Materiały źródłowe

• #1 Pathogenesis of Crohn’s disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4447044/

  Significant progress in our understanding of Crohn’s disease (CD), an archetypal common, complex disease, has now been achieved. […] Although the etiology is complex, the most widely accepted hypothesis purports CD as an immune-mediated condition in genetically susceptible individuals, where disease onset is triggered by environmental factors that perturb the mucosal barrier, alter the healthy balance of the gut microbiota, and abnormally stimulate gut immune responses. […] CD pathogenesis involves a complex interplay over time between genetic, epigenetic, immunological, and microbiological mechanisms affected by exposure to triggering factors. […] The successful genome-wide association studies (GWASs) have provided a rational framework for new mechanistic insights and directions for research in CD.

• #1 Pathogenesis of Crohn’s disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4447044/

  Overall, 163 IBD loci that meet genome-wide significance thresholds were discovered; this is substantially more than other complex diseases. […] Most genetic associations are shared between CD and UC (110 loci), and 30 loci were specifically associated with CD. […] NOD2 is a cytosolic pattern recognition receptor (PRR) that controls immunity against intracellular bacteria. […] NOD2 provides critical host anti-bacterial defense and pro-inflammatory responses […] NOD2 plays a key role in amplifying the release of certain pro-inflammatory cytokines in this context, particularly IL-1, IL-6, and IL-23, from DCs and macrophages. […] Loss of autophagy function appears to be a fundamental driver […] The ATG16L1 protein plays an essential role in triggering all forms of autophagy involving the recruitment of microtubule-associated protein 1 light chain 3 (LC3) to membranes.

• #1 Inflammatory Bowel Disease (IBD): Pathogenesis – Creative Med Doses

  https://creativemeddoses.com/topics-list/inflammatory-bowel-disease-ibd-pathogenesis/

  Inflammatory bowel disease is a chronic relapsing inflammatory disorder of intestine. Although the exact etiology of IBD is unknown, it involves a complex interaction between the genetic, environmental or microbial factors and the immune responses. […] NOD2 senses microbiota-derived products and activates NF-B which is critical for the bacterial killing activity of Paneth cells via the secretion of anti-bacterial compounds. Loss of function NOD2 mutants disturb many characteristics of gut immune homeostasis, including reduced bacterial product sensing, and impaired antimicrobial responses in Paneth cells, leading to defective bacterial clearance. It creates dysbiosis in microbiota of intestine which is, characterized by increased load of bacteria and activates immune system for continuous attack.

• #1 Pathogenesis of Crohn’s disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4447044/

  Loss of autophagy leading to Paneth cell dysfunction has been a strong focus; these cells are highly metabolically active and specialized enterocytes in the small bowel responsible for AMP production. […] Following on from autophagy-related epithelial dysfunction, unresolved endoplasmic reticulum (ER) stress in intestinal epithelial cells (IECs) has also emerged as an important factor that initiates gut inflammation relevant to CD. […] The dynamic crosstalk between the gut microbiota, IECs, and mucosal immune cells is essential to maintain intestinal homeostasis. […] The gut microbiota regulates both Th17 and Treg cell responses, which appear to be reciprocally related. […] Advances in culture-free techniques, next-generation high-throughput sequencing platforms, and the use of larger and more sophisticated human cohorts have ushered in a dramatic era in understanding the role of the gut microbiota in IBD. […] The importance of the gut microbiota in the pathogenesis of CD is strikingly demonstrated clinically where the diversion of fecal stream treats and prevents recurrence of CD.

• #1 Crohn Disease: Update on Diagnosis, Pathophysiology, and Treatment

  https://www.clinicaladvisor.com/features/crohn-disease-diagnosis-pathophysiology-treatment/

  Crohn disease is believed to occur because of an interplay between genetic susceptibility, immunologic factors, environmental influences, and intestinal microflora, resulting in an abnormal mucosal immune response and compromised epithelial barrier function.1 […] Both subtypes of IBD CD and UC result from a dysregulated response of the mucosal immune system to the bacterial flora that reside within the intestinal lumen.5,18 In IBD, the intestinal epithelial layer has excessive permeability that allows pathogens to leak through to the underlying mucosal layers.19 It is believed that this triggers an autoimmune reaction with persistent activation of immune cells. Neutrophils, lymphocytes, and lymphoid tissue produce pro-inflammatory cytokines such as tumor necrosis factor- (TNF-) and interleukins (ILs) that perpetuate the inflammatory response.20

