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Are pathogenic bacteria just looking for food? Metabolism and microbial pathogenesis

2011; Elsevier BV; Volume: 19; Issue: 7 Linguagem: Inglês

10.1016/j.tim.2011.04.003

1878-4380

Laurence Rohmer, Didier Hocquet, Samuel I. Miller,

Probiotics and Fermented Foods

It is interesting to speculate that the evolutionary drive for microbes to develop pathogenic characteristics was to access the nutrient resources that animals provided. Animal environments that pathogens colonize have likely driven the evolution of new bacterial characteristics to maximize these new nutritional opportunities. This review focuses on genomic and functional aspects of pathogen metabolism that allow efficient utilization of nutrient resources provided by animals. Similar to genes encoding specific virulence traits, genes encoding metabolic functions have been horizontally acquired by pathogens to provide a selective advantage in host tissues. Selective advantage in host tissues can also be gained by loss of function mutations that alter metabolic capabilities. Greater understanding of bacterial metabolism within host tissues should be important for increased understanding of host–pathogen interactions and the development of future therapeutic strategies. It is interesting to speculate that the evolutionary drive for microbes to develop pathogenic characteristics was to access the nutrient resources that animals provided. Animal environments that pathogens colonize have likely driven the evolution of new bacterial characteristics to maximize these new nutritional opportunities. This review focuses on genomic and functional aspects of pathogen metabolism that allow efficient utilization of nutrient resources provided by animals. Similar to genes encoding specific virulence traits, genes encoding metabolic functions have been horizontally acquired by pathogens to provide a selective advantage in host tissues. Selective advantage in host tissues can also be gained by loss of function mutations that alter metabolic capabilities. Greater understanding of bacterial metabolism within host tissues should be important for increased understanding of host–pathogen interactions and the development of future therapeutic strategies. Animals can be considered an excellent source of nutrients for bacteria. Animal tissues contain a rich diversity of nutrients, including sugars, amino acids and simple nitrogen-containing compounds such as urea and ammonia. This source of nutrients is part of the symbiotic relationship with the microbiota (see Glossary). Pathogens have evolved specific mechanisms to access host nutrients. In this review, we will discuss the intimate evolutionary and functional link between metabolic and bacterial virulence traits. The interaction of bacterial pathogens with their hosts is distinguished from host–microbiota interactions by resultant host damage [1Casadevall A. Pirofski L.A. Host–pathogen interactions: basic concepts of microbial commensalism, colonization, infection, and disease.Infect. Immun. 2000; 68: 6511-6518Crossref PubMed Scopus (400) Google Scholar]. Host–pathogen interactions result in the production and delivery of specific virulence factors that manipulate host cellular processes and cause further responses from the host, including the production of antibacterial factors by the mammalian innate immune system [2Brodsky I.E. Medzhitov R. Targeting of immune signalling networks by bacterial pathogens.Nat. Cell Biol. 2009; 11: 521-526Crossref PubMed Scopus (148) Google Scholar, 3Diacovich L. Gorvel J.-P. Bacterial manipulation of innate immunity to promote infection.Nat. Rev. Microbiol. 2010; 8: 117-128Crossref PubMed Scopus (208) Google Scholar]. This complex host–pathogen interplay is well described for bacterial virulence secretion systems and innate immune recognition of conserved bacterial molecules [4Haraga A. et al.Salmonellae interplay with host cells.Nat. Rev. Microbiol. 