Normal bacterial makeup has huge implications for health

The team made up of 200 researchers from the Human Microbiome Project Consortium, or HMP, and based at 80 research institutions, reports that while nearly everyone carries pathogens -- which are microorganisms that cause illness -- pathogens cause no disease in healthy individuals. Instead, they co-exist with their host and the rest of the human microbiome, which is the collection of all microorganisms living in the human body.

Although the human body contains trillions of microorganisms -- outnumbering human cells by 10 to one -- they make up only 1 to 3 percent of human body mass but play a vital role in human health, said CU-Boulder Associate Professor Rob Knight of the BioFrontiers Institute. "Many people were sampled so we could get a better idea of variability, and how microbes work together in complex communities," he said.

The trick now is to understand why some pathogens turn deadly under what conditions, said Knight, also a faculty member in the chemistry and biochemistry and computer science departments.

The new findings on the microbial mapping project were published in a series of reports published June 14 in the journal Nature and several journals in the Public Library of Science, or PLoS. Launched in 2007, the HMP received $156 million from the NIH Common Fund, an initiative that finances high-impact, large-scale research. Knight is a co-author on the two Nature studies.

In 2009, a group of researchers from CU-Boulder and the Washington University School of Medicine in St. Louis led by Knight developed the first atlas of bacterial diversity across the human body. The study, published in Science magazine, used swab samples from nine volunteers targeting 27 specific sites on the body, showing humans carry "personalized" bacterial communities that vary widely from our foreheads and feet to our navels and noses.

"By better understanding this microbial variation we can begin searching for genetic biomarkers for disease," said Knight. "Because the human microbiome is much more variable than the human genome, and because it also is much easier to modify, it provides a much more logical starting point for personalized medicine."

In the new 2012 studies, HMP researchers sampled 242 healthy U.S. volunteers -- 129 males and 113 females -- collecting tissues from 15 body sites in men and 18 body sites in women. The researchers collected samples at up to three "time-points" from each volunteer at places including the mouth, nose, skin, ears, elbows and lower intestine. According to Knight, each body site can be inhabited by organisms that are as different from each other as are microbial communities from oceans and deserts.

Instead of isolating and culturing individual pathogens -- an inefficient method -- the team purified all human and microbial DNA in each of more than 5,000 samples and analyzed them with DNA sequencing machines. It then used computers to sort through the data and identify specific genetic signals found only in bacteria -- the variable genes of bacterial ribosomal RNA that help form the cellular structures that manufacture protein and can identify the presence of different microbial species.

Focusing on the microbial signature allowed the HMP researchers to ignore the human genome sequences and analyze only bacterial DNA, said Knight. In addition, "metagenomic" sequencing -- sequencing all of the DNA in a microbial community -- allowed the researchers to study the metabolic capabilities encoded in the genes of the microbial communities.

"Like 15th century explorers describing the outline of a new continent, HMP researchers employed a new technological strategy to define for the first time the microbial makeup of the human body," said NIH Director Francis Collins. "This lays the foundation for accelerating infectious disease research previously impossible without this community resource."

Other CU-Boulder participants in the HMP include faculty members Norman Pace, Andrew Martin and Manuel Lladser, postdoctoral researchers Jose Clemente and Catherine Lozupone, graduate students Antonio Gonzalez and Daniel McDonald and recent CU-Boulder graduate Dan Knights.

The HMP researchers calculated that more than 10,000 microbial species occupy the human "ecosystem," said Knight. The researchers believe they have now identified between 81 and 99 percent of all genera of microorganisms in healthy adults in the United States. In one of the new Nature studies led by Dr. Jeffrey Gordon of Washington University and involving Knight, the team demonstrated that at least in the gut, children and adults from other countries like Malawi and Venezuela differ dramatically from adults in the United States in terms of their microbial communities.

"We are only beginning to scratch the surface of understanding how the human microbiome develops from infancy to adulthood across cultures and across habitats within the human body," said Knight. "Of particular interest are non-Western populations that do not develop the suite of diseases associated with the Western lifestyle, including obesity, inflammatory bowel disease, asthma and allergies."

Knight said HMP researchers have found the plethora of microbes on the human body contributes more genes responsible for human metabolism than people do. While the human genome carries roughly 22,000 protein-coding genes, the human microbiome contributes about 8 million unique protein-coding genes. If it weren't for bacteria in the gastrointestinal tract, humans could not fully digest foods and absorb nutrients.

Microbes not only break down proteins, lipids and carbohydrates in the gut, they produce beneficial compounds like vitamins and anti-inflammatories. One surprising discovery by the researchers was that the distribution of microbial metabolic activities matters more than the species providing them, said Knight.

In the healthy gut, for example, there always will be a population of bacteria needed to help digest fats. But it may not always be the same bacterial species carrying out the job -- the bacteria appear to be "pinch-hitting" for each other, said the researchers.

The HMP is currently funding additional clinical studies looking for associations between the microbiome and diseases. The studies include looking at changes in the vaginal microbiome of pregnant women; analyzing viral DNA in the nostrils of children with unexplained fevers; investigating the role of the gut microbiome in Crohn's disease, ulcerative colitis and esophageal cancer; charting the relationship of skin bacteria to psoriasis, dermatitis and immunodeficiency; and understanding the role of the microbiome in childhood disorders like pediatric abdominal pain and intestinal inflammation.

The Human Microbiome Project is managed by the National Human Genome Research Institute in partnership with the NIH Office of the Director, the National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Cancer Institute, National Institute of Dental and Craniofacial Research, and National Institute of Diabetes and Digestive and Kidney Diseases, all part of NIH.