• #1 Pathogenesis of Crohn’s disease: Bug or no bug

  https://www.wjgnet.com/2150-5330/full/v6/i1/1.htm

  It has become evident that IBD patients show an intestinal dysbiosis, with a decrease in the number of potentially beneficial bacteria such as Bifidobacteria, Lactobacilli and Firmicutes, and an increase in that of putative pathogenic bacteria such as Escherichia coli (E. coli) and other Enterobacteria. […] Over the years, many organisms have been proposed as etiological agents for IBD, to the extent of suggesting that CD, for example, is a manifestation of chronic mycobacterial infection or E. coli adherence and invasion. […] Many observations implicate bacteria as a trigger for the development of CD: lesions occur in regions with the highest bacterial concentrations; aphthous ulcers, the earliest lesion in CD, occur in Peyers patches, the site of bacterial sampling; inflammation resolves when the faecal stream is diverted and is reactivated following reinfusion of bowel contents; severity of the disease is correlated with bacterial density in the mucosa; granulomas contain bacteria; and susceptible mice raised in germ-free conditions only develop inflammation when non-pathogenic bacteria are introduced.

• #1 Crohn Disease: Update on Diagnosis, Pathophysiology, and Treatment

  https://www.clinicaladvisor.com/features/crohn-disease-diagnosis-pathophysiology-treatment/

  Approximately one-third of patients with CD have an increased amount of mucosa-associated, adherent-invasive Escherichia coli.21 These bacteria cross the mucosal barrier, adhere to and invade intestinal epithelial cells, and replicate within macrophages, which provokes the secretion of high amounts of TNF-. The intestinal inflammatory infiltrate in CD contains T cells and antibodies that act against the intestinal bacteria.22,23 The key pathologic findings on intestinal biopsies in CD are granulomatous inflammatory changes characterized by focal collections of macrophages, epithelioid cells, and multinucleated giant cells.24

