A role for bacterial urease in gut dysbiosis and Crohn’s disease

Abstract

Gut dysbiosis during inflammatory bowel disease involves alterations in the gut microbiota associated with inflammation of the host gut. We used a combination of shotgun metagenomic sequencing and metabolomics to analyze fecal samples from pediatric patients with Crohn’s disease and found an association between disease severity, gut dysbiosis, and bacterial production of free amino acids. Nitrogen flux studies using 15N in mice showed that activity of bacterial urease, an enzyme that releases ammonia by hydrolysis of host urea, led to the transfer of murine host-derived nitrogen to the gutmicrobiota where it was used for amino acid synthesis. Inoculation of a conventional murine host (pretreated with antibiotics and polyethylene glycol) with commensal Escherichia coli engineered to express urease led to dysbiosis of the gut microbiota, resulting in a predominance of Proteobacteria species. This was associated with a worsening of immune-mediated colitis in these animals. A potential role for altered urease expression and nitrogen flux in the development of gut dysbiosis suggests that bacterial urease may be a potential therapeutic target for inflammatory bowel diseases.

Proteus spp. as Putative Gastrointestinal Pathogens

“…Urease confers a survival advantage to Proteus by providing nitrate for nonfermentative anaerobic respiration. This in turn promotes the population expansion of the Enterobacteriaceae (including Proteus) (48,49). Additionally, as with Helicobacter pylori, the presence of this enzyme likely confers a survival advantage through increasing the local pH of the environment, allowing urease-positive organisms to survive in more-acidic environments such as the upper digestive tract.…”

“…Crohn's disease has been associated with changes in nitrogen metabolism. Ammonia produced from the breakdown of urea by bacterial urease provides a source of nitrogen for respiration and amino acid synthesis by pathogenic facultative anaerobes from the Proteobacteria phylum (49).…”

Global and Simultaneous Hypothesis Testing for High-Dimensional Logistic Regression Models

“…We illustrate our proposed methods by analyzing a dataset from the Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition (PLEASE) study, a prospective cohort study to investigate the effects of inflammation, antibiotics, and diet as environmental stressors on the gut microbiome in pediatric Crohn's disease (Lewis et al, 2015;Lee et al, 2015;Ni et al, 2017).…”

2019 Gut Microbiota for Health World Summit

“…Studies regarding alterations of diet can help identify candidate metabolites for the prevention or treatment of many diseases. Gary Wu presented data obtained from the Pediatric Longitudinal Study of Elemental Diet and Stool Microbiome Composition trial 10 showing that fecal nitrogen metabolites (amino acids) are associated with disease activity in IBD. Disease activity is also associated with microbial dysbiosis in these patients and anti-inflammatory diets may act by rapidly restoring the microbiome.…”