Lipocalin 2 Protects from Inflammation and Tumorigenesis Associated with Gut Microbiota Alterations

• Antimicrobial peptide Lipocalin-2 (Lcn2) is strongly induced in Il10–/– colitic mice
• Lcn2 deficiency exacerbates Il10–/– colitis and causes spontaneous right-sided tumors
• Inflammation and tumorigenesis are due to altered gut microbiota and are transmissible
• Alistipes spp. is sufficient to induce colitis and site-specific tumors in Il10–/– mice

SummaryHigh mucosal and fecal concentrations of the antimicrobial siderophore-binding peptide Lipocalin-2 (Lcn2) are observed in inflammatory bowel disease. However, Lcn2 function in chronic intestinal inflammation remains unclear. Here, we demonstrate that Lcn2 protects from early-onset colitis and spontaneous emergence of right-sided colonic tumors resulting from IL-10 deficiency. Exacerbated inflammation in Lcn2–/–/Il10–/– mice is driven by IL-6, which also controls tumorigenesis. Lcn2–/–/Il10–/– mice exhibit profound alterations in gut microbial composition, which contributes to inflammation and tumorigenesis, as demonstrated by the transmissibility of the phenotype and protection conferred by antibiotics. Specifically, facultative pathogenic Alistipes spp. utilize enterobactin as iron source, bloom in Lcn2–/–/Il10–/– mice, and are sufficient to induce colitis and right-sided tumors when transferred into Il10–/– mice. Our results demonstrate that Lcn2 protects against intestinal inflammation and tumorigenesis associated with alterations in the microbiota.

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