• #1 Pathophysiology of Crohn’s disease inflammation and recurrence

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7648997/

  Crohns disease pathogenesis is based on tissue inflammation, caused by an unrestrainable immune response against luminal bacterial antigens. Immune cells like CD4 T-Cells, CD8 T-Cells, B-Cells, CD14 monocytes and natural killers, are involved in this process as they infiltrate the gut of CD patients. Part of the immune-mediated susceptivity to CD resides in some innate mechanisms of defense form infectious diseases and the intestinal mucus secretion is part of those. It has been shown that variants of the Muc2 gene reducing mucus production are associated to CD in a mouse model. Moreover, molecules that are mediating bacterial adhesion have been correlated to the disease. This is the case of FUT2, which encodes for the fucosyltransferase enzyme, responsible for the secretion of soluble forms of the ABO antigens. People harboring a FUT2 variants decreasing the secretion of the antigens, have an altered interaction with bacteria and are more prone to developing CD. The pathogenesis is also sustained by the interaction of these cells with integrins, adhesion molecules and multiple chemokines, responsible for the production of elevated levels of inflammatory cytokines, representing the target of immune and non-immune cells and the promotion of mucosal inflammation. As such, among many adhesion molecules, some evidences on the involvement of the leucocyte MAcCAM-1, receptor for the 44 integrin, seems to play a crucial role. Together with leucocyte adhesion, the role of the extracellular matrix on their activation has been explored. Proteins like CD44 and CD26 where shown to play a role as well as metalloproteins (MMP), being MMP1 and MMP3 abundant in the granular tissue close to CD sites of inflammation, therefore responsible for leucocytes activation. In the mucosa of CD patients, a dysregulation of various components of the immune system is invariably found. The most pronounced alteration is the hyperactivity of T cells with excessive production of cytokines, between which IL-12 and IFN-, promoting a TH1 lymphocytic phenotype, opposed to the TH2 one, correlating to ulcerative colitis. Moreover, TNF- production has also been demonstrated to increase the number of CD4+ FoxP3+ TREG cells, especially in the mucosa of children affected by CD. The inhibition of the effector cytokines, like TNF-, attenuates the detrimental effects in subsets of CD patients. Furthermore, the expression of the interleukins, a subgroup of cytokines implicated in the enhanced or inhibition of other cytokines in many different regulatory pathways such as maturation, growth and responsiveness of immune cells population, is to be considered anomalous in CD patients. Further analysis of T cell subsets has revealed the presence of TH1 and TH17 cells in CD, whereas the cytokines considered more involved are TNF, IL12 and IL23. Apart from the cited cytokines, IL-34 has also been associated to IBD and CD in particular. IL34 expression is more pronounced in the areas of active inflammation, especially in CD, and seems to induce TNF- and IL6 expression through a ERK-mediated mechanism. Moreover, IL-34 has been described as an inducer of CCL20 through the interaction with its receptor the M-CSFR1, abundantly expressed in the inflamed colonic epithelium but not in the healthy controls. On the contrary, IL-25 inversely correlates to the inflammatory state of the patients with IBD, being reduced in CD patients as opposing to healthy subject, and being reduced in the affected areas of the colon if compared to the surrounding adjacent normal tissue from the same subject. Among all the possible interleukins associated to CD pathogenesis, IL-12 and IL-23 represent the target of still inadequate therapies because of potential side effects, such as increased risk for infection, and the blockade of specific immunological targets, capable of induction of alternative signaling or homing pathways. The latter mechanism may also partially explain the frequent lack of response to therapy with biologics such as Infliximab (Remicade), a chimeric monoclonal antibody used to treat autoimmune diseases, that works by binding to TNF- causing the reduction of IL-34 expression, implicated in monocyte and macrophage differentiation, survival and function.

• #1 Updated review on immune factors in pathogenesis of Crohn’s disease

  https://www.wjgnet.com/1007-9327/full/v24/i1/15.htm

  Immunity is now a universally acknowledged cause of CD, and hormone therapy can cause remission, demonstrating that CD is an immune-related disease. […] At present, the specific processes involved in the breakdown of immune tolerance and the associated sequence of genetic changes are still unclear. […] The specific mechanisms leading to this immune imbalance, which causes persistent intestinal mucosal damage, and the source of the inflammatory cascade reaction remain unclear. […] Here we present the most current research on immune factors in the pathogenesis of CD with regard to the mechanisms about T cell immunity, innate cell immunity, and cytokines. […] Studies have found that CD results mainly from chronic inflammation of T lymphocytes, especially CD4+ T cells. […] CD4+ T cells are the main effector lymphocytes in intestinal inflammatory tissue.

• #1 Updated review on immune factors in pathogenesis of Crohn’s disease

  https://www.wjgnet.com/1007-9327/full/v24/i1/15.htm

  In CD, there are two simultaneous changes in the initial stage of inflammation: the induction phase and the effector phase. […] Both Th1 and Th2 may participate in each phase simultaneously or sequentially. […] The inflammatory response appears to be related to CD4+ T cells, and the role of CD8+ T cells in CD remains unclear. […] However, the pathological effect of CD8+ cells should not be ruled out completely. […] The role of CTLs in the pathogenesis of CD has been investigated in few studies, but CD8+ cell subsets and T lymphocytes (CTLs, CD8, and CD28+) are believed to play a key role in the recognition and elimination of mutant cells, and inflammation caused by graft-versus-host reactions. […] Studies have found that increased ILC3 can overexpress major histocompatibility complex (MHC) II.

• #1 Pathophysiology of Crohn’s disease inflammation and recurrence

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7648997/

  The complex milieu that is created by the interaction of the inflammatory cells with the intestinal epithelium is sustained by a complex network of cytokines and chemokines, which direct T lymphocytes towards a TH1 response, mediated by the expression of the FoxP3 transcription factor in the TREG population. Among the cytokines involved in CD pathogenesis, IL-34 and IL-25 seem to play opposing roles, the first increased in the injured tissue, the second one diminished. Other cytokines such as IL-12 and IL-23 have been demonstrated paying a key role in the inflammatory response and are some of the few current medical therapeutic targets for CD.

