Materiały źródłowe

• #1 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  Inflammatory Bowel Diseases (IBD), represented by Crohns Disease (CD) and Ulcerative Colitis (UC), are associated with significant morbidity in western countries and with increasing incidence in the developing world. While analysis of the genome of IBD patients, 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 has demonstrated that environmental factors also play a significant 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 shown to be dysregulated in this patient population. Therefore, IBD pathogenesis is a result of the interplay of genetic susceptibility, environmental impact on the microbiome that through a weakened intestinal barrier will lead to inappropriate intestinal immune activation.

• #2 Novel Insights into the Pathogenesis of Inflammatory Bowel Diseases

  https://www.mdpi.com/2227-9059/13/2/305

  Inflammatory bowel diseases (IBDs), encompassing Crohn’s disease and ulcerative colitis, are complex chronic disorders characterized by an intricate interplay between genetic predisposition, immune dysregulation, gut microbiota alterations, and environmental exposures. […] Immune dysregulation, including macrophage polarization (M1 vs. M2) and Th17 activation, emerges as a cornerstone of IBD pathogenesis. […] Dysbiosis, as a result of reduced alpha and beta diversity and overgrowth of harmful taxa, is one of the main contributing factors in causing inflammation in IBD. […] The pathogenesis of IBD is a multifaceted interplay between genetic susceptibility, environmental triggers, immune system dysregulation, and gut microbiota alterations. […] The mainstay of IBD pathogenesis lies in a dysregulated immune response to gut microbiota.

• #3

  https://consensus.app/papers/inflammatory-bowel-disease-pathogenesis-zhang-li/a8c8ce88b054584386c1dd6bb25e1b67/

  Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation. […] It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut, catalyzed by the genetic susceptibility of the individual. […] Although the etiology of IBD remains largely unknown, it involves a complex interaction between the genetic, environmental or microbial factors and the immune responses. […] Of the four components of IBD pathogenesis, most rapid progress has been made in the genetic study of gut inflammation. […] The latest internationally collaborative studies have ascertained 163 susceptibility gene loci for IBD. […] However, the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD.

• #4 Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome | Gut

  https://gut.bmj.com/content/62/10/1505

  In this review, we provide a brief overview of the recent advances that have shaped our understanding of the complex interplay of the gut microbiome and genetic susceptibility to IBD. […] More than a decade ago, nucleotide oligomerisation domain 2 (NOD2) was identified as the first susceptibility gene for CD. […] In the last 5 years, population-based genome-wide association studies (GWAS), followed by subsequent meta-analysis of GWAS and Immunochip data, have greatly expanded the number of IBD-associated loci to more than 160. […] These types of genetic studies have reinforced the importance of genes and pathways previously known to be involved in IBD pathogenesis, such as barrier function, the role of T cell subsets and cytokine-cytokine receptor signalling. […] In addition, these studies have helped uncover unanticipated new genes and pathways, including autophagy, regulation of interleukin 23 (IL-23) signalling and others.

• #5 IBD: Recent Molecular Pathophysiology Advances | BTT

  https://www.dovepress.com/a-review-on-inflammatory-bowel-diseases-recent-molecular-pathophysiolo-peer-reviewed-fulltext-article-BTT

  In contrast to monogenic IBD, the effects of genetics on classical IBD (polygenic IBD) are also considerable. […] Our knowledge of the genetic makeup and underlying mechanisms behind IBD has significantly increased as a result of genome-wide association studies (GWAS), which have discovered roughly 240 disease loci associated with the classic adult-onset form of the disease. […] Under IBD condition, the influence of combined endogenous (genetic) and exogenous (genetic, microbial, dietary, stress) factors can lead to intestinal barrier dysfunction by increasing its permeability, which promotes translocation of microorganisms and products of microbial origin from the intestinal lumen into the mucous layer and intestinal epithelium, subsequently leading to an activation of immune cells, a Th17 /Treg imbalance and cytokine production with consequent development of chronic inflammation.

• #6 Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome | Gut

  https://gut.bmj.com/content/62/10/1505

  IBD-associated genes in host cells indicate altered response to gut microbiota as a primary determinant of disease risk and a likely mechanism for the disease. […] A number of host biological functions related to protection from and management of gut bacteria are susceptible to deleterious genetic mutations in constituent genes. […] These include NOD2, which stimulates the immune system to respond to the presence of certain bacteria-produced peptidoglycans. […] Several NOD2 mutations are known to be pathogenic in CD. […] Although NOD2-deficient mice are more susceptible to infection by specific bacterial pathogens, it is not known the extent to which NOD2 deficiencies alter host immune response to gut commensal bacteria. […] The IL-23 receptor (IL23R) also plays an important role in response to pathogens and mutations of IL23R associate with increased IBD risk. […] Elevated levels of IL-23 have been found in the epithelial mucosal barrier in subjects with IBD, further indicating the role of IL-23 in the chronic inflammatory response to luminal bacteria.

• #7 IBD: Recent Molecular Pathophysiology Advances | BTT

  https://www.dovepress.com/a-review-on-inflammatory-bowel-diseases-recent-molecular-pathophysiolo-peer-reviewed-fulltext-article-BTT

  The dysregulation or interruption of autophagy may be related to IBD since it plays a part in preserving biological homeostasis under stress. […] NOD2 belongs to the leucine repeat-rich family of cytoplasmic proteins that can recognize various bacteria, acting as intracellular sensors for bacterial peptidoglycans. […] This protein binds to the muramyldipeptide of gram-positive and gram-negative bacteria, leading to the activation of signaling pathways mediated by the Nuclear Factor (NFkB). […] The existence of monogenic IBD, which is brought on by a single gene deficiency, is one of the most crucial pieces of evidence. […] The number of monogenic IBD disorders is increasing, with genes divided into six groups based on the biologic mechanism. […] Monogenic IBD frequently exhibits partial autosomal dominant and autosomal recessive IBD phenotypic expression.

• #8 Investigating disease pathogenesis | CGHC

  https://ccgh.medschl.cam.ac.uk/research/investigating-disease-pathogenesis

  Mutations in NOD2 lead to impaired autophagy and bacterial clearance, contributing to chronic intestinal inflammation and dysbiosis (community of microogranisms). […] Equally important is the role of the gut microbiota. IBD patients often exhibit dysbiosis, characterised by a reduced diversity of beneficial microbes and an increase in pathogenic bacteria. […] This microbial imbalance makes inflammation worse by disrupting the epithelial barrier, allowing bacterial products to creep past the mucosa and trigger an immune response. […] The interaction between these environmental triggers and genetic susceptibility is key to understanding the complex mechanisms driving IBD pathogenesis. […] In conclusion, IBD arises from a convergence of genetic, microbial, and environmental factors, with immune system dysregulation serving as the central mediator of chronic inflammation.

