December 5, 2017

Changing gut bacteria in Crohn’s disease

At a Glance

  • Researchers discovered that an enzyme called urease altered the composition of bacteria in the guts of mice and led to an inflammatory bowel disease.
  • The study suggests that urease may be a potential target for treating inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.
Man on park bench holding his stomach in discomfort The findings suggest a potential approach for developing new treatments for inflammatory bowel diseases. Champja/iStock/Thinkstock

Crohn’s disease is a chronic disease that causes inflammation and irritation in the digestive tract. This can lead to severe pain, diarrhea, and poor absorption of nutrients, which can stunt a child’s growth in severe cases. The disease most often begins gradually and can become worse over time. Doctors aren’t sure what causes Crohn’s disease. Some experts suggest that changes in the gut microbiome—the community of microbes, like bacteria and viruses, living in the gut—may play a role.

Gut bacteria metabolize nitrogen in our intestine to produce the amino acids and enzymes they need to flourish. Certain types of bacteria taking over the gut may contribute to inflammatory bowel disease, including Crohn’s disease.

To investigate the relationship between bacterial nitrogen metabolism and inflammatory bowel diseases, a team led by Dr. Gary D. Wu at the University of Pennsylvania analyzed gut microbes and amino acids in patients with Crohn’s disease. The research was supported in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of General Medical Sciences (NIGMS). Results were published in Science Translational Medicine on November 15, 2017.

The team's previous work showed increased activity in genes associated with nitrogen metabolism in stool samples taken from 90 children with Crohn’s disease compared with samples from 26 healthy children. In the current study, the researchers found higher levels of amino acids and their derivatives in stool samples from the people with Crohn’s disease. These were correlated with high levels of a group of gut bacteria called Proteobacteria.

Some bacteria in the colon use an enzyme called urease to produce ammonia. The ammonia serves as a major source of nitrogen to feed their growth. The researchers tracked nitrogen in mice with normal gut bacteria, depleted gut bacteria, or guts that were depleted and recolonized with bacteria that have low levels of urease. They found that the enzyme allows gut bacteria to produce ammonia that is then used to make amino acids.

The scientists wiped out gut microbiomes in mice and then introduced Escherichia coli (a type of Proteobacteria) that were genetically engineered to produce either high or low levels of urease. High levels of urease caused Proteobacteria to flourish in the mouse guts. Low levels of urease led to healthier gut microbiomes.

In mice prone to colitis, the high levels of urease worsened colitis. These mice lost more weight and had more inflammation than mice given E. coli that produced low levels of urease.

Using a technique similar to that used to wipe out the gut microbiome in mice, the team showed that they could reduce gut bacteria in five people. This suggests a way to alter gut bacteria in people that may lead to a healthier microbiome.

“Because it’s a single enzyme that is involved in this process, it might be a targetable solution,” says Wu. “The idea would be that we could ‘engineer’ the composition of the microbiota in some way that lacks this particular [enzyme].”

The group is now investigating treatments for Crohn’s disease based on these findings in clinical studies.

—Tianna Hicklin, Ph.D.

Related Links

References: A role for bacterial urease in gut dysbiosis and Crohn's disease. Ni J, Shen TD, Chen EZ, Bittinger K, Bailey A, Roggiani M, Sirota-Madi A, Friedman ES, Chau L, Lin A, Nissim I, Scott J, Lauder A, Hoffmann C, Rivas G, Albenberg L, Baldassano RN, Braun J, Xavier RJ, Clish CB, Yudkoff M, Li H, Goulian M, Bushman FD, Lewis JD, Wu GD. Sci Transl Med. 2017 Nov 15;9(416). pii: eaah6888. doi: 10.1126/scitranslmed.aah6888. PMID: 29141885.

Funding: NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of General Medical Sciences (NIGMS); Crohn’s & Colitis Foundation of America Microbiome Consortium; American Gastroenterological Association; Takeda Pharmaceuticals; the University of Pennsylvania; Children’s Hospital of Philadelphia; and the Sheila and Stanley Greenberg Fund.