Our bodies are hosts to some hundreds of thousands of bacteria that live in harmony with each other, helping the body be healthy, in return for the food and shelter it provides to these tiny organisms . Collectively, all the microorganisms inside the human body are referred to as the microbiome, most of whom are found in the gastrointestinal (GI) tract – in particular, the colon. Scientists have known for many years that the bacteria inside our bodies are indispensable for human health, but what has always bothered them is a pestering puzzle that until recently has remained largely unsolved. Considering the gut is such a flexible system where food, fecal matter and other fluids are constantly interchanged, how do bacteria thrive in such a system – namely, how do they manage stable microbial colonization of the gut?
A recent study performed by researchers at California Institute of Technology (Caltech), led biologist Sarkis Mazmanian, may have finally come up with an answer. After studying one common group of bacteria, the scientists found evidence that a set of genes is paramount to gut colonization. In addition, the Caltech researchers also found out that the bacteria, some of them at least, are in direct contact with the host body – something that was unperceivable until of late. These advances in our understanding of how the bacteria inside the gut work and flourish might help scientists devise ways to correct for abnormal changes in bacterial communities—changes that are thought to be connected to disorders like obesity, inflammatory bowel disease and autism.
Colonizing the human gut
The focus of the researchers’ experiments was on a genus of microbes called Bacteriodes, a group of bacteria that has several dozen species and which can be found in the greatest abundance in the human microbiome. Bacteriodes wasn’t chosen because of its popularity, however, instead because it also makes for an excellent lab pet – it can be cultured in the lab (unlike most gut bacteria), and can be genetically modified to introduce specific mutations, fundamental criteria in order to test what effects and consequences these bacteria pose in the human body.
A few different species of the bacteria were added to one mouse, which was sterile (germ-free), to see if they would compete with each other to colonize the gut. They appeared to peacefully coexist, as expected, but then the researchers first colonized a mouse with one particular species, Bacteroides fragilis, and inoculated the mouse with the same exact species as in the first instance, to see if they would co-colonize the same host. To the researchers’ surprise, the newly introduced bacteria could not maintain residence in the mouse’s gut, despite the fact that the animal was already populated by the identical species.
“We know that this environment can house hundreds of species, so why the competition within the same species?” says Lead author S. Melanie Lee (PhD ’13), who was an MD/PhD student in Mazmanian’s lab at the time of the research. “There certainly isn’t a lack of space or nutrients, but this was an extremely robust and consistent finding when we tried to essentially ‘super-colonize’ the mice with one species.”
To explain the results, Lee and the team developed what they called the “saturable niche hypothesis.” The idea is that by saturating a specific habitat, the organism will effectively exclude others of the same species from occupying that niche. It will not, however, prevent other closely related species from colonizing the gut, because they have their own particular niches. A genetic screen revealed a set of previously uncharacterized genes—a system that the researchers dubbed commensal colonization factors (CCF)—that were both required and sufficient for species-specific colonization by B. fragilis.
“Melanie hypothesized that this saturable niche was part of the host tissue”—that is, of the gut itself—Mazmanian says. “When she postulated this three to four years ago, it was absolute heresy, because other researchers in the field believed that all bacteria in our intestines lived in the lumen—the center of the gut—and made zero contact with the host…our bodies. The rationale behind this thinking was if bacteria did make contact, it would cause some sort of immune response.”
“We are not alone…”
Upon using advanced imaging techniques and technology to survey colonic tissue in B. fragilis colonized mice, the researchers found a small population of microbes living in tiny pockets called crypts. The discovery is extremely important because it explains how the bacteria protect themselves from the constant flow of matter that passes through the GI tract. An even more important discovery came later on. In order to test if these CCF genes had anything to do with how the bacteria colonize the crypts that shelter them from harm, the researchers injected mutant bacteria (without CCF) into the colons of sterile mice. Those bacteria couldn’t colonize the crypts, proving they’re indispensable to the colonization mechanism of gut bacteria.
“There is something in that crypt—and we don’t know what it is yet—that normal B. fragilis can use to get a foothold via the CCF system,” Mazmanian explains. “Finding the crypts is a huge advance in the field because it shows that bacteria do physically contact the host. And during all of the experiments that Melanie did, homeostasis, or a steady state, was maintained. So, contrary to popular belief, there was no evidence of inflammation as a result of the bacteria contacting the host. In fact, we believe these crypts are the permanent home of Bacteroides, and perhaps other classes of microbes.”
The discovery doesn’t however explain however how other bacteria colonize the gut, considering they don’t have CCF genes at all. A hypothesis proposed by the Caltech researchers is that Bacteroides are keystone species—a necessary factor for building the gut ecosystem.
“This research highlights the notion that we are not alone. We knew that bacteria are in our gut, but this study shows that specific microbes are very intimately associated with our bodies,” Mazmanian says. “They are living in very close proximity to our tissues, and we can’t ignore microbial contributions to our biology or our health. They are a part of us.”
The findings appeared in the journal Nature.