• #9 Pathology Outlines – Ulcerative colitis

  https://www.pathologyoutlines.com/topic/colonuc.html

  Disruption in the homeostatic balance of the mucosal immunity and the enteric nonpathogenic bacteria, resulting in the patient’s aberrant immune response to the enteric commensal bacteria […] Increased number of colonic epithelium activated and mature dendritic cells with increased stimulatory capacity […] Increased expression of TLR4 by lamina propria cells and TLR4 polymorphism, which can alter susceptibility to enteric infections and tolerance to commensal bacteria […] Disruption in the homeostatic balance between regulatory and effector T cells, leading to a nonclassic natural killer T cell production of IL5 and IL13, which have cytotoxic effects on epithelial cells, mediating an atypical Th2 response […] Increase in proinflammatory cytokines, chemoattractants such as CXCL8 and adhesion molecules such as MadCAM1 recruit increased leukocytes to the colonic mucosa […] Other genetic risk loci include IL23 and IL10, JAK2 kinase pathway genes, hepatocyte nuclear factor 4α, CDH1 and laminin β1.

• #10 Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome | Gut

  https://gut.bmj.com/content/62/10/1505

  Recent studies have also highlighted the importance of host defence pathways, specifically those involved in the handling of mycobacteria, as important in balancing inflammatory responses. […] IBD GWAS have also demonstrated a significant degree of overlap between loci for UC and CD, as well as a high degree of overlap between susceptibility genes for IBD and for other complex diseases. […] Given this overlap, it is likely that similar pathways underlie IBD and that small differences result in diverse phenotypic presentations of UC and CD. […] Potentially the same polymorphism can have different cell- or tissue type-specific effects. […] Also, additional sequencing studies in carefully phenotyped patients may identify additional variants within the same loci that result in different phenotypes.

• #11 Pathogenesis of Inflammatory Bowel Disease

  https://www.hcplive.com/view/pathogenesis-of-inflammatory-bowel-disease

  Well, some of the learnings we’ve had over the last decade are that ulcerative colitis and Crohn disease are in some ways more similar than they are different. In terms of shared genetics, there are about 250 gene associations now, and many of those are shared between the 2 diseases and many other autoimmune diseases. They have a fairly common genetic background, but theyre not identical. That’s the first thing. […] The second thing is that we always knew that the environment was important, and we still think that there are some very important unidentified external forces that impact the actual occurrence of IBD in the genetically susceptible person. What we’ve come to understand is that our microbiome external environment in the lumen is a huge aspect, and we’re still in the very early days of understanding how that directly impacts individual patients, but I believe that that will be an important part of the future.

• #12

  https://consensus.app/papers/inflammatory-bowel-disease-pathogenesis-zhang-li/a8c8ce88b054584386c1dd6bb25e1b67/

  Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is characterized by chronic relapsing intestinal inflammation. […] It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut, catalyzed by the genetic susceptibility of the individual. […] Although the etiology of IBD remains largely unknown, it involves a complex interaction between the genetic, environmental or microbial factors and the immune responses. […] Of the four components of IBD pathogenesis, most rapid progress has been made in the genetic study of gut inflammation. […] The latest internationally collaborative studies have ascertained 163 susceptibility gene loci for IBD. […] However, the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD.

• #13 Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome | Gut

  https://gut.bmj.com/content/62/10/1505

  Consistent with this hypothesis, dramatic shifts in the gut microbiota have been associated with IBD. […] These include alterations in the relative abundances of approximately a dozen bacterial taxa, as well as a decrease in the diversity of the community. […] It remains largely unknown whether the severity of gut dysbiosis is the cause of, or the response to, the severity of the disease. […] Although certain opportunistic pathogens such as Enterobacteriaceae have increased relative abundance in IBD patients and in mouse models of intestinal inflammation, in most cases causal connections remain elusive, and the possibility remains that alterations in the abundance of gut commensal bacteria play a role in IBD pathogenesis. […] A severe imbalance in the composition of the gut microbiome is often referred to as dysbiosis, but the term is poorly defined.

• #14 Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome | Gut

  https://gut.bmj.com/content/62/10/1505

  Consistent with this hypothesis, dramatic shifts in the gut microbiota have been associated with IBD. […] These include alterations in the relative abundances of approximately a dozen bacterial taxa, as well as a decrease in the diversity of the community. […] It remains largely unknown whether the severity of gut dysbiosis is the cause of, or the response to, the severity of the disease. […] Although certain opportunistic pathogens such as Enterobacteriaceae have increased relative abundance in IBD patients and in mouse models of intestinal inflammation, in most cases causal connections remain elusive, and the possibility remains that alterations in the abundance of gut commensal bacteria play a role in IBD pathogenesis. […] A severe imbalance in the composition of the gut microbiome is often referred to as dysbiosis, but the term is poorly defined.

• #15 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #16 Paediatric IBD: the host, diet & microbes in pathogenesis & treatment: a narrative review – Dijk – Digestive Medicine Research

  https://dmr.amegroups.org/article/view/7168/html

  The worldwide incidence of paediatric inflammatory bowel diseases (pIBD) is increasing, especially in the Western world, but the pathophysiology of these diseases remains poorly understood. Genetic susceptibility, an aberrant immune response, alterations in the intestinal microbiome, and a patients environment, including diet, have been found to contribute to disease development. […] Certain dietary factors, such as fibres, are fermented by gut microbes, resulting in key regulators of the host gut environment, including short-chain fatty acids (SCFA) and other metabolites. Several SCFA-producing commensal bacteria, including Roseburia and Faecalibacteria, are reduced in pIBD, further illustrated by lower SCFA levels. SCFAs are thought to improve barrier integrity and regulate immune tolerance, two areas shown to be deficient in active pIBD. An altered host-microbe relationship, partly mediated by microbial metabolites (e.g., SCFAs), is evident and often varies with disease activity.

• #17 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #18 Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome | Gut

  https://gut.bmj.com/content/62/10/1505

  Consistent with this hypothesis, dramatic shifts in the gut microbiota have been associated with IBD. […] These include alterations in the relative abundances of approximately a dozen bacterial taxa, as well as a decrease in the diversity of the community. […] It remains largely unknown whether the severity of gut dysbiosis is the cause of, or the response to, the severity of the disease. […] Although certain opportunistic pathogens such as Enterobacteriaceae have increased relative abundance in IBD patients and in mouse models of intestinal inflammation, in most cases causal connections remain elusive, and the possibility remains that alterations in the abundance of gut commensal bacteria play a role in IBD pathogenesis. […] A severe imbalance in the composition of the gut microbiome is often referred to as dysbiosis, but the term is poorly defined.

• #19

  https://link.springer.com/article/10.1007/s12328-017-0813-5

  As for IBD, many studies have reported that the composition of microbiota in IBD is altered compared with that in healthy subjects. […] However, a direct causal relationship between dysbiosis and IBD has not been established in humans. […] The sharp increase in the affected population suggests that diet, which is an environmental factor, and the intestinal microbiota influenced by it are involved in the pathogenesis of IBD. […] The decrease of bacteria with anti-inflammatory capacities and the increase of bacteria with inflammatory capacities are observed in patients with IBD when compared to healthy individuals. […] The most consistent changes are a reduction in the diversity of gut microbiota and the lower abundance of Firmicutes. […] The production of metabolites affected by the disruption of gut microbiota is associated with the pathogenesis of IBD. […] Collectively, these data strongly indicate that the alteration of gut microbiota is associated with the pathogenesis of IBD.

