Recent advances in inflammatory bowel disease: mucosal immune cells in intestinal inflammation
TL;DR: This work reviews key immune cells that maintain intestinal homeostasis and describes how altered function and imbalances may lead to inflammatory bowel disease (IBD), and highlights the latest developments within this field.
Abstract: The intestine and its immune system have evolved to meet the extraordinary task of maintaining tolerance to the largest, most complex and diverse microbial commensal habitat, while meticulously attacking and containing even minute numbers of occasionally incoming pathogens. While our understanding is still far from complete, recent studies have provided exciting novel insights into the complex interplay of the many distinct intestinal immune cell types as well as the discovery of entirely new cell subsets. These studies have also revealed how proper development and function of the intestinal immune system is dependent on its specific microbiota, which appears to have evolutionarily coevolved. Here we review key immune cells that maintain intestinal homeostasis and, conversely, describe how altered function and imbalances may lead to inflammatory bowel disease (IBD). We highlight the latest developments within this field, covering the major players in IBD including intestinal epithelial cells, macrophages, dendritic cells, adaptive immune cells, and the newly discovered innate lymphoid cells, which appear of characteristic importance for immune function at mucosal surfaces. We set these mucosal immune pathways in the functional context of IBD risk genes where such insight is available. Moreover, we frame our discussion of fundamental biological pathways that have been elucidated in model systems in the context of results from clinical trials in IBD that targeted key mediators secreted by these cells, as an attempt of ‘functional’ appraisal of these pathways in human disease.
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01 Jan 2010
816 citations
01 Jan 2011
TL;DR: In this paper, the authors colonized GF mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota.
Abstract: Gut microbial induction of host immune maturation exemplifies host-microbe mutualism. We colonized germ-free (GF) mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota. Gut bacterial numbers and phylum abundance were similar in MMb and HMb mice, but bacterial species differed, especially the Firmicutes. HMb mouse intestines had low levels of CD4(+) and CD8(+) T cells, few proliferating T cells, few dendritic cells, and low antimicrobial peptide expression--all characteristics of GF mice. Rat microbiota also failed to fully expand intestinal T cell numbers in mice. Colonizing GF or HMb mice with mouse-segmented filamentous bacteria (SFB) partially restored T cell numbers, suggesting that SFB and other MMb organisms are required for full immune maturation in mice. Importantly, MMb conferred better protection against Salmonella infection than HMb. A host-specific microbiota appears to be critical for a healthy immune system.
768 citations
01 Jan 2019
TL;DR: IBD pathogenesis is a result of the interplay of genetic susceptibility and environmental impact on the microbiome that through a weakened intestinal barrier will lead to inappropriate intestinal immune activation, and mechanisms proposed to cause IBD are reviewed from the genetic, environmental, intestinal barrier, and immunologic perspectives.
Abstract: Inflammatory bowel diseases (IBDs), represented by Crohn disease and ulcerative colitis, are associated with major morbidity in Western countries and with increasing incidence in the developing world. Although analysis of the genome of patients with IBD, especially through genome-wide association studies, has unraveled multiple pathways involved in IBD pathogenesis, only part of IBD heritability has been explained by genetic studies. This finding has revealed that environmental factors also play a major role in promoting intestinal inflammation, mostly through their effects in the composition of the microbiome. However, in order for microbial dysbiosis to result in uncontrolled intestinal inflammation, the intestinal barrier formed by intestinal epithelial cells and the innate immune system should also be compromised. Finally, activation of the immune system depends on the working balance between effector and regulatory cells present in the intestinal mucosa, which have also been found to be dysregulated in this patient population. Therefore, IBD pathogenesis is a result of the interplay of genetic susceptibility and environmental impact on the microbiome that through a weakened intestinal barrier will lead to inappropriate intestinal immune activation. In this article, we will review the mechanisms proposed to cause IBD from the genetic, environmental, intestinal barrier, and immunologic perspectives.
405 citations
TL;DR: The mechanisms of actions of COS have been found to involve the modulation of several important pathways including the suppression of nuclear factor kappa B and mitogen‐activated protein kinases (MAPK and the activation of AMP‐activatedprotein kinase (AMPK).
341 citations
Cites background from "Recent advances in inflammatory bow..."
...IBD is characterized by chronic inflammation and extensive damage to the intestinal mucosa (Cader & Kaser, 2013; Gunther et al., 2013)....
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TL;DR: Beyond conventional immunesuppressive therapy, the development of biological agents that target specific disease mechanisms has resulted in more frequent and deeper remission in IBD patients, with mucosal healing as a treatment goal of therapy.