2008; 6: 53-66Crossref PubMed Scopus (609) Google Scholar]. In addition to these exchanges, to grow and replicate bacteria need to extract energy, specifically carbon and nitrogen, from compounds found in this dynamic environment. Bacterial replication is a key factor for pathogen colonization and transmission, hence understanding bacterial metabolism within the host is essential to understand host–pathogen interactions. In most habitats, a wide variety of bacteria compete for space and resources. In nutrient-limiting conditions, species that process nutrients more efficiently might outgrow others [5Hibbing M.E. et al.Bacterial competition: surviving and thriving in the microbial jungle.Nat. Rev. Microbiol. 2010; 8: 15-25Crossref PubMed Scopus (1582) Google Scholar]. It is estimated that there are tenfold more bacterial than human cells within the human body. Therefore, in most cases, pathogens have to invade niches that are already occupied by many perfectly adapted resident bacteria. These residents have developed efficient ways to process available nutrients as well as active mechanisms to protect their environment against competing bacterial species [5Hibbing M.E. et al.Bacterial competition: surviving and thriving in the microbial jungle.Nat. Rev. Microbiol. 2010; 8: 15-25Crossref PubMed Scopus (1582) Google Scholar]. On the skin, the predominant aerobic bacterial species Staphylococcus epidermidis produces antimicrobial peptides that are toxic to pathogenic Staphylococcus aureus and Streptococcus pyogenes [6Davis C.P. Normal flora.in: Baron S. Medical Microbiology. 4th edn. University of Texas Medical Branch at Galveston, 1996Google Scholar, 7Cogen A.L. et al.Skin microbiota: a source of disease or defence? Br.J. Dermatol. 2008; 158: 442-455Crossref Scopus (624) Google Scholar]. In the digestive tract, resident microbiota form a vast heterogeneous microbial ecosystem comprising up to 1014 bacteria from more than 400 species. Besides the production of antimicrobial compounds by resident species, the intestinal flora can modulate bone marrow and spleen macrophage cytokine production to promote defense against intracellular microorganisms [8Lievin-Le Moal V. Servin A.L. The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota.Clin. Microbiol. Rev. 2006; 19: 315-337Crossref PubMed Scopus (413) Google Scholar, 9Endt K. et al.The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea.PLoS Pathog. 2010; 6: e1001097Crossref PubMed Scopus (262) Google Scholar]. The vaginal microbiota of healthy, fertile women contains lactic acid generating Lactobacilli spp., which maintain the acidic pH of the vagina. The acidic pH as well as hydrogen peroxide production by some Lactobacilli spp. can inhibit the growth of many potential colonizers [10Martin R. Suarez J.E. Biosynthesis and degradation of H2O2 by vaginal Lactobacilli.Appl. Environ. Microbiol. 2010; 76: 400-405Crossref PubMed Scopus (76) Google Scholar]. Therapeutic vaginal re-colonization with hydrogen peroxide producing Lactobacillus crispatus prevents recurrent urinary tract infection in susceptible women and reduces the likelihood of urinary tract infection recurrence, which implicates this mechanism as important for vaginal health [11Stapleton A.E. et al.Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection.Clin. Infect. Dis. 2011; 52: 1212-1217Crossref PubMed Scopus (321) Google Scholar]. In the second section of the paper, we will discuss how pathogens can use original metabolic functions to utilize their niche's resources to overcome competition with resident flora. Pathogens invading animal hosts colonize diverse changing environments. The pH within the human body is mostly neutral (7.4), but can range from 1.0 in the stomach to 8.0 in the urine. Drastically different environments are also observed as pathogens move from mucosal surfaces deeper into host tissues, such as those observed within the lumen, the multilamellar mucus and the epithelial cells of the stomach [12Yoshiyama H. Nakazawa T. Unique mechanism of Helicobacter pylori for colonizing the gastric mucus.Microb. Infect. 