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A key role of the gut microbiota in the establishment and maintenance of health, as well as in the pathogenesis of disease, has been identified over the past two decades. One of the primary modes by which the gut microbiota interacts with the host is by means of metabolites, which are small molecules that are produced as intermediate or end products of microbial metabolism. These metabolites can derive from bacterial metabolism of dietary substrates, modification of host molecules, such as bile acids, or directly from bacteria. Signals from microbial metabolites influence immune maturation, immune homeostasis, host energy metabolism and maintenance of mucosal integrity. Alterations in the composition and function of the microbiota have been described in many studies on IBD. Alterations have also been described in the metabolite profiles of patients with IBD. Furthermore, specific classes of metabolites, notably bile acids, short-chain fatty acids and tryptophan metabolites, have been implicated in the pathogenesis of IBD. This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation.Alterations in the gut microbiota and metabolite profiles of patients with IBD have been described. In this Review, Lavelle and Sokol discuss these alterations and their pathophysiological basis, and identify future targets for precision therapeutic modulation.

Very early onset inflammatory bowel disease (VEO-IBD) reflects IBD presenting before 6 years of age. We provide an approach to diagnosis and management of patients with VEO-IBD, based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org).AbstractVery early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.

A meta-analysis of previous genome-wide association studies of Crohn’s disease and ulcerative colitis, the two most common forms of inflammatory bowel disease, with a combined total of more than 75,000 cases and controls, finds that most loci contribute to both phenotypes and other immune-mediated disorders. Pathogenesis of inflammatory bowel disease Genetic studies have implicated unsuspected mechanisms in the pathogenesis of Crohn's disease and ulcerative colitis, two of the most common forms of inflammatory bowel disease. This paper presents a meta-analysis of published genome-wide association studies, together with validation in more than 75,000 cases and controls. In addition to several new associations, the authors find that most loci contribute to both phenotypes, but also to other immune-mediated disorders. The data reveal an overlap between susceptibility loci for inflammatory bowel disease and mycobacterial infection, and between the pathways that govern host responses to mycobacteria and those predisposing to inflammatory bowel disease. Crohn’s disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations 1 . Genome-wide association studies and subsequent meta-analyses of these two diseases 2 , 3 as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy 4 , in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5 . Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

Research on IBDs has identified disrupted immune responses in the gastrointestinal mucosa and putative disruptions in the gut microbiome as causative agents. This work has led to better therapeutic control of IBDs with the use of various antiinflammatory agents.

Inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis, affect several million individuals worldwide. Crohn’s disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study’s infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi’omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases. The Inflammatory Bowel Disease Multi’omics Database includes longitudinal data encompassing a multitude of analyses of stool, blood and biopsies of more than 100 individuals, and provides a comprehensive description of host and microbial activities in inflammatory bowel diseases.

The human microbiota is a diverse microbial ecosystem associated with many beneficial physiological functions as well as numerous disease etiologies. Dominated by bacteria, the microbiota also includes commensal populations of fungi, viruses, archaea, and protists. Unlike bacterial microbiota, which was extensively studied in the past two decades, these non-bacterial microorganisms, their functional roles, and their interaction with one another or with host immune system have not been as widely explored. This review covers the recent findings on the non-bacterial communities of the human gastrointestinal microbiota and their involvement in health and disease, with particular focus on the pathophysiology of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune–microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention. This Review examines inflammatory bowel disease in the context of human genetics studies that help to identify pathways that regulate homeostasis of the mucosal immune system and discusses future prospects for disease-subtype classification and therapeutic intervention.

Abstract Background We report a prospective, nationwide cohort evaluating the safety and effectiveness of CT-P13. Methods A structured database was used to record serious adverse events (SAEs), clinical remission/response, inflammatory biomarkers (CRP and calprotectin), and endoscopic findings. Results Eight hundred ten patients with inflammatory bowel disease (IBD) (452 Crohn’s disease [CD]) were enrolled. Four hundred fifty-nine patients were naïve to anti-TNFα (group A), 196 had a previous exposure (group B), and the remaining 155 were switched to CT-P13 (group C). All patients were included in the safety evaluation with a mean follow-up of 345 ± 215 days and a total number of 6501 infusions. One hundred fifty-four SAEs were reported (19%), leading to cessation of the biosimilar in 103 subjects (12.7%). Infusion reactions were 71, leading to cessation of the biosimilar in 53 subjects (6.5%), being significantly more frequent in patients pre-exposed to anti-TNFα (P = 0.017). The efficacy of therapy was calculated in 754 IBD patients, with a mean follow-up of 329 ± 202 days. Forty-eight patients had a primary failure (6.4%), and 188 (25.6%) lost response during follow-up. Six hundred twenty-eight (364 CD) and 360 IBD patients (222 CD) completed the follow-up at 6 and 12 months, respectively. At 12 months, patients without loss of response were 71%, 64%. and 82% in groups A, B, and C, respectively (log rank P = 0.01). Clinical/endoscopic scores and inflammatory biomarkers dropped significantly in CD and UC patients (P = 0.01 and P < 0.0001) compared with baseline. Conclusions In this large prospective cohort, no further signals of difference in safety and effectiveness of CT-P13 in IBD has been observed.

Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades, Escherichia coli, and the adherent-invasive E coli (AIEC) pathotype in particular, has been implicated in the pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn’s disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future.