NIH Roadmap Effort to Use Genomic Technologies To Explore Role of Microbes in Human Health and Disease.
The human body contains trillions of microorganisms, living together with human cells, usually in harmony. Because of their small size, however, microorganisms make up only about one to two percent of the body’s mass. Many microbes maintain our health, while others cause illness. Yet, surprisingly little is known about the role this astounding assortment of bacteria, fungi and other microbes play in human health and disease. To better understand these interactions, the National Institutes of Health (NIH) today announced the official launch of the Human Microbiome Project. The human microbiome is the collective genomes of all microorganisms present in or on the human body.
“The human microbiome is largely unexplored,” said NIH Director Elias A. Zerhouni, M.D. “It is essential that we understand how microorganisms interact with the human body to affect health and disease. This project has the potential to transform the ways we understand human health and prevent, diagnose and treat a wide range of conditions.”
Part of the NIH’s Roadmap for Medical Research, the Human Microbiome Project will award a total of $115 million to researchers over the next five years. Initially, researchers will sequence 600 microbial genomes, completing a collection that will total some 1,000 microbial genomes and providing a resource for investigators interested in exploring the human microbiome. Other microbial genomes are being contributed to the collection by individual NIH institutes and internationally funded projects. A meeting between international partners was recently convened to discuss forming an international consortium.
Researchers will then use new, comprehensive laboratory technologies to characterize the microbial communities present in samples taken from healthy human volunteers, even for microbes that cannot be grown in the laboratory. The samples will be collected from five body regions known to be inhabited by microbial communities: the digestive tract, the mouth, the skin, the nose, and the female urogenital tract. Demonstration projects will subsequently be funded to sample the microbiomes from volunteers with specific diseases. This will allow researchers to correlate the relationship between changes in a microbiome present at a particular body site to a specific illness.
“We now understand that there are more microbial cells than human cells in the human body. The Human Microbiome Project offers an opportunity to transform our understanding of the relationships between microbes and humans in health and disease,” said Dr. Alan Krensky, the director of the Office of Portfolio Analysis and Strategic Initiatives (OPASI), which oversees the NIH Roadmap for Medical Research.
While the term “microbiome” may be relatively new in biomedical research, most people are familiar with some of the effects — both good and bad — that microbes can have on our health. Consider the example of the biggest reservoir of microbes in humans: the digestive tract. The human gut harbors many beneficial microorganisms, including certain bacteria called probiotics. There is evidence these probiotics, found in dietary supplements, yogurt and other dairy products as well as various soy products, can stimulate the immune system and improve digestive functions. In contrast, previous research suggests that variations in the composition of microbial communities may contribute to chronic health conditions, including diabetes, asthma, obesity and digestive disorders. […]
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The human skin microbiome plays important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that while the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may play roles in determining virulence properties of P. acnes strains and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain level analysis of the human microbiome to define the role of commensals in health and disease.
The diversity of the human microbiota at the strain level and its association with human health and disease is largely unknown. However, many studies have shown that microbe-related human diseases are often caused by certain strains of a species, rather than the entire species being pathogenic. Examples include methicillin-resistant Staphylococcus aureus (MRSA) (Chambers and Deleo, 2009; Chen et al., 2010; Hansra and Shinkai) and Escherichia coli O157 (Chase-Topping et al., 2008; Tarr et al., 2005). Acne vulgaris (commonly called acne) is one of the most common skin diseases with a prevalence of up to 85% of teenagers and 11% of adults (White, 1998). Although the etiology and pathogenesis of acne are still unclear, microbial involvement is considered one of the main mechanisms contributing to the development of acne (Bojar and Holland, 2004; Cunliffe, 2002). In particular, Propionibacterium acnes has been hypothesized to be an important pathogenic factor (Webster, 1995). Antibiotic therapy targeting P. acnes has been a mainstay treatment for more than 30 years (Leyden, 2001). However, despite decades of study, it is still not clear how P. acnes contributes to acne pathogenesis while being a major commensal of the normal skin flora (Bek-Thomsen et al., 2008; Cogen et al., 2008; Costello et al., 2009; Dominguez-Bello et al., 2010; Fierer et al., 2008; Gao et al., 2007; Grice et al., 2009). Whether P. acnes protects the human skin as a commensal bacterium or functions as a pathogenic factor in acne, or both, remains to be elucidated. […]
For years, bacteria have had a bad name. They are the cause of infections, of diseases. They are something to be scrubbed away, things to be avoided.
