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The diet and gut microbiota have been extensively interrogated as a fuel for gut inflammation in inflammatory bowel diseases (IBDs) in the last few years. Here, we review how specific nutrients, typically enriched in a Western diet, instigate or deteriorate experimental gut inflammation in a genetically susceptible host and we discuss microbiota-dependent and independent mechanisms. We depict the study landscape of nutritional trials in paediatric and adult IBD and delineate common grounds for dietary advice. Conclusively, the diet reflects a critical rheostat of microbial dysbiosis and gut inflammation in IBD. Dietary restriction by exclusive enteral nutrition, with or without a specific exclusion diet, is effectively treating paediatric Crohn’s disease, while adult IBD trials are less conclusive. Insights into molecular mechanisms of nutritional therapy will change the perception of IBD and will allow us to enter the era of precision nutrition. To achieve this, we discuss the need for carefully designed nutritional trials with scientific rigour comparable to medical trials, which also requires action from stake holders. Establishing evidence-based dietary therapy for IBD does not only hold promise to avoid long-term immunosuppression, but to provide a widely accessible therapy at low cost. Identification of dietary culprits disturbing gut health also bears the potential to prevent IBD and allows informed decision making in food politics.

Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease. Emerging evidence indicates that these disorders are characterized by alterations in the intestinal microbiota composition and its metabolites, which translocate from the gut across a disrupted intestinal barrier to affect various metabolic organs, such as the liver and adipose tissue, thereby contributing to metabolic inflammation. Here, we discuss some of the recently identified mechanisms that showcase the role of the intestinal microbiota and barrier dysfunction in metabolic inflammation. We propose a concept by which the gut microbiota fuels metabolic inflammation and dysregulation.

The incidence of inflammatory bowel diseases (IBD) emerged with Westernisation of dietary habits worldwide. Crohn’s disease and ulcerative colitis are chronic debilitating conditions that afflict individuals with substantial morbidity and challenge healthcare systems across the globe. Since identification and characterisation of calprotectin (CP) in the 1980s, faecal CP emerged as significantly validated, non-invasive biomarker that allows evaluation of gut inflammation. Faecal CP discriminates between inflammatory and non-inflammatory diseases of the gut and portraits the disease course of human IBD. Recent studies revealed insights into biological functions of the CP subunits S100A8 and S100A9 during orchestration of an inflammatory response at mucosal surfaces across organ systems. In this review, we summarise longitudinal evidence for the evolution of CP from biomarker to rheostat of mucosal inflammation and suggest an algorithm for the interpretation of faecal CP in daily clinical practice. We propose that mechanistic insights into the biological function of CP in the gut and beyond may facilitate interpretation of current assays and guide patient-tailored medical therapy in IBD, a concept warranting controlled clinical trials.

Crohn’s disease and ulcerative colitis, phenotypically comprising a spectrum of inflammatory bowel diseases (IBDs), spread globally during the westernization of lifestyle and dietary habits over the past few decades. Here, we review experimental and clinical evidence for the metabolic nature of gut inflammation in IBD and delineate distinct parallels to the inflammatory state in metabolic diseases. Experimental evidence indicates that excessive intake of specific macronutrients in a Western diet fuels an inflammatory response in the gut by exploiting sensors of innate immunity and perturbation of gut microbial metabolism. Genetic IBD risk partly affects metabolism and stress signalling of innate immunity, and immunometabolism controls susceptibility to gut inflammation. Epidemiological and clinical studies indicate that specific nutrients in the Western diet pose a risk for the development of IBD and a poor disease course. Translational studies in IBD indicate perturbation of energy metabolism in immune cells and perturbation of gut microbial metabolism, which can be shaped by diet. In turn, dietary restriction by exclusive enteral nutrition induces remission in patients with IBD. Collectively, these studies support a metabolic underpinning of gut inflammation in IBD as described for metabolic inflammation in obesity and related disorders.Experimental and clinical evidence supports a role of metabolic perturbation in the development of gut inflammation in inflammatory bowel disease (IBD). This Review discusses the role of diet and metabolic inflammation in IBD, outlining key concepts and highlighting the links between metabolism and inflammation in IBD.

Non-alcoholic fatty liver disease (NAFLD) has emerged pandemically across the globe and particularly affects patients with obesity and type 2 diabetes. NAFLD is a complex systemic disease that is characterised by hepatic lipid accumulation, lipotoxicity, insulin resistance, gut dysbiosis and inflammation. In this review, we discuss how metabolic dysregulation, the gut microbiome, innate and adaptive immunity and their interplay contribute to NAFLD pathology. Lipotoxicity has been shown to instigate liver injury, inflammation and insulin resistance. Synchronous metabolic dysfunction, obesity and related nutritional perturbation may alter the gut microbiome, in turn fuelling hepatic and systemic inflammation by direct activation of innate and adaptive immune responses. We review evidence suggesting that, collectively, these unresolved exogenous and endogenous cues drive liver injury, culminating in liver fibrosis and advanced sequelae of this disorder such as liver cirrhosis and hepatocellular carcinoma. Understanding NAFLD as a complex interplay between metabolism, gut microbiota and the immune response will challenge the clinical perception of NAFLD and open new therapeutic avenues. Tilg et al. explore how metabolic dysfunction, altered gut microbiome and dysregulated innate and adaptive immunity contribute to NAFLD and how the interplay between these factors mediates disease progression.