• #1 Mechanisms of Disease: pathogenesis of Crohn’s disease and ulcerative colitis | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/ncpgasthep0528

  Crohn’s disease and ulcerative colitis are idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated. […] 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.

• #1 Pathophysiology of Crohn’s disease inflammation and recurrence | Biology Direct | Full Text

  https://biologydirect.biomedcentral.com/articles/10.1186/s13062-020-00280-5

  The pathogenesis is also sustained by the interaction of these cells with integrins, adhesion molecules and multiple chemokines, responsible for the production of elevated levels of inflammatory cytokines, representing the target of immune and non-immune cells and the promotion of mucosal inflammation. […] The most pronounced alteration is the hyperactivity of T cells with excessive production of cytokines, between which IL-12 and IFN-, promoting a TH1 lymphocytic phenotype, opposed to the TH2 one, correlating to ulcerative colitis. […] The complex milieu that is created by the interaction of the inflammatory cells with the intestinal epithelium is sustained by a complex network of cytokines and chemokines, which direct T lymphocytes towards a TH1 response, mediated by the expression of the FoxP3 transcription factor in the TREG population. Among the cytokines involved in CD pathogenesis, IL-34 and IL-25 seem to play opposing roles, the first increased in the injured tissue, the second one diminished. Other cytokines such as IL-12 and IL-23 have been demonstrated paying a key role in the inflammatory response and are some of the few current medical therapeutic targets for CD. […] The same factors that underline the pathogenesis of CD at its first stages are thought to be responsible for post-operative recurrence (POR) setting, being the result of interplay of microbial, environmental, immunological and genetic variables.

• #1 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.

• #1 Crohn Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172940-overview

  Chronic inflammation from T-cell activation leading to tissue injury is implicated in the pathogenesis of Crohn disease. […] After activation by antigen presentation, unrestrained responses of type 1 T helper (Th1) cells predominate in Crohn disease as a consequence of defective regulation. Th1 cytokines such as interleukin (IL)-12 and TNF- stimulate the inflammatory response. Inflammatory cells recruited by these cytokines release nonspecific inflammatory substances, including arachidonic acid metabolites, proteases, platelet activating factor, and free radicals, which result in direct injury to the intestine. […] In a study from 2012, investigators suggested that genetic predispositions for inflammatory bowel disease (IBD) lead to abnormal epithelial barrier integrity and homeostasis, deficits in autophagy, deficiencies in innate pattern recognition receptors, and problems with lymphocyte differentiation, especially in Crohn disease.

• #1 Crohn Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172940-overview

  Although granuloma formation is pathognomonic of Crohn disease, its absence does not exclude the diagnosis. […] Transmural inflammation results in thickening of the bowel wall and narrowing of the lumen. As Crohn disease progresses, it is complicated by obstruction or deep ulceration leading to fistulization by way of the sinus tracts penetrating the serosa, microperforation, abscess formation, adhesions, and malabsorption. […] Fistulae may be enteroenteral, enterovesical, enterovaginal, or enterocutaneous. The inflammation extending through the bowel wall may also involve the mesentery and surrounding lymph nodes. […] Infectious agents such as Mycobacterium paratuberculosis, Pseudomonas species, and Listeria species have all been implicated in the pathogenesis of Crohn disease, suggesting that the inflammation seen with the disease is the result of a dysfunctional, but appropriate, response to an infectious source.

• #1 Crohn Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172940-overview

  Interleukins and TNF- have also been implicated in the disease process. Crohn disease is characterized by a Th1 cellular immune response pattern that leads to production of IL-12, TNF-, and interferon gamma. TNF- has been shown to play a critical role in the inflammation in this disease. Increased production of TNF- by macrophages in patients with Crohn disease results in increased concentrations of TNF- in the stool, blood, and mucosa. […] Studies have also provided strong support for IBD susceptibility genes on chromosome 5p13.1, which is a gene desert but does modulate expression of the PTGER4 gene.