But now researchers have taken a detailed look at another set of bacteria that may play even bigger roles in health and disease: the 100 trillion good bacteria that live in or on the human body.
No one really knew much about them. They are essential for human life, needed to digest food, to synthesize certain vitamins, to form a barricade against disease-causing bacteria. But what do they look like in healthy people, and how much do they vary from person to person?
In a new five-year federal endeavor, the Human Microbiome Project, which has been compared to the Human Genome Project, 200 scientists at 80 institutions sequenced the genetic material of bacteria taken from nearly 250 healthy people.
They discovered more strains than they had ever imagined — as many as a thousand bacterial strains on each person. And each person’s collection of microbes, the microbiome, was different from the next person’s. To the scientists’ surprise, they also found genetic signatures of disease-causing bacteria lurking in everyone’s microbiome. But instead of making people ill, or even infectious, these disease-causing microbes simply live peacefully among their neighbors.
The results, published on Wednesday in Nature and three PLoS journals, are expected to change the research landscape.
The work is “fantastic,” said Bonnie Bassler, a Princeton University microbiologist who was not involved with the project. “These papers represent significant steps in our understanding of bacteria in human health.”
Until recently, Dr. Bassler added, the bacteria in the microbiome were thought to be just “passive riders.” They were barely studied, microbiologists explained, because it was hard to know much about them. They are so adapted to living on body surfaces and in body cavities, surrounded by other bacteria, that many could not be cultured and grown in the lab. Even if they did survive in the lab, they often behaved differently in this alien environment. It was only with the advent of relatively cheap and fast gene sequencing methods that investigators were able to ask what bacteria were present.
Examinations of DNA sequences served as the equivalent of an old-time microscope, said Curtis Huttenhower of the Harvard School of Public Health, an investigator for the microbiome project. They allowed investigators to see — through their unique DNA sequences — footprints of otherwise elusive bacteria.
The work also helps establish criteria for a healthy microbiome, which can help in studies of how antibiotics perturb a person’s microbiome and how long it takes the microbiome to recover.
In recent years, as investigators began to probe the microbiome in small studies, they began to appreciate its importance. Not only do the bacteria help keep people healthy, but they also are thought to help explain why individuals react differently to various drugs and why some are susceptible to certain infectious diseases while others are impervious. When they go awry they are thought to contribute to chronic diseases and conditions like irritable bowel syndrome, asthma, even, possibly, obesity.
Humans, said Dr. David Relman, a Stanford microbiologist, are like coral, “an assemblage of life-forms living together.”
Dr. Barnett Kramer, director of the division of cancer prevention at the National Cancer Institute, who was not involved with the research project, had another image. Humans, he said, in some sense are made mostly of microbes. From the standpoint of our microbiome, he added, “we may just serve as packaging.”
The microbiome starts to grow at birth, said Lita Proctor, program director for the Human Microbiome Project. As babies pass through the birth canal, they pick up bacteria from the mother’s vaginal microbiome.
“Babies are microbe magnets,” Dr. Proctor said. Over the next two to three years, the babies’ microbiomes mature and grow while their immune systems develop in concert, learning not to attack the bacteria, recognizing them as friendly.
Babies born by Caesarean section, Dr. Proctor added, start out with different microbiomes, but it is not yet known whether their microbiomes remain different after they mature. In adults, the body carries two to five pounds of bacteria, even though these cells are minuscule — one-tenth to one-hundredth the size of a human cell. The gut, in particular, is stuffed with them.
“The gut is not jam-packed with food; it is jam-packed with microbes,” Dr. Proctor said. “Half of your stool is not leftover food. It is microbial biomass.” But bacteria multiply so quickly that they replenish their numbers as fast as they are excreted.
The bacteria also help the immune system, Dr. Huttenhower said. The best example is in the vagina, where they secrete chemicals that can kill other bacteria and make the environment slightly acidic, which is unappealing to other microbes.
Including the microbiome as part of an individual is, some researchers said, a new way to look at human beings.
