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Could Research into the Human Microbiome Lead to a Revolution in Human Health?
We each have trillions of microbial hitchhikers living in and on our bodies. These symbiotic organisms have co-evolved with us over millions of years and increasingly are being seen as essential to our health and well being, researchers said at the 2012 Abelson Symposium at AAAS.
The effort to understand the human microbiome—the full complement of 4 million or more genes contained in the microbial community we each harbor—is one of the hottest fields of scientific research.
The effort is revealing how crucial these inhabitants are to our development, metabolism, immune defenses, and susceptibility to a variety of infectious and non-communicable diseases. Symposium speakers discussed how knowledge of host-microbe interactions might be exploited to develop new treatments for intractable infections, malnutrition, metabolic disorders such as type II diabetes and obesity, and inflammatory disorders such as colitis and Crohn’s disease.
Using powerful gene sequencing methods and computational tools, researchers have learned much about the number and composition of microbial species in the human gut and elsewhere. (A European research effort has found a total of at least 1000 different bacterial species inhabiting the guts of 124 subjects from Denmark and Spain, with each person harboring 160 species on average).
But Jeffrey I. Gordon, chair of the 27 June Abelson Symposium and director of the Center for Genome Sciences and Systems Biology at Washington University in St. Louis, said the grand challenge now is to “move beyond the allure and seduction” of describing the components of the microbiome to truly understand the functional roles the microbes play as they interact with their human hosts and with invasive species.
“This field is quite humbling,” Gordon said. “The science is incredibly complex and incredibly dynamic.” But, he added, the research “is allowing us to see ourselves as intimately connected with the microbial world.”
The Abelson Symposium honors the late Philip Hauge Abelson, editor of the journal Science for 22 years and then senior adviser to AAAS. It was held in conjunction with publication on 6 June by Science and Science Translational Medicine of a special section on the gut microbiota, the community of microbes that live in the intestinal tract.
Seeing Health as Microbial Ecology
A healthy microbiome in the human gut depends on a constant chatter that goes on between host and microbes. The microbes “look upon us as a house,” said Sven Pettersson, professor of host-microbe interactions at the Karolinska Institute in Stockholm, Sweden. And in that house, he said, a microbe is in constant communication with the host so that “the house won’t kick [it] out.”
Jeremy K. Nicholson, head of the Departments of Surgery and Cancer at Imperial College, London, said the microbes in the gut shape the development of our immune system, which in turn shapes the composition of the gut microbiota. The cross-talk between the microbes and the host’s immune system is transmitted by hundreds of different molecules in dozens of signaling pathways.
A sample of blood or urine contains thousands of metabolites from the chemical reactions that occur as part of the cross-talk, Nicholson said, and the number is well beyond what textbooks had described even recently. Nicholson is interested in such metabolites as markers of human health. “Microbes create things that change your disease risk factors,” he said.
Microbial activities in the gut can affect how well we respond to various medications, for example. Production of a molecule called 4-cresol sulfate by gut-dwelling bacteria affects the uptake of the pain killer acetaminophen in humans, Nicholson said, and also may affect the sulfate chemistry of hundreds of other drugs as well.
Researchers may someday be able to improve health outcomes by, in effect, treating bacteria whose metabolites are influencing the effectiveness of particular medications. “If we know which bugs go with which drugs,” Nicholson said, “we can think about ‘drugging’ the microbiome.” He cited a 2010 study in mice which showed that the toxic side-effects of a colon cancer drug called CPT-11 were lessened by inhibiting the production of a specific bacterial enzyme.
David A. Relman, a professor of medicine, microbiology and immunology at Stanford University, studies the microbiome as an ecologist, looking at the entire community as a unit. In his view, each of us can be seen as an island-like “patch” of habitat occupied by assemblages of microbes that arise due to fundamental ecological processes such as dispersal, local diversification, environmental selection and ecological drift. To understand this “metacommunity” of host and microbes, Relman says, it is important to understand how it can vary over space and time (or what ecologists call biogeography).
Nicholson discussed, for example, how the microbial community starts to assemble itself over time when a baby is born. The infant picks up microbes from the mother’s vaginal canal during birth and ingests some of them. The dominant species is a bacterium called Lactobacillus. Infants born by cesarean section are exposed initially to skin microbes. Infants delivered at home also may be colonized by different species of microbes than if they are delivered in a hospital.
