Cause Of Crohn's Disease Research Articles

Contribution of Toxin-Antitoxin Systems to Adherent-Invasive E. coli Pathogenesis.

Pathobionts have been implicated in various chronic diseases, including Crohn's disease (CD), a multifactorial chronic inflammatory condition that primarily affects the gastrointestinal tract, causing inflammation and damage to the digestive system. While the exact cause of CD remains unclear, adherent-invasive Escherichia coli (AIEC) strains have emerged as key contributors to its pathogenesis. AIEC are characterized by their ability to adhere to and invade intestinal epithelial cells and survive and replicate inside macrophages. However, the mechanisms underlying the virulence and persistence of AIEC within their host remain the subject of intensive research. Toxin-antitoxin systems (TAs) play a potential role in AIEC pathogenesis and may be therapeutic targets. These systems generally consist of two components: a toxin harmful to the cell and an antitoxin that neutralizes the toxin's effects. They contribute to bacterial survival in adverse conditions and regulate bacterial growth and behavior, affecting various cellular processes in bacterial pathogens. This review focuses on the current information available to determine the roles of TAs in the pathogenicity of AIEC. Their contribution to the AIEC stress response, biofilm formation, phage inhibition, the maintenance of mobile genetic elements, and host lifestyles is discussed.

Mycobacterium avium ssp. paratuberculosis and Crohn's Disease-Diagnostic Microbiological Investigations Can Inform New Therapeutic Approaches.

Mycobacterium avium ssp. paratuberculosis (MAP) is the cause of Johne's disease (JD), which is a chronic infectious gastrointestinal disease of ruminants and is often fatal. In humans, MAP has been associated with Crohn's disease (CD) for over a century, without conclusive evidence of pathogenicity. Numerous researchers have contributed to the subject, but there is still a need for evidence of the causation of CD by MAP. An infectious aetiology in CD that is attributable to MAP can only be proven by bacteriological investigations. There is an urgency in resolving this question due to the rising global incidence rates of CD. Recent papers have indicated the "therapeutic ceiling" may be close in the development of new biologics. Clinical trial outcomes have demonstrated mild or inconsistent improvements in therapeutic interventions over the last decades when compared with placebo. The necessity to revisit therapeutic options for CD is becoming more urgent and a renewed focus on causation is essential for progress in identifying new treatment options. This manuscript discusses