In a new study published in the journal Cell Systems, researchers reveal how they have engineered a common gut bacterium to have new functions, enabling control of gene expression in the intestinal tracts of mice.
Study leaders Timothy K. Lu and Christopher Voigt, of the Massachusetts Institute of Technology (MIT), and colleagues say their study could pave the way for the development of microbes that detect illness in the gut or that can deliver drugs.
Researchers have been increasingly investigating how to engineer gut bacteria so it holds therapeutic potential.
Last year, for example, Medical News Today reported on a study by researchers from Vanderbilt University in Nashville, TN, which detailed how Escherichia coli bacteria were modified to reduce food intake and obesity in mice.
The MIT team notes, however, that E. coli is not present in the gut in abundance – it can be cleared within days of introduction. As such, they turned their attention to Bacteroides – specifically, a species called Bacteroides thetaiotaomicron.
“Compared to E. coli, Bacteroides populations exhibit low variation in abundance and long-term colonization,” the authors explain. “B. thetaiotaomicron is both prevalent (present in 46% of humans) and abundant […] making it a promising organism for both understanding and manipulating the gut environment.”
In addition, the researchers say these bacteria are able to express genes “on demand” and engage in long-term interactions with human cells and other gut bacteria. This means a form of this bacteria engineered to deliver drugs and its expressed genes could remain in the gut for longer.
To engineer B. thetaiotaomicron, the MIT team combined a number of tools researchers have previously used to engineer other bacteria, including promoters, ribosome-binding sequences, memory switches and CRISPR interference, and introduced them to the bacterium.
“We then showed that genetic devices could be implemented in the bacteria and be shown to function in the context of the mouse gut microbiome.” says Lu.
Explaining what these findings mean, Voigt says:
“The culmination of the work is not only do you have an engineered bacterium that’s colonized the mouse gut, but you can turn on which genes in the bacterium are active based on what you feed the mouse. That’s really something new. It allows you to control what the bacterium is doing at the site of where it’s operating.”
The researchers hope to move their work to human trials, but note there are some barriers to overcome first. For example, in this study, the mice had to be given antibiotics before their gut could be colonized with B. thetaiotaomicron.
Also, the team says they need to demonstrate that the bacteria can be engineered to perform more complex functions, such as the ability to respond to a variety of sensory inputs.
The researchers say the long-term goal is to use intestinal signaling to modify gene expression via engineered bacteria, which could offer new treatment strategies for a variety of health conditions.
“The big picture is that the bacteria that live in us or on us impact human health in very significant ways and the existing techniques we have to modulate the microbiome – taking antibiotics or changing our diet – are relatively limited,” notes Lu.
“We’re hoping that with these tools to precisely engineer the intimate interface between bacteria and humans we’re going to be able to tackle some major health-related problems.”