Human Microbiome Project may hold promise for future

The microbiome could someday help physicians treat patients for a medical condition before symptom onset

Anyone who has ever seen an episode of Star Trek is familiar with a hand-held device known as the tricorder. This device is used to scan the body and assist the ship’s physician with the patient’s diagnosis. But can the stuff of science fiction actually become reality?

Although science and medicine have not quite realized the tricorder yet, researchers working on the federally funded Human Microbiome Project (HMP) are hoping that someday their research can help physicians hone in on tricky diagnoses before a problem even arises — similar to the tricorder.

“Just like a diabetic who checks their sugar levels, we would hope that, in the future, people could check their microbiome and see if they are getting into a state of microbiome shift,” said Julia Segre, PhD, who is a scientist looking at atopic dermatitis flares in children as part of the project. “Just as you wouldn’t wait for the signs of hypoglycemia for a child with diabetes, we would hope we could predict when there was a potential for a microbiome shift. That would lead to earlier treatment, and not having to treat something that is as extreme. This could provide a tremendous benefit.”

Project overview

Launched in 2007 as part of the NIH Roadmap for Medical Research, the HMP serves as an umbrella for dozens of researchers who are examining samples from some 1,000 microbial genomes and the role these genomes play in illness and other types of health issues. The samples are derived from five body regions known to be inhabited by microbial communities: the digestive tract, skin, mouth, nose and the female urogenital tract.

The myriad of researchers on the project have several ways to study microbial diversity. These include fingerprinting, using PhyloChips or GeoChip that act similar to a microarray, and also sequencing, which entails taxonomic classification and function, dynamic range and comparing multiple samples.

“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,” Alan M. Krensky, MD, the director of the Office of Portfolio Analysis and Strategic Initiatives (OPASI), which oversees the NIH Roadmap for Medical Research, said in a release about the project.

In a review article published recently in Pediatrics, Coreen L. Johnson, PhD, and James Versalovic, MD, PhD, of the department of pathology and immunology at Baylor College of Medicine, highlighted the importance of this research in the future of medicine.

“Recent advances in genome sequencing technology and metagenomic analysis are providing a broader understanding of resident microbes and highlighting differences between healthy and disease states,” Johnson wrote.

The digestive tract

More than a year ago, researchers on the project located previously unknown proteins produced by bacteria that live in the stomach that may cause gastric ulceration. In addition, the researchers noted a small number of newly identified novel proteins associated with how sugars and amino acids are metabolized.

Johnson wrote in her paper that “bacterial cells outnumber human cells in the body by an estimated factor of 10, with some 10 (trillion) to 100 trillion microbes living in the gastrointestinal tract alone.”

Phillip I. Tarr, MD, of the Washington University School of Medicine in St. Louis, said in an interview that examining the digestive tract, particularly as it relates to neonates, is an important component of this research.

“If we can learn early on what ordains good and bad physiologic outcomes-in the gut, while these children are encountering the greatest influx and re-assortments of microbial populations of their entire lives, then we might be able to influence gut-driven healthy development for years to come. The potential to beneficially alter outcomes such as obesity, metabolism, and infections is immense. This is a new vista on human biology,” Tarr told Infectious Diseases in Children.

He said several papers presented at the 2012 Pediatric Academic Societies Annual Meeting indicated how much research is being conducted on this subject. One such paper by Susan LaTuga, MD, and colleagues looked at lactating mothers of very low birth weight babies and showed an unusual presence of Escherichia coli in peripheral blood and absence of Bacteroidetes in their stool. The researchers concluded from this finding that it “may reflect a unique metabolic and immunologic state.”

Tarr said research such as that of LaTuga and others is important so that, in the future, it may be possible to interpret the roles the microbiome can play in states of health and illness for both the mother and child.

Judith O’Connor, MD, who is a pediatric gastroenterologist and hepatologist at the University of Oklahoma Health Science Center, said research on the gut microbiome is critical because unlocking how the bacteria in the gut triggers the immune system could have broad-reaching implications in illnesses such as necrotizing enterocolitis or food allergies.

“We are now able to identify bacteria in intestines and how they changed,” O’Connor said. “With newer technology, we can discern how the presence of bacteria can influence inflammation by either aggravating or suppressing it.”

She said probiotic research is one area that has demonstrated the “teeter-totter” effect of proinflammatory and anti-inflammatory responses.

Although the data do not indicate a need for probiotics in all formulas, published studies have shown a benefit for probiotics in some patients, particularly those with antibiotic-associated diarrhea or those with recurrent Clostridium difficile infection.

