Understanding how the thousands of species of bacteria that call our gut home survive and thrive in a stable ecosystem when our digestive system is in a constant state of flux from food and liquid ingestion has been a question that has puzzled many for some time.
Now, researchers from the USA may have the answer. It's in our genes.
Writing in Nature, a team of scientists from California Institute of Technology (Caltech), led by Professor Sarkis Mazmanian have identified a set of genes that promotes stable microbial colonisation of the gut for one of our most common groups of bacteria - the Bacteriodes.
"By understanding how these microbes colonize, we may someday be able to 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," explained Mazmanian.
Mazmanian and his team began their study by running a series of experiments to introduce Bacteriodes to sterile, or germ-free, mice. The Bacteriodes group of bacteria was chosen because it is one of the most abundant genuses in the human microbiome, can be cultured in the lab (unlike most gut bacteria), and can be genetically modified to introduce specific mutations, said the researchers.
"Bacteriodes are the only genus in the microbiome that fit these three criteria," said Mazmanian.
First the team added several different species of the bacteria to one mouse to see if they would compete with each other to colonize the gut. The strains appeared to peacefully coexist and colonise the gut of the mouse, said the team.
However, when they colonised a mouse with one particular species, Bacteroides fragilis, and then inoculated that mouse with the same exact species, to see if they would co-colonize the same host, 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?" questioned Dr Melanie Lee, first author of the study. "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 her colleagues team developed a new theory - which they called the 'saturable niche hypothesis.' This is based on a premise that individual species may saturating a specific habitat, and by doing so will effectively exclude others of the same species from occupying that niche. However, this saturation would not prevent other closely related species from colonising because they have their own particular niches.
The team used genetic screening to look for something to back up this theory - and found a set of previously uncharacterised genes that were both required and sufficient for species-specific colonization by B. Fragilis. The team dubbed this genetic system commensal colonization factors (CCF).
In the process of their research, Lee and the team also made another vital discovery: our gut microbiota may live in our gut lining, rather than in the centre of the gut.
"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," explained Mazmanian. "The rationale behind this thinking was if bacteria did make contact, it would cause some sort of immune response."
However, using advanced imaging approaches to survey colonic tissue in mice colonized with B. fragilis, Lee and her team revealed a population of microbes living in tiny pockets— known as crypts—in the colon.
By colonising these crypts, the bacteria are protected from the constant flow of material that passes through the GI tract, the team said.
To test whether or not the newly discovered CCF system regulated bacterial colonisation within the crypts, the researchers then injected mutant bacteria—without the CCF system—into the colons of sterile mice. Those bacteria were unable to colonize the crypts, said Masmanian.
"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," he said.
"Finding the crypts is a huge advance in the field because it shows that bacteria do physically contact the host."
The expert noted that homeostasis was maintained during all of the experiments performed by the team: "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."
Mazmanian said that by pinpointing the CCF system as a mechanism for bacterial colonisation and resilience, in addition to the discovery of crypts in the colon that are species specific, the team's research in Nature has solved long standing mysteries in the field about how microbes establish and maintain long-term colonization.
"We've studied only a handful of organisms, and though they are numerically abundant, they are clearly not representative of all the organisms in the gut," explained Lee.
"A lot of those other bacteria don't have CCF genes, so the question now is: Do those organisms somehow rely on interactions with Bacteroides for their own colonization, or their replication rates, or their localization?"
The team now believe that Bacteroides may be a 'keystone' species - that is necessary for building the gut ecosystem - and as a result plan to investigate whether or not functional abnormalities, like an inability to adhere to crypts, could affect the entire microbiome and potentially lead to a diseased state in the body.
"We knew that bacteria are in our gut, but this study shows that specific microbes are very intimately associated with our bodies," commented Mazmanian. "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."