2000; 2: 55-60Crossref PubMed Scopus (58) Google Scholar]. Many environments encountered by bacteria after invasion beyond animal mucosal surfaces are well oxygenated, but the oral cavity, large intestine, female genital tract, abscesses, damaged tissues and the airways of cystic fibrosis patients have areas of low oxygen tension. The level of free iron within mammals is variable (with a mean of 10–18 M), but always far below that required for bacterial optimal growth (10–6 M), which demands that bacteria rely on their own strategies for scavenging iron [13Litwin C.M. Calderwood S.B. Role of iron in regulation of virulence genes.Clin. Microbiol. Rev. 1993; 6: 137-149Crossref PubMed Scopus (516) Google Scholar]. An infected site can be subdivided into numerous physiologically specialized environments that bacteria might encounter or colonize [14Eisenreich W. et al.Carbon metabolism of intracellular bacterial pathogens and possible links to virulence.Nat. Rev. Microbiol. 2010; 8: 401-412Crossref PubMed Scopus (277) Google Scholar]. For example, variable conditions are found between the small intestine, caecum and colon within the intestine [15Vogel-Scheel J. et al.Requirement of purine and pyrimidine synthesis for colonization of the mouse intestine by Escherichia coli.Appl. Environ. Microbiol. 2010; 76: 5181-5187Crossref PubMed Scopus (36) Google Scholar]. Pathogens might move through multiple diverse environments throughout their life cycle, which could require regulation, coordination and diverse utilization of multiple bacterial metabolic pathways. Bacteria often use metabolic cues to regulate their metabolism and virulence functions. Metabolic modulations within host tissues can also be used by pathogens to coordinately regulate virulence factor expression [16Somerville G.A. Proctor R.A. At the crossroads of bacterial metabolism and virulence factor synthesis in Staphylococci.Microbiol. Mol. Biol. Rev. 2009; 73: 233-248Crossref PubMed Scopus (281) Google Scholar]. Carbon catabolite repression triggered in response to carbon source availability influences the virulence of various Gram-negative or Gram-positive pathogens [17Poncet S. et al.Correlations between carbon metabolism and virulence in bacteria.Contrib. Microbiol. 2009; 16: 88-102Crossref PubMed Scopus (106) Google Scholar, 18Le Bouguenec C. Schouler C. Sugar metabolism, an additional virulence factor in enterobacteria.Int. J. Med. Microbiol. 2011; 301: 1-6Crossref PubMed Scopus (60) Google Scholar]. Changes in nutrient supplies, including amino acid and fatty acid limitation, can also trigger the activation of virulence factors via the so-called stringent response through (p)ppGpp [19Dalebroux Z.D. et al.ppGpp conjures bacterial virulence.Microbiol. Mol. Biol. Rev. 2010; 74: 171-199Crossref PubMed Scopus (282) Google Scholar]. Nutrient availability is obviously not constant in the host. For example, the amount of iron available to bacteria is even lower during infection after the production of host proteins that interact with iron metabolism. First, iron is sequestered by inflammation-induced lactoferrin [20Schaible U.E. Kaufmann S.H. Iron and microbial infection.Nat. Rev. Microbiol. 2004; 2: 946-953Crossref PubMed Scopus (745) Google Scholar]. Second, lipochelin-2, an antimicrobial protein that captures the bacterial siderophore enterochelin, prevents bacterial iron acquisition. Lipochelin-2 is overproduced in the inflamed intestine in response to enteric pathogens [21Raffatellu M. et al.Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine.Cell Host Microbe. 2009; 5: 476-486Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar]. Many bacterial pathogens sense iron depletion as a signal that they are within a vertebrate host and subsequently modulate the production of virulence factors [22Skaar E.P. The battle for iron between bacterial pathogens and their vertebrate hosts.PLoS Pathog. 2010; 6: e1000949Crossref PubMed Scopus (557) Google Scholar]. The inhibition of diphtheria toxin expression in Corynebacterium diphtheriae and Shiga toxin in Shigella spp. by the iron-activated global repressors DtxR and Fur, respectively, are among the best studied examples [23Love J.F. Murphy J.R. Corynebacterium diphtheriae: iron-mediated activation of DtxR and regulation of diphtheria toxin expression.in: Fischetti V.A. Gram-positive Pathogens. 2nd edn. ASM Press, 2006Google Scholar, 24Payne S.M. et al.Iron and pathogenesis of Shigella: iron acquisition in the intracellular environment.Biometals. 