• #20 Paediatric IBD: the host, diet & microbes in pathogenesis & treatment: a narrative review – Dijk – Digestive Medicine Research

  https://dmr.amegroups.org/article/view/7168/html

  The worldwide incidence of paediatric inflammatory bowel diseases (pIBD) is increasing, especially in the Western world, but the pathophysiology of these diseases remains poorly understood. Genetic susceptibility, an aberrant immune response, alterations in the intestinal microbiome, and a patients environment, including diet, have been found to contribute to disease development. […] Certain dietary factors, such as fibres, are fermented by gut microbes, resulting in key regulators of the host gut environment, including short-chain fatty acids (SCFA) and other metabolites. Several SCFA-producing commensal bacteria, including Roseburia and Faecalibacteria, are reduced in pIBD, further illustrated by lower SCFA levels. SCFAs are thought to improve barrier integrity and regulate immune tolerance, two areas shown to be deficient in active pIBD. An altered host-microbe relationship, partly mediated by microbial metabolites (e.g., SCFAs), is evident and often varies with disease activity.

• #21 IBD: Recent Molecular Pathophysiology Advances | BTT

  https://www.dovepress.com/a-review-on-inflammatory-bowel-diseases-recent-molecular-pathophysiolo-peer-reviewed-fulltext-article-BTT

  In contrast to monogenic IBD, the effects of genetics on classical IBD (polygenic IBD) are also considerable. […] Our knowledge of the genetic makeup and underlying mechanisms behind IBD has significantly increased as a result of genome-wide association studies (GWAS), which have discovered roughly 240 disease loci associated with the classic adult-onset form of the disease. […] Under IBD condition, the influence of combined endogenous (genetic) and exogenous (genetic, microbial, dietary, stress) factors can lead to intestinal barrier dysfunction by increasing its permeability, which promotes translocation of microorganisms and products of microbial origin from the intestinal lumen into the mucous layer and intestinal epithelium, subsequently leading to an activation of immune cells, a Th17 /Treg imbalance and cytokine production with consequent development of chronic inflammation.

• #22 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #23 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #24 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #25 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #26 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #27 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #28 :: Immune Network ::

  https://immunenetwork.org/DOIx.php?id=10.4110/in.2017.17.1.25

  Therapeutic attempts to restore mucosal barrier function have also been attempted. […] Genetic alterations or ER stress causing Paneth cell dysfunction or depletion result in dysbiosis of commensal flora and increased susceptibility to intestinal inflammation. […] The accumulation of both macrophages and DCs is observed in the lamina propria of IBD patients and in experimental colitis models. […] An impaired innate immune response might promote IBD development via inappropriate stimulation of adaptive immunity through failure to control microorganisms. […] Chronic inappropriate activation of the adaptive immune system against commensal microorganism has been thought to be the main pathogenesis of IBD. […] Classically, immune-modulating treatments of IBD have focused on adaptive immunity.

• #29 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #30 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  The pathways of several key genetic risk factors of IBD impair Paneth cell function leading to colitis, most notably: NOD2 and autophagy. NOD2 is expressed by Paneth cells, dendritic Cells, macrophages and absorptive IEC. NOD2 risk variants are associated with lower levels of -defensins in Paneth cells leading to impaired antimicrobial function. Not only through NOD2 but also via CD risk locus ATG16L1, Paneth cells function in autophagy is compromised in patients with CD. […] The disturbed balance between anti and pro-inflammatory signals with consequent migration of leukocytes to the intestinal mucosa results in and is perpetuated by an exaggerated T cell immune response, which is seen in both CD and UC. The T cells involved on immune responses in both diseases, however, seem to be different, what may explain phenotypic differences seen in clinical practice as well as response to new targeted therapies.

• #31 :: Immune Network ::

  https://immunenetwork.org/DOIx.php?id=10.4110/in.2017.17.1.25

  Recently, however, activation of Th17 cells and imbalance of Th17/regulatory T (Treg) cells are recognized to be an important component in the development of intestinal inflammation. […] Since tumor necrosis factor (TNF)- has been identified as a key cytokine in IBD pathogenesis, the introduction of anti-TNF- treatment has led to the development of disease-modifying drugs. […] This high rate of treatment failure suggests that there are still unknown aspects regarding the mechanism of IBD. […] In this review, we will describe our current knowledge of the mucosal immune system in terms of IBD pathogenesis and discuss its therapeutic implications. […] When the integrity of the intestinal epithelial layer is broken, a high influx of intestinal contents and/or a high burden of microorganisms is thought to initiate and maintain a sustained inflammatory response, which is considered to be one of the mechanisms underlying IBD.

• #32 :: Immune Network ::

  https://immunenetwork.org/DOIx.php?id=10.4110/in.2017.17.1.25

  Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder with an unknown etiology. IBD has been thought to be idiopathic but has two main attributable causes that include genetic and environmental factors. 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. […] IBD is a multifactorial immune disorder characterized by chronic relapsing inflammation of the intestine. Currently, the exact etiology of IBD is unclear. However, it is believed that disturbance of the immune system and/or imbalanced interactions with microbes leads to development of chronic intestinal inflammation when certain environmental factors trigger genetically susceptible hosts.

• #33 Pathophysiology of Inflammatory Bowel Disease: Innate Immune System

  https://www.mdpi.com/1422-0067/24/2/1526

  Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. […] Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. […] A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. […] The etiology of IBD remains elusive, but IBD appears to be sustained in genetically susceptible individuals by an impaired immune response against intestinal microorganisms. This abnormal immune response is associated with dysregulation of both innate and adaptive immune responses. […] In IBD, the innate immune system is the first responder to PAMPs and to molecules released from damaged or dying cells, known as DAMPs. DAMPs and PAMPs activate the innate immune system by interacting with PRRs.

• #34 Pathophysiology of Inflammatory Bowel Disease: Innate Immune System

  https://www.mdpi.com/1422-0067/24/2/1526

  The implication of IIC in IBD is the focus of this review. […] In IBD, large numbers of Ly6C^high inflammatory monocytes are recruited to the intestine in a CCR2-dependent manner, becoming pro-inflammatory effector cells. These inflammatory macrophages produce TNF-α, IL-6, and iNOS, and directly cause the onset and development of fibrosis through a disproportionate accumulation of ECM. […] Macrophages play an important role in homeostasis and in the development of IBD, both in mouse models and in patients, by phagocytosing cellular debris, producing multiple cytokines, and regulating tissue repair. […] In summary, macrophages play an important role in homeostasis and in the development of IBD.