It was a daunting task, though, to investigate the normal human microbiome. Previous studies of human microbiomes had been small and had looked mostly at fecal bacteria or bacteria in saliva in healthy people, or had examined things like fecal bacteria in individuals with certain diseases, like inflammatory bowel disease, in which bacteria are thought to play a role.
But, said Barbara B. Methé, an investigator for the microbiome study and a microbiologist at the J. Craig Venter Institute, it was hard to know what to make of those studies.
“We were stepping back and saying, ‘We don’t really have a population study. What does a normal microbiome look like?’ ” she said.
The first problem was finding completely healthy people for the study. The investigators recruited 600 subjects, ages 18 to 40, poking and prodding them. They brought in dentists to probe their gums, looking for gum disease, and pick at their teeth, looking for cavities. They brought in gynecologists to examine the women to see if they had yeast infections. They examined skin and tonsils and nasal cavities. They made sure the subjects were not too fat and not too thin. Even though those who volunteered thought they filled the bill, half were rejected because they were not completely healthy. And 80 percent of those who were eventually accepted first had to have gum disease or cavities treated by a dentist.
When they had their subjects — 242 men and women deemed free of disease in the nose, skin, mouth, gastrointestinal tract and, for the women, vagina — the investigators collected stool samples and saliva, and scraped the subjects’ gums and teeth and nostrils and their palates and tonsils and throats. They took samples from the crook of the elbow and the folds of the ear. In all, women were sampled in 18 places, including three sites in the vagina, and men in 15. The investigators resampled subjects three times during the course of the study to see if the bacterial composition of their bodies was stable, generating 11,174 samples.
To catalog the body’s bacteria, researchers searched for DNA with a specific gene, 16S rRNA, that is a marker for bacteria and whose slight sequence variations can reveal different bacterial species. They sequenced the bacterial DNA to find the unique genes in the microbiome. They ended up with a deluge of data, much too much to study with any one computer, Dr. Huttenhower said, creating “a huge computational challenge.”
The next step, he said, is to better understand how the microbiome affects health and disease and to try to improve health by deliberately altering the microbiome.
But, Dr. Relman said, “we are scratching at the surface now.”
Probiotics are live microorganisms which upon ingestion in sufficient concentrations can exert health benefits to the host.
This definition of probiotics was derived in 2001 by the United Nations Food and Agriculture Organization (FAO) and the World Health Organization (WHO), and has been the term of reference for science and regulation thereafter.
Demand for food containing probiotics are expanding globally due to the continuous generation of research evidence indicating their potential health benefits to consumers.
Hundreds of different bacteria species are the natural and predominant constituents of intestinal microbiota.
Among the numerous intestinal microbes, those anticipated to exhibit potential health benefits to the host through modulation of the intestinal microbiota are commonly selected as probiotics. Species belonging to the genera Lactobacillus and Bifidobacterium have been reported to be the beneficial probiotic bacterial strains. The representative species include L. acidophilus, L. casei, L. plantarum, B. lactis, B. longum, and B. bifidum.
Some of the major health benefits attributed to probiotics include:
improvement of gastrointestinal microflora
enhancement of immune system
reduction of serum cholesterol
cancer prevention
treatment of irritable bowel-associated diarrheas
antihypertensive effects
improvement of lactose metabolism
This article reviews past studies involving the use of probiotics in:
strengthening the immune system
prevention of bowel diseases
modulation of hypocholesterolemic effect
enhancing dermal health
promoting oral health
Additionally, potential uses of probiotics for the management of anxiety and depression as well as boosting dermal and oral health are also discussed. […]
The health benefits imparted by probiotics and prebiotics as well as synbiotics have been the subject of extensive research in the past few decades. These food supplements termed as functional foods have been demonstrated to alter, modify and reinstate the pre-existing intestinal flora. They also facilitate smooth functions of the intestinal environment. Most commonly used probiotic strains are: Bifidobacterium, Lactobacilli, S. boulardii, B. coagulans.
Prebiotics like FOS, GOS, XOS, Inulin; fructans are the most commonly used fibers which when used together with probiotics are termed synbiotics and are able to improve the viability of the probiotics.
Present review focuses on composition and roles of Probiotics, Prebiotics and Synbiotics in human health.
Furthermore, additional health benefits like immune-modulation, cancer prevention, inflammatory bowel disease are also discussed. […]
