Overview

Urease is an nickel-dependent enzyme produced by many bacteria and some fungi that catalyzes the hydrolysis of urea into ammonia and carbonic acid. This reaction raises the local pH due to the accumulation of ammonia (a basic compound), which can neutralize acidic environments.^[1] No urease gene is present in the mammalian genome, so the breakdown of urea in the body is carried out exclusively by urease-producing microorganisms. ^[2] Activity of the enzyme is widespread across microbes in human- and animal-associated microbiomes, where it plays diverse roles in health and disease. For example, microbial ureases contribute to normal nitrogen metabolism (by recycling waste urea into ammonia as a nutrient) and help certain commensal bacteria maintain environmental pH, but they are also key virulence factors for some pathogens (enabling survival in harsh conditions and damaging host tissues).^[3] In essence, it is a pivotal microbial enzyme in both human and animal microbiomes, influencing microbial ecology and host physiology through its urea-degrading, ammonia-generating activity.

Urease Activity in the Microbiome

Urease catalyzes the hydrolysis of urea into ammonia and carbonic acid, a reaction that significantly influences host–microbe dynamics. The resulting increase in local pH supports microbial survival in acidic environments like the stomach and vagina, which is especially important in conditions like bacterial vaginosis and endometriosis. ^[4] This acid-neutralizing function enables pathogens such as Helicobacter pylori and Yersinia enterocolitica to colonize hostile niches and promote infection. Beyond acid resistance, the enzyme plays a critical role in nitrogen recycling: up to 30% of host urea is metabolized by the microbiota, releasing ammonia that fuels microbial amino acid biosynthesis. ^[5] In infants and ruminants, this contributes to nitrogen economy and nutrient salvage. However, the same enzymatic activity can be pathological. In the urinary tract, urease-driven alkalinization facilitates struvite stone formation and catheter encrustation, while in the gut, excess ammonia from urease-positive taxa contributes to hepatic encephalopathy and colitis.^[6] Commensals can also benefit the host; in the oral cavity, alkali production by urease-positive bacteria buffers acid and protects against tooth decay. ^[7] Thus, urease activity is functionally ambivalent: it supports metabolic cooperation and microbial colonization, yet also mediates inflammation, stone formation, dysbiosis, and toxicity depending on microbial context and host physiology.

Mechanisms and Microbiome-Level Impacts

Urease exerts multifaceted effects on host physiology and microbiome dynamics through its enzymatic breakdown of urea into ammonia. This reaction influences local pH, nitrogen metabolism, microbial competition, and host immune responses. The consequences are context-dependent: it can support commensal resilience and nutrient cycling or drive pathogenic outcomes such as urolithiasis, mucosal inflammation, dysbiosis, and systemic toxicity. The table below summarizes the major mechanistic roles of urease and their implications across different host environments.

Mechanistic Role	Microbiome and Host Impact of Urease
pH Modulation	Ammonia generation increases local pH, allowing survival of microbes in acidic niches (e.g., stomach, oral cavity, vagina). Enables pathogens like H. pylori to colonize gastric mucosa and commensals like S. salivarius to prevent tooth decay.[8]
Nitrogen Recycling	Microbial urease salvages nitrogen from host urea, supporting microbial amino acid biosynthesis. Critical in breastfed infants (B. infantis) and in ruminants, where urease facilitates microbial protein synthesis.[9]
Microbial Competitive Advantage	Urease-positive organisms gain ecological advantage in acidic environments by creating alkaline micro-niches, often enabling overgrowth of Proteobacteria and other pathogens under dysbiotic conditions. [10]
Pathogenesis in UTIs	P. mirabilis, U. urealyticum, and C. urealyticum alkalinizes urine, promoting struvite and apatite crystallization, epithelial injury, and catheter encrustation.[11]
Tissue Damage and Immunomodulation	Ammonia disrupts epithelial integrity and suppresses phagocyte activity. Critical for fungal virulence in Cryptococcus and Coccidioides. Promotes microbial persistence and invasion.[12]
Neurotoxicity via Hyperammonemia	Gut-derived ammonia from urease-positive taxa (Klebsiella, Proteus) exacerbates hepatic encephalopathy or triggers hyperammonemic coma during UTIs, even in non-cirrhotic patients.[13]
Microbiome Resilience or Dysbiosis	The enzyme alters microbial community structure. In oral health, increases in alkali-producing commensals are protective. In colitis, urease-expressing E. coli shift the microbiome toward inflammatory taxa like Proteobacteria.[14]

Urease-Positive Microbial Taxa and Clinical Relevance

The table below lists notable urease-producing microorganisms (bacteria and fungi) found in human-associated microbiomes or infections, along with their known or suspected clinical relevance in human or animal health.

