Engineering the microbiome: Bacterial enzyme 'removal' may offer Crohn's disease promise

The new study, published in Science Translational Medicine​, suggests engineering the gut microbiome to shift away from urease producing bacteria and towards bacteria that do not produce the enzyme could help to combat Crohn’s disease.

In a series of human and mouse studies, the researchers led by senior author Dr Gary D. Wu at that University of Pennsylvania, discovered that a type of bacteria known as Proteobacteria​ which feeds on urea, a waste product that can end up back in the colon, played an important role in the development of an imbalance in the gut, known as dysbiosis.

These ‘bad’ bacteria harbour the urease enzyme and convert urea into ammonia, which is then reabsorbed by bacteria to make amino acids that are associated with dysbiosis in Crohn's disease, said the team.

Wu said the study is important because it shows that shows that the movement of nitrogen into bacteria is an important process in the development of dysbiosis.

"It also proves using a single enzyme can reconfigure the entire composition of the gut microbiota.”​

"Because it's a single enzyme that is involved in this process, it might be a targetable solution,"​ he said. "The idea would be that we could 'engineer' the composition of the microbiota in some way that lacks this particular one."​

Human study​

The study was conducted by Wu and colleagues from Penn Medicine and the Children's Hospital of Philadelphia (CHOP), under the PennCHOP Microbiome Program with funding from the Crohn's and Colitis Foundation.

To investigate the role of nitrogen metabolism in dysbiosis, the team first performed a metabolomic analysis characterising small molecules in faecal samples from 90 patients with Crohn's disease from the Pediatric Longitudinal Study of Elemental Diet and Stool Microbiota Composition (PLEASE) study, and 26 healthy children.

Results showed that faecal amino acids, a result of bacterial nitrogen metabolism, were significantly associated with Crohn's disease, dysbiosis, and an abundance of Proteobacteria in patients.

This led the researchers to track nitrogen metabolism activity in a mouse model – which helped reveal mechanisms that might be targets for the reversal of the condition.

Mouse data​

To do this, and demonstrate fully that urease is the key regulator of bacterial nitrogen metabolism that leads to dysbiosis, the team ‘wiped clean’ the microbiome before it was re-engineered into a specific configuration.

Using this approach, Wu and his team showed that inoculating pre-treated mice with a single bacterial species, Escherichia coli, altered the gut microbiome in a significant way – depending on the presence of urease.

Mice injected with urease-negative E. coli did not lead to dysbiosis, while mice with urease-positive E. coli did, they noted – adding that the urease-positive E. coli also exacerbated colitis in the mice.

Back to humans?​

Following the mouse study, the team then tested the potential for engineering the human microbiome in the same way – using five human subjects who were given the same two antibiotics and PEG given to the mice.

This successfully reduced bacterial load in their intestinal tract by 100,000-fold, suggesting that it might be possible to engineer the composition of the gut microbiota in patients with inflammatory bowel disease, said the team.

"Now that we can effectively reduce bacterial load in humans it may now be possible to engineer the microbiota into a different configuration in a manner similar to what we have achieved in mice," Wu​ said. "Although we're closer now, there is still more work to be done."​

Indeed, the Penn and CHOP team are currently conducting a therapeutic clinical study in patients with refractory Crohn's disease using a strategy based on data from this study – focusing on deeply altering the gut microbiota.

"The outcomes of this study and the analysis of collected bio-specimens will be an important first step in building a technology platform to engineer a beneficial composition of the gut microbiota for the treatment of inflammatory bowel diseases," ​Wu said.

Source: Science Translational Medicine​
Vol. 9, Issue 416, doi: 10.1126/scitranslmed.aah6888​
“A role for bacterial urease in gut dysbiosis and Crohn’s disease”​
Authors: Josephine Ni, et al​