Abstract: Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder with an unknown etiology. IBD is composed of two different disease entities: Crohn's disease (CD) and ulcerative colitis (UC). IBD has been thought to be idiopathic but has two main attributable causes that include genetic and environmental factors. The gastrointestinal tract in which this disease occurs is central to the immune system, and the innate and the adaptive immune systems are balanced in complex interactions with intestinal microbes under homeostatic conditions. However, in IBD, this homeostasis is disrupted and uncontrolled intestinal inflammation is perpetuated. Recently, the pathogenesis of IBD has become better understood owing to advances in genetic and immunologic technology. Moreover, new therapeutic strategies are now being implemented that accurately target the pathogenesis of IBD. Beyond conventional immunesuppressive therapy, the development of biological agents that target specific disease mechanisms has resulted in more frequent and deeper remission in IBD patients, with mucosal healing as a treatment goal of therapy. Future novel biologics should overcome the limitations of current therapies and ensure that individual patients can be treated with optimal drugs that are safe and precisely target IBD.
205 citations
Cites background from "Recent advances in inflammatory bow..."
...The accumulation of both macrophages and DCs is observed in the lamina propria of IBD patients and in experimental colitis models (3)....
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...These cells structurally constitute crypts and villi, with a single columnar cell lining with a tight junction, and secrete mucus containing anti-microbial peptides; these cells separate intra-luminal pathogens from the subepithelial lamina propria (3,10,11)....
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...Increased production of IFN-g from Th1 cells and cytokines related with Th17 cell, such as IL-17A/F, IL-21, IL-22, and CXCL8, are observed in the intestine of CD patients, while T cells from the lamina propria of UC patients highly produce Th2 cell-related cytokines, such as IL-5 and IL-13 (3,76,77)....
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...For various reasons, idiopathic intestinal inflammations such as inflammatory bowel disease (IBD) can occur when this homeostasis is disrupted (2,3)....
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References
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TL;DR: The Human Microbiome Project Consortium reported the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome as discussed by the authors.
Abstract: The Human Microbiome Project Consortium reports the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome.
8,410 citations
Journal Article•
TL;DR: The Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far, finding the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals.
Abstract: Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.
6,350 citations
TL;DR: This Review summarizes recent advances in understanding the physiological functions of autophagy and its possible roles in the causation and prevention of human diseases.
6,301 citations
Wellcome Trust Sanger Institute1, Broad Institute2, University of Groningen3, University of Pittsburgh4, Cedars-Sinai Medical Center5, Yale University6, University of Cambridge7, University of Chicago8, Harvard University9, Katholieke Universiteit Leuven10, University of Liège11, King's College London12, Université de Montréal13, New Jersey Institute of Technology14, Cleveland Clinic15, Peninsula College of Medicine and Dentistry16, Université libre de Bruxelles17, Aarhus University18, University of Adelaide19, University of Kiel20, Flinders University21, McGill University22, Ludwig Maximilian University of Munich23, Charité24, Icahn School of Medicine at Mount Sinai25, University of Bonn26, Karolinska Institutet27, Torbay Hospital28, University of Auckland29, Christchurch Hospital30, Imperial College London31, Queen's University32, University of Oslo33, Lithuanian University of Health Sciences34, Emory University35, Casa Sollievo della Sofferenza36, Ghent University37, University of Western Australia38, University of Edinburgh39, Queensland Health40, Newcastle University41, University of Dundee42, University of Manchester43, University of Amsterdam44, University of Maribor45, Royal Hospital for Sick Children46, Guy's and St Thomas' NHS Foundation Trust47, QIMR Berghofer Medical Research Institute48, Norfolk and Norwich University Hospital49, Leiden University50, Technische Universität München51, University of Toronto52, University of Pennsylvania53, Johns Hopkins University54, University of Queensland55
TL;DR: A meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans is undertaken, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls.
Abstract: 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. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. 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.
4,094 citations
TL;DR: Patient stratification by GI microbiota provides further evidence that CD represents a spectrum of disease states and suggests that treatment of some forms of IBD may be facilitated by redress of the detected microbiological imbalances.
Abstract: The two primary human inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are idiopathic relapsing disorders characterized by chronic inflammation of the intestinal tract. Although several lines of reasoning suggest that gastrointestinal (GI) microbes influence inflammatory bowel disease (IBD) pathogenesis, the types of microbes involved have not been adequately described. Here we report the results of a culture-independent rRNA sequence analysis of GI tissue samples obtained from CD and UC patients, as well as non-IBD controls. Specimens were obtained through surgery from a variety of intestinal sites and included both pathologically normal and abnormal states. Our results provide comprehensive molecular-based analysis of the microbiota of the human small intestine. Comparison of clone libraries reveals statistically significant differences between the microbiotas of CD and UC patients and those of non-IBD controls. Significantly, our results indicate that a subset of CD and UC samples contained abnormal GI microbiotas, characterized by depletion of commensal bacteria, notably members of the phyla Firmicutes and Bacteroidetes. Patient stratification by GI microbiota provides further evidence that CD represents a spectrum of disease states and suggests that treatment of some forms of IBD may be facilitated by redress of the detected microbiological imbalances.
3,967 citations