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‘Personalizing’ Gut Microbial Communities to Achieve Innovative Medical Treatments

What determines the stability of multi-species ecosystems, and how might a community be supplanted by invaders? This fundamental scientific question doesn’t just apply to animal and plant species but also to competing species of bacteria.

There has been a lot in the press recently about “probiotics,” the gut-dwelling microorganisms believed to provide health benefits when consumed and allowed to thrive in a rich – and, one hopes, properly balanced – internal ecosystem.

Inspired by recent research revealing the health benefits of microbiota in the gut, researchers Raghuveer Parthasarathy, physics, University of Oregon; Brian Hammer, biology, Georgia Institute of Technology; and Joao B. Xavier, computational biology, Memorial Sloan Kettering Cancer Center, New York City, have embarked on a long-term project to “personalize” the microbial communities in our stomachs and intestines, tailoring them to specific health and medical needs.

The first step in this quest is to come up with a way to “reboot” the system, as it were. And, because this is a basic research project seeking to advance our knowledge, Parthasarathy, Hammer and Xavier hope to answer the big question above as it pertains to bacteria.

Their first move will make use of a microbe skilled at “community displacement.” Vibrio cholerae is a comma-shaped bacterium, some strains of which cause cholera. An ages-old plague on humanity, the disease brings severe diarrhea and dehydration; as late as 2010 cholera is estimated to have afflicted three- to five-million victims and killed 58,000 to 100,000.

“The bacterium is notorious for its toxin-mediated ‘flushing’ of the intestine,” the researchers observed somewhat clinically. However, rather than focusing on its disease inducing effects, they hope to make use of its ability to efficiently colonize “chitinous” surfaces in the environment. Chitin, from the Greek chiton, meaning “covering,” is a cellulose-like material found in many organisms – in butterfly wings as well as the cell walls of fungi, and in the shells of crabs, lobsters and shrimp.

For their experiments, Parthasarathy, Hammer and Xavier will use the larval zebrafish, which has plenty of chitinous material in its tiny gut, as a model organism. As it competes with other microbes for nutrients, Vibrio cholerae, an aggressive bacterium, interacts by direct contact with other bacteria in a process microbiologists have labeled “dueling behavior.” Vibrio cholerae extends a hollow sheath containing a deadly protein molecule, injecting it into its cellular victim.

As they manipulate the various genetic and ecological factors that activate Vibrio cholerae’s dueling behavior, the researchers will use fluorescence microscopy, a process that attaches light-absorbing and emitting molecules to key sites within the sample. This is expected to yield three-dimensional and time-related data about Vibrio’s “community displacement” skills. Xavier will then use the experimental data to develop mathematical models of the bacterium’s aggressive behavior and its ability to purge the zebrafish larva’s normal gut community.

Assuming that works – and there are no guarantees in fundamental research such as this – their next major project will be to reboot the ecosystem with a new microbial community. To do this, they will genetically program Vibrio cholerae to self-destruct once it has accomplished its task. Next they will assemble new communities of microbiota likely to displace the remaining Vibrio cholerae.

It’s certainly not as easy as spooning down your favorite carton of “live-culture” yogurt. But if successful, their work could open new avenues for balancing and controlling the several hundred species of bacteria in the human gut, providing new ways to maintain human health.

Parthasarathy, Hammer and Xavier’s research is being funded through the Scialog program jointly sponsored by Research Corporation for Science Advancement (RCSA) and the Gordon and Betty Moore Foundation. Scialog supports research, intensive dialog and community building to address scientific challenges of global significance. Within each multi-year initiative, Scialog Fellows collaborate in high-risk discovery research on untested ideas and communicate their progress and form new collaborations in annual conferences.

Parthasarathy, Hammer and Xavier are participants in a two-year Scialog program entitled Molecules Come to Life. The program focuses on such questions as, what are the fundamental principles that make a collection of molecules within a cell produce behaviors that we associate with life? How do molecules combine and dynamically interact to form functional units in cells, and how do cells themselves interact to form more complex lifeforms?

The researchers formed their collaboration at a Scialog conference held earlier this year at Biosphere2 north of Tucson, Arizona. There, 50 or so leading young scientists from divergent fields of biology, physics and chemistry engaged in intensive discussions designed to produce creative ideas for innovative research.

“Scialog aims to encourage collaborations between theorists and experimentalists,” said RCSA Program Director Richard Wiener. “And, we encourage approaches that are driven by theory and coarse-grained modeling, that are testable by experiments.”

The next Molecules Come to Life Scialog conference will be held in March 2016. 

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