A role for bacterial urease in Crohn’s disease
Urease serves as a nitrogen source provider for amino acid synthesis and thus for bacterial growth. It is associated with gut dysbiosis during chronic inflammatory bowel disease.
Bacterial urease plays the role of substrate in the bacterial production of amino acids by serving as a nitrogen source provider for the intestinal microbiota. It seems to be critical in the onset of dysbiosis during chronic inflammatory bowel diseases (CIBD). Researchers took an interest in the high concentration of amino acids observed in the stool of patients with CIBD because it suggested a significant amount of nitrogen was used for amino acid synthesis, and thus demonstrated that bacterial urease was involved in the conversion of urea into ammonia. Moreover, the microbiota of patients with CIBD shows an abundance of Proteobacteria, which are high nitrogen-consumers.
By studying 90 patients under 22 of age with Crohn’s disease (PLEASE cohort), the researchers first confirmed that high levels of amino acids in the stool were correlated to the calprotectin level and thus to the disease severity. These patients also had an increased amount of Proteobacteria in their microbiota, compared to healthy subjects. Researchers then used a mouse model to confirm the role of urease in the bacterial production of amino acids from host nitrogen. To this end, they used 15N-labeled urea. The significant amount of nitrogen isotope in the amino acids found in the stool proved that labeled urea was incorporated through its conversion into ammonia by the bacterial urease.
In order to confirm the role of this enzyme, researchers then inoculated mice (pretreated with antibiotics and polyethylene glycol (PEG) to cleanse the colon) with urease-positive (Ure+) and urease-negative (Ure-) strains of Escherichia coli. The administration of E. coli promotes intestinal bacterial recolonization but the Ure+ strain generates dysbiosis with a predominance of Proteobacteria species and a decrease in Firmicutes compared to the Ure- strain. It was thus demonstrated that activity of bacterial urease is sufficient to generate gut dysbiosis. This same experiment carried out with a mouse model of inflammatory bowel disease (activated T cell transfer induced colitis) showed that the administration of the Ure+ strain increases the symptoms of the disease and the amount of amino acids in the stool, compared to the Ure- strain.
Although these experiments do not provide any explanation on how urease generates the observed dysbiosis, they do illustrate the involvement of nitrogen flux via the bacterial urease in this process and in the pathogenesis of inflammatory bowel disease. Urease may be a potential therapeutic target in the management of Crohn’s disease.
Josephine Ni et al. A role for bacterial urease in gut dysbiosis and Crohn’s disease. Science Translational Medicine, 2017:9 (416)