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

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

  TNF- is thought to play a role in the pathogenesis of IBD via fibroblast activation, enhanced production of pro-inflammatory cytokines, and enhanced T-cell resistance to apoptosis. […] The genetic, microbial, dietary, and metabolic associations in IBD suggest that dysregulated host-microbe relationships, further influenced by diet, are important in the pathogenesis of IBD. […] As the global prevalence of pIBD increases, improved understanding of the pathogenesis of these diseases is warranted to prevent poor outcomes in these patients.

• #1 Inflammatory bowel disease (IBD) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/symptoms-causes/syc-20353315

  Crohn’s disease affects the full thickness of the bowel wall. Over time, parts of the bowel can thicken and narrow, which may block the flow of digestive contents. […] Sometimes inflammation can extend completely through the intestinal wall and create a fistula a connection between different body parts that is not typical.

• #1 Crohn’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/crohns-disease/symptoms-causes/syc-20353304

  Crohn’s disease can affect the entire thickness of the intestinal wall. Over time, parts of the bowel can scar and narrow, which may block the flow of digestive contents, often known as a stricture. […] Ongoing inflammation can lead to open sores called ulcers anywhere in the digestive tract. […] Sometimes ulcers can extend completely through the intestinal wall, creating a connection between different body parts that shouldn’t be there. This is known as a fistula. […] Diarrhea, belly pain and cramping may make it difficult to eat or for the intestine to absorb enough nutrients. It’s also common to develop anemia due to low iron or vitamin B-12 caused by the disease. […] Having Crohn’s disease that affects the colon increases the risk of colon cancer.

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

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

  Crohn disease is categorized into 3 principal patterns: (1) primarily inflammatory, which after several years commonly evolves into (2) primarily stenotic or obstructing or (3) primarily penetrating or fistulizing. […] There is an increased risk of cancer in affected small-bowel segments. Patients with colonic involvement have a long-term risk of colorectal cancer equal to that of ulcerative colitis, given the same extent and duration of disease. […] Chronic malabsorption may cause nutritional deficiencies, particularly of vitamins D and B12. […] Ultimately, further surgery is required in nearly 35% of cases in 10 years. However, recurrence rates seem to be reduced by early postoperative prophylaxis with 6-mercaptopurine or azathioprine, metronidazole, or infliximab.

• #1 The role of epigenetic modifications for the pathogenesis of Crohn’s disease | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01089-3

  Epigenetics has become a promising field for finding new biomarkers and improving diagnosis, prognosis, and drug response in inflammatory bowel disease. Crohn’s disease is assumed to be the result of a complex interplay between genetic susceptibility, environmental factors, and altered intestinal microbiota, leading to dysregulation of the innate and adaptive immune response. While many genetic variants have been identified to be associated with Crohn’s disease, less is known about the influence of epigenetics in the pathogenesis of this disease. […] Epigenetic modifications influenced by environmental factors might help to understand the increasing CD incidence. […] Recently, the analysis of epigenetic changes like DNA methylation or histone modification is recognized as highly useful to identify new biomarkers or targets for drug therapy, which is essential to apply a more targeted treatment in CD.

• #1 The role of epigenetic modifications for the pathogenesis of Crohn’s disease | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01089-3

  Epigenetic changes are involved in the correct development of cells and their functions, cell differentiation, and homeostasis but are also associated with numerous diseases. […] The most widely studied epigenetic modification in mammals is DNA methylation, which occurs through the covalent bonding of a methyl group to the 5 carbon of the cytosine residue. […] When methylation occurs near a promoter sequence, gene expression is inactivated, either because proteins bind to the methylated CpG island and initiate DNA compensation and inactivation or methylation itself blocks the DNA sequence and transcription factors are unable to bind. […] The DNA themselves is packed together with histones to form chromatin, whereby 147 bp of DNA is wrapped 1.7 times around a core of 8 histone proteins.

• #1 The role of epigenetic modifications for the pathogenesis of Crohn’s disease | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01089-3

  It can therefore be assumed that histone acetylation is associated with intestinal inflammation in CD patients and may represent a new therapeutic target for mucosal healing. […] Changes in the DNA methylation status of CD-associated genes significantly alter transcriptional activity and expression levels of genes, thereby influencing disease risk and progression. […] Future studies would have to take into account that different cell types may have diverse DNA methylation landscapes, which is crucial to decipher and elucidate the exact functional consequences of epigenetic changes in IBD pathogenesis.