Over the first several months of life, the composition and structure of the infant’s microbial community is established in a pattern of shifts that Relman called “punctuated equilibrium.” Events such as fevers, formula feeding, or administration of antibiotics have been linked to these shifts. Abrupt shifts also may be linked to invasions by better- adapted species of microbes.
An example of the microbiome’s spatial dimension can be found in the human mouth, Relman said. “Each of our teeth is like an island,” he said, and the local colonies of bacteria on teeth and in gum pockets can vary widely from one tooth to the next. There appears to be very little mixing of bacterial species below the gum line, he said. As researchers better identify how bacterial species tend to segregate within the mouth, Relman said, it should provide opportunities for promoting communities that are resistant to gum disease. Dentists might, for example, transplant bacteria from healthy gum pockets to deep pockets affected by periodontal disease.
Relman argues that medicine, often described as a battle or war against invading pathogens, really has more in common with park management with its focus on habitat restoration, promotion of native species and targeted removal of invasive species. Much as a park ranger may refer to a park management plan, he said, “we need a management guide to the human habitat.”
The emphasis, he said, should be on maintaining a proper ecological balance in the body. When that balance is disrupted, such as through use of a powerful, broad-spectrum antibiotic to kill invading “bad” bacteria, there can be serious consequences for the microbiome.
To Restore Health, Restore the Microbiome?
Katherine P. Lemon, assistant in medicine at Boston Children’s Hospital, who works on the developing infant microbiome, said studies suggest that 10% to 40% of children treated with broad spectrum antibiotics will develop a condition called pediatric antibiotic associated diarrhea (or AAD). There have been a number of promising clinical trials indicating that use of probiotics—ingestion of beneficial microorganisms—might prevent pediatric AAD. But Lemon said more trials are needed with a standard definition of AAD and standard preparations and dosing of probiotics.
In some cases, the disruption of the microbiome by antibiotics is severe enough that clinicians have resorted to replacing the gut microbes entirely with a fecal microbial transplant. The fecal material is obtained from a healthy donor, usually a household member. Lemon said the treatment has had success rates above 90% in a small number of cases of recurrent colitis caused by a bug called C. difficile. Other diseases also could be susceptible to microbiota transplants or major microbial adjustments, Lemon suggested, including recurrent middle ear infections, inflammatory bowel disease, allergies, and atopic dermatitis
Lemon also discussed what can happen when normally well-behaved members of our microbial community get out of hand. For example, about 30% of the U.S. population harbors a common bacterium called Staphylococcus aureus in the nostrils. Usually, there are few consequences. But if the bug spreads beyond the nose (yes, picking the nose can be one means of dispersal), it can cause a variety of skin infections as well as pneumonia, septicemia, and other conditions if it spreads internally within the body.
The good news is that 70% of us do not harbor the bug routinely in our nostrils. One possible explanation: Lemon’s research with chemist Michael Fischbach (involving isolates from five subjects) suggests that two other microbes residing in the nostril—Propionibacterium and Corynebacterium— produce small molecules with anti-bacterial properties. They can create a zone of inhibition against Staphylococcus aureus and help ward off infection. It should be possible, Lemon said, to mine the human microbiota for agents effective against Staphylococcus aureus and other bugs.
There is no substitute for a healthy immune system, of course, and basic studies on the microbiome are showing in some detail the fundamental role that the resident bugs in our system play in fostering normal development of disease-fighting immune cells such as the white blood cells called T lymphocytes.
Andrew J. Macpherson, director of gastroenterology at University Hospital in Bern, Switzerland, said that on the front lines of our immune system response, “we are as we are because of microbes.” That front line defense, the mucosal immune system, is powerfully shaped by resident microbes, Macpherson said. Studies in mice have shown that species of intestinal microbes called clostridia induce the appearance of regulatory T cells—vital to immune responses—both in the mucous membranes and systemically.
