Exploring the Microbiome

On every part of the human body, from our nose to our gut, live ten to a hundred trillion microbes. They outnumber our own cells 10 to 1, our genome 100 to 1. Indeed, these tiny living organisms, many of which are bacteria, line every surface of the human body, both inside and out. Yet most bacteria are far from foreign invaders, as they have been passed down from our mothers during birth and with us our entire lives, while we picked up other bacteria along the way. With each diaper change, these bacteria grew and multiplied, frantically racing to cover us with a protective blanket of good bacteria before any of their harmful cousins took residence. From our first cut, to our last breath, microbes live alongside our own cells in harmony. Together, the genes these microorganisms encode what scientists call the human microbiome.

What is the Microbiome?

The term microbiome may seem contradictory at first. When ecologists talk about biomes, they are usually referring to expansive regions on Earth like the tropical rainforests of South America or the great Savannahs of Africa. In reference to size, the microbiome is different; its organisms are microscopic. If all the microbes inside a single human were weighed, it may amount to less than a single rabbit. Yet what the microbiome lacks in mass, it more than makes up for in diversity.

“What is great about the gut is that the density of bacteria is incredibly high…higher than any other ecological location that we know of,” explains Dr. Andrew Goodman, an associate professor in microbial pathogenesis at Yale University. A single human gut houses more species of microbes than species of animals in an entire forest.

Biomes are more than just the species within them. When ecologists venture through the frigid Arctic tundra, they are not solely in search of samples to classify. What scientists care most about biomes is how the organisms inside interact and adapt. Scientists want to know why one species of fox survives better than another. It is this competition among species that interests scientists most.

Similarly, with the microbiome, scientists are comparing variations on the micro scale. How do these variations lead to differences between people? “This variation matters,” says Goodman, “ and it has consequences on health.” Numerous modern diseases may potentially have roots in the microbiome. For example, scientists find that the guts of obese individuals contained more firmicutes, a common type of bacteria, than their healthier counterparts. Using zebrafish specially raised with and without firmicutes in their guts, researchers found that these bacteria help increase fat absorption in the gut. What may have initially been an adaptation to help our ancestors survive famine may now contribute to the obesity epidemic.

Over 90 percent of the cells on the human body are actually microbes. Courtesy of Dr. Andrew Goodman.

The Microbiome as a Genome

Even amongst the most passionate scientists, few would ever opt for a safari through the gut over the savannah. Diversity among bacteria does not entail brightly colored feathers or exotic mating rituals. All of this diversity exists instead as differences in bacterial genomes in the A’s, T’s, G’s, and C’s found within their DNA.

Broadly put, the genome contains all the instructions necessary for a cell to survive and grow. Imagine a genome as a recipe book, with each recipe producing a new protein. While there are slight differences in flavor between different human genomes, often dictating differences in physical features, each bacterial genome has entire recipes not found in the human genome. The microbiome has trillions of bacteria and adds volumes of new recipes to the human genome — 8 million new ones to our existing 22,000 — forming a library of recipe books scientist call the Metagenome. What scientists see is that the human body does not rely solely on human genes. These extra bacterial genes help make new proteins to break down toxins and perform other functions that would otherwise not be possible within the human body.

Understanding the Metagenome Through the Human Microbiome Project

Goodman describes the metagenome as a “description of the capacity of a [bacterial] community to carry out a function.” The metagenome is a collection of all the possible recipes, or genes, that bacteria add to humans. While many of these genes only perform functions for the bacteria, some provide vital functions to their human hosts. Scientists have known about this enormous cache of genes for quite some time, yet it was not until recently that they were actually able to determine the sequence of a human metagenome.

In 2008, the National Institute of Health launched the Human Microbiome Project as an attempt to sequence the microbiomes of 242 healthy adult volunteers. Ultimately, scientists wanted to understand the variations among different humans. Do humans host the same types of microbes or are these microbes unique to each individual?

“It hasn’t been the case that we mostly have the same species, at least in our guts. It’s almost the opposite. We mostly have our own in our guts,” says Goodman. Indeed, the project leaders found that the human microbiome was more dynamic than constant. Each individual has his or her own set of microbes, but the surprising thing was that despite this variation, parts of the metagenome remained relatively the same. As one bacterial species died, another arose to take its place, ensuring that some of the most crucial recipes are never completely lost.

Agar plates and tubes are used to study bacteria outside of the gut. Courtesy of Jane Long, Yale Student.

Next Steps

Sequencing the metagenome is only the first step in understanding how humans vary. Projects like the Human Microbiome Project provide a stepping stone for future research into the consequences of such variation.

“It is becoming very clear that sick people have a different microbiome than healthy people,” explains Goodman. Despite this, he finds that one of the major obstacles of microbiome research is the fact that the microbiome is so susceptible to other factors. “It’s shaped by what foods you eat, it’s shaped by your own genome, what your parents or outside forces gave you,” says Goodman. Often, it proves too difficult to separate out the environment from the disease.

One solution Dr. Goodman proposes is through the use of germ-free mice. “If you can take the microbiome of a person and transplant it to a germ-free mouse…you’ve controlled for a lot of these questions about background variation.”

The concept of germ-free mice is relatively new in the research community and requires specialized facilities. In Goodman’s lab, mice are raised in a truly alien environment, one completely devoid of any form of bacterial life. Everything they come in contact with, from air, water, and food, is purified. All these added precautions ensure that these mice live completely without a microbiome, and it shows. “They are by no means healthy,” says Goodman. “While they survive in the lab, it is unlikely that they would survive in the wild.”

However, Goodman believes that germ-free mice provide a “clean slate” for researchers. By transferring what amounts to human fecal matter into the mice gut, researchers are able create almost exact replicas of diseased microbiomes. This allows researchers to study disease on much larger scales. Instead of observing the microbiome of a single obese human, researchers can instead observe the same microbiome cultivated in hundreds of mice. Ultimately researchers like Goodman hope that the added similarities these mice have to their humans will help revolutionize biomedical research.