“Research from the project and other data show that if you don’t repopulate the colon with what should be there, there can be very bad effects for the patient,” O’Connor said. “However, the jury is still out on whether this needs to be ubiquitous, like fluoride and water. The areas that need to be examined are whether probiotics can be better utilized in patient populations and can they be utilized as a prophylaxis to prevent diseases.”

O’Connor said research in the project will open up dialogues on issues such as these, and it is an exciting time in medicine: “It is going to help us change diseases of the gut from a clinical description to a metabolic description and change the way we look at ailments such as Crohn’s disease or food allergies.”

The skin

In her review, Johnson said, “Actinobacteria, Proteobacteria, Firmicutes, and Bacteroidetes represent the predominant phyla colonizing the adult human skin, and considerable bacterial diversity was observed at the species level. Metagenomic sequencing also revealed significant interpersonal variation among individuals and temporal variation depending on the specific body site.”

Nonbacterial microorganisms have also been isolated from the skin, including Malassezia spp. and Demodex mites.

Segre, who is a senior investigator with the National Human Genome Research Institute, said her area of focus has been on children with severe eczema and how infants become colonized with bacteria.

“The idea is that there is a dynamic period in the first year or so of life, in which your microbiome is in flux because you are colonized postbirth,” she said. “And then postnatally, your immune system is maturing, so you are being exposed to everything and going from breast milk to very diverse foods, and that has an effect on everything.”

In a paper in Nature Reviews Microbiology, Segre and colleagues wrote, “An enhanced understanding of the skin microbiome is necessary to gain insight into microbial involvement in human skin disorders and to enable novel promicrobial and antimicrobial therapeutic approaches.”

Segre also said research into the rising incidence of atopy has doubled in the past few decades, and this includes what role the microbiome plays on atopy development.

“The goal here is two-pronged. First, we are looking at what is the most effective treatment for an individual patient, either steroids, antibiotics, topical antibiotics, bleach baths and so on,” she said. “The second goal is determining whether we can use the microbiome as a biomarker to suggest which treatment would be most effective for each child.”

Segre likened this principle to a diabetic who regularly checks his sugar level because skin disorders occur as episodic flares.

“If that child or their parent saw they were getting into a state of dysbiosis, you could then step up the therapy, bleach baths or whatever, rather than waiting until getting into a full-blown flare,” she said.

Other areas of research

Researchers on the HMP have also evaluated the microbial diversity present in the HMP reference collection. For example, the researchers reported on 29,693 previously undiscovered, unique proteins in the reference collection — more proteins than there are estimated genes in the human genome. They compared their results with the same number of previously sequenced microbial genomes randomly selected from public databases. In the microbial genome from public databases, they found 14,064 novel proteins. These data, the researchers said, suggest that the HMP reference collection has nearly twice the amount of microbial diversity than is represented by microbial genomes already in public databases.

Maria Giovanni, PhD, of the National Institute of Allergy and Infectious Diseases, said now that much of the descriptive work has been done — identifying these unique proteins and demonstrating changes in the microbiome during illness — the key now is to find out what these proteins are doing.

“In infectious diseases, you typically look at the individual diseases as they occur. The idea with this project is to push the field to say instead of studying one package at a time, like a patient with influenza, let’s look instead at the body as a community, and see what’s happening with the microbiome,” Giovanni said.

She said for infectious diseases, “We’ve always thought of microbes as bad actors, but they are doing some good things for us, so this helps us look at all that data and what changes in the microbiome is doing to the immune system.”

One of the primary goals of the HMP reference collection is to expand researchers’ ability to interpret data from metagenomic studies. Metagenomics is the study of a collection of genomes from a mixed community of organisms. Comparing metagenomic sequence data with genomes in the reference collection can help researchers determine whether they are novel or already existing sequences.

To evaluate whether the reference collection of genomes was meeting its goal, the researchers compared 16.8 million microbial sequences found in public databases with the genome sequences in the HMP reference collection. They found that 62 genomes in the reference collection showed similarity with 11.3 million microbial sequences in public databases and 6.9 million of these correspond with genome sequences in the reference collection.

Future efforts

The initial stage of the HMP focused on bacteria, but future genome sequencing and project studies also will capture information about more complex microbes and viruses. The effort so far has allowed researchers to create a framework for data resources and standards.

Johnson wrote in her review that sequencing based studies are “expanding our appreciation of diverse and abundant communities in the respiratory tracts of health patients and those with cystic fibrosis.”

Other areas of research are focusing on manipulating the human microbiome, using supplements such as probiotics or prebiotics and microbial suppression strategies, besides restoration of normal bacterial communities, such as those focusing on transplantation of fecal microbiota from a health donor to a patient.

