Novel molecular tools are revolutionizing the field of microbiology. In lieu of growing microbes in a laboratory Petri dish, researchers can now perform metagenomic analyses that directly extract and clone DNA from communities of microorganisms in order to identify the body’s microbial inhabitants. This allows for an understanding of the expressed genetic information of entire microbial ecosystems. In addition to pyrosequencing and shotgun sequencing, today’s molecular-based techniques can even identify DNA sequences present in a single cell.
These tools have allowed researchers to identify so many novel microbes in the human body that entire new databases and methodologies have had to be created in order to document them. We now realize that only a handful of the microbes that persist in the human body can be successfully identified using traditional laboratory cultivation techniques.
Two recent large-scale collaborations spearheaded the use of these metagenomic technologies over the past decade. One was the Human Microbiome Project (2008-2012), a US-based initiative funded by the US National Institutes of Health. The Project sampled the microbial populations of 242 healthy adults across 15 to 18 body sites, and generated over 3.5 terabases pairs of metagenomic sequences.
Another initiative was MetaHIT, its European-based equivalent (2008-2012), which focused largely on better characterizing the gut microbiome. These projects, along with private initiatives, detected and characterized so many novel microbes in the human body that it is now estimated that at least 90% of cells in the human body are bacterial, fungal, or otherwise non-human in origin.
The sheer number of non-human genes represented by the human microbiome – more than nine million unique genes compared to the meager 20,500 that comprise the human genome – implies we have just begun to fathom the full extent to which microbes impact both health and disease processes. We now know humans are controlled by a metagenome – a tremendous number of different microbial and human genomes working in tandem. This knowledge is actively re-defining the human/microbe relationship. The human body is increasingly described as a superorganism whose metabolism represents a combination of microbial and human attributes.
Just a decade ago, microbiologists were able to study just a fraction of bacterial species. The Genomes Online database tracks metagenome sequencing projects around the world. The database lists at least 50,000 bacterial genomes currently under study. Even so, each new metagenomic analysis continues to demonstrate the presence of previously unknown bacteria.
The number of bacterial genomes under study in the GOLD database, as seen over time. Taken from https://gold.jgi.doe.gov/
Similarly, our knowledge of the chronic viruses that persist in the human body is rapidly evolving. Several well-characterized viruses are already known to infect the majority of humans by early childhood, persisting with the host throughout life. For example, polyomaviruses infect between 72% and 98% of humans, surviving in the kidney, lung, and skin. Combinations of these viral genomes with other components of an individual’s metagenome may well be a critical factor in the long-term health of the individual. However, the vast majority of our viral passengers are also just beginning to be identified. In addition, microbes called bacteriophages are increasingly identified at various body sites. Bacteriophages are viruses that infect bacteria and can multiply inside bacterial cells. A recent study by Pride found that previously uncharacterized bacteriophages dominate the oral cavity microbiome.
While pathogens clearly persist on mucosal surfaces, they are also present in blood and tissue. Microbes can be easily detected in healthy human blood and have been identified in atherosclerotic plaque. Nearly every body tissue has now been shown capable of harboring microbial populations. These areas include the lungs, the bladder, the amniotic fluid, the liver, the brain, and other organs previously considered to be sterile.