Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine Original paper

What was studied?

This original research article investigated how Salmonella enterica serotype Typhimurium gains a survival edge in the inflamed gut by resisting the host antimicrobial protein lipocalin-2 (LCN2), a key mediator of “nutritional immunity” that restricts bacterial iron acquisition. The authors focused on the IL-17/IL-22 inflammatory axis, asking whether these cytokines drive epithelial lipocalin-2 production and whether S. Typhimurium possesses specific iron-scavenging mechanisms that bypass lipocalin-2 inhibition. Using polarized human intestinal epithelial cells (T84), they mapped cytokine-induced gene expression responses and confirmed lipocalin-2 secretion into apical and basolateral compartments. They then integrated these in vitro data with an in vivo rhesus macaque ileal loop infection model to determine whether epithelial lipocalin-2 is induced during acute infection and accumulates in the intestinal lumen. Finally, they tested causality in mice using competitive infection experiments comparing lipocalin-2–resistant wild-type S. Typhimurium against mutants lacking the salmochelin system (iroBCDE iroN/iroN), including experiments in lipocalin-2–deficient animals to isolate the specific contribution of this antimicrobial barrier.

Who was studied?

Three complementary host contexts were used. First, polarized human T84 colonic epithelial cells served as an intestinal epithelium model to define IL-17/IL-22-driven antimicrobial programming and quantify lipocalin-2 secretion by ELISA. Second, adult healthy rhesus macaques underwent ligated ileal loop surgery, with loops inoculated with S. Typhimurium or mock medium and sampled within hours to localize and quantify LCN2 transcription (in situ hybridization and qPCR) and luminal lipocalin-2 accumulation (ELISA). Third, streptomycin-pretreated mice were infected to induce acute cecal inflammation, enabling in vivo competition assays that compared colonization of lipocalin-2–resistant versus lipocalin-2–sensitive S. Typhimurium strains in wild-type versus lipocalin-2–deficient (Lcn2−/−) backgrounds. Together, these models allowed mechanistic linkage from cytokine signaling to epithelial antimicrobial output and pathogen fitness within the inflamed intestinal niche.

Most important findings

The central microbiome-relevant insight is that inflammation does not simply suppress pathogens—rather, it reshapes luminal nutrient and antimicrobial landscapes in ways that can selectively favor organisms equipped to exploit them. IL-22 induced robust epithelial antimicrobial gene programs, and IL-17 synergized with IL-22 to markedly increase LCN2 transcription and protein secretion from T84 epithelia, yielding luminal concentrations sufficient to suppress growth of lipocalin-2–sensitive S. Typhimurium mutants. Mechanistically, lipocalin-2 blocks enterochelin (enterobactin)-mediated iron acquisition, but S. Typhimurium evades this through the iroBCDE iroN locus that produces and imports salmochelin, a glycosylated siderophore not bound by lipocalin-2. In rhesus macaques, LCN2 expression localized strongly to intestinal epithelial cells during infection and lipocalin-2 accumulated in loop luminal fluid, establishing that this antimicrobial barrier is present in vivo. In mice, an iroN mutant (lipocalin-2 sensitive) showed reduced competitive fitness specifically during inflammation; critically, this disadvantage disappeared in Lcn2−/− mice or when inflammation was not elicited (T3SS-deficient strains), demonstrating that lipocalin-2 is the selective pressure driving this pathogen advantage. Clinically and microbiome-wise, the work positions epithelial lipocalin-2 as an inflammation-linked ecological filter that can suppress enterochelin-dependent Enterobacteriaceae (e.g., some E. coli) while enriching for lipocalin-2–resistant pathobionts like Salmonella.

Key implications

This study clarifies a concrete mechanism by which intestinal inflammation can generate a microbiome “signature” that is both host-driven and pathogen-exploitable: IL-17/IL-22 induce epithelial lipocalin-2, which restricts iron by neutralizing enterochelin, thereby suppressing lipocalin-2–susceptible bacteria and selecting for organisms with salmochelin-based iron acquisition. For clinicians, it reframes lipocalin-2 not only as an inflammatory biomarker (already relevant in IBD contexts) but also as an active ecological determinant that can unintentionally promote expansion of specific Enterobacteriaceae with lipocalin-2 resistance traits. For microbiome signature databases, the most actionable mapping is: “intestinal inflammation → high luminal lipocalin-2 → enrichment of lipocalin-2–resistant siderophore systems (iroA/salmochelin pathway) in Enterobacteriaceae,” a pattern that may help interpret dysbiosis states where pathogen blooms occur despite strong innate immune activation.

Citation

Raffatellu M, George MD, Akiyama Y, 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(5):476-486. doi:10.1016/j.chom.2009.03.011