J Clin Immunol (2010) 30:196–203 the mucosal response is thus effective in keeping pathogens confined to the gut mucosa, it has the unfortunate side effect of promoting pathogen overgrowth in the intestinal lumen. The mechanisms by which the inflammatory response promotes pathogen growth are not completely understood. One hypothesis is that pathogens thrive in the inflamed gut because they have adapted to access nutrients during inflammation to a higher degree than the resident microbiota. One potential nutrient source during intestinal inflammation may be represented by mucins, which are upregulated by IL- 17 and IL-22 stimulation of intestinal epithelial cells [49]. The ability of S. typhimurium to swim in the direction of nutrients increases the fitness of the organism in the inflamed intestine, but not in the normal gut [71]. Induction of the mucin MUC1 was observed in the distal colon of patients infected with Salmonella saintpaul and Campylobacter jejuni [72], suggesting that pathogen colonization of the mucus layer may be relevant for the pathogenesis of inflammatory diarrhea in humans. Fitting in with this idea, it was recently demonstrated that mucin can be degraded by a serine protease autotransporter (the Pic mucinase) expressed by enteroaggregative E. coli (EAEC) and Shigella flexneri [73, 74]. In a mouse model of infection, the Pic mucinase enhances EAEC colonization and growth in the presence of mucins, thereby enhancing fitness of this pathogen [74]. While the acquisition of carbon, nitrogen, and oxygen atoms are essential for the growth of any organism, so too is the acquisition metal ions. One host strategy to fight infections is to reduce the accessibility of metal ions. The most studied metal ion with regards to bacterial infection is iron, an essential micronutrient. Under normal conditions, iron is largely bound to serum transferrin. In the inflamed gut, lactoferrin secreted by neutrophils functions as another iron-binding molecule, exhibiting greater iron affinity at low Ph than transferrin [75]. To overcome these host defense mechanisms, bacteria secrete iron chelators known as siderophores which have a higher affinity for iron than either transferrin or lactoferrin [76, 77]. Once bound to iron, siderophores are internalized by specialized bacterial transport systems, thereby providing an iron source during iron starvation. The siderophore enterochelin (produced by most mem- bers of Enterobacteriaceae), is a target of the host antimicrobial protein lipocalin-2 [78]. Lipocalin-2 binds to iron-laden enterochelin and prevents its uptake by bacteria, thereby inhibiting growth of susceptible strains [78, 79]. Both in vitro and in vivo, lipocalin-2 expression and secretion is dependent on stimulation of epithelial cells with IL-17 and IL-22 [49, 58]. Thus, lipocalin-2 expression is increased in mucosal surfaces, including the gut, during the course of mucosal infections. As an adaptation to this host defense, pathogens such as S. typhimurium, pathogenic E. coli, and some strains of K. pneumoniae have developed 199 resistance to lipocalin-2 by encoding for at least one additional siderophore, termed salmochelin [80–83]. Sal- mochelin is a glycosylated form of enterochelin that is not bound by lipocalin-2, thus its expression restores the ability of bacterial pathogens to acquire iron [49, 84–86]. Iron acquisition through salmochelin promotes S. typhimu- rium colonization of the inflamed gut, but not of the normal gut or in the absence of lipocalin-2 [49]. Thus, the capacity to acquire iron during intestinal inflammation is an important virulence trait for survival in the inflamed gut. Other mucosal pathogens have additional siderophores (yersiniabactin, aerobactin) which also provide an advantage for colonization of mucosal surfaces, although their role in iron acquisition in the inflamed gut remains to be determined [87–89]. Lipocalin-2 is also induced by pathogens at other mucosal surfaces including Streptococcus pneumoniae and Haemo- philus influenzae in the nasal mucosa, Helicobacter pylori in the stomach, and C. albicans in the oral cavity [90–92]. These pathogens are not susceptible to lipocalin-2 mediated iron withholding because they do not acquire iron through enterochelin. Although its role in these infection models has yet to be established, it is plausible that lipocalin-2 Fig. 1 Th17 cytokines and the gut mucosal barrier. Dendritic cells activated by pathogens secrete several cytokines including IL-22 and IL-23. IL-23 stimulates several subsets of T cells (Th17 cells, γδ T cells, NK, and NK-T cells) to secrete IL-17 and IL-22. T cells promote amplification of the host response by stimulating the intestinal epithelium to secrete CXC chemokines (neutrophil chemoattractants) and antimicrobial peptides (lipocalin-2, calprotectin, Reg3γ, and β- defensins). While the Th17 response prevents bacterial dissemination from the gut, it also promotes colonization of the mucosa by pathogens that are resistant to some of the induced antimicrobial responses. The ability to acquire nutrients and associate with the expanded mucous layer during inflammation promotes colonization of pathogenic microbes