2006; 19: 173-180Crossref PubMed Scopus (53) Google Scholar]. To succeed in a mammal host, bacterial pathogens compete with the resident flora and resist host immune responses. They sense specific environments through variations of nutrient concentrations and subsequently regulate the expression of their virulence factors [16Somerville G.A. Proctor R.A. At the crossroads of bacterial metabolism and virulence factor synthesis in Staphylococci.Microbiol. Mol. Biol. Rev. 2009; 73: 233-248Crossref PubMed Scopus (281) Google Scholar]. In the following section, we illustrate how pathogens utilize metabolic pathways to compete with the resident flora and to cope with harsh environments in the host. From an evolutionary point of view, metabolic genes are then acquired by pathogens in the same way as classical virulence genes. We give examples of metabolic genes linked to pathogenicity and then examine how metabolic constraints can influence the further evolution of pathogens following settlement of a new niche, which could be characteristic of the evolution of virulence (Figure 1). It has been observed time and again that pathogens acquire virulence factors to access new niches [25Schmidt H. Hensel M. Pathogenicity islands in bacterial pathogenesis.Clin. Microbiol. Rev. 2004; 17: 14-56Crossref PubMed Scopus (481) Google Scholar]. To thrive in these new environments, pathogens also require new metabolic pathways that allow them to exploit available food sources (Figure 1 and Table 1). In these cases, genes that are directly or indirectly implicated in metabolic pathways specific to pathogenic bacteria are absent in their less virulent counterparts. Often these 'metabolic' genes are located on genetic elements (e.g. pathogenicity islands), recently acquired in evolution.Table 1Examples of acquisition or loss of metabolic-related genes in pathogenic bacteriaBacterial speciesInfected siteMetabolic or regulation pathway acquired or lostContribution to virulenceRefsGain of function Salmonella enterica subsp. enterica serotype TyphimuriumIntestineCluster ttrABC, ttrRS (on SPI2) for utilization of tetrathionate as an electron acceptorDetoxification, growth27Winter S.E. et al.Gut inflammation provides a respiratory electron acceptor for Salmonella.Nature. 2010; 467: 426-429Crossref PubMed Scopus (864) Google Scholar, 29Price-Carter M. et al.The alternative electron acceptor tetrathionate supports B12-dependent anaerobic growth of Salmonella enterica serovar Typhimurium on ethanolamine or 1,2-propanediol.J. Bacteriol. 2001; 183: 2463-2475Crossref PubMed Scopus (157) Google Scholar Vibrio choleraeIntestineCluster nan–nag (on VPI2) for utilization of sialic acidsGrowth35Almagro-Moreno S. Boyd E.F. Sialic acid catabolism confers a competitive advantage to pathogenic Vibrio cholerae in the mouse intestine.Infect. Immun. 2009; 77: 3807-3816Crossref PubMed Scopus (140) Google Scholar Helicobacter pyloriStomachGene nixA (transferable genomic island) for transport of nickelEnhanced activity of urease, pH neutralization, chemotactism, inflammation and cell damage39Follmer C. Ureases as a target for the treatment of gastric and urinary infections.J. Clin. Pathol. 2010; 63: 424-430Crossref PubMed Scopus (140) Google Scholar, 40Bauerfeind P. et al.Allelic exchange mutagenesis of nixA in Helicobacter pylori results in reduced nickel transport and urease activity.Infect. Immun. 1996; 64: 2877-2880Crossref PubMed Google Scholar, 41Nolan K.J. et al.In vivo behavior of a Helicobacter pylori SS1 nixA mutant with reduced urease activity.Infect. Immun. 2002; 70: 685-691Crossref PubMed Scopus (68) Google Scholar, 42Kusters J.G. et al.Pathogenesis of Helicobacter pylori infection.Clin. Microbiol. Rev. 2006; 19: 449-490Crossref PubMed Scopus (1671) Google Scholar, 44Fischer W. et al.Strain-specific genes of Helicobacter pylori: genome evolution driven by a novel type IV secretion system and genomic island transfer.Nucleic Acids Res. 2010; 38: 6089-6101Crossref PubMed Scopus (154) Google ScholarLoss of function Shigella spp., enteroinvasive Escherichia coliIntestineOperon mhp for propionate degradationReduced production of 2-methylcitrate, a gluconeogenesis blocker52Touchon M. et al.Organised genome dynamics in the Escherichia coli species results in highly diverse adaptive paths.PLoS Genet. 