“By engineering these bacteria, we are able to control how they operate in the human gastrointestinal tract,” said Caroline Kurtz at Synlogic, which was co-founded by Massachusetts Institute of Technology. “It allows us to think about many other diseases where you may need to produce something beneficial, or remove something that is toxic for the patient.”
The scientists focused on a disorder called hyperammonaemia. It occurs when levels of toxic ammonia build up in the blood and affect the brain. In mild cases people can feel sick, lose their appetite and be hard to rouse, but in severe cases it causes irreversible and sometimes fatal brain damage.
Most people who are treated for hyperammonaemia have liver damage that prevents the organ from converting ammonia in the blood into urea. But the condition also affects those with rare genetic disorders that disrupt the liver’s ability to process ammonia. About half of the ammonia circulating in the body is thought to come from bugs in the gut.
Writing in the journal Science Translational Medicine, the scientists describe how they took a strain of bacteria called E coli nissle as the starting point for their living medicine. Humans have taken E coli nissle as a probiotic for more than a century. In the gut, it converts ammonia into arginine, an amino acid which may lower blood pressure.
The researchers tweaked the bug’s genes so that when it reached the low-oxygen world of the intestines, it consumed far more ammonia than usual. Further tweaks ensured it was unable to multiply and so become established in the gut.
The scientists then gave the modified bugs to mice with an impaired ability to process ammonia. The microbes cut ammonia levels by as much as half and boosted the animals’ survival rates. While all untreated mice died within a week, half of those given modified microbes were still alive 10 days later.
To test the treatment’s safety in humans, the bugs were then given to 52 healthy volunteers in a phase one trial. It found no major side effects and showed that the microbes appeared to behave as intended. When the bacteria convert ammonia to arginine, the amino acid is broken down into nitrates which are swiftly passed out in urine. Tests showed that those on the highest doses had most nitrates in their urine, implying more ammonia had been mopped up.
Aoife Brennan, Synlogic’s president, said the bacteria were cleared from the body within two weeks of stopping the treatment, suggesting that the bugs had not set up a permanent home in the gut.
Another issue the scientists had to consider was whether other microbes that live in the intestines might acquire new genes from the modified bugs. Bacteria are not particularly choosy over who they share genes with and species often swap DNA through a process known as horizontal gene transfer.
According to the researchers, the strain of E coli used in the medicine does not tend to couple with other bacteria. But if some modified genes did find their way into other bacteria, the bugs would not have an advantage that allowed them to run amok, they said. “We have designed the bacteria such that any transfer is extremely unlikely,” Brennan said.
Paul Freemont, co-director of the UK Innovation and Knowledge Centre for Synthetic Biology at Imperial College, said: “The idea of using an engineered gut microbe in a probiotic therapy was considered fanciful only a few years ago but now we are beginning to see the promise of applying synthetic biology to develop completely new therapies. By engineering a gut microbe to remove and convert high levels of ammonia to the harmless amino acid arginine is amazing.”