• #35 Immunopathogenesis of inflammatory bowel disease

  https://www.wjgnet.com/1007-9327/full/v14/i3/390.htm

  Studies described above indicate that microbial structures can cause gut mucosal inflammation by involving the innate immune system. Adhesion molecules such as intercellular cell adhesion molecule 1 (ICAM1) are important for circulating mononuclear and polymorphonuclear cells to adhere and migrate to the inflamed gut mucosa. […] NOD proteins are a distinct subset of PRRs that have important roles in innate immunity as cytoplasmic sensors of microbial components, allowing for regulation of inflammatory processes and apoptosis. The importance of these PRRs is highlighted by the fact that mutations in the gene that encodes NOD2 occur in a subset of patients with CD and polymorphisms in the gene that encodes NOD1 are associated with IBD. […] Eleven TLRs have been identified which are characterized by three common structural features: (1) divergent ligand binding extracellular domain with leucine rich repeats; (2) short transmembrane region; (3) a highly homologous cytoplasmic Toll/interleukin 1 receptor (TIR) domain. Even though each type of TLR engages a different PAMPs, a major convergent pathway is through myeloid differentiation primary response protein MyD88, which activates NF-B.

• #36 Gastroenterology Education and CPD for trainees and specialists » Pathogenesis of IBD

  https://www.gastrotraining.com/inflammatory-bowel-disease/pathogenesis

  Crohns disease is a predominantly TH1- and TH17-mediated process, while ulcerative colitis seems to be an atypical TH2 disorder. […] Chronic intestinal inflammation results from the interactions of genetic, immunologic, microbial and environmental factors. […] IBD results from the failure to appropriately down regulate nonspecific inflammation initiated by an environmental trigger, such as an acute, self-limited infection or NSAID use. […] By contrast, genetically susceptible hosts who are unable to clear an invading pathogen and/or generate tolerogenic immune response to commensal microbial agents by mounting appropriate innate immunity, down regulating immune responses or healing the mucosal barrier subsequently activate pathogenic T-cell responses to commensal bacteria and proceed to chronic, relapsing intestinal inflammation. […] Resistance to T-cell apoptosis, lack of response to down regulatory signals and continuous exposure to luminal antigens and adjuvants help sustain this inflammatory response.

• #37 Immunopathogenesis of inflammatory bowel disease

  https://www.wjgnet.com/1007-9327/full/v14/i3/390.htm

  Either a mucosal susceptibility or defect in sampling of gut luminal antigen leads to activation of innate immune response, possibly mediated by enhanced Toll-like receptor (TLR) activity. The stimulated dendritic cells (DC) then mediate the differentiation of nave T-cells into effector T-cells. Crohns disease (CD) is a predominately Th1 and Th17 mediated process, while ulcerative colitis (UC) appears to be predominately mediated through Th2 and NK T-cells. […] The importance of the microflora in the induction of and maintenance of disease has been demonstrated in murine model of colitis. For example, mice that are deficient in the cytokines IL-2 or IL-10 or rats containing the HLA-B27 transgene develop IBD in the presence of a normal microflora but not in a sterile germ-free environment.

• #38 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  In CD, the differentiation of Th type 1 and 17 occurs in response to the production of IL-12, IL-18, IL-23 and transforming growth factor beta (TGF) by antigen presenting cells (APC) and macrophages. In turn Th1 and Th17 cells secrete the pro-inflammatory cytokines IL-17, INF- and TNFa that feed into a self-sustaining amplification cycle whereby they stimulate APC, macrophages, fibroblasts and endothelial cells to produce TNF, IL-1, IL-6, IL-8, IL-12 and IL-18. […] Understanding the mechanisms that lead to IBD pathogenesis is crucial in order to find new therapeutic strategies to improve patient therapies.

• #39 IBD: Recent Molecular Pathophysiology Advances | BTT

  https://www.dovepress.com/a-review-on-inflammatory-bowel-diseases-recent-molecular-pathophysiolo-peer-reviewed-fulltext-article-BTT

  IBD can be considered a kind of polymicrobial disease, in which the altered intestinal microbiota dysbiosis has a major role. […] Evidence points to abnormalities in innate and adaptive immune responses against intestinal microbiota, harmful antigens, or extrinsic pathogens that may have crossed the intestinal barrier as playing a significant role in the inflammatory process associated with the disease in those who are genetically susceptible. […] Given the significance of Tregs in controlling immunological responses, it has been proposed that abnormalities in Tregs and their mediators play a key role in the pathogenesis of IBD. […] An increase in the number of pro-inflammatory microorganisms may contribute to the activation of pro-inflammatory T-cells, causing, in genetically susceptible people, a Th17-mediated autoimmune response. […] Another possible mechanism of microbiota participation in the modulation of inflammation in the intestine may be its interaction with Nod-like receptors.

• #40 IBD: Recent Molecular Pathophysiology Advances | BTT

  https://www.dovepress.com/a-review-on-inflammatory-bowel-diseases-recent-molecular-pathophysiolo-peer-reviewed-fulltext-article-BTT

  IBD can be considered a kind of polymicrobial disease, in which the altered intestinal microbiota dysbiosis has a major role. […] Evidence points to abnormalities in innate and adaptive immune responses against intestinal microbiota, harmful antigens, or extrinsic pathogens that may have crossed the intestinal barrier as playing a significant role in the inflammatory process associated with the disease in those who are genetically susceptible. […] Given the significance of Tregs in controlling immunological responses, it has been proposed that abnormalities in Tregs and their mediators play a key role in the pathogenesis of IBD. […] An increase in the number of pro-inflammatory microorganisms may contribute to the activation of pro-inflammatory T-cells, causing, in genetically susceptible people, a Th17-mediated autoimmune response. […] Another possible mechanism of microbiota participation in the modulation of inflammation in the intestine may be its interaction with Nod-like receptors.

• #41 Gastroenterology Education and CPD for trainees and specialists » Pathogenesis of IBD

  https://www.gastrotraining.com/inflammatory-bowel-disease/pathogenesis

  Crohns disease is a predominantly TH1- and TH17-mediated process, while ulcerative colitis seems to be an atypical TH2 disorder. […] Chronic intestinal inflammation results from the interactions of genetic, immunologic, microbial and environmental factors. […] IBD results from the failure to appropriately down regulate nonspecific inflammation initiated by an environmental trigger, such as an acute, self-limited infection or NSAID use. […] By contrast, genetically susceptible hosts who are unable to clear an invading pathogen and/or generate tolerogenic immune response to commensal microbial agents by mounting appropriate innate immunity, down regulating immune responses or healing the mucosal barrier subsequently activate pathogenic T-cell responses to commensal bacteria and proceed to chronic, relapsing intestinal inflammation. […] Resistance to T-cell apoptosis, lack of response to down regulatory signals and continuous exposure to luminal antigens and adjuvants help sustain this inflammatory response.