2009; 5: e1000344Crossref PubMed Scopus (827) Google Scholar Pseudomonas aeruginosaCF lungMutation in the quorum sensing major regulator lasRReduced virulence and growth advantage in CF lung59Smith E.E. et al.Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients.Proc. Natl. Acad. Sci. U.S.A. 2006; 103: 8487-8492Crossref PubMed Scopus (1045) Google Scholar, 64D'Argenio D.A. The pathogenic lifestyle of Pseudomonas aeruginosa in model systems of virulence.in: Ramos J.L. Pseudomonas. Kluwer, 2004: 477-503Crossref Google Scholar, 67D'Argenio D.A. et al.Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patients.Mol. Microbiol. 2007; 64: 512-533Crossref PubMed Scopus (266) Google Scholar Open table in a new tab The acquisition of genomic islands encoding virulence factors, termed pathogenicity islands, is often essential for the colonization of new host niches. Pathogenicity islands found in pathogens, but not in their non-pathogenic close relatives, often show evidence of lateral transfer [26Hacker J. Kaper J.B. Pathogenicity islands and the evolution of microbes.Ann. Rev. Microbiol. 2000; 54: 641-679Crossref PubMed Scopus (960) Google Scholar]. They sometimes carry genes encoding specific metabolic pathways [25Schmidt H. Hensel M. Pathogenicity islands in bacterial pathogenesis.Clin. Microbiol. Rev. 2004; 17: 14-56Crossref PubMed Scopus (481) Google Scholar]. Among numerous publications, we took the examples of pathogenic Salmonella, Vibrio and Helicobacter that indicate that these metabolic genes are as important for a successful infection as their classic virulence gene neighbors. A recent study demonstrated that tetrathionate respiration confers a growth advantage for Salmonella enterica subsp. enterica serotype Typhimurium in the lumen of the inflamed human intestine [27Winter S.E. et al.Gut inflammation provides a respiratory electron acceptor for Salmonella.Nature. 2010; 467: 426-429Crossref PubMed Scopus (864) Google Scholar]. As illustrated in Figure 2, colonic bacteria produce large quantities of highly toxic hydrogen sulfide (H2S) and the caecal mucosa protects itself by converting H2S to thiosulfate (S2O32–) [27Winter S.E. et al.Gut inflammation provides a respiratory electron acceptor for Salmonella.Nature. 2010; 467: 426-429Crossref PubMed Scopus (864) Google Scholar]. Intestinal inflammation induced by S. Typhimurium virulence factors (encoded on Salmonella Pathogenicity Islands 1 and 2, SPI1 and SPI2, respectively) results in the production of large amounts of nitric oxide radicals and reactive oxygen species in the lumen of the gut. In these conditions, thiosulfate can be oxidized to tetrathionate (S4O62–), which selectively inhibits coliforms [27Winter S.E. et al.Gut inflammation provides a respiratory electron acceptor for Salmonella.Nature. 2010; 467: 426-429Crossref PubMed Scopus (864) Google Scholar, 28Muller L. Un nouveau milieu d'enrichissement pour la recherche du bacille typhique et paratyphique.C. R. Seances Soc. Biol. Fil. 1923; 89: 434-437Google Scholar]. In contrast to coliforms, Salmonella can use tetrathionate to utilize ethanolamine or 1,2-propanediol as carbon sources for anaerobic growth in the intestinal lumen [29Price-Carter M. et al.The alternative electron acceptor tetrathionate supports B12-dependent anaerobic growth of Salmonella enterica serovar Typhimurium on ethanolamine or 1,2-propanediol.J. Bacteriol. 2001; 183: 2463-2475Crossref PubMed Scopus (157) Google Scholar]. This process gives S. Typhimurium a competitive edge over the gut microbiota, which allows the pathogen to successfully infect the host and ultimately to achieve transmission to new recipients [30Stecher B. et al.Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota.PLoS Biol. 2007; 5: 2177-2189Crossref PubMed Scopus (770) Google Scholar, 31Lawley T.D. et al.Host transmission of Salmonella enterica serovar Typhimurium is controlled by virulence factors and indigenous intestinal microbiota.Infect. Immun. 2008; 76: 403-416Crossref PubMed Scopus (219) Google Scholar]. The five genes responsible for tetrathionate respiration form the ttrABCRS cluster located on SPI2, a pathogenicity island critical for the proliferation of S. Typhimurium [32Hensel M. Salmonella pathogenicity island 2.Mol. Microbiol. 