As Johnson stated in her review, “Fecal transplantation has been increasingly used in the last two decades for

C. difficile infection, with a success rate of greater than 90%.”

She said analyzing the microbiota could potentially yield drugs to treat chronic inflammation.

The HMP is also supporting the development of innovative technologies and computational tools. In her paper, Segre wrote that the evolving molecular approaches and tools to characterize microbial diversity have “dramatically changed our view of the microbiome, subsequently raising many important questions about the host–microorganism relationship and its relevance to skin disease.”

Perhaps the tricorder will not remain science fiction after all. — by Colleen Zacharyczuk

References:

Grice EA and Segre JA. Nat Rev Microbiol. 2011 Apr;9(4):244-53.

Johnson CL. Pediatrics. 2012;129:950-960.

LaTuga MS. Abstract 3415A.4. Presented at: the 2012 PAS Annual Meeting; April 28-May 1, 2012; Boston.

Disclosures:

Drs. Giovanni, O’Connor and Segre report no relevant financial disclosures. Dr. Tarr did not provide financial disclosures.

 

Considering the five body regions that are areas of focus in the Human Microbiome Project, which area holds the most promise for making a difference on pediatric health? Why?

The Human Microbiome Project promises to generate vast dividends to benefit child health. Never has the importance of the microbiome been so appreciated or so tractable. Using current technologies, we can exhaustively characterize the microbial constituents of any body compartment, including elucidation of unculturable and previously undiscovered species. Emerging technologies will make this undertaking still faster and more economical, enabling characterization of microbiomes at the human population level. This technological power is essential: There may be 1,000 taxonomic units in the intestine of a single individual, and teasing out statistically significant associations with clinically relevant outcomes will require very large human subject sample sizes. But the opportunity is irresistible.

Of the microbiome projects ongoing, perhaps none promises to be more fruitful than the gut microbiome project. The gastrointestinal tract harbors more microbial cells than exist in the entire human body (by more than 10-fold), and a great many are utterly cryptic. In addition to the great variety of bacterial species present in stable gut microbiomes, the complexity is compounded by the great variation in the rate and nature of microbial succession during the first years of life. The succession of microbiota is influenced by route of the infant’s delivery, administration of antibiotics, feeding practices and almost undoubtedly the genetic background of the host. Given this remarkable variation in exposure, associating characteristics of the gut microbiome with health-related outcomes will require the articulation of clear hypotheses. Generating these hypotheses will be the role not only of scientists but also the pediatric community. Studies already available suggest remarkable health effects of the gut microbiota: The composition of our microbiota may impact our nutritional status and body weight, our propensity to atopic disease and inflammatory syndromes, our response to vaccination, our bowel habits and much more. These studies may be constrained less by technology than by our own scientific imagination.

A thorough understanding of the roles of the human microbiomes will yield surprises. True, the prodigious abundance of the gut microbiome predicts vast contributions to health, but the relative paucity of microbiota at other sites may not confer lesser roles. And some of the other sites, the skin for example, are prone to greater perturbation in hyper-clean modern societies than is the gut. The microbiome projects will generate exciting and important data for many years to come.

James P. Nataro, MD, PhD, MBA, is the Benjamin Armistead Shepherd Professor and Chair of the Department of Pediatrics at the University of Virginia School of Medicine, and Pediatrician-in-Chief at the University of Virginia Children’s Hospital in Charlottesville, Va. Disclosure: Dr. Nataro reports no relevant financial disclosures.

Understanding the human microbiome holds the potential to help us unlock a range of new diagnostics and therapeutic options. That said, the area of research that holds the most potential for pediatrics is the gut. Understanding this microbiome is key to understanding early childhood diseases, like necrotizing enterocolitis, and long-range problems, like ulcerative colitis, Clostridium difficile and potentially cardiometabolic issues later in life. We know there is a limited window in that first year where children’s systems are being exposed to more than they would at any other point in their lifetime, so that first year of life presents a real opportunity to study what influences the microbiome, whether it be breast-feeding, probiotics or other changes to this microbiome, that influence disease development and outcomes later on in life.

James Versalovic, MD, PhD, is Professor in the departments of Pathology & Immunology; Pediatrics; and Molecular Virology & Microbiology; Programs in Cell and Molecular Biology and Translational Biology & Molecular Medicine at Baylor College of Medicine. He is also Director of the Microbiome Center, Texas Children’s Hospital and Head of the Department of Pathology at Texas Children’s Hospital, Houston. Disclosure: Dr. Versalovic receives restricted research support from BioGaia.