You may already know that we host many species of bacteria in and on our bodies. The community of microbes in the gastrointestinal tract has been shown to play a significant role in our health, and scientists are studying that gut microbiome intensely. Any of around 1,000 types of bacteria can live in that community, and they can communicate with one another. We don’t know much about the signals they send to each other, however, which may be about health or physiology, for example. Researchers at the Wyss Institute at Harvard University, Harvard Medical School (HMS), and Brigham and Women's Hospital have now successfully engineered a system in which a bacterium can send a signal in response to a cue. This research is a step toward creating a synthetic microbiome, composed of engineered microbes that function in specific ways. This work has been reported in ACS Synthetic Biology.
"In order to improve human health through engineered gut bacteria, we need to start figuring out how to make the bacteria communicate," explained first author Suhyun Kim, a graduate student in the lab of Pamela Silver at the Wyss Institute and HMS. "We want to make sure that, as engineered probiotics develop, we have a means to coordinate and control them in harmony."
Some strains of bacteria can naturally communicate with one another when they live in a group, called quorum sensing (animated in the above video). This system can regulate gene expression and provide feedback about colony density, to preserve overall health in the community. The team modified a type of quorum sensing not yet found in the mammalian gut, acyl-homoserine lactone (acyl-HSL) sensing, to transmit new information.
Circuits were introduced into E. coli bacteria, one to send a signal and one to respond. As a signal, the circuit employs a luxI gene, which is activated by a molecule called anhydrotetracycline (ATC). When ATC binds to the responder, a gene called cro makes a Cro protein, stimulating a so-called memory element in the responder. Two more genes are then activated: one to produce a blue color for a visual signal, another to keep the responder's memory element activated.
This system was also confirmed in the S. typhimurium bacterium; responder bacteria emitted blue when ATC was added to the signaler. It also worked in vivo. When the engineered bacteria were given to mice through drinking water, mouse fecal samples showed the signal was being transmitted between the bacteria.
"It was exciting and promising that our system, with single copy-based circuits, can create functional communication in the mouse gut," said Kim. "Traditional genetic engineering introduces multiple copies of a gene of interest into the bacterial genome via plasmids, which places a high metabolic burden on the engineered bacteria and causes them to be easily outcompeted by other bacteria in the host."
The in-vivo system was created with S. typhimurium bacteria as signalers, and E. coli bacteria as responders. Incredibly, the signal was even transmitted between these different types of microbes. That shows that in the mammalian gut, communication can happen between different bacterial species.
"Ultimately, we aim to create a synthetic microbiome with completely or mostly engineered bacteria species in our gut, each of which has a specialized function (e.g., detecting and curing disease, creating beneficial molecules, improving digestion, etc.) but also communicates with the others to ensure that they are all balanced for optimal human health," said corresponding author Pamela Silver, Ph.D., a Founding Core Faculty member of the Wyss Institute who is also the Elliot T. and Onie H. Adams Professor of Biochemistry and Systems Biology at HMS.
"The microbiome is the next frontier in medicine as well as wellness. Devising new technologies to engineer intestinal microbes for the better while appreciating that they function as part of a complex community, as was done here, represents a major step forward in this direction," said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children's Hospital, as well as Professor of Bioengineering at SEAS. He is featured in the video above.