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High 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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Background and Aims The microbial ecosystem seems to be an important player for therapeutic interception in inflammatory bowel disease (IBD). We assessed longitudinal microbiome changes in IBD patients undergoing therapy with either azathioprine (AZA) or anti-tumor-necrosis-factor (anti-TNF) antibodies. We predicted the metabolic microbial community exchange and linked it to clinical outcome. Methods Fecal and blood samples were collected from 65 IBD patients at baseline and after 12 and 30 weeks on therapy. Clinical remission was defined as i.e. CDAI < 150 in Crohn´s disease (CD), partial Mayo score < 2 in ulcerative colitis (UC) and fecal calprotectin values < 150µg/g and C-reactive protein < 5mg/dl. 16S rRNA amplicon sequencing was performed. To predict microbial community metabolic processes, we constructed multi-species genome-scale metabolic network models. Results Paired Bray-Curtis distance between baseline and follow-up timepoints was significantly different for UC patients treated with anti-TNF antibodies. Longitudinal changes in taxa composition at phylum level showed a significant decrease of Proteobacteria and an increase of Bacteroidetes in CD patients responding to both therapies. At family level, Lactobacilli were associated with persistent disease and Bacteroides abundance with remission in CD. In-silico simulations of microbial metabolite exchange predicted a 1.7-fold higher butyrate production capacity of patients in remission compared to patients without remission (p=0.041). In this model, the difference of butyrate production between patients in remission and patients without remission was most pronounced in the CD group treated with AZA (p=0.008). Conclusions In-silico simulation identifies microbial butyrate synthesis predictive of therapeutic efficacy in IBD.