• #42 Paediatric IBD: the host, diet & microbes in pathogenesis & treatment: a narrative review – Dijk – Digestive Medicine Research

  https://dmr.amegroups.org/article/view/7168/html

  The worldwide incidence of paediatric inflammatory bowel diseases (pIBD) is increasing, especially in the Western world, but the pathophysiology of these diseases remains poorly understood. Genetic susceptibility, an aberrant immune response, alterations in the intestinal microbiome, and a patients environment, including diet, have been found to contribute to disease development. […] Certain dietary factors, such as fibres, are fermented by gut microbes, resulting in key regulators of the host gut environment, including short-chain fatty acids (SCFA) and other metabolites. Several SCFA-producing commensal bacteria, including Roseburia and Faecalibacteria, are reduced in pIBD, further illustrated by lower SCFA levels. SCFAs are thought to improve barrier integrity and regulate immune tolerance, two areas shown to be deficient in active pIBD. An altered host-microbe relationship, partly mediated by microbial metabolites (e.g., SCFAs), is evident and often varies with disease activity.

• #43 Inflammatory bowel disease: symptoms and diagnosis – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/inflammatory-bowel-disease-symptoms-and-diagnosis

  Diets high in animal fats, sugar and processed foods and low in fruit and vegetables can increase risk of developing IBD or experiencing a relapse. Vitamin D deficiency is common in IBD patients and emerging data suggest that it might have a role in its pathogenesis and course. It is unclear if obesity is associated with increased risk; however, accumulation of intra-abdominal fat may contribute to mucosal inflammation. […] People who smoke are twice as likely to develop CD than non-smokers. Smoking worsens the clinical course of the disease and increases the risk of relapse and the need for surgery. UC is more common in non-smokers and those who have recently quit, particularly within the first 2–5 years following cessation. […] NSAIDs may precipitate a relapse in up to one third of users. It is thought this may result from the non-selective inhibition of cyclo-oxygenase (COX) enzymes. Higher doses and longer duration of use confer increased risk. […] Chronic inflammation in the gastrointestinal tract triggers cellular events that promote malignant transformation of normal epithelial cells. This increases the risk of dysplasia and progression to cancer.

• #44 Inflammatory bowel disease: symptoms and diagnosis – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/inflammatory-bowel-disease-symptoms-and-diagnosis

  Diets high in animal fats, sugar and processed foods and low in fruit and vegetables can increase risk of developing IBD or experiencing a relapse. Vitamin D deficiency is common in IBD patients and emerging data suggest that it might have a role in its pathogenesis and course. It is unclear if obesity is associated with increased risk; however, accumulation of intra-abdominal fat may contribute to mucosal inflammation. […] People who smoke are twice as likely to develop CD than non-smokers. Smoking worsens the clinical course of the disease and increases the risk of relapse and the need for surgery. UC is more common in non-smokers and those who have recently quit, particularly within the first 2–5 years following cessation. […] NSAIDs may precipitate a relapse in up to one third of users. It is thought this may result from the non-selective inhibition of cyclo-oxygenase (COX) enzymes. Higher doses and longer duration of use confer increased risk. […] Chronic inflammation in the gastrointestinal tract triggers cellular events that promote malignant transformation of normal epithelial cells. This increases the risk of dysplasia and progression to cancer.

• #45 Inflammatory bowel disease: symptoms and diagnosis – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/inflammatory-bowel-disease-symptoms-and-diagnosis

  Diets high in animal fats, sugar and processed foods and low in fruit and vegetables can increase risk of developing IBD or experiencing a relapse. Vitamin D deficiency is common in IBD patients and emerging data suggest that it might have a role in its pathogenesis and course. It is unclear if obesity is associated with increased risk; however, accumulation of intra-abdominal fat may contribute to mucosal inflammation. […] People who smoke are twice as likely to develop CD than non-smokers. Smoking worsens the clinical course of the disease and increases the risk of relapse and the need for surgery. UC is more common in non-smokers and those who have recently quit, particularly within the first 2–5 years following cessation. […] NSAIDs may precipitate a relapse in up to one third of users. It is thought this may result from the non-selective inhibition of cyclo-oxygenase (COX) enzymes. Higher doses and longer duration of use confer increased risk. […] Chronic inflammation in the gastrointestinal tract triggers cellular events that promote malignant transformation of normal epithelial cells. This increases the risk of dysplasia and progression to cancer.

• #46 :: Immune Network ::

  https://immunenetwork.org/DOIx.php?id=10.4110/in.2017.17.1.25

  Recently, however, activation of Th17 cells and imbalance of Th17/regulatory T (Treg) cells are recognized to be an important component in the development of intestinal inflammation. […] Since tumor necrosis factor (TNF)- has been identified as a key cytokine in IBD pathogenesis, the introduction of anti-TNF- treatment has led to the development of disease-modifying drugs. […] This high rate of treatment failure suggests that there are still unknown aspects regarding the mechanism of IBD. […] In this review, we will describe our current knowledge of the mucosal immune system in terms of IBD pathogenesis and discuss its therapeutic implications. […] When the integrity of the intestinal epithelial layer is broken, a high influx of intestinal contents and/or a high burden of microorganisms is thought to initiate and maintain a sustained inflammatory response, which is considered to be one of the mechanisms underlying IBD.

• #47 :: Immune Network ::

  https://immunenetwork.org/DOIx.php?id=10.4110/in.2017.17.1.25

  Therefore, thiopurine probably works by multiple mechanisms to improve IBD. […] The era of biologic therapy began with an anti-TNF agent, infliximab, in patients with CD. […] Excessive production of TNF- using experimental deletion of the adenosine-uracil (AU)-rich elements (ARE) from the 38-untranslated region (38-UTR) of the TNF- gene in mice resulted in development of chronic inflammatory arthritis and CD-like IBD phenotype. […] Therefore, TNF- has been thought to play a pivotal role in the development of IBD. […] Considering the complex interactions between various cytokines that contribute IBD, the targeting of multiple cytokines is thought to be a reasonable approach in the treatment of IBD.

• #48 What is the pathophysiology of inflammatory bowel disease?

  https://medical.lilly.com/us/products/answers/what-is-the-pathophysiology-of-inflammatory-bowel-disease-103272

  Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. […] The important role of interleukin-23 (IL-23) in the pathophysiology of IBD and the relevance of targeting IL-23 have been established via genetic studies, functional assessment in murine models, and studies using patient cells. […] Although the immune response to commensal microbiota is usually self-limiting, in patients with UC or CD, environmental factors and genetic susceptibility can combine with overactivation of the immune response to cause impaired barrier function of the intestinal wall. […] Interleukin-23 released from activated dendritic cells and macrophages plays a role in the amplification of the inflammatory response.