• #1 Novel Models of Crohn’s Disease Pathogenesis Associated with the Occurrence of Mitochondrial Dysfunction in Intestinal Cells

  https://www.mdpi.com/1422-0067/23/9/5141

  Crohn’s disease remains one of the challenging problems of modern medicine, and the development of new and effective and safer treatments against it is a dynamic field of research. […] During the recent years, the involvement of mitochondrial dysfunction and associated chronic inflammation in these processes became evident. […] Currently, the dominant hypothesis of CD pathogenesis is the development of an aggressive immune response to the gut microbiome in genetically predisposed individuals. […] One likely cause of chronic inflammation is mitochondrial dysfunction. […] Mitochondrial dysfunction was also described in CD. […] The effect of mitochondrial dysfunction in CD development can be divided into two distinct pathways. […] The first one is the impact of energy shortage through impaired ATP synthesis, which leads to disruption of a number of processes important for the proper functioning of the intestine.

• #1 Novel Models of Crohn’s Disease Pathogenesis Associated with the Occurrence of Mitochondrial Dysfunction in Intestinal Cells

  https://www.mdpi.com/1422-0067/23/9/5141

  The second pathway is based not on an energy deficit in the intestinal cells, but on increased generation of reactive oxygen species (ROS) and disruption of mitophagy, which leads to the accumulation of defective mitochondria. […] Mitochondrial dysfunction is a well-known feature of various chronic diseases associated with low-level sustained inflammation. […] This hypothesis is confirmed by the presence of mitochondrial dysfunction in CD. […] Mitochondrial damage could influence increased intestinal barrier permeability for pathogens. […] The increase in ROS production is associated with disturbances in the respiratory complexes functioning, with increased proton leakage and excessive oxygen consumption, accompanied by a further increase in ROS generation. […] Increasing the number of defective mitochondria leads to even greater DAMP generation, which triggers an inflammatory response.

• #1 Novel Models of Crohn’s Disease Pathogenesis Associated with the Occurrence of Mitochondrial Dysfunction in Intestinal Cells

  https://www.mdpi.com/1422-0067/23/9/5141

  Thus, mtDNA acts as an intracellular activator of the inflammatory reaction. […] We propose four pathogenetic models for the development of CD, with mitochondrial dysfunction development as a central event, and one model based on the lack of butyrate, an important anti-inflammatory mediator, in the intestine.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20240313/Scientists-uncover-an-overlooked-mechanism-in-the-gut-immune-system-of-Crohns-disease-patients.aspx

  A team of scientists from DTU and other European universities have uncovered an overlooked mechanism in the gut immune system of patients suffering from severe cases of Crohn’s disease. […] A new study by researchers from DTU and 3 European universities shows that antibodies in the gut immune system, which line the stomach and intestinal walls and keep harmful bacteria at bay, may be crucial in understanding why some CD patients suffer more than others. […] The main issue regarding Crohn’s disease, specifically, is that there isn’t enough evidence to explain precisely why some people end up with severe inflammation in their gut. […] We know that some bacteria can hide from the immune system, and in this study, we find that especially two – Campylobacter and Mannheimia – seem to be prevalent in severe cases.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20240313/Scientists-uncover-an-overlooked-mechanism-in-the-gut-immune-system-of-Crohns-disease-patients.aspx

  The study shows that the immune system of patients with severe Crohn’s disease holds a remarkably high coating of certain gut bacteria with a specific antibody type indicative of inflammation. […] However, the new paper shows that IgG plays a significant role in the gut immune system, especially concerning severe cases of Crohn’s disease. […] The immune system of patients with severe CD is thus acting differently from healthy individuals and patients with less severe CD. […] Although it is a bit weird to try and differentiate between people with Crohn’s disease because everyone is suffering, we do show that the level of IgG2 bacterial coating in Crohn’s patients can be used to differentiate between those who have severe disease and those who may have a slightly milder disease course.

