Like humans, bacteria in nature often live in communities. New research studying the interactions within these microbial communities shows how bacteria can cooperate with each other to resolve a form of social conflict.
Many bacteria live stuck together on surfaces, in communities known as biofilms. These masses of bacteria, sugars, proteins and fragments of DNA are found everywhere – inside pipes, on medical implants and in your gut, to name a few examples – and they are how most bacteria exist in nature.
Like any community, bacteria within biofilms have competing interests and needs. On the one hand, bacteria on the edges of the biofilm are vulnerable to external attack – from antibiotics or other bacteria – while those on the inside are protected. On the other hand, these peripheral bacteria have better access to a key commodity: food. So much so that, if left unchecked, cells on the outer edges would consume all the available nutrients in the environment, causing the interior bacteria to starve and die.
Now, research published in Nature reveals a mechanism that allows bacteria to resolve this social conflict in a way which benefits the whole community.
The discovery came from a surprising initial observation made by the researchers while studying biofilms. They used special devices to grow biofilms in very thin layers and captured high-resolution images of the process. The team noticed that after a biofilm of B. subtillis reached a certain size, something strange happened: its growth speed suddenly began to oscillate between fast and slow.
At around 09:00 hours, you can see the growth begin to oscillate. (Image courtesy of Suel Lab, UC San Diego)
“These oscillations were a surprise,” says Gürol Süel from UC San Diego, the corresponding author of the paper. “But then we realised that we were looking at a kind of social conflict resolution process.”
The team was able to show that these pulses in growth allow the bacteria to share food. Periodically slowing down growth of the bacteria on the outside prevents them from depleting all the nutrients and starving those on the inside.
The mechanism involves a molecule called ammonium, which is needed for growth. Bacteria can make their own ammonium, but for cells on the outside of the biofilm, it quickly escapes into the environment. This makes the peripheral “protectors” reliant on the interior cells for their ammonium supply. And so, if the inside of the biofilm starts to run out of food, interior production of ammonium begins to slow down too, which reins in the growth of cells on the outside, forming a classic feedback loop.
(Image courtesy of Süel Lab, UC San Diego)
Regulating growth in this way allows the biofilm to keep growing and actually makes the community more resilient. Ordinarily, it’s very difficult to penetrate the interior of a biofilm with antimicrobials, meaning we can only kill the edges. In fact, if the peripheral cells die, it means more nutrients for the interior of the colony, and they actually grow faster. In this way, the colony is able to regenerate itself.
But when the researchers engineered the peripheral bacteria to mass-produce ammonium, they were no longer reliant on the inner cells. This broke the feedback loop and stopped the oscillations, making biofilm growth constant. The inner cells were deprived of nutrients and died as predicted, and the biofilm was then much more vulnerable to attack from toxic substances like hydrogen peroxide.
Biofilm resilience has puzzled scientists for some time – they can be up to 1,000 times more resistant to antibiotics than free-living bacteria. Current theories include the biofilm matrix acting as a physical barrier to antibiotics, or groups of bacteria becoming dormant and regrowing once antibiotic levels drop. But oscillatory growth could be part of the explanation.
“This is a mechanism of biofilm resistance that we haven’t ever thought about before,” says Munehiro Asally from Warwick University, who also worked on the paper. “It doesn’t come from a specific resistant gene or from a super cell type, it emerges from the dynamics of the community.”
The authors say that this research could open up novel avenues for killing biofilms that haven’t previously been explored. For example, providing biofilms with ammonium could make antibiotics more effective – the peripheral cells would no longer have to rely on interior cells, meaning the latter would starve and die. Then we could mop up the remaining cells and destroy the whole community.
“The trick is, if you understand the social conflict, you can turn the bacteria against each other so they do the dirty work for us,” says Süel. “Ours is a different perspective that doesn’t necessarily require new drugs. We’re very excited about this research, and we hope it will give us more tools in our arsenal against pathogenic biofilms.”
Liu, J., Prindle, A., Humphries, J., Gabalda-Sagarra, M., Asally, M., Dong-yeon, D. L., Ly, S., Garcia-Ojalvo, J. & Süel, G. M. (2015). Metabolic co-dependence gives rise to collective oscillations within biofilms. Nature 523, 550-554 DOI: 10.1038/nature14660