Researchers Engineer Bacterial Enzyme In Gut Microbiome To Treat Crohn's Disease
등록일 2019년 01월 07일 목요일
수정일 2017년 11월 16일 목요일

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Chronic inflammation of the gut can be quite stressful.In fact, most of the diseases linked with this do not have a cure.However, there may be some good news for individuals diagnosed with Crohn's disease as researchers may finally have found a better way of treating it.Previous studies on Crohn's disease, which is an inflammatory bowel disease known to affect the lining of the gut show that although treatment helps in relieving pain, this condition can't be cured.Crohn's disease has no exact proven cause.Scientists believe that it is caused by a combination of immune system problems, environmental and genetic factors.

The new research carried out on Crohn's disease by Penn Medicine researchers from the University of Pennsylvania School of Medicine involves singling out a bacterial enzyme that is responsible for the imbalance in the gut microbiome which is known to cause the disease.

The research was published in Science Translational Medicine Journal.The study suggests that Crohn's can be treated if a significant portion of bacterial enzyme causing it is wiped out in the gut and replaced with good bacteria known as urease which lacks this enzyme.According to the study's senior author Gary D.W, the gut bacteria has a single enzyme making it a targetable solution.The scientists from the university's Gastroenterology division intend to engineer the microbiota's composition in a way that it lacks the enzyme.

Environmental stressors such as diet and antibiotics are known to cause the imbalance in the gut microbiome.This imbalance also known as gut dysbiosis is believed to fuel Crohn's disease.Therefore, striking a healthier, bacterial balance for patients with the disease is crucial in its treatment.According to a series of studies conducted on both humans and mice, researchers found a bacteria known as proteobacteria that was involved in the development of dysbiosis.

This bad bacteria feeds on urea which is a waste product that ends up back in the colon.It has the urease enzyme which helps it convert urea into ammonia that is absorbed by bacteria to make amino acids believed to cause dysbiosis in Crohn's disease.On the other hand, good bacteria respond differently hence serving as a potential therapeutic approach that scientists may use to treat the disease.

This study, carried under the PennCHOP Microbiome Program and with funding from Crohn's and Colitis Foundation was set out also to investigate the role that nitrogen metabolism plays in dysbiosis.The study involved performing metabolomic analysis on small molecules in samples collected from 90 Crohn's disease patients.They also took fecal samples from 26 healthy children from Pediatric Longitudinal Study of Elemental Diet for comparison.

Analysis of the samples showed that fecal amino acids resulting from bacterial nitrogen metabolism were associated with Crohn's disease as well as an abundance of Proteobacteria.The next step involved tracking nitrogen metabolism activity in mouse models.This was essential in helping researchers reveal the mechanisms required for the treatment of the disease.

In addition, the researchers wanted to show that the urease enzyme was involved in the regulation of bacterial nitrogen metabolism which ultimately leads to gut dysbiosis.To do this, they wiped the microbiomes slate clean before they could engineer the microbiota into a specific configuration.Previous studies carried out on mice, where researchers pretreated mice with antibiotics and polyethylene glycol (PEG), showed that the treatment reduced the bacterial load in their guts.This created an opportunity for the researchers to introduce a new bacterial community to the mice.The polyethylene glycol is an intestinal purging agent used on patients undergoing a colonoscopy.

The published research showed that after introducing a single bacterial species such as Escherichia coli in pretreated mice changed the mice's gut microbiome significantly depending on whether urease was present.Researchers found that mice injected with urease-positive E.Coli lead to gut dysbiosis while those injected with urease-negative did not.In addition, they found that urease-positive worsened colitis in the subjects.

Just like in mice, if five human subjects were treated with the same two antibiotics and the Polyethylene glycol there would be a reduction in the subject's bacterial load by 100000-fold.This means that it may be possible to configure gut microbiota in patients with this inflammatory bowel disease.According to Wu, having successfully reduced the bacterial load in humans it is possible to engineer microbiota in their guts in a manner that is similar to what was achieved in mice.

D.Wu claims that this study is important in that it shows the importance of the movement of nitrogen into bacteria in gut dysbiosis.He also adds that the research proves that it is possible to reconfigure the entire gut microbiota composition using a single enzyme.With this in mind, the CHOP and Penn team are conducting a clinical study in patients with refractory Crohn's disease using results from this research to help them focus more on altering gut microbiota.

According to Wu the outcomes of this research will push scientists a step closer in building a technology platform that will help in engineering gut microbiota to be used in the treatment of Crohn's disease and other inflammatory bowel diseases.

Liza Tan기자  
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