Impaired Intestinal Permeability Contributes to Ongoing Bowel Symptoms in Patients With Inflammatory Bowel Disease and Mucosal Healing
TL;DR: Impaired intestinal permeability is associated with ongoing bowel symptoms; increases in permeability correlated with increased severity of diarrhea and Resolution of mucosal permeability beyond mucosal healing might improve outcomes of patients with IDB.
About: This article is published in Gastroenterology.The article was published on 2017-09-01. It has received 171 citations till now. The article focuses on the topics: Crohn's disease & Inflammatory bowel disease.
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06 Nov 2017
TL;DR: The present review summarizes the evidences related to the age-associated changes in intestinal microbiota and vice-versa, mechanisms involved in this bi-directional relationship, and the prospective for development of microbiota-based interventions such as probiotics for healthy aging.
Abstract: The development of human gut microbiota begins as soon as the neonate leaves the protective environment of the uterus (or maybe in-utero) and is exposed to innumerable microorganisms from the mother as well as the surrounding environment. Concurrently, the host responses to these microbes during early life manifest during the development of an otherwise hitherto immature immune system. The human gut microbiome, which comprises an extremely diverse and complex community of microorganisms inhabiting the intestinal tract, keeps on fluctuating during different stages of life. While these deviations are largely natural, inevitable and benign, recent studies show that unsolicited perturbations in gut microbiota configuration could have strong impact on several features of host health and disease. Our microbiota undergoes the most prominent deviations during infancy and old age and, interestingly, our immune health is also in its weakest and most unstable state during these two critical stages of life, indicating that our microbiota and health develop and age hand-in-hand. However, the mechanisms underlying these interactions are only now beginning to be revealed. The present review summarizes the evidences related to the age-associated changes in intestinal microbiota and vice-versa, mechanisms involved in this bi-directional relationship, and the prospective for development of microbiota-based interventions such as probiotics for healthy aging.
401 citations
TL;DR: Therapeutic drug monitoring in inflammatory bowel disease patients receiving anti‐tumour necrosis factor agents can help optimise outcomes and consensus statements based on current evidence will help the development of treatment guidelines.
Abstract: SummaryBackground
Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines.
Aim
To develop evidence-based consensus statements for TDM-guided anti-TNF therapy in IBD.
Methods
A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted.
Results
22/24 statements met criteria for consensus. For anti-TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12 μg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints—such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti-TNF biological agents.
Conclusion
Consensus statements support the role of TDM in optimising anti-TNF agents to treat IBD, especially in situations of treatment failure.
210 citations
Cites background from "Impaired Intestinal Permeability Co..."
...value for functional gut disorder or impaired intestinal permeability.(66,75) Infective colitis with C....
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...Up to 60% of IBD patients with ongoing bowel symptoms have mucosal healing.(66-75) A normal faecal calprotectin in the context of underlying IBD and ongoing bowel symptoms has high predictive...
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TL;DR: This Review describes how epithelial recognition of bacteria through Toll-like receptors participates in establishing homeostasis, and how dysregulation of these receptors can lead to dysbiosis, increasing susceptibility to colitis and tumorigenesis.
Abstract: The human gastrointestinal tract is colonized by trillions of microorganisms that interact with the host to maintain structural and functional homeostasis. Acting as the interface between the site of the highest microbial burden in the human body and the richest immune compartment, a single layer of intestinal epithelial cells specializes in nutrient absorption, stratifies microorganisms to limit colonization of tissues and shapes the responses of the subepithelial immune cells. In this Review, we focus on the expression, regulation and functions of Toll-like receptors (TLRs) in the different intestinal epithelial lineages to analyse how epithelial recognition of bacteria participates in establishing homeostasis in the gut. In particular, we elaborate on the involvement of epithelial TLR signalling in controlling crypt dynamics, enhancing epithelial barrier integrity and promoting immune tolerance towards the gut microbiota. Furthermore, we comment on the regulatory mechanisms that fine-tune TLR-driven immune responses towards pathogens and revisit the role of TLRs in epithelial repair after injury. Finally, we discuss how dysregulation of epithelial TLRs can lead to the generation of dysbiosis, thereby increasing susceptibility to colitis and tumorigenesis. Interactions between intestinal epithelial cells, the gut microbiota and immune cells have a key role in maintaining gut homeostasis. This Review describes how epithelial recognition of bacteria through Toll-like receptors participates in establishing homeostasis, and how dysregulation of these receptors can lead to dysbiosis, increasing susceptibility to colitis and tumorigenesis.