• #49 What is the pathophysiology of inflammatory bowel disease?

  https://medical.lilly.com/us/products/answers/what-is-the-pathophysiology-of-inflammatory-bowel-disease-103272

  Binding of IL-23 to its receptor on macrophages promotes secretion of additional proinflammatory cytokines, including TNF-alpha and interleukin-1 beta (IL-1). […] Interleukin-23 also contributes to the differentiation, expansion, and stabilization of Th17 and other interleukin-17 (IL-17)-producing cells, and in synergy with IL-1, increases IL-17 secretion from effector T cells. […] Interleukin-17 is involved in the recruitment of neutrophils from nearby capillaries into the mucosa, where they degranulate and release toxic molecules, thus amplifying the inflammatory activity. […] The exacerbated inflammatory response leads to epithelial breakdown, depleted goblet cells, an impaired mucus layer in UC, or intestinal wall fibrosis in CD. […] The important role of IL-23 in the inflammatory response has been recognized, and IL-23 inhibition offers new therapeutic options in the treatment of IBD.

• #50 What is the pathophysiology of inflammatory bowel disease?

  https://medical.lilly.com/us/products/answers/what-is-the-pathophysiology-of-inflammatory-bowel-disease-103272

  Binding of IL-23 to its receptor on macrophages promotes secretion of additional proinflammatory cytokines, including TNF-alpha and interleukin-1 beta (IL-1). […] Interleukin-23 also contributes to the differentiation, expansion, and stabilization of Th17 and other interleukin-17 (IL-17)-producing cells, and in synergy with IL-1, increases IL-17 secretion from effector T cells. […] Interleukin-17 is involved in the recruitment of neutrophils from nearby capillaries into the mucosa, where they degranulate and release toxic molecules, thus amplifying the inflammatory activity. […] The exacerbated inflammatory response leads to epithelial breakdown, depleted goblet cells, an impaired mucus layer in UC, or intestinal wall fibrosis in CD. […] The important role of IL-23 in the inflammatory response has been recognized, and IL-23 inhibition offers new therapeutic options in the treatment of IBD.

• #51 What is the pathophysiology of inflammatory bowel disease?

  https://medical.lilly.com/us/products/answers/what-is-the-pathophysiology-of-inflammatory-bowel-disease-103272

  Binding of IL-23 to its receptor on macrophages promotes secretion of additional proinflammatory cytokines, including TNF-alpha and interleukin-1 beta (IL-1). […] Interleukin-23 also contributes to the differentiation, expansion, and stabilization of Th17 and other interleukin-17 (IL-17)-producing cells, and in synergy with IL-1, increases IL-17 secretion from effector T cells. […] Interleukin-17 is involved in the recruitment of neutrophils from nearby capillaries into the mucosa, where they degranulate and release toxic molecules, thus amplifying the inflammatory activity. […] The exacerbated inflammatory response leads to epithelial breakdown, depleted goblet cells, an impaired mucus layer in UC, or intestinal wall fibrosis in CD. […] The important role of IL-23 in the inflammatory response has been recognized, and IL-23 inhibition offers new therapeutic options in the treatment of IBD.

• #52 Inflammatory Bowel Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470312/

  Inflammatory bowel disease (IBD) occurs in genetically susceptible individuals after an inappropriate immune response to the intestinal flora. […] The CARD15 gene has been associated with IBD, but because of its polymorphic features, it is not possible to determine which part of the GI tract will be affected. The role of genes in ulcerative colitis is not as strong as in Crohn disease. […] The histopathology in ulcerative colitis will show the involvement of only the mucosa and submucosa with the formation of cryptic abscesses and mucosal ulcers. Biopsy specimens show neutrophilic infiltrate along with crypt distortion and crypt abscesses. Granulomas are not seen in ulcerative colitis. The disease is contiguous and usually involves the rectum. […] In Crohn disease, the entire intestinal wall is involved, and granulomas may be seen. Inflammation in Crohn disease is transmural and characterized by lymphocytic infiltrate.

• #53 Inflammatory Bowel Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470312/

  Inflammatory bowel disease (IBD) occurs in genetically susceptible individuals after an inappropriate immune response to the intestinal flora. […] The CARD15 gene has been associated with IBD, but because of its polymorphic features, it is not possible to determine which part of the GI tract will be affected. The role of genes in ulcerative colitis is not as strong as in Crohn disease. […] The histopathology in ulcerative colitis will show the involvement of only the mucosa and submucosa with the formation of cryptic abscesses and mucosal ulcers. Biopsy specimens show neutrophilic infiltrate along with crypt distortion and crypt abscesses. Granulomas are not seen in ulcerative colitis. The disease is contiguous and usually involves the rectum. […] In Crohn disease, the entire intestinal wall is involved, and granulomas may be seen. Inflammation in Crohn disease is transmural and characterized by lymphocytic infiltrate.

• #54 Inflammatory Bowel Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470312/

  Inflammatory bowel disease (IBD) occurs in genetically susceptible individuals after an inappropriate immune response to the intestinal flora. […] The CARD15 gene has been associated with IBD, but because of its polymorphic features, it is not possible to determine which part of the GI tract will be affected. The role of genes in ulcerative colitis is not as strong as in Crohn disease. […] The histopathology in ulcerative colitis will show the involvement of only the mucosa and submucosa with the formation of cryptic abscesses and mucosal ulcers. Biopsy specimens show neutrophilic infiltrate along with crypt distortion and crypt abscesses. Granulomas are not seen in ulcerative colitis. The disease is contiguous and usually involves the rectum. […] In Crohn disease, the entire intestinal wall is involved, and granulomas may be seen. Inflammation in Crohn disease is transmural and characterized by lymphocytic infiltrate.

• #55 Inflammatory Bowel Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470312/

  Inflammatory bowel disease (IBD) occurs in genetically susceptible individuals after an inappropriate immune response to the intestinal flora. […] The CARD15 gene has been associated with IBD, but because of its polymorphic features, it is not possible to determine which part of the GI tract will be affected. The role of genes in ulcerative colitis is not as strong as in Crohn disease. […] The histopathology in ulcerative colitis will show the involvement of only the mucosa and submucosa with the formation of cryptic abscesses and mucosal ulcers. Biopsy specimens show neutrophilic infiltrate along with crypt distortion and crypt abscesses. Granulomas are not seen in ulcerative colitis. The disease is contiguous and usually involves the rectum. […] In Crohn disease, the entire intestinal wall is involved, and granulomas may be seen. Inflammation in Crohn disease is transmural and characterized by lymphocytic infiltrate.

• #56 Inflammatory Bowel Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470312/

  Inflammatory bowel disease (IBD) occurs in genetically susceptible individuals after an inappropriate immune response to the intestinal flora. […] The CARD15 gene has been associated with IBD, but because of its polymorphic features, it is not possible to determine which part of the GI tract will be affected. The role of genes in ulcerative colitis is not as strong as in Crohn disease. […] The histopathology in ulcerative colitis will show the involvement of only the mucosa and submucosa with the formation of cryptic abscesses and mucosal ulcers. Biopsy specimens show neutrophilic infiltrate along with crypt distortion and crypt abscesses. Granulomas are not seen in ulcerative colitis. The disease is contiguous and usually involves the rectum. […] In Crohn disease, the entire intestinal wall is involved, and granulomas may be seen. Inflammation in Crohn disease is transmural and characterized by lymphocytic infiltrate.

