 2013, the more often participants ate red meat, the more TMAO they produced in response to a red-meat meal.

In January, Dr. Hazen published a new study linking chronic kidney disease to the same metabolites produced in the gut and then converted in the liver. “TMAO is cleared by the kidneys, so we thought perhaps patients with impaired kidney function might be at higher risk for heart disease,” he says. His research proved the theory true. TMAO leads to fibrosis, or a type of scarring of tissue, in the kidneys, Dr. Hazen says, which he and his team learned by noting the increase of two biomarkers that indicate injury to the organs. That injured tissue eventually leads to decreased renal function. And as kidney function begins to fail, it can no longer clear TMAO from the body, thus furthering the risk of clogged arteries and accelerated kidney injury. (Dr. Hazen also found that those with normal renal function yet high TMAO had increased risk of cardiovascular disease, as well.)

Since discovering these pathways, Dr. Hazen has himself cut back on the amount of red meat, egg yolks (which are high in choline), and high-fat dairy he consumes, but he does not necessarily advocate for total abstinence. “A balanced, moderate approach is most reasonable,” he says. “It depends on your gut bacteria and TMAO level.”

He is excited about future research that could provide dietary interventional approaches for kidney disease, something that has not been explored before. Dr. Hazen is also hopeful that drugs might be developed that can block the pathway between the intestinal flora and TMAO. “There is not a single bug you can point at; many bacteria are involved,” he says. “What is important is the bacterial pathway.”

Bugs and the Brain

The microbiome also appears to influence the brain and emotional health. Scientists are focused on connections between the brain and the enteric nervous system, “networks of nerves that are sandwiched between the gut layers,” explains Emeran Mayer, MD, PhD, director of the Oppenheimer Family Center for Neurobiology of Stress at UCLA. The vagus nerve carries chemical messages primarily back and forth from the gut to the brain.

In a small, recent study, Dr. Mayer and his colleagues asked healthy young women to eat yogurt containing a mix of probiotics twice a day for four weeks. Test subjects then completed an emotion-recognition task in which they viewed angry or frightened faces while their brain activity was tracked by fMRI. Compared with participants who did not eat yogurt, the women experienced decreased activity in the insula, a part of the brain that processes and integrates internal body sensations, including those from the gut. Bottom “The study confirmed the observation from rodent studies that there is a communication between the gut microbiota and the brain,” Dr. Mayer says.

Because gastrointestinal problems are common in people with autism spectrum disorders, researchers are intrigued by possible gut-brain links. In the Caltech lab of biologist Sarkis Mazmanian, PhD, mice bred to exhibit autism-like symptoms received the probiotic Bacteroides fragilis. The treatment appeared to heal intestinal permeability (also called “leaky gut”) in the autistic mice, which began to communicate with other mice and exhibit less anxiety. In a separate study, Dr. Walker at MGH is analyzing stool samples from new mothers and babies with a family history of autism to look for links between the microbiota and brain development.

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Feeding Frenzy

Many researchers believe diet is among the most important factors that shape an individual’s microbiome. One potential reason: Plant foods contain fibers that the human body cannot digest, so they travel unscathed to the colon, “where most of our microbes exist” and serve as fuel for beneficial gut bacteria, explains Eugene B. Chang, MD, Martin Boyer Professor of Medicine at the Knapp Center for Biomedical Discovery at the University of Chicago. Microbes break these fibers into short-chain fatty acids (SCFAs), which studies show regulate immune cells in the colon, providing protection against conditions like IBD. In contrast, Dr. Chang and his colleagues found in mouse studies that diets rich in concentrated milk fats—which are abundant in ice cream and typically found in dairy and bakery products—disrupted the balance of gut bacteria, allowing IBD to flourish in individuals who are genetically prone to the condition. 

Knight adds that he and his team can guess a person’s diet by the bacteria predominant in his or her microbiome. The presence of the strain Oxalobacter suggests that the individual consumes lots of leafy green vegetables. People with Prevotella tend to have diets heavy in pasta, sugar, or other carbs, and the strain Bacteroides corresponds with diets that include plenty of meat. So far, data from the food frequency questionnaires of American Gut Project participants show that when people describe their diets as Western, Mediterranean, vegan, or Paleo, there is little effect on the microbiome, “suggesting that subtle details of diet are more important than overall self-reported categories,” Knight says.

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Looking Ahead

Researchers say that in the near future, a medical workup may involve analyzing a stool sample (or possibly blood or urine) to check a patient’s microbiome for markers of gastrointestinal problems such as ulcerative colitis or Crohn’s disease. “We currently don’t look at the microbial contribution,” says Dr. Chang. “I believe that by profiling gut microbial composition and function, and analyzing this information, we can achieve a better understanding of why an individual might be at higher risk, develop the disease, or have a specific outcome. We can tailor our interventions to prevent IBD, monitor disease progress, and optimize therapies.”

In the next few months, expect to see a new clinical test become available that will allow physicians to measure TMAO levels in blood and have a clearer picture of a patient’s cardiovascular risk, says Cleveland Clinic’s Dr. Hazen. 

Knowledge of the microbiome could also bring us closer to that long-predicted era of personalized medicine. Knight of UC San Diego believes that within the next five years, physicians will be looking at data on a patient’s microbiome to decide which treatments are likely to be most effective; for example, isolated studies show that it is possible to identify people prone to liver damage from the painkiller acetaminophen. If an individual does not respond to a particular heart medicine or chemotherapy, Knight sees a future where we might “move ourselves from the nonresponder category to a responder by changing the microbiome in a directed fashion,” he says. That could involve taking a drug to alter resident microbes or eating a new diet, or possibly choosing the right country in which to “go and live in a grass hut for a month,” Knight adds. (He is only partially joking.) 

He also envisions the possibility of microbiome engineering, “not just to rescue people from a disease state, but to prevent disease and even optimize human performance. There are all kinds of applications, ranging from the frivolous to the critically important,” he says. “There’s a lot of exciting potential out there.” And in there.

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What’s in your Gut?

The American Gut Project was launched to sequence and analyze the diverse range of microbial communities living in and on people in the United States. Cofounded by researcher Rob Knight, PhD, of the University of California, San Diego, School of Medicine, the project involves crowd-sourced funding and microbiome samples. For a donation of $99, participants receive a kit to collect samples of their stool, skin cells, and mouth cells, as well as a food frequency questionnaire to complete in the days leading up to sampling. People can also receive kits to sample their romantic partners, their children, and even the family dog; it can be fascinating to see how many microorganisms families and their pets have in common, Knight says.

After samples are sequenced in the lab, participants receive a report on the state of their microbiomes, including predominant taxa and an analysis of how their microbiota compares to the microbial communities of other people worldwide already sequenced. The project currently includes data from nearly 4,000 people, and has already yielded compelling findings. Eating a wide range of plant foods, for example, “has one of the largest effects on the microbiome,” Knight says. And people who get more sleep and who exercise outdoors appear to have more diverse microbiota.

Knight and his colleagues are now particularly interested in samples from people with diagnosed conditions such as inflammatory bowel disease (IBD), autism, Parkinson’s disease, multiple sclerosis, depression, and rheumatoid arthritis, all of which have at least some research suggesting—or confirming, in the case of IBD—links between the disease and the microbiome. Knight and his team also seek donors with interest in particular conditions to consider covering the cost of sampling kits for people with those diseases so researchers can look for potential links to gut bacteria. 

The American Gut Project is an open-access dataset, meaning that anyone can study it. “It’s intended as a discovery platform,” Knight explains. “Any researcher, educator, student, member of the public, or company with an idea about the microbiome can now test that idea very rapidly using these data.”

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