Urease-Positive Microbe	Clinical Relevance of Urease in Humans/Animals
Helicobacter pylori (gastric bacterium)	H. pylori causes chronic gastritis and peptic ulcers; the enzyme is essential for colonization of the acidic stomach and contributes to mucosal injury, leading to ulceration and increased risk of gastric cancer.[15]
Proteus mirabilis (gut bacterium; opportunistic)	Common cause of UTIs and kidney stones; it alkalinizes urine, causing crystallization of struvite stones and damage to urinary epithelium. Urease-negative mutants show greatly reduced virulence in UTI models.[16]
Staphylococcus saprophyticus (skin/urogenital bacterium)	Second-leading cause of community-acquired UTIs in young women; it raises urine pH and can contribute to bladder inflammation and stone formation. Its activity is linked to this organism’s ability to colonize and damage the urinary tract.[17]
Ureaplasma urealyticum (urogenital mycoplasma)	Implicated in urethritis and chronic UTIs; strong activity can alkalinize the urinary tract. Infections with Ureaplasma urealyticum promote struvite kidney stone formation, and this organism has been isolated from infection-induced calculi in patients.[18]
Klebsiella pneumonia (gut commensal & opportunist)	Urease-positive strains can cause UTIs, pneumonia, and sepsis. In cirrhosis patients, overgrowth of Klebsiella in the gut contributes to hyperammonemia and hepatic encephalopathy via urease-generated ammonia.[19] UTI with Klebsiella can also lead to hyperammonemic encephalopathy even without liver disease. [20]
Yersinia enterocolitica (food-borne bacterium)	Causes gastroenteritis (yersiniosis). The enzyme allows this pathogen to survive gastric acidity during ingestion, facilitating infection of the gut. Acid survival via urease is important for its infectious dose and invasiveness.[21]
Streptococcus salivarius (oral commensal)	Urease-positive oral bacterium that generates ammonia from salivary urea, helping to neutralize plaque acids. Ammonia production by S. salivarius and related commensals raises dental plaque pH and is associated with lower risk of dental caries (tooth decay).[22]
Actinomyces naeslundii (oral commensal)	Urease-producing plaque bacterium; contributes to oral pH homeostasis. Alkali generation by Actinomyces spp. in dental biofilms inhibits the development of cavities by counteracting acid from fermenting bacteria. [23]
Bifidobacterium longum subsp. infantis (infant gut commensal)	Early-life gut bacterium that produces the enzyme to utilize urea as a nitrogen source. This helps release ammonia that can be used for amino acid synthesis, supporting infant nutrition and microbial growth in the nitrogen-limited infant gut.[24]
Corynebacterium urealyticum (skin commensal; opportunist)	Urease-positive corynebacteria that colonize skin and can infect the urinary tract, especially in hospitalized or immunosuppressed patients. Causes “encrusted” cystitis and pyelitis – chronic UTIs with extensive bladder stone crusts – due to vigorous urease activity and urine alkalinization. [25][26]
Cryptococcus neoformans (environmental fungus)	Opportunistic fungal pathogen (yeast) that causes cryptococcal pneumonia and meningitis in immunocompromised hosts. It is a major virulence factor: fungal urease generates ammonia in lung tissue, which inhibits immune cells and damages tissue, aiding the fungus’s survival and dissemination to the brain.[27]
Coccidioides posadasii (environmental fungus)	Pathogenic fungus (causes Valley Fever) that infects the lungs when inhaled as spores. Its activity in Coccidioides releases ammonia in pulmonary foci, contributing to tissue destruction and impairing host immune response during infection.[28]

FAQs

What is urease and why is it important in microbiome research?

Urease is a nickel-dependent enzyme produced by many bacteria and fungi that catalyzes the hydrolysis of urea into ammonia and carbon dioxide. In microbiome research, urease is recognized as a key virulence factor that enables microbes to neutralize acidic environments, outcompete commensals, and alter host-microbe interactions in diseases such as gastritis, urinary tract infections, and chronic gut inflammation.

Why is urease considered a metallomic trait?

Urease requires nickel ions as cofactors to function. Its expression, activation, and stability depend on microbial access to nickel and associated chaperones. This makes it both a marker and a functional driver of microbial adaptation in metal-rich environments, integrating it squarely into microbial metallomics.

Can urease activity be targeted in diseases where it is elevated?

Yes. Elevated microbial urease activity is implicated in conditions such as Helicobacter pyloriinfection, chronic urinary tract infections, hepatic encephalopathy, SIBO, and inflammatory bowel diseases. In these conditions, microbial metabolism of urea leads to ammonia accumulation, tissue alkalinization, and dysbiosis. Therapeutically, urease can be targeted using inhibitors like acetohydroxamic acid or through dietary nickel restriction, or Low-Nickel diet (LNiD). Additionally, compounds like lactoferrin may chelate nickel and inhibit urease function, offering a strategy to reduce pathogen virulence.

Research Feed

References

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2. Gut microbiota and dynamics of ammonia metabolism in liver disease.. Jakhar, D., Sarin, S.K. & Kaur, S.. (npj Gut Liver 1, 11 (2024))
3. Microbial Urease in Health and Disease.. Mora D, Arioli S. (PLoS Pathog. 2014.)
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