• #57 Inflammatory Bowel Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470312/

  Inflammatory bowel disease (IBD) occurs in genetically susceptible individuals after an inappropriate immune response to the intestinal flora. […] The CARD15 gene has been associated with IBD, but because of its polymorphic features, it is not possible to determine which part of the GI tract will be affected. The role of genes in ulcerative colitis is not as strong as in Crohn disease. […] The histopathology in ulcerative colitis will show the involvement of only the mucosa and submucosa with the formation of cryptic abscesses and mucosal ulcers. Biopsy specimens show neutrophilic infiltrate along with crypt distortion and crypt abscesses. Granulomas are not seen in ulcerative colitis. The disease is contiguous and usually involves the rectum. […] In Crohn disease, the entire intestinal wall is involved, and granulomas may be seen. Inflammation in Crohn disease is transmural and characterized by lymphocytic infiltrate.

• #58 Inflammatory Bowel Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470312/

  Inflammatory bowel disease (IBD) occurs in genetically susceptible individuals after an inappropriate immune response to the intestinal flora. […] The CARD15 gene has been associated with IBD, but because of its polymorphic features, it is not possible to determine which part of the GI tract will be affected. The role of genes in ulcerative colitis is not as strong as in Crohn disease. […] The histopathology in ulcerative colitis will show the involvement of only the mucosa and submucosa with the formation of cryptic abscesses and mucosal ulcers. Biopsy specimens show neutrophilic infiltrate along with crypt distortion and crypt abscesses. Granulomas are not seen in ulcerative colitis. The disease is contiguous and usually involves the rectum. […] In Crohn disease, the entire intestinal wall is involved, and granulomas may be seen. Inflammation in Crohn disease is transmural and characterized by lymphocytic infiltrate.

• #59 Crohn Disease – Gastrointestinal Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gastrointestinal-disorders/inflammatory-bowel-disease-ibd/crohn-disease

  Crohn disease begins with crypt inflammation and abscesses, which progress to tiny focal aphthoid ulcers. These mucosal lesions may develop into deep longitudinal and transverse ulcers with intervening mucosal edema, creating a characteristic cobblestoned appearance to the bowel. […] Transmural spread of inflammation leads to lymphedema and thickening of the bowel wall and mesentery. Mesenteric fat typically extends onto the serosal surface of the bowel. Mesenteric lymph nodes often enlarge. Extensive inflammation may result in hypertrophy of the muscularis mucosae, fibrosis, and stricture formation, which can lead to bowel obstruction. […] Noncaseating granulomas can occur in lymph nodes, peritoneum, the liver, and all layers of the bowel wall. Although pathognomonic when present, granulomas are not detected in about half of patients with Crohn disease. The presence of granulomas does not seem to be related to the clinical course.

• #60 Crohn Disease – Gastrointestinal Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gastrointestinal-disorders/inflammatory-bowel-disease-ibd/crohn-disease

  Crohn disease begins with crypt inflammation and abscesses, which progress to tiny focal aphthoid ulcers. These mucosal lesions may develop into deep longitudinal and transverse ulcers with intervening mucosal edema, creating a characteristic cobblestoned appearance to the bowel. […] Transmural spread of inflammation leads to lymphedema and thickening of the bowel wall and mesentery. Mesenteric fat typically extends onto the serosal surface of the bowel. Mesenteric lymph nodes often enlarge. Extensive inflammation may result in hypertrophy of the muscularis mucosae, fibrosis, and stricture formation, which can lead to bowel obstruction. […] Noncaseating granulomas can occur in lymph nodes, peritoneum, the liver, and all layers of the bowel wall. Although pathognomonic when present, granulomas are not detected in about half of patients with Crohn disease. The presence of granulomas does not seem to be related to the clinical course.

• #61 Crohn Disease – Gastrointestinal Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gastrointestinal-disorders/inflammatory-bowel-disease-ibd/crohn-disease

  Crohn disease begins with crypt inflammation and abscesses, which progress to tiny focal aphthoid ulcers. These mucosal lesions may develop into deep longitudinal and transverse ulcers with intervening mucosal edema, creating a characteristic cobblestoned appearance to the bowel. […] Transmural spread of inflammation leads to lymphedema and thickening of the bowel wall and mesentery. Mesenteric fat typically extends onto the serosal surface of the bowel. Mesenteric lymph nodes often enlarge. Extensive inflammation may result in hypertrophy of the muscularis mucosae, fibrosis, and stricture formation, which can lead to bowel obstruction. […] Noncaseating granulomas can occur in lymph nodes, peritoneum, the liver, and all layers of the bowel wall. Although pathognomonic when present, granulomas are not detected in about half of patients with Crohn disease. The presence of granulomas does not seem to be related to the clinical course.

• #62 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #63 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #64 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  IBD pathogenesis is a result of the interplay between genetic, environmental, intestinal barrier and immune response factors. […] Upon exposure to environmental factors, patients with IBD develop microbial dysbiosis with decrease of short-chain fatty acids (SCFA) producing bacteria and increase in Proteobacteria. Mechanisms that maintain the intestinal barrier are also disrupted in the IBD mucosa, including: down regulation of E-cadherin in tight junctions; thickness of the mucus layer; abnormal goblet cell function, including Muc2 and RELM proteins; and dysfunctional Paneth cells associated mechanisms, including secretion of antimicrobial products, NOD2 and ATG16L1 gene associated functions. […] The intestinal mucosa exists in a functional equilibrium with the luminal contents, and disturbance of this equilibrium can lead to pathology such as IBD. The Intestinal Barrier composed by intestinal epithelial cells (IEC) and innate immune cells, maintains this balance between luminal contents and the mucosa. The importance of the epithelial barrier in IBD predisposition is supported by the finding of abnormal intestinal permeability in patients with CD and some of their first-degree relatives. Furthermore, analysis of intestinal biopsies from patients with CD has demonstrated down regulation of the junctional protein E-cadherin, which comprises the tight junctions of this physical barrier.

• #65 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  The pathways of several key genetic risk factors of IBD impair Paneth cell function leading to colitis, most notably: NOD2 and autophagy. NOD2 is expressed by Paneth cells, dendritic Cells, macrophages and absorptive IEC. NOD2 risk variants are associated with lower levels of -defensins in Paneth cells leading to impaired antimicrobial function. Not only through NOD2 but also via CD risk locus ATG16L1, Paneth cells function in autophagy is compromised in patients with CD. […] The disturbed balance between anti and pro-inflammatory signals with consequent migration of leukocytes to the intestinal mucosa results in and is perpetuated by an exaggerated T cell immune response, which is seen in both CD and UC. The T cells involved on immune responses in both diseases, however, seem to be different, what may explain phenotypic differences seen in clinical practice as well as response to new targeted therapies.