2000; 36: 1015-1023Crossref PubMed Scopus (269) Google Scholar]. These genes encode the structural components of the anaerobic tetrathionate reductase (ttrABC) and a two-component regulatory system (ttrRS) required for the regulation of structural ttr genes (Table 1). Because ttr seems useful only when inflammatory responses are produced as a result of the production of the SPI1 type III secretion system and its use for invasion, the fixation of SPI2 within the S. Typhimurium genome might have been a direct result of the success of strains harboring the ttrABCRS cluster. Here, both 'metabolic' and virulence genes are located on the same pathogenicity island (SPI2) and both contribute to intestinal colonization and invasion. This is an interesting example of the physical and functional linkage between virulence and metabolism. A physical linkage between genes encoding metabolic and virulence functions has also been observed for Vibrio cholerae [33Jermyn W.S. Boyd E.F. Characterization of a novel Vibrio pathogenicity island (VPI-2) encoding neuraminidase (nanH) among toxigenic Vibrio cholerae isolates.Microbiology. 2002; 148: 3681-3693Crossref PubMed Scopus (124) Google Scholar]. The Vibrio pathogenicity island VPI2 is exclusively found in toxigenic strains and encodes a neuraminidase (from the nan–nag cluster) that converts host cell surface polysialogangliosides to GM1 monoganglioside, which specifically binds cholera toxin, by releasing the sialic acid attached to polysialogangliosides (Figure 2). The release of sialic acid from the receptor allows binding of cholera toxin to host intestinal epithelial cells [33Jermyn W.S. Boyd E.F. Characterization of a novel Vibrio pathogenicity island (VPI-2) encoding neuraminidase (nanH) among toxigenic Vibrio cholerae isolates.Microbiology. 2002; 148: 3681-3693Crossref PubMed Scopus (124) Google Scholar, 34Galen J.E. et al.Role of Vibrio cholerae neuraminidase in the function of cholera toxin.Infect. Immun. 1992; 60: 406-415Crossref PubMed Google Scholar]. The neuraminidase could therefore specifically provide an energy source (sialic acid) to VPI2-carrying V. cholerae. Indeed, in addition to a neuraminidase, the VPI2 pathogenicity island harbors a cluster of genes (nan–nag) putatively involved in the scavenging (nanH), transport (dctPQM) and catabolism (nanA, nanE, nanK and nagA) of sialic acids (Figure 2 and Table 1). Inactivation of this catabolic pathway reduced the ability of V. cholerae to colonize infant mice, an important animal model for human cholera [35Almagro-Moreno S. Boyd E.F. Sialic acid catabolism confers a competitive advantage to pathogenic Vibrio cholerae in the mouse intestine.Infect. Immun. 2009; 77: 3807-3816Crossref PubMed Scopus (140) Google Scholar]. Hence the presence of a sialic acid utilization pathway on VPI2 is very important for a successful infection of the human gut by V. cholerae. Interestingly, the nan cluster, which allows bacteria to use sialic acid as a carbon source, is found almost exclusively in genomes from bacterial species intimately associated with mammals, most of them pathogens (e.g. Escherichia coli, Shigella spp., Salmonella enterica, S. aureus and Clostridium spp.). In these species, the nan cluster shows extensive signs of horizontal transfer (i.e. incongruent phylogeny and GC content, association with mobile elements and operon structure diversity) [36Almagro-Moreno S. Boyd E.F. Insights into the evolution of sialic acid catabolism among bacteria.BMC Evol. Biol. 2009; 9: 118Crossref PubMed Scopus (133) Google Scholar]. There are few bacteria in the stomach due to the acidic pH, as low as 2, and these consist of mostly transient bacteria swallowed with food and those dislodged from the mouth [6Davis C.P. Normal flora.in: Baron S. Medical Microbiology. 4th edn. University of Texas Medical Branch at Galveston, 1996Google Scholar]. For bacteria, urea is an available nutrient in the stomach. It is secreted into the gastric juice through capillary networks beneath the gastric epithelial surface [12Yoshiyama H. Nakazawa T. Unique mechanism of Helicobacter pylori for colonizing the gastric mucus.Microb. Infect. 