201 citations
TL;DR: A subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections is discovered, and Clostridium innocuum is identified as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments.
162 citations
Cites background from "Impaired Intestinal Permeability Co..."
...Increasing evidence suggests that intestinal permeability is an integral component of chronic intestinal inflammatory diseases (Chang et al., 2017; Mankertz and Schulzke, 2007) and that impaired barrier function is among the constellation of accepted pathologies in IBDs (Jäger et al....
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TL;DR: It appears that the relative weight given to different therapeutic targets in the development and improvement of UC treatments could be optimized, with an increased emphasis on endoscopic and histological targets over clinical or symptomatic targets.
146 citations
References
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Book•
23 Sep 2019TL;DR: The Cochrane Handbook for Systematic Reviews of Interventions is the official document that describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of healthcare interventions.
Abstract: The Cochrane Handbook for Systematic Reviews of Interventions is the official document that describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of healthcare interventions.
21,235 citations
Additional excerpts
...For purposes of calculation, standard deviation was estimated at three quarters of the inter-quartile range (IQR).(21) Assuming a 1....
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TL;DR: The prevalence of IBS varies among countries, as well as criteria used to define its presence, and women are at slightly higher risk for IBS than men.
1,620 citations
"Impaired Intestinal Permeability Co..." refers result in this paper
...The prevalence of ongoing bowel symptoms was similar to the prevalence of IBS in the general population of 11% according to a recent meta-analysis.(24) A previous meta-analysis had estimated a prevalence of symptoms meeting the criteria for IBS in IBD in remission of 31% in...
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TL;DR: These studies indicate that Crohn's disease and ulcerative colitis are heterogeneous diseases characterized by various genetic abnormalities that lead to overly aggressive T-cell responses to a subset of commensal enteric bacteria.
Abstract: In the past few years, data obtained from work in animal models, human genetics, basic science and clinical trials, has provided new insights into the mechanisms underlying Crohn's disease and ulcerative colitis. In this review, the author discusses the evidence underlying the disparate theories on the pathogenesis of these diseases and attempts to reconcile them into a coherent hypothesis based on the experimental data. Crohn's disease and ulcerative colitis are idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated. Although their exact etiologies remain uncertain, results from research in animal models, human genetics, basic science and clinical trials have provided important new insights into the pathogenesis of chronic, immune-mediated, intestinal inflammation. These studies indicate that Crohn's disease and ulcerative colitis are heterogeneous diseases characterized by various genetic abnormalities that lead to overly aggressive T-cell responses to a subset of commensal enteric bacteria. The onset and reactivation of disease are triggered by environmental factors that transiently break the mucosal barrier, stimulate immune responses or alter the balance between beneficial and pathogenic enteric bacteria. Different genetic abnormalities can lead to similar disease phenotypes; these genetic changes can be broadly characterized as causing defects in mucosal barrier function, immunoregulation or bacterial clearance. These new insights will help develop better diagnostic approaches that identify clinically important subsets of patients for whom the natural history of disease and response to treatment are predictable.
1,608 citations
"Impaired Intestinal Permeability Co..." refers background in this paper
...While the exact pathogenic mechanisms remain unknown, IBD is thought to arise from the complex interplay of environmental, genetic, immunological and intestinal microbial factors.(1,2) Current medical therapies aim to modulate the intestinal immune system, but up to 35% of IBD patients remain symptomatic with abdominal pain and altered bowel habit, symptoms that overlap with irritable bowel syndrome (IBS)....