The increased incidence of inflammatory bowel disease (IBD) has become a global phenomenon that could be related to adoption of a Western life-style. 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. Dietary lipids are linked to the development of inflammatory bowel diseases through unclear mechanisms. Here, the authors report that dietary polyunsaturated fatty acids trigger intestinal inflammation resembling aspects of Crohn’s disease, which is restricted by glutathione peroxidase 4 in the intestinal epithelium.

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.

‘Westernization’, which incorporates industrial, cultural and dietary trends, has paralleled the rise of noncommunicable diseases across the globe. Today, the Western-style diet emerges as a key stimulus for gut microbial vulnerability, chronic inflammation and chronic diseases, affecting mainly the cardiovascular system, systemic metabolism and the gut. Here we review the diet of modern times and evaluate the threat it poses for human health by summarizing recent epidemiological, translational and clinical studies. We discuss the links between diet and disease in the context of obesity and type 2 diabetes, cardiovascular diseases, gut and liver diseases and solid malignancies. We collectively interpret the evidence and its limitations and discuss future challenges and strategies to overcome these. We argue that healthcare professionals and societies must react today to the detrimental effects of the Western diet to bring about sustainable change and improved outcomes in the future. This Review outlines how Western-style diets contribute to the rising incidence of chronic, noncommunicable diseases by converging on key mechanisms, including gut microbial rarefaction and chronic inflammation.

Adipose tissue is an immunologically active organ that controls host physiology, partly through the release of mediators termed adipokines. In obesity, adipocytes and infiltrating leukocytes produce adipokines, which include the hormones adiponectin and leptin and cytokines such as tumour necrosis factor and IL-1β. These adipokines orchestrate immune responses that are collectively referred to as metabolic inflammation. Consequently, metabolic inflammation characterizes metabolic disorders and promotes distinct disease aspects, such as insulin resistance, metabolic dysfunction-associated liver disease and cardiovascular complications. In this unifying concept, adipokines participate in the immunological cross-talk that occurs between metabolically active organs in metabolic diseases, highlighting the fundamental role of adipokines in obesity and their potential for therapeutic intervention. Here, we summarize how adipokines shape metabolic inflammation in mice and humans, focusing on their contribution to metabolic disorders in the setting of obesity and discussing their value as therapeutic targets. This Review discusses how adipose tissue can regulate host immune function via the release of adipokines, including adiponectin, leptin and various cytokines. These adipokines contribute to immune responses and metabolic inflammation and can have both beneficial and detrimental effects on host physiology. In obesity, adipokine release can promote insulin resistance and cardiovascular diseases; as such, there is interest in targeting these mediators for therapy of various metabolic disorders.

ObjectivesMetabolic inflammation is a hallmark of obesity and related disorders, afflicting substantial morbidity and mortality to individuals worldwide. White visceral and subcutaneous adipose tissue not only serves as energy storage but also controls metabolism. Adipose tissue inflammation, commonly observed in human obesity, is considered a critical driver of metabolic perturbation while molecular hubs are poorly explored. Metabolic stress evoked by e.g. long-chain fatty acids leads to oxidative perturbation of adipocytes and production of inflammatory cytokines, fuelling macrophage infiltration and systemic low-grade inflammation. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation, accumulation of oxygen-specific epitopes and cell death, collectively referred to as ferroptosis. Here, we explore the function of adipocyte GPX4 in mammalian metabolism.MethodsWe studied the regulation and function of GPX4 in differentiated mouse adipocytes derived from 3T3-L1 fibroblasts. We generated two conditional adipocyte-specific Gpx4 knockout mice by crossing Gpx4fl/fl mice with Adipoq-Cre+ (Gpx4−/−AT) or Fabp4-Cre+ (Gpx4+/−Fabp4) mice. Both models were metabolically characterized by a glucose tolerance test and insulin resistance test, and adipose tissue lipid peroxidation, inflammation and cell death were assessed by quantifying oxygen-specific epitopes, transcriptional analysis of chemokines, quantification of F4/80+ macrophages and TUNEL labelling.ResultsGPX4 expression was induced during and required for adipocyte differentiation. In mature adipocytes, impaired GPX4 activity spontaneously evoked lipid peroxidation and expression of inflammatory cytokines such as TNF-α, interleukin 1β (IL-1β), IL-6 and the IL-8 homologue CXCL1. Gpx4−/−AT mice spontaneously displayed adipocyte hypertrophy on a chow diet, which was paralleled by the accumulation of oxygen-specific epitopes and macrophage infiltration in adipose tissue. Furthermore, Gpx4−/−AT mice spontaneously developed glucose intolerance, hepatic insulin resistance and systemic low-grade inflammation, when compared to wildtype littermates, which was similarly recapitulated in Gpx4+/−Fabp4 mice. Gpx4−/−AT mice exhibited no signs of adipocyte death.ConclusionAdipocyte GPX4 protects against spontaneous metabolic dysregulation and systemic low-grade inflammation independent from ferroptosis, which could be therapeutically exploited in the future.