2000; 2: 55-60Crossref PubMed Scopus (58) Google Scholar]. Helicobacter pylori colonizes the stomach and causes gastric lesions such as gastritis, peptic ulcers and gastric cancer [37Brown L.M. Helicobacter pylori: epidemiology and routes of transmission.Epidemiol. Rev. 2000; 22: 283-297Crossref PubMed Scopus (794) Google Scholar, 38Cover T.L. Blaser M.J. Helicobacter pylori in health and disease.Gastroenterology. 2009; 136: 1863-1873Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar]. Urease activity is an essential factor for stomach colonization by H. pylori [12Yoshiyama H. Nakazawa T. Unique mechanism of Helicobacter pylori for colonizing the gastric mucus.Microb. Infect. 2000; 2: 55-60Crossref PubMed Scopus (58) Google Scholar]. H. pylori urease is necessary for the bacteria to survive in the low pH found in vitro, and urease inhibition abolishes H. pylori-related gastric lesions in various animal models [39Follmer C. Ureases as a target for the treatment of gastric and urinary infections.J. Clin. Pathol. 2010; 63: 424-430Crossref PubMed Scopus (140) Google Scholar]. Ammonia generated from urea is a high-quality nitrogen source, neutralizing gastric acidity to give bacteria a neutral microenvironment for their survival and also causing host cell damage and inflammation [39Follmer C. Ureases as a target for the treatment of gastric and urinary infections.J. Clin. Pathol. 2010; 63: 424-430Crossref PubMed Scopus (140) Google Scholar]. Urease activity requires nickel and the high affinity nickel transporter NixA, which contributes to urease activity and full virulence of H. pylori (Table 1) [40Bauerfeind P. et al.Allelic exchange mutagenesis of nixA in Helicobacter pylori results in reduced nickel transport and urease activity.Infect. Immun. 1996; 64: 2877-2880Crossref PubMed Google Scholar, 41Nolan K.J. et al.In vivo behavior of a Helicobacter pylori SS1 nixA mutant with reduced urease activity.Infect. Immun. 2002; 70: 685-691Crossref PubMed Scopus (68) Google Scholar, 42Kusters J.G. et al.Pathogenesis of Helicobacter pylori infection.Clin. Microbiol. Rev. 2006; 19: 449-490Crossref PubMed Scopus (1671) Google Scholar]. Homology search revealed that nixA is solely present in the genomes of gastritis-causing Helicobacter spp. (e.g. H. pylori, H. felis and H. mustelae) but is missing from the genomes of other Helicobacter species that colonize different niches (e.g. H. hepaticus and H. bilis). Although it is possible that nixA was lost in these close relatives, it is more probable that it was acquired by gastritis-causing species subsequent to differentiation between the bacteria that colonize the stomach and those that do not. This is suggested by the fact that the closest homolog to H. pylori nixA is found in genomes of S. aureus, a species which can cause urinary tract infections, in which optimal urease activity is necessary for virulence [43Hiron A. et al.A nickel ABC-transporter of Staphylococcus aureus is involved in urinary tract infection.Mol. Microbiol. 2010; 77: 1246-1260Crossref PubMed Scopus (66) Google Scholar]. In addition, the genomic region encoding NixA has a significantly lower GC content than the rest of the genome, which suggests horizontal transfer [44Fischer W. et al.Strain-specific genes of Helicobacter pylori: genome evolution driven by a novel type IV secretion system and genomic island transfer.Nucleic Acids Res. 2010; 38: 6089-6101Crossref PubMed Scopus (154) Google Scholar]. Hence, nixA acquisition might have been crucial in the metabolic adaptation of H. pylori to stomach colonization. Genetic links between new metabolic capacities and virulence factors illustrate that metabolic pathways are acquired as part of the pathogens' evolution towards colonizing new niches with new food sources. Once settled in these new niches, the genome of the pathogen might further evolve to optimize its metabolism through loss of function (Figure 1 and Table 1). The pathogen life cycle might involve different hosts and host niches with different metabolic nutrient availabilities, which constrains the bacteria to a certain metabolic versatility. This versatility is necessary for a pathogen circulating through different niches in different hosts. For a given pathogen, the metabolic requirement greatly depends on the host infected and the route of i