• #1 High Fat Diet Accelerates Pathogenesis of Murine Crohn’s Disease-Like Ileitis Independently of Obesity | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071661

  Obesity has been associated with a more severe disease course in inflammatory bowel disease (IBD) and epidemiological data identified dietary fats but not obesity as risk factors for the development of IBD. […] Despite recent observations that high fat diets (HFD) impair intestinal barrier functions and drive pathobiont selection relevant for chronic inflammation in the colon, mechanisms of high fat diets in the pathogenesis of Crohns disease are not known. […] HFD aggravated ileal inflammation but did not induce significant overweight or typical metabolic disorders in TNFARE/WT. […] Expression of the tight junction protein Occludin was markedly reduced in the ileal epithelium of HFD mice independently of inflammation, and translocation of endotoxin was increased. […] HFD feeding, independently of obesity, accelerated disease onset of small intestinal inflammation in Crohns disease-relevant mouse model through mechanisms that involve increased intestinal permeability and altered luminal factors, leading to enhanced dendritic cell recruitment and promoted Th17 immune responses.

• #1 High Fat Diet Accelerates Pathogenesis of Murine Crohn’s Disease-Like Ileitis Independently of Obesity | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071661

  We here show that a palm-oil based HFD accelerates the onset of small intestinal inflammation in TNFARE/WT mice, a model of CD-like ileitis, and additionally promotes expansion of inflammation into the proximal colon. […] We hypothesize that the observed aggravation of ileitis in the present study is independent of obesity, but is rather a consequence of altered luminal composition, increased intestinal permeability and so-called metabolic endotoxemia secondary to dietary lipids. […] Our finding that luminal factors and not the development of obesity and obesity-associated metabolic parameters are prerequisites for aggravation of IBD is supported by the results of a recent prospective cohort study reporting a lack of association of body mass index with IBD development. […] The impaired Occludin expression observed in the present study might contribute to an increased translocation of microbiota-derived endotoxin under HFD, often referred to as metabolic endotoxemia, and therefore trigger proinflammatory mechanisms leading to recruitment and activation of immune cells.

• #1 High Fat Diet Accelerates Pathogenesis of Murine Crohn’s Disease-Like Ileitis Independently of Obesity | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071661

  We demonstrated that the expression and secretion of CCL20 and the subsequent recruitment of DCs is amplified in vivo upon HFD feeding. […] Our present results indicate that these findings are related to alterations of luminal factors as well as epithelium-derived signals rather than the state of obesity.

• #2 Pathophysiology of Crohn’s disease inflammation and recurrence | Biology Direct | Full Text

  https://biologydirect.biomedcentral.com/articles/10.1186/s13062-020-00280-5

  Chrons Disease is a chronic inflammatory intestinal disease, first described at the beginning of the last century. The disease is characterized by the alternation of periods of flares and remissions influenced by a complex pathogenesis in which inflammation plays a key role. Crohns disease evolution is mediated by a complex alteration of the inflammatory response which is characterized by alterations of the innate immunity of the intestinal mucosa barrier together with a remodeling of the extracellular matrix through the expression of metalloproteins and increased adhesion molecules expression, such as MAcCAM-1. This reshaped microenvironment enhances leucocytes migration in the sites of inflammation, promoting a TH1 response, through the production of cytokines such as IL-12 and TNF-. […] Crohns disease pathogenesis is based on tissue inflammation, caused by an unrestrainable immune response against luminal bacterial antigens. Immune cells like CD4 T-Cells, CD8 T-Cells, B-Cells, CD14 monocytes and natural killers, are involved in this process as they infiltrate the gut of CD patients.

• #2 Pathogenesis of Ulcerative Colitis and Crohn’s Disease: Sim

  https://www.longdom.org/open-access/pathogenesis-of-ulcerative-colitis-and-crohn8217s-disease-similarities-differences-and-a-lot-of-things-we-do-not-know-ye-49592.html

  Of the 163 identified loci, 110 are linked to both CD and UC, while 30 are specific for CD, and 23 are specific for UC. […] Several genes that are associated with both CD and UC play a role in the interleukin (IL)-23 signalling pathway (such as IL23R, Janus kinase [JAK] 2, signal transducer and activator of transcription [STAT] 3 and IL12B). […] These recent findings have questioned the previous theory of a clear Th2-driven inflammation in UC and Th1-driven responses in CD, and have drawn attention to the role of Th17 lymphocytes in the pathogenesis of both disorders. […] The role of IL-17 was at least partly elucidated by animal experiments, which have suggested that IL-17A protects from intestinal inflammation, while IL-17F promotes it. […] Autophagy is a pathomechanism in IBD that previously has been only implicated in CD, but the association of death associate protein (DAP), also with UC suggests a possible role of autophagy in both disorders.