• #66 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  The pathways of several key genetic risk factors of IBD impair Paneth cell function leading to colitis, most notably: NOD2 and autophagy. NOD2 is expressed by Paneth cells, dendritic Cells, macrophages and absorptive IEC. NOD2 risk variants are associated with lower levels of -defensins in Paneth cells leading to impaired antimicrobial function. Not only through NOD2 but also via CD risk locus ATG16L1, Paneth cells function in autophagy is compromised in patients with CD. […] The disturbed balance between anti and pro-inflammatory signals with consequent migration of leukocytes to the intestinal mucosa results in and is perpetuated by an exaggerated T cell immune response, which is seen in both CD and UC. The T cells involved on immune responses in both diseases, however, seem to be different, what may explain phenotypic differences seen in clinical practice as well as response to new targeted therapies.

• #67 Mechanisms of Disease: Inflammatory Bowel Diseases

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6386158/

  In CD, the differentiation of Th type 1 and 17 occurs in response to the production of IL-12, IL-18, IL-23 and transforming growth factor beta (TGF) by antigen presenting cells (APC) and macrophages. In turn Th1 and Th17 cells secrete the pro-inflammatory cytokines IL-17, INF- and TNFa that feed into a self-sustaining amplification cycle whereby they stimulate APC, macrophages, fibroblasts and endothelial cells to produce TNF, IL-1, IL-6, IL-8, IL-12 and IL-18. […] Understanding the mechanisms that lead to IBD pathogenesis is crucial in order to find new therapeutic strategies to improve patient therapies.

• #68 Inflammatory bowel disease (IBD) – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/diagnosis-treatment/drc-20353320

  The goal of inflammatory bowel disease treatment is to reduce the inflammation that triggers symptoms. In the best cases, this may lead not only to symptom relief but also to long-term remission and reduced risk of complications. IBD treatment usually involves either medicines or surgery. […] Anti-inflammatory medicines are often the first step in the treatment of ulcerative colitis, typically for mild to moderate disease. Anti-inflammatories include aminosalicylates, such as mesalamine (Delzicol, Rowasa, others), balsalazide (Colazal) and olsalazine (Dipentum). […] These drugs work in a variety of ways to suppress the immune response that releases inflammation-inducing chemicals into the body. When released, these chemicals can damage the lining of the digestive tract. […] Biologics are a newer category of therapy in which treatment is directed toward neutralizing proteins in the body that are causing inflammation. Some of these medicines are administered via intravenous, also called IV, infusions and others are injections you give yourself. Examples include infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), certolizumab (Cimzia), vedolizumab (Entyvio), ustekinumab (Stelara) and risankizumab (Skyrizi).

• #69 What is the pathophysiology of inflammatory bowel disease?

  https://medical.lilly.com/us/products/answers/what-is-the-pathophysiology-of-inflammatory-bowel-disease-103272

  Binding of IL-23 to its receptor on macrophages promotes secretion of additional proinflammatory cytokines, including TNF-alpha and interleukin-1 beta (IL-1). […] Interleukin-23 also contributes to the differentiation, expansion, and stabilization of Th17 and other interleukin-17 (IL-17)-producing cells, and in synergy with IL-1, increases IL-17 secretion from effector T cells. […] Interleukin-17 is involved in the recruitment of neutrophils from nearby capillaries into the mucosa, where they degranulate and release toxic molecules, thus amplifying the inflammatory activity. […] The exacerbated inflammatory response leads to epithelial breakdown, depleted goblet cells, an impaired mucus layer in UC, or intestinal wall fibrosis in CD. […] The important role of IL-23 in the inflammatory response has been recognized, and IL-23 inhibition offers new therapeutic options in the treatment of IBD.

• #70 Current Therapy in Inflammatory Bowel Disease: Why and How We Need to Change? – European Medical Journal

  https://www.emjreviews.com/innovations/article/current-therapy-in-inflammatory-bowel-disease-why-and-how-we-need-to-change-j080121/

  If the complexity of IBD is accepted, and the fact that the single target-single medicine approach has stalled progress, one solution is to think about IBD in a completely different way. If IBD is complex, healthcare professionals should embrace its complexity: IBD has multiple components with multiple links, comparable to what happens in most networks. Thinking in terms of an IBD network, a network medicine approach should be applied. Network medicine is based on the principle that rather than trying to force disease pathogenesis into a reductionist model, network medicine embraces the complexity of multiple influences on disease and relies on many different types of networks. […] This omic- and AI-based approach will drastically change the way IBD is treated as each patient will receive drugs specifically designed for their underlying mechanism of disease, unlike drugs that broadly block mechanisms of inflammation.

• #71 Novel Insights into the Pathogenesis of Inflammatory Bowel Diseases

  https://www.mdpi.com/2227-9059/13/2/305

  Gut microbiota contributes to determining intestinal inflammation mainly through its interaction with the immune system. […] The taxonomical impairment in gut microbiota results in a shift in the metabolomic profile of IBD patients. […] The role of environmental exposures across childhood, cumulative lifetime, and adulthood in IBD pathogenesis is summarized in Figure 3. […] Our findings from the most recent research confirm that IBDs are complex disorders driven by the intricate interplay between genetic predisposition, immune dysregulation, gut microbiota alterations, and environmental exposures.

• #72 Novel Insights into the Pathogenesis of Inflammatory Bowel Diseases

  https://www.mdpi.com/2227-9059/13/2/305

  Inflammatory bowel diseases (IBDs), encompassing Crohn’s disease and ulcerative colitis, are complex chronic disorders characterized by an intricate interplay between genetic predisposition, immune dysregulation, gut microbiota alterations, and environmental exposures. […] Immune dysregulation, including macrophage polarization (M1 vs. M2) and Th17 activation, emerges as a cornerstone of IBD pathogenesis. […] Dysbiosis, as a result of reduced alpha and beta diversity and overgrowth of harmful taxa, is one of the main contributing factors in causing inflammation in IBD. […] The pathogenesis of IBD is a multifaceted interplay between genetic susceptibility, environmental triggers, immune system dysregulation, and gut microbiota alterations. […] The mainstay of IBD pathogenesis lies in a dysregulated immune response to gut microbiota.

• #73 Current Therapy in Inflammatory Bowel Disease: Why and How We Need to Change? – European Medical Journal

  https://www.emjreviews.com/innovations/article/current-therapy-in-inflammatory-bowel-disease-why-and-how-we-need-to-change-j080121/

  If the complexity of IBD is accepted, and the fact that the single target-single medicine approach has stalled progress, one solution is to think about IBD in a completely different way. If IBD is complex, healthcare professionals should embrace its complexity: IBD has multiple components with multiple links, comparable to what happens in most networks. Thinking in terms of an IBD network, a network medicine approach should be applied. Network medicine is based on the principle that rather than trying to force disease pathogenesis into a reductionist model, network medicine embraces the complexity of multiple influences on disease and relies on many different types of networks. […] This omic- and AI-based approach will drastically change the way IBD is treated as each patient will receive drugs specifically designed for their underlying mechanism of disease, unlike drugs that broadly block mechanisms of inflammation.

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