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July 22, 2015

Biofilm Harmony Arises from Metabolic Codependence, Not Bacterial Altruism

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    Growth oscillations, shown here as colored contour lines emanating from a central biofilm, reflect metabolic codependence, a mechanism for resolving biofilm community conflict between reproduction at the periphery and survival at the core. [Süel Lab, UC San Diego]

    Cooperative behavior on the part of mindless organisms such as bacteria is always a puzzle, for it is typically an emergent property, not something deliberate. Bacteria, for example, somehow manage to balance cooperation and competition in communities called biofilms, surface-hugging structures that are highly resistant to chemicals and antibiotics.

    The best-known biofilms are the tartar deposits on teeth. Biofilms are also responsible for two-thirds of infections in hospital clinics. They can be dangerous because they harbor bacteria that are a thousand times more resistant to antibiotics than they would be outside the biofilm

    Bacteria at the outer edges of a biofilm are the most vulnerable within their community to chemical and antibiotic attacks. At the same time, they also provide protection to the interior cells. But the bacteria at the outer edge are the closest to nutrients necessary for growth. So if they grow unchecked, they can consume all the food and starve the sheltered interior cells.

    Needless to say, that doesn’t happen. But why not? One possibility is that the outer bacteria and inner bacteria have some sort of reciprocal arrangement. Besides creating a division of labor, a biofilm institutes, however spontaneously, a division of spoils.

    To investigate how the outer bacteria in a biofilm avoid growing uncontrollably, to the detriment of the bacterial community as a whole, researchers at UC San Diego used a microfluidics platform and time-lapse microscopy to observe growing biofilms. The researchers discovered that when the biofilm community reached a certain size, it suddenly began to oscillate in its growth.

    By complementing their experiments with mathematical modeling, the researchers came to the realization that oscillating growth could help a biofilm resolve its intrinsic organizational conflict—the conflict between slower peripheral growth (protecting interior cells) and faster peripheral growth (starving interior cells).

    Oscillating growth, the UC San Diego team concluded, was a manifestation of “metabolic codependence.” Essentially, the interior cells produce a metabolite necessary for the growth of the bacteria on the outside. This provides the inner cells with the ability to periodically put the brakes on the growth of outer cells, which otherwise would consume all the food and starve the cells they are protecting from attack. By periodically preventing the growth on the periphery, inner cells ensure that they have sufficient access to nutrients. By keeping the protected inner cells alive, the biofilm has a much higher chance of surviving antibiotic treatment.

    These findings were presented July 22 in Nature, in an article entitled, “Metabolic co-dependence gives rise to collective oscillations within microbial communities.”

    “This collective oscillation in biofilm growth benefits the community in the event of a chemical attack,” the authors wrote. “These findings indicate that oscillations support population-level conflict resolution by coordinating competing metabolic demands in space and time, suggesting new strategies to control biofilm growth.”

    According to the leader of the study, Gürol Süel, Ph.D., these new strategies would involve the undermining of biofilm cooperation: “We allow the peripheral cells to become selfish or independent and then they kill the protected interior cells for us.”

    “We developed new techniques to precisely measure biofilm growth, and then quantitatively perturbed the system,” explained Dr. Süel. “And what we found was that the metabolic pathway in question may have been selected for this process by evolution because it involves a small molecule, ammonium, which can diffuse, that is, can get in and out of the cell quickly and can be shared among bacteria.”

    The discovery that bacteria essentially signal one another with this ammonium metabolite also allows them to chemically communicate with one another over very long distances.

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