So while resident bacteria in our guts do more than simply help us digest food, their value also depends on our ability to peacefully co-exist with them and prevent them from spreading to other parts of the body where they could cause harm. Lora V. Hooper, associate professor of immunology at the University of Texas Southwestern Medical Center in Dallas, described how interactions at the inner lining of the gut may help us tolerate the presence of about 100 trillion intestinal bacteria.
Hooper’s team has shown that a microbe-killing protein called RegIII gamma, produced by the epithelial cells that line the surface of the gut, helps maintain a small but important buffer between that surface and the gut’s resident microbes. The protein works in conjunction with a thin mucous layer that coats the epithelial cells. Those cells also secrete other anti-microbial proteins called alpha defensins, and these can help shape the composition of the microbial community in the gut, Hooper said.
The absence of certain microbes within that gut community may contribute to the onset of complex diseases, including debilitating autoimmune disorders such as inflammatory bowel disease (or IBD), said Richard S. Blumberg, co-director of the Harvard Digestive Disease Center in Boston. He noted that despite substantial progress in identifying common genetic susceptibilities for autoimmune diseases, genetics alone is not sufficient to explain the increasing incidence of IBD over the past several decades.
Environmental factors involving the microbiome may provide answers, Blumberg said. Studies have shown that IBD patients have a decreased abundance and diversity of three classes of bacteria called Bacteroidetes and a decreased number of protective microbes such as Faecalibacterium prausnitzii. Without early exposure to such microbes, we may be more susceptible to IBD later in life.
In studies with germ-free mice, described in a Science paper published earlier this year, Blumberg and his colleagues found the absence of intestinal microbes triggers production of a signaling molecule called CXCL16, which in turn stimulates high levels of immune cells called invariant natural killer T cells. Those cells can cause harmful inflammatory and autoimmune conditions such as IBD and asthma.
A Research-Based, Hype-Free Approach
While speakers at the symposium highlighted advances in understanding the intimate co-existence between humans and their microbes, they also cautioned against overblown expectations for commercial probiotic products containing bacteria meant to keep the gut microbes in balance and improve health. The evidence so far for their effectiveness remains sketchy, they said. Asked whether healthy individuals should be taking pro-biotics, Nicholson said simply: “If it ain’t broke, don’t fix it.”
Although there is good evidence that the microbiome is dynamic and can be manipulated to improve health, Gordon said there remain important legal and ethical issues regarding clinical research, including who should be the first research subjects for studies of next-generation probiotics; whether such products are going to be considered drugs or not by regulators; the risks in trying to manipulate the diet of mothers and their infants; and intellectual property questions regarding ownership of the microbes being manipulated.
“This work could herald a new epoch in precision nutrition,” Gordon said, with an increasing emphasis on the use of foods as drugs for disease prevention. But he said researchers should embrace the precautionary principle and thoroughly discuss the implications of their work when designing future clinical studies.
The use of fecal transplants is an area where speakers also urged caution. Gordon said he was concerned about the long-term safety and reproducibility of the promising work so far. He said it is important to keep detailed records on how the transplant was formulated, the diets of the recipients, the biomarkers that might be useful for tracking a successful outcome, and other factors. Macpherson expressed concerns about the possible impact of fecal transplants on patients with long-term inflammatory bowel disease.
“Often these are very heavily immune-suppressed patients,” Macpherson said. “It’s a very important issue. I personally don’t send patients for these fecal transplants.”
More broadly, panelists said it remains a challenge for researchers to find ways to tease out cause-and-effect between the state of the microbiome and human health. “Establishing causality remains a fundamental question,” Gordon said.
Relman said one approach is to do long-term population studies of individuals from birth, monitoring them for chance disruptions in their microbiomes and related health impacts. Such studies must be done carefully to take into account confounding factors, such as incidental antibiotic use that can complicate the analysis. A second, more active approach, would be to deliberately perturb the microbiome with antibiotics or other agents and analyze the possible impacts on health. “I’m more a proponent of the first [approach],” Relman said.
Lemon said that, while there is more emphasis these days on limiting the use of antibiotics in children, there remain cohorts of children who do receive the drugs for medically appropriate reasons. “I think we need to take advantage of studying those children,” Lemon said, following them for five years or more to see how the early perturbation of their microbiome may affect their subsequent health.
11 July 2012