• #2 Crohn Disease: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/172940-overview

  Chronic inflammation from T-cell activation leading to tissue injury is implicated in the pathogenesis of Crohn disease. […] After activation by antigen presentation, unrestrained responses of type 1 T helper (Th1) cells predominate in Crohn disease as a consequence of defective regulation. Th1 cytokines such as interleukin (IL)-12 and TNF- stimulate the inflammatory response. Inflammatory cells recruited by these cytokines release nonspecific inflammatory substances, including arachidonic acid metabolites, proteases, platelet activating factor, and free radicals, which result in direct injury to the intestine. […] In a study from 2012, investigators suggested that genetic predispositions for inflammatory bowel disease (IBD) lead to abnormal epithelial barrier integrity and homeostasis, deficits in autophagy, deficiencies in innate pattern recognition receptors, and problems with lymphocyte differentiation, especially in Crohn disease.

• #2 Pathophysiology of Crohn’s disease inflammation and recurrence | Biology Direct | Full Text

  https://biologydirect.biomedcentral.com/articles/10.1186/s13062-020-00280-5

  The pathogenesis is also sustained by the interaction of these cells with integrins, adhesion molecules and multiple chemokines, responsible for the production of elevated levels of inflammatory cytokines, representing the target of immune and non-immune cells and the promotion of mucosal inflammation. […] The most pronounced alteration is the hyperactivity of T cells with excessive production of cytokines, between which IL-12 and IFN-, promoting a TH1 lymphocytic phenotype, opposed to the TH2 one, correlating to ulcerative colitis. […] The complex milieu that is created by the interaction of the inflammatory cells with the intestinal epithelium is sustained by a complex network of cytokines and chemokines, which direct T lymphocytes towards a TH1 response, mediated by the expression of the FoxP3 transcription factor in the TREG population. Among the cytokines involved in CD pathogenesis, IL-34 and IL-25 seem to play opposing roles, the first increased in the injured tissue, the second one diminished. Other cytokines such as IL-12 and IL-23 have been demonstrated paying a key role in the inflammatory response and are some of the few current medical therapeutic targets for CD. […] The same factors that underline the pathogenesis of CD at its first stages are thought to be responsible for post-operative recurrence (POR) setting, being the result of interplay of microbial, environmental, immunological and genetic variables.

• #2

  https://step1.medbullets.com/evidence/16819502

  Crohn’s disease and ulcerative colitis are idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated. […] 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.

• #3 Pathogenesis of Ulcerative Colitis and Crohn’s Disease: Sim

  https://www.longdom.org/open-access/pathogenesis-of-ulcerative-colitis-and-crohn8217s-disease-similarities-differences-and-a-lot-of-things-we-do-not-know-ye-49592.html

  The most well-known gene associated with CD is CARD15, encoding nucleotide-binding oligomerization domain 2 (NOD2). […] NOD2 plays a role in pattern recognition of pathogen microbiota, activates nuclear factor (NF)-B in monocytes following lipopolysaccharide stimulation, and leads to the induction of proinflammatory cytokines. […] A relatively new discovery in the pathogenesis of CD is the association of the disease with autophagy genes (ATG16L1 and IRGM). […] Deficiency in autophagy related to a homozygous ATG16L1 allele causes impaired engulfment and degradation of the cytoplasmic content and microorganisms, defective presentation of bacterial antigens to CD4+ T-cells, and increased inflammatory cytokine production by Paneth-cells. […] Perturbation of bacterial killing and defective antimicrobial pathways may cause an uncontrolled inflammation and ultimately lead to CD.

Zobacz więcej