Scientists working on a huge project that has mapped all the different microbes that live in and on a healthy human body have made a number of remarkable discoveries, including the fact that harmful bacteria can live in healthy bodies and co-exist with their host and other microbes without causing disease.
This week sees the publication of several papers from the Human Microbiome Project (HMP), including two in Nature and two in PLoS ONE.
The microbiome is the sum of all the microbes that colonize the body: it comprises trillions of microorganisms that outnumber human cells by 10 to 1. The microbes inhabit every nook and cranny of the body, and most of the time the relationship is a friendly one, because they help digest food, strengthen the immune system and fight off dangerous pathogens.
Colorado University (CU)-Boulder Associate Professor Rob Knight of the BioFrontiers Institute is co-author on the two Nature papers. He told the press that the microbiome may only make up 1 to 3% of human body mass, but it plays a key role in human health.
One of the fascinating features of the microbiome is that different body sites have different communites of microorganisms that are as different from each other as the differences between microbial communities in oceans and deserts.
“By better understanding this microbial variation we can begin searching for genetic biomarkers for disease.”
Another of the curious features the HMP has discovered is that even healthy people carry low levels of harmful bacteria, but as long as the body remains healthy, they don’t cause disease, they just coexist alongside beneficial microbes.
Knight said we now need to find out why: what happens to cause pathogens to become deadly?
The Human Microbiome Project (HMP) Consortium is a collaborative group of over 200 researchers from 80 research centers that is organized and funded by the National Institutes of Health (NIH) in the United States. The project has been going since 2007.
Many scientists now regard human bodies as “supra-organisms”, collections of communities made up of human and microbial cells coexisting in a whole that is more than the sum of its parts.
The idea behind the HMP is that because the microbiome is more varied than the genome, and easier to modify, it gives a more logical starting point for individually tailoring treatments, the goal of personalized medicine.
Knight said the HMP has sampled the microbiome of many people, to “get a better idea of variability, and how microbes work together in complex communities”.
In 2009, a team from CU-Boulder and the Washington University School of Medicine in St. Louis, led by Knight, published the first atlas of bacterial diversity across the human body in a paper in Science.
For that study they took swab samples from 27 sites on the bodies of 9 volunteers and found that we human beings have personal bacterial communities that vary widely over our bodies: the ones on our forehead have a different signature to the ones on our feet, and to the ones in our navels and the ones in our noses.
For the recently published 2012 studies, HMP researchers sampled the microbiomes of 242 healthy Americans: collecting tissue at three different times from 15 body sites in 129 males and from 18 sites in 113 females. The sites included the skin, nose, mouth, elbows, and lower intestines.
An important feature of the project is the method the researchers used to identify the microorganisms. Instead of isolating and culturing individual pathogens, they purified and analyzed all the human and microbe DNA together sample by sample, for over 5,000 samples.
For the analysis they used DNA sequencing machines and computers to look for specific genetic signals that they knew were present only in bacteria. These signals come from the variable ribosomal RNA genes in bacteria that help create cellular structures that make proteins. Using these the researchers were able to trace the signatures of different microbial species.
Using microbial signatures the HMP researchers could ignore any human genome sequences and focus on bacterial DNA.
Another method they used is called “metagenomic” sequencing. This sequences the DNA of the entire microbial community and allows, for instance, the researchers to study the metabolic capabilities encoded in the genes of the microbial community.
The HMP researchers established that more than 10,000 microbial species inhabit the human “ecosystem”. Knight said they believe they have now found between 81 and 99% of all genera of microorganisms in healthy adult Americans.
One of the key findings was the stark differences in microbial communities across the human body. For instance, the microbial communities that live on the teeth are different from those in saliva.
And the most diverse collection of microbes was found to inhabit the skin, which is probably not that surprising because the skin is the main barrier between the body and the outside world.
In one of the Nature studies, led by Dr Jeffrey Gordon of Washington University, the researchers found dramatic differences in gut microbes of Americans compared to people from other countries such as Malawi and Venezuela, in adults and children.
Knight said they are only “beginning to scratch the surface” in terms of finding out how the human microbiome develops from infancy to adulthood in different parts of the body and in different countries.
He said they were particularly interested in how non-Western populations don’t suffer from the diseases we typically associate with a Western lifestyle, such as asthma, allergies, obesity, and inflammatory bowel disease.
Another interesting discovery is that of the genes that influence human metabolism, most of them are in the microbiome and not in the human genome.
The human genome has about 22,000 genes for encoding proteins, but the human microbiome has about 8 million unique genes that encode proteins.
The upshot is, we could not digest our food and absorb vital nutrients if it wasn’t for the bacteria in our gut.
And within this complexity of gut processes, the HMP researchers made another remarkable discovery: the distribution of metabolic processes provided by microorganisms is more important than which species actually do the work.
For example, a healthy gut will always contain a community of microbes that helps to digest fats. But this job does not have to be done by the same species every time: the researchers said it was like the bacteria were “pinch-hitting” from each other.
The new research also confirmed findings of earlier, smaller studies: that the components of the human microbiome change during illness. When a patient is sick or takes antibiotics, the species of the microbiome may shift substantially as one bacterial species or another is affected. Eventually, however, the microbiome settles into a new state of equilibrium, even if the previous composition is not completely restored.
One of the PLoS studies, led by Gregory A Storch, the Ruth L Siteman Professor of Pediatrics at Washington University, examined the microbes in the noses and blood of children who develop sudden, unexplained fever. This is a common problem in babies under the age of 3, and antibiotics are often given as a precaution, but this is also problematic because it contributes to antibiotic resistance.
The researchers in this study found that samples from the sick children had more species of virus, some of them new, than samples from children without fever, which they had also taken for comparison.
While fever is one of the ways the body defends against viruses that can cause disease, this study shows that even children without fever carry viruses, though in lower numbers.
This sets the stage for further research to look into the differences between viral infections with and without fever, leading to new ways to apply microbiome knowledge in the clinic, said the researchers.
In another PLoS study, researchers from the Genome Institute and the University of California, San Francisco, found previously unknown groups (taxa) of microorganisms in stool samples from 11 healthy individuals.
While they only found low levels of these not-yet-named microorganisms, the researchers suggest they are probably quite common because they found them in several people.
The HMP researchers are now planning clinical studies looking for links between the microbiome and disease. These include: examining changes in the vaginal microbiome during pregnancy; investigating the role of the gut microbiome in ulcerative colitis, esophageal cancer and Crohn’s disease; further investigation of the viral DNA in the nostrils of children with unexplained fevers; looking at the skin microbiome in psoriasis, dermatitis and immunodeficiency; and understanding how the microbiome contributes to childhood disorders like pediatric abdominal pain and intestinal inflammation.
Written by Catharine Paddock PhD