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TL;DR: Elucidation of immunological and genetic factors indicate multiple points at which the inflammatory cascade may be interrupted, yielding the possibility of precise, targeted therapies for IBD.
Abstract: Ulcerative colitis (UC) and Crohn's disease (CD), the primary constituents of inflammatory bowel disease (IBD), are precipitated by a complex interaction of environmental, genetic, and immunoregulatory factors. Higher rates of IBD are seen in northern, industrialized countries, with greater prevalence among Caucasians and Ashkenazic Jews. Racial gaps are closing, indicating that environmental factors may play a role. IBD is multigenic, with the most clearly established genetic link between certain NOD2 variants and CD. Regardless of the underlying genetic predisposition, a growing body of data implicates a dysfunctional mucosal immune response to commensal bacteria in the pathogenesis of IBD, especially CD. Possible triggers include a chronic inflammatory response precipitated by infection with a particular pathogen or virus or a defective mucosal barrier. The characteristic inflammatory response begins with an infiltration of neutrophils and macrophages, which then release chemokines and cytokines. These in turn exacerbate the dysfunctional immune response and activate either TH1 or TH2 cells in the gut mucosa, respectively associated with CD and, less conclusively, with UC. Elucidation of immunological and genetic factors indicate multiple points at which the inflammatory cascade may be interrupted, yielding the possibility of precise, targeted therapies for IBD.
934 citations
"Impaired Intestinal Permeability Co..." refers background in this paper
...While the exact pathogenic mechanisms remain unknown, IBD is thought to arise from the complex interplay of environmental, genetic, immunological and intestinal microbial factors.(1,2) Current medical therapies aim to modulate the intestinal immune system, but up to 35% of IBD patients remain symptomatic with abdominal pain and altered bowel habit, symptoms that overlap with irritable bowel syndrome (IBS)....
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TL;DR: A histological activity system was developed for ulcerative colitis that showed good reproducibility and modest agreement with the endoscopic grading system which it complemented and has potential value both clinically and in clinical trials.
Abstract: BACKGROUND Evaluation of histological activity in ulcerative colitis needs to be reproducible but has rarely been tested. This could be useful both clinically and in clinical trials. AIM To develop reproducible criteria which are valid in the assessment of acute inflammation (activity) and chronicity, and to evaluate these features in an interobserver variability study. METHODS A six grade classification system for inflammation was developed which could also be fine tuned within each grade. The grades were: 0, structural change only; 1, chronic inflammation; 2, lamina propria neutrophils; 3, neutrophils in epithelium; 4, crypt destruction; and 5, erosions or ulcers. Ninety nine haematoxylin-eosin sections from endoscopically inflamed and non-inflamed mucosa from patients with distal ulcerative colitis were assessed in two separate readings by three pathologists independently and without knowledge of the clinical status. Interobserver agreement was compared pairwise using kappa statistics. RESULTS Initially, kappa values between the observers were 0.20, 0.42, and 0.26, which are too low to be of value. Following development of a semiquantitative pictorial scale for each criterion, kappa values improved to 0.62, 0.70, and 0.59. For activity defined by neutrophils between epithelial cells, kappa values were 0.903, 1.000, and 0.907. Complete agreement was reached in 64% of samples of endoscopically normal and in 66% of endoscopically inflamed tissue. Neutrophils in epithelium correlated with the presence of crypt destruction and ulceration. CONCLUSION A histological activity system was developed for ulcerative colitis that showed good reproducibility and modest agreement with the endoscopic grading system which it complemented. It has potential value both clinically and in clinical trials.
748 citations
"Impaired Intestinal Permeability Co..." refers background in this paper
...Non-acute inflammatory changes (crypt distortion, branching) were not excluded.(12,13)....
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