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Bacterial enzyme implicated in inflammatory bowel disease

Using human samples and animal models, researchers have found that an enzyme produced by certain bacteria could disrupt the gut microbiome, potentially playing a significant role in the development of inflammatory bowel disease. People with inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis suffer from symptoms such as diarrhea, cramping, and unintended weight loss. Among other factors, inflammatory bowel disease is associated with changes in the makeup of the microbiome, including the trillions of bacteria living in the gut. Like other organisms, these bacteria thrive by breaking down nutrients to produce components that are critical for growth and survival. However, it is not clear how these bacterial products, or “metabolites,” affect the microbiome and disease development.

In a recent study, researchers attempted to determine whether specific bacterial metabolites could be altering the gut microbiome in people with Crohn’s disease. They analyzed fecal samples from 90 individuals younger than 22 years old with Crohn’s disease and compared them to samples from healthy persons of similar age to identify metabolites associated with disease. Most of the metabolites that were found at higher levels in the samples from people with Crohn’s disease were amino acids, which are the building blocks of proteins. Knowing that many types of bacteria will produce amino acids by breaking down a nitrogen-rich compound called urea, the scientists focused on an enzyme—urease—that is critical for this process. The researchers first sought to establish mouse models that harbored bacteria with high urease levels to determine if bacterial urease might be important for the development of Crohn’s disease. To do this, they treated mice with antibiotics and a gut-purging agent to deplete their microbiomes, clearing the way for the establishment of new microbiomes in the guts of these mice. They next inoculated the mice with either bacteria lacking urease (Ure- bacteria) or bacteria engineered to produce urease (Ure+ bacteria) and allowed the mice to naturally re-establish their microbiomes over the next month. The scientists found that the two groups of mice developed significantly different microbiomes: the mice initially inoculated with the Ure+ bacteria were more likely to develop microbiomes that contained relatively greater numbers of bacteria that are associated with poor health. In fact, when this experiment was repeated in mice that were engineered to develop a form of inflammatory bowel disease, the mice that were inoculated with Ure+ bacteria showed a more aggressive form of the disease. These results suggest that urease may play a role in exacerbating inflammation in the gut by disrupting the microbiome. This research also points to urease as a possible target for therapy, either by direct inhibition or by manipulating the microbiome’s bacterial components to decrease the amount of urease in the gut. The findings also indicate that a therapeutic strategy to rehabilitate the gut microbiome may require first removing some of the existing bacteria before administering a probiotic with a more healthy bacterial mix. However, more research is needed to determine whether these results seen in mice translate to humans.

References

Ni J, Shen TD, Chen EZ,…Wu GD.  A role for bacterial urease in gut dysbiosis and Crohn’s disease. Sci Transl Med.  doi: 10.1126/scitranslmed.aah6888, 2017.
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