Gut bacteria infrequently modify their CRISPR immune mechanisms in humans.
In the realm of our digestive tract, an incredible multitude of bacteria, hailing from a gazillion different species, thrive and form complex communities. These critters aide in the digestion of food, protect against harmful microbes, and perform a myriad of other functions to keep us in tip-top shape.
These bacteria, however, can fall prey to viral infections called bacteriophages. One of their primary defenses against these viral interlopers is the CRISPR system, a brilliant evolutionary development that allows them to recognize and annihilate viral DNA.
A team of biological engineers from MIT has delved deeper into the intricate world of these gut bacteria and their CRISPR defenses. Their research led to the discovery that while bacteria bred in labs can quickly incorporate new viral recognition sequences in a matter of days, their counterparts living in our gut do so much slower— approximately once every three years.
This revelation stirs up questions about the frequency and opportunities for bacteria-phage interactions within our digestive tract. It also opens up the possibility that certain defense mechanisms other than CRISPR might be more crucial to bacteria's survival inside us.
An-Ni Zhang, former MIT postdoc and now an assistant professor at Nanyang Technological University, is the lead author of the study, which has been published in the journal Cell Genomics. Eric Alm, director of MIT’s Center for Microbiome Informatics and Therapeutics and a professor at the Institute, served as the senior author.
Phages in the Gut: Lion in the Sheepfold?
When bacteria come into contact with viral DNA, they can incorporate parts of the sequence into their own DNA for future recognition purposes. These chunks are known as spacers, and a single cell can carry over 200 spacers. These sequences can be passed down to offspring and shared with other bacteria through horizontal gene transfer.
Previous studies have shown that spacer acquisition occurs swiftly in the lab, but the process appears slower in natural environments. In this research, the MIT team aimed to investigate how often this process occurs in bacteria living in the human gut.
"We were curious about how the CRISPR system updates its spacers in the gut microbiome more effectively to understand the interactions between bacteria and viruses within our body," Zhang says. "We sought to identify the key factors that influence the timescale of this immune update."
To achieve this, the researchers analyzed data from two different datasets representing bacterial genomes from the human digestive tract. They discovered that in this microbial community, the acquisition of new spacers was surprisingly slow, taking a staggering 2.7 to 2.9 years on average for a bacterial species to gain a single spacer.
The researchers then set about unraveling the reasons behind this sluggish process. Their model showed that spacers are incorporated more swiftly when bacteria dwell in high-density populations. However, the human digestive tract is diluted with the consumption of food multiple times a day, flushing out some bacteria and reducing the overall density, making spacer acquisition less frequent.
Another factor that may explain this phenomenon is the spatial distribution of microbes, with certain populations staying far from potential phage exposure in the mucus layer and further away from viruses.
"Sometime one population of bacteria might never or rarely encounter a phage because they are closer to the epithelium in the mucus layer and thereby protected from potential phage exposure,” Zhang explains.
Bacterial Matters
The researchers identified a specific bacterial species, Bifidobacteria longum, that had recently acquired several new spacers. These sequences were found in samples collected from unrelated people, living on different continents, indicating a possible evolutionary pressure on B. longum from these specific phages.
"This research sheds light on the significant role of horizontal gene transfer in shaping the dynamic nature of microbial communities,” Zhang says. “Within bacterial communities, the interactions between bacteria can play a pivotal role in the development of viral resistance."
Understanding the workings of these immune defenses may pave the way for the development of targeted treatments more tailored to each patient's unique microbiome. This could increase the chances of success for therapeutic measures.
"We could study the viral composition in patients and then identify which microbiome species or strains have better resistance to local viruses,” Zhang concludes.
The research was funded, in part, by the Broad Institute and the Thomas and Stacey Siebel Foundation.
- The discovery made by the MIT team suggests that the acquisition of new viral recognition sequences by bacteria living in our digestive tract happens much slower compared to their lab-bred counterparts, around once every three years.
- The sluggish process of spacer acquisition in the human gut might be due to the dilution of bacteria in the digestive tract with food consumption multiple times a day, reducing the overall density and thus, the frequency of spacer acquisition.
- Another reason behind the slow spacer acquisition in the human gut could be the spatial distribution of microbes, with certain populations staying far from potential phage exposure in the mucus layer and further away from viruses.
- A specific bacterial species, Bifidobacteria longum, has been identified to have recently acquired several new spacers, which were found in samples collected from unrelated people living on different continents, indicating a possible evolutionary pressure on B. longum from these specific phages.
- This research underscores the significant role of horizontal gene transfer in shaping the dynamic nature of microbial communities, and how the interactions between bacteria can play a crucial role in the development of viral resistance.
- By studying the viral composition within patients and identifying which microbiome species or strains have better resistance to local viruses, targeted treatments can be developed that are more tailored to each patient's unique microbiome, potentially increasing the success rate of therapeutic measures.
