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Supercomputers reveal mouth bacteria can change its diet

"How do mouth bacteria act when you're healthy, and how do they act when they're in a diseased state? The really big finding is that they do act very differently," says Marvin Whiteley, professor of molecular biosciences and director of the Center for Infectious Disease at The University of Texas at Austin, US.

Whiteley and Turner reconstructed the metabolic network based on gene expression of the diseased periodontal microbiome. The black line was unchanged in disease and in health. The red line indicates genes upregulated during disease, and the blue line is upregulated during health. Yellow highlights show important pathways upregulated during disease. Image courtesy Marvin Whiteley.

According to new research published in the journal mBio, bacteria inside your mouth drastically change how they act when you're diseased. Scientists say these surprising findings might lead to better ways to prevent or even reverse gum disease, diabetes, and Crohn's disease.

Bacteria share nutrients; one species will even feed on another as they constantly interact. "This sharing and how they interact with each other," Whiteley says, "changes more drastically in disease than it does in health."

The researchers used shotgun metagenomic sequencing, a non-targeted way to study all the genetic material of the bacterial communities. Whiteley and colleagues analyzed the collected RNA with the Lonestar and Stampede supercomputers at the Texas Advanced Computing Center (TACC), also at The University of Texas at Austin. The research was funded by grants from the US National Institutes of Health (NIH), administered by the US National Institute of Dental and Craniofacial Research.

It may come as a surprise that microbes, mainly bacteria, outnumber human cells in our body by 10 to one. According to the Human Microbiome Project, a five-year, $115m research effort by the NIH, scientists have identified 10,000 different species of bacteria that live inside each person.

These microbial communities are known collectively as the human microbiome. "We think of it as not only the bacteria, but also the genetic composition," explains Whiteley, "and from that we can infer what these bacteria might be doing for us."

Whiteley's lab began by isolating RNA from collected plaque samples. "RNA, for those who know about computers, is kind of like the RAM - the working memory of the cell," adds study co-author Keith Turner.

The RNA sample acts like a memory image or 'core dump' that reveals the processes of the as-yet unknown bacterium where it originated. Unfortunately, says Turner, you can't get a full picture of the activity because there are so many molecules in the sample. "But you get what you can, and profile it by sequencing using recent technological advances. Then it's essentially a search problem."

Hundredsof different bacteria live in our mouths, all playing different roles in a complex microbial ecosystem. Some are pathogens that contribute to diseases, and some are commensals - meaning organisms that benefit without affecting others - that live with us in relative harmony. The interactions between all of these species affect our overall health. In this image (a confocal micrograph with increased resolution and contrast), a pathogen (red) in close association with a commensal (green) is found to facilitate feeding on waste products produced by the commensal. Image courtesy Keith Turner.

Turner searched a metagenomic database, essentially a vast genetic clearinghouse sampled from the environment instead of lab grown. He looked for matches at the NIH's Human Microbiome Project. A match reveals the bacterium where a gene in the sample originated. "The shotgun approach, as you might imagine, is very computationally intensive, which is why we turned to TACC for some of these problems," says Turner.

Turner and colleagues chose 60 different species of bacteria to represent the total community. They analyzed more than 160,000 genes, which yielded 28 to 85 million reads of RNA snippets, including about 17 million messenger RNA reads for each sample. Their findings show that bacteria act differently when healthy compared to when diseased.

"When they go from health to disease, they change their metabolism," says Whiteley. In other words, a species of bacteria that ate one thing, fructose for example, can switch to feeding on a different kind of sugar if diseased.

"The kind of thing that might have taken a desktop computer a week, two weeks to run we can run at TACC in just a couple of hours," Turner says. "Stampede allows us to use 6,400 desktop computers, all at the same time. There are a lot of problems in biology that can benefit from the supercomputing approach."

"What our study says is that it doesn't really matter what bacteria you have, because the communities are acting very similarly," Whiteley explains. "So a healthy community has this metabolism, no matter what the members are. And a diseased community has a very different metabolism, no matter what the members are. It's this conservation of a metabolic community."

According to science results from the Human Microbiome Project, a shift to more harmful bacteria in the community is linked to wide-ranging diseases like periodontitis, diabetes, and Crohn's disease. Whiteley's research could be used as the basis for developing biomarkers that predict if a person's health is in decline - and preventative measures once milestones are reached.

Pathogenic bacterial communities that rewire themselves to be harmful might also be rewired for health. "You can manipulate bacterial populations numerically very easily," adds Whiteley. "You feed them something else and you might be able to shift them back. These are some of the ideas that we've been thinking about in our lab that might be more pervasive as we move forward."

"Medicine is going to change a lot in the next 10 to 50 years. We're going to be thinking about these sort of questions a lot more, questions like what is your microbiome actually doing, and is that impacting why you're in the doctor's office."

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