Bacterial Enzyme Responsible for Crohn's Disease Development

A single bacterial enzyme may be the culprit behind the development of Crohn’s disease, according to new findings from a study published by Science Translational Medicine.

The study authors found that eliminating a majority of bacteria in the gut microbiome and re-introducing good bacteria that lacks the urease enzyme may effectively treat Crohn’s disease.

“Because it’s a single enzyme that is involved in this process, it might be a targetable solution,” said senior author Gary D. Wu, MD. “The idea would be that we could ‘engineer’ the composition of the microbiota in some way that lacks this particular one.”

Dysbiosis—the imbalance of the gut microbiome—can be caused by inflammation, antibiotics, or diet. Although dysbiosis is thought to be an underlying cause of Crohn’s disease and other conditions, the mechanisms are currently unknown.

In both human and mouse studies, the authors found that Proteobacteria, a so-called bad bacteria, feeds on urea, which is a waste product that can wind up in the colon and spur dysbiosis.

The bacteria harbor the urease enzyme and convert it into ammonia, which is reabsorbed to make amino acids that cause dysbiosis in Crohn’s disease, according to the study.

The authors hypothesize that good bacteria may not behave similarly and could present a potential approach to shift the gut microbiome to treat diseases.

“The study is important is because it shows that the movement of nitrogen into bacteria is an important process in the development of dysbiosis,” Dr Wu said. “It also proves using a single enzyme can reconfigure the entire composition of the gut microbiota.”

The investigators conducted a metabolomics analysis to determine the role of urease conversion into ammonia (nitrogen metabolism). They characterized small molecules in fecal samples from 90 patients with Crohn’s disease and 26 healthy pediatric patients.

The authors found that fecal amino acids resulting from bacterial nitrogen metabolism were strongly linked to Crohn’s disease, dysbiosis, and an abundance of Proteobacteria, according to the study.

The investigators then tracked nitrogen metabolism activity in mouse models to determine novel therapies for Crohn’s disease.

To show that urease played a significant role in bacterial nitrogen metabolism and can result in dysbiosis, the investigators cleared the gut microbiome of mice before it could be engineered, according to the study. The authors previously discovered that administering antibiotics (vancomycin and neomycin) and polyethylene glycol (PEG) to mice diminished gut bacteria enough to allow newly introduced bacteria to become established.

The authors found that introducing Escherichia coli to antibiotic- and PEG-treated mice caused changes to the gut microbiome, but the changes hinged on urease. They discovered that mice administered urease-negative E. coli did not experience dysbiosis, while mice administered urease-positive E. coli developed dysbiosis, according to the study.

Urease-positive E. coli was also observed to worsen colitis in the mice, according to the authors.

In humans, treatment with antibiotics and PEG reduced bacterial load in the intestines. The authors said these findings suggest that it may be possible to engineer the gut microbiome of patients with inflammatory bowel disease.

“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,” Dr Wu said. “Although we’re closer now, there is still more work to be done.”

The authors are currently conducting a clinical trial of human patients with Crohn’s disease based on these data.

“The outcomes of this study and the analysis of collected biospecimens 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,” Dr Wu concluded.