Experimental evidence from the past years highlights a key role for the intestinal microbiota in inflammatory and malignant gastrointestinal diseases. Diet exhibits a strong impact on microbial composition and provides risk for developing colorectal carcinoma (CRC). Large metagenomic studies in human CRC associated microbiome signatures with the colorectal adenoma-carcinoma sequence, suggesting a fundamental role of the intestinal microbiota in the evolution of gastrointestinal malignancy. Basic science established a critical function for the intestinal microbiota in promoting tumorigenesis. Further studies are needed to decipher the mechanisms of tumor promotion and microbial co-evolution in CRC, which may be exploited therapeutically in the future.

Ethanol exposure diminishes intestinal abundance in both mice and humans and can be recovered in experimental ALD by oral supplementation. promotes intestinal barrier integrity and ameliorates experimental ALD. Our data suggest that patients with ALD might benefit from supplementation.

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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.

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western lifestyle. Westernization of dietary habits is partly characterized by enrichment with the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid (AA), which entails risk for developing IBD. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation (LPO) and cell death termed ferroptosis. We report that small intestinal epithelial cells (IECs) in Crohn's disease (CD) exhibit impaired GPX4 activity and signs of LPO. PUFAs and specifically AA trigger a cytokine response of IECs which is restricted by GPX4. While GPX4 does not control AA metabolism, cytokine production is governed by similar mechanisms as ferroptosis. A PUFA-enriched Western diet triggers focal granuloma-like neutrophilic enteritis in mice that lack one allele of Gpx4 in IECs. Our study identifies dietary PUFAs as a trigger of GPX4-restricted mucosal inflammation phenocopying aspects of human CD.

Whereas prototypic adipocytokines such as adiponectin or leptin are mainly derived from adipocytes, others such as pre-B cell colony enhancing factor (PBEF)/nicotinamide phosphoribosyl transferase (NAMPT)/visfatin or resistin are produced by various cell types throughout the body. Although first discovery of this molecule as PBEF suggested primarily a cytokine function, its rediscovery as the key enzyme in nicotinamide adenine dinucleotide (NAD) generation has considerably widened its biological perspective. Finally, the same molecule was introduced as visfatin claiming an insulin-mimetic effect which has been questioned. Both extracellular (cytokinelike) and intracellular (enzymatic) functions are responsible for its relevance in immune, metabolic and stress responses. Its cytokine functions are mainly pro-inflammatory as it induces potently various other pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFa) or interleukin-6 (IL-6). Its intracellular functions concentrate on the regulation of the activity of NAD-consuming enzymes such as various sirtuins thereby also affecting (TNFa) biosynthesis, cell life-span and longevity. Biochemical neutralization of PBEF/NAMPT/visfatin has been proven effective in various models of inflammation including sepsis/arthritis and in various models of cancer. Patients with non-alcoholic fatty liver disease (NAFLD) exhibit increased serum concentrations of PBEF/Nampt/visfatin and weight loss is associated both with a decrease in serum levels and reduced liver expression. Many of the biological functions of this "cytokine-enzyme" have been characterized in the last years, however, its definite role in various metabolic, inflammatory and malignant diseases has yet to be defined.

ObjectiveNicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism.DesignWe investigated the impact of NAMPT inhibition by the small-molecule inhibitor FK866 in the dextran sulfate sodium (DSS) model of colitis and the azoxymethane/DSS model of colitis-associated cancer. The impact of NAD depletion on differentiation of mouse and human primary monocytes/macrophages was studied in vitro. Finally, we tested the efficacy of FK866 compared with dexamethasone and infliximab in lamina propria mononuclear cells (LPMNC) isolated from patients with IBD.ResultsFK866 ameliorated DSS-induced colitis and suppressed inflammation-associated tumorigenesis in mice. FK866 potently inhibited NAMPT activity as demonstrated by reduced mucosal NAD, resulting in reduced abundances and activities of NAD-dependent enzymes including PARP1, Sirt6 and CD38, reduced nuclear factor kappa B activation, and decreased cellular infiltration by inflammatory monocytes, macrophages and activated T cells. Remarkably, FK866 effectively supressed cytokine release from LPMNCs of patients with IBD. As FK866 was also effective in Rag1−⁄− mice, we mechanistically linked FK866 treatment with altered monocyte/macrophage biology and skewed macrophage polarisation by reducing CD86, CD38, MHC-II and interleukin (IL)-6 and promoting CD206, Egr2 and IL-10.ConclusionOur data emphasise the importance of NAD immunometabolism for mucosal immunity and highlight FK866-mediated NAMPT blockade as a promising therapeutic approach in acute intestinal inflammation.

Ulcerative colitis (UC) is driven by disruptions in host-microbiota homeostasis, however current treatments exclusively target host inflammatory pathways. To understand how host-microbiota interactions become disrupted in UC, we collected and analyzed six fecal or serum based –omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic, and amplicon sequencing profiles of fecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic, and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn’s disease (CD), 20 healthy controls) was collected and analyzed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an over-abundance of proteases that originated from the bacterium, Bacteroides vulgatus . To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus -induced barrier dysfunction in vitro , and prevented colitis in B. vulgatus monocolonized, IL-10 deficient mice. Furthermore, transplantation of feces from UC patients with a high abundance of B. vulgatus proteases into germ-free mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provides a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.