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The current coronavirus pandemic is an ongoing global health crisis due to COVID-19, caused by severe acute respiratory syndrome coronavirus 2. Although COVID-19 leads to little or mild flu-like symptoms in the majority of affected patients, the disease may cause severe, frequently lethal complications such as progressive pneumonia, acute respiratory distress syndrome and organ failure driven by hyperinflammation and a cytokine storm syndrome. This situation causes various major challenges for gastroenterology. In the context of IBD, several key questions arise. For instance, it is an important question to understand whether patients with IBD (eg, due to intestinal ACE2 expression) might be particularly susceptible to COVID-19 and the cytokine release syndrome associated with lung injury and fatal outcomes. Another highly relevant question is how to deal with immunosuppression and immunomodulation during the current pandemic in patients with IBD and whether immunosuppression affects the progress of COVID-19. Here, the current understanding of the pathophysiology of COVID-19 is reviewed with special reference to immune cell activation. Moreover, the potential implications of these new insights for immunomodulation and biological therapy in IBD are discussed.

Inflammation and its resolution is under-studied in medicine despite being essential for understanding the development of chronic inflammatory disease. In this review article, we discuss the resolution of inflammation in both a biological and translational context. We introduce the concept of impaired resolution leading to diseases like rheumatoid arthritis, Crohn's disease, and asthma, as well as the cellular and molecular components that contribute to resolution of joint, gut, and lung inflammation, respectively. Finally, we discuss potential intervention strategies for fostering the resolution process, and their implications for the therapy of inflammatory diseases. Inflammation is a component of many chronic inflammatory diseases and yet it is understudied in medicine. Here, the authors review novel insights in to inflammation and how impairment of its resolution can lead to diseases.

Key studies published in 2019 highlight novel concepts regarding the pathogenesis of inflammatory bowel disease: the emerging role of host–microorganism interactions and the regional microbiota as disease drivers, and the identification of new therapeutic targets. These findings suggest new avenues for research and define important hallmarks for clinical diagnosis and therapy.Key advancesSpecific microbial pathways control intestinal epithelial cell and barrier function and determine responsiveness to anti-TNF therapy, suggesting that targeting of these pathways is relevant for inflammatory bowel disease (IBD) therapy3; increased Bifidobacterium, Collinsella, Lachnospira, Lachnospiraceae, Roseburia and Eggerthella taxa are related to successful outcome (clinical response or remission) of anti-TNF therapy in Crohn’s disease.Many defined microbial metabolites are depleted in individuals with IBD versus control individuals, indicating that loss of metabolic diversity occurs with dysbiosis and loss of taxonomic diversity in the IBD microbiome4.The transcription factor c-MAF is a key factor in gut regulatory T cells that maintains host–microorganism homeostasis and prevents gut inflammation5.

Crohn’s disease (CD) is a chronic relapsing disorder of the gastrointestinal tract and represents one of the main entities of inflammatory bowel disease (IBD). CD affects genetically susceptible patients that are influenced by environmental factors and the intestinal microbiome, which results in excessive activation of the mucosal immune system and aberrant cytokine responses. Various studies have implicated the pro-inflammatory cytokines IL17 and IL23 in the pathogenesis of CD. IL23 is a member of the IL12 family of cytokines and is able to enhance and affect the expansion of pathogenic T helper type 17 (Th17) cells through various mechanisms, including maintenance of Th17 signature genes, upregulation of effector genes or suppression of repressive factors. Moreover, IL17 and IL23 signaling is able to induce a cascade of pro-inflammatory molecules like TNF, IFNγ, IL22, lymphotoxin, IL1β and lipopolysaccharide (LPS). Here, IL17A and TNF are known to mediate signaling synergistically to drive expression of inflammatory genes. Recent advances in understanding the immunopathogenetic mechanisms underlying CD have led to the development of new biological therapies that selectively intervene and inhibit inflammatory processes caused by pro-inflammatory mediators like IL17 and IL23. Recently published data demonstrate that treatment with selective IL23 inhibitors lead to markedly high response rates in the cohort of CD patients that failed previous anti-TNF therapy. Macrophages are considered as a main source of IL23 in the intestine and are supposed to play a key role in the molecular crosstalk with T cell subsets and innate lymphoid cells in the gut. The following review focuses on mechanisms, pathways and specific therapies in Crohn’s disease underlying the IL23/IL17 pathway.

We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut–brain axis or gut–liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.

Cytokines produced by immune cells contribute to the development and perpetuation of inflammatory bowel disease (IBD), namely Crohn’s disease and ulcerative colitis, by regulating various aspects of the inflammatory response. Pro-inflammatory cytokines trigger chronic intestinal inflammation, tissue damage, carcinogenesis and perpetuation of disease and suppress the resolution of inflammation in IBD. The clinical success of antibodies that neutralize tumour necrosis factor (TNF) and the cytokine IL-12p40 in individuals with IBD has underscored this concept. Moreover, genetic and preclinical studies have emphasized the crucial role of IL-23 in IBD, leading to clinical approval of antibodies targeting this cytokine. Multiple studies have also investigated the administration of cytokines with assumed anti-inflammatory effects, but this approach has yet to show any real clinical benefit in individuals with IBD. Recent studies have targeted the cytokine network through the use of multi-cytokine blockers (for example, Janus kinase (JAK) inhibitors), IL-2-induced regulatory T cells or advanced combination therapies that use multiple cytokine blockers simultaneously (for example, anti-TNF along with anti-IL-23 antibodies). This Review will focus on our current understanding of how cytokines produced by innate and adaptive immune cells contribute to IBD pathogenesis and discuss how their modulation may inform future treatments for IBD.This Review explains how cytokines contribute to the pathogenesis of inflammatory bowel disease (IBD). The author highlights the cytokine-targeting drugs that are already being successfully used in the clinic and discusses the potential of other cytokine-modulating drugs in IBD.

Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis are characterized by uncontrolled activation of intestinal immune cells in a genetically susceptible host. Due to the progressive and destructive nature of the inflammatory process in IBD, complications such as fibrosis, stenosis or cancer are frequently observed, which highlights the need for effective anti-inflammatory therapy. Studies have identified altered trafficking of immune cells and pathogenic immune cell circuits as crucial drivers of mucosal inflammation and tissue destruction in IBD. A defective gut barrier and microbial dysbiosis induce such accumulation and local activation of immune cells, which results in a pro-inflammatory cytokine loop that overrides anti-inflammatory signals and causes chronic intestinal inflammation. This Review discusses pathogenic cytokine responses of immune cells as well as immune cell trafficking as a rational basis for new translational therapies in IBD. Underlying inflammatory bowel disease is a complex web of activated immune cells. In this Review, Neurath delineates the cells, pathways and signals that contribute to the pathology of inflammatory bowel disease and the potential for therapeutic intervention.

ObjectiveTo investigate the humoral and cellular immune response to messenger RNA (mRNA) COVID-19 vaccines in patients with immune-mediated inflammatory diseases (IMIDs) on immunomodulatory treatment.MethodsEstablished patients at New York University Langone Health with IMID (n=51) receiving the BNT162b2 mRNA vaccination were assessed at baseline and after second immunisation. Healthy subjects served as controls (n=26). IgG antibody responses to the spike protein were analysed for humoral response. Cellular immune response to SARS-CoV-2 was further analysed using high-parameter spectral flow cytometry. A second independent, validation cohort of controls (n=182) and patients with IMID (n=31) from Erlangen, Germany, were also analysed for humoral immune response.ResultsAlthough healthy subjects (n=208) and patients with IMID on biologic treatments (mostly on tumour necrosis factor blockers, n=37) demonstrate robust antibody responses (over 90%), those patients with IMID on background methotrexate (n=45) achieve an adequate response in only 62.2% of cases. Similarly, patients with IMID on methotrexate do not demonstrate an increase in CD8+ T-cell activation after vaccination.ConclusionsIn two independent cohorts of patients with IMID, methotrexate, a widely used immunomodulator for the treatment of several IMIDs, adversely affected humoral and cellular immune response to COVID-19 mRNA vaccines. Although precise cut-offs for immunogenicity that correlate with vaccine efficacy are yet to be established, our findings suggest that different strategies may need to be explored in patients with IMID taking methotrexate to increase the chances of immunisation efficacy against SARS-CoV-2 as has been demonstrated for augmenting immunogenicity to other viral vaccines.

Key Points Genome-wide association studies have identified several inflammatory bowel disease (IBD) susceptibility loci that contain genes that encode cytokines and proteins involved in cytokine signalling. In particular, recent work has found that loss-of-function mutations in the genes encoding interleukin-10 (IL-10) and the IL-10 receptor are associated with very early-onset IBD. Cytokines not only drive intestinal inflammation and diarrhoea in IBD but may also regulate extra-intestinal disease manifestations (for example, arthralgia or arthritis) and systemic effects. Furthermore, cytokines seem to have a crucial role in driving complications of IBD such as intestinal stenosis, fistula formation and colitis-associated neoplasias. Studies using tissue from patients with IBD and animal models of IBD have identified cytokines as potential new targets for the therapy of intestinal inflammation. Relevant targets include pro-inflammatory cytokines, such as IL-6, IL-12, IL-23 and IL-21, as well as anti-inflammatory cytokines, such as IL-10 and transforming growth factor-β. Anti-cytokine therapies involving tumour necrosis factor (TNF)-specific agents form an important cornerstone of clinical therapy in both Crohn's disease and ulcerative colitis. TNF-specific antibodies suppress chronic intestinal inflammation and may induce mucosal healing in IBD. Several new anti-cytokine agents have shown little or no efficacy in IBD, suggesting the existence of a highly regulated cytokine network. New approaches for anti-cytokine therapies may include multi-cytokine blockers, such as tofacitinib. New cytokine targets, optimized delivery systems for anti-cytokine agents and personalized medicine may pave the way towards more effective clinical approaches by targeting the expression or function of pro-inflammatory and anti-inflammatory cytokines in patients with IBD. This Review covers the cellular sources and immune functions of the various cytokines that have been associated with inflammatory bowel disease (IBD). The author details how the dysregulated production of pro-inflammatory and anti-inflammatory cytokines can drive IBD pathology, and discusses the feasibility of targeting different cytokines for the future therapy of IBD. Cytokines have a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, where they control multiple aspects of the inflammatory response. In particular, the imbalance between pro-inflammatory and anti-inflammatory cytokines that occurs in IBD impedes the resolution of inflammation and instead leads to disease perpetuation and tissue destruction. Recent studies suggest the existence of a network of regulatory cytokines that has important implications for disease progression. In this Review, we discuss the role of cytokines produced by innate and adaptive immune cells, as well as their relevance to the future therapy of IBD.

Interleukin-12 (IL-12) and interleukin-23 (IL-23), which belong to the IL-12 family of cytokines, have a key role in intestinal homeostasis and inflammation and are implicated in the pathogenesis of inflammatory bowel disease. Upon their secretion by antigen-presenting cells, they exert both pro-inflammatory and anti-inflammatory receptor-mediated effects. An increased understanding of these biological effects, particularly the pro-inflammatory effects mediated by IL-12 and IL-23, has led to the development of monoclonal antibodies that target a subunit common to IL-12 and IL-23 (p40; targeted by ustekinumab and briakinumab), or the IL-23-specific subunit (p19; targeted by risankizumab, guselkumab, brazikumab and mirikizumab). This Review provides a summary of the biology of the IL-12 family cytokines IL-12 and IL-23, discusses the role of these cytokines in intestinal homeostasis and inflammation, and highlights IL-12- and IL-23-directed drug development for the treatment of Crohn’s disease and ulcerative colitis.IL-12 and IL-23 have been implicated in inflammatory bowel disease. In this Review, Vande Casteele and colleagues summarize the mechanistic role of IL-12 and IL-23 in inflammatory bowel disease, and discuss the clinical development of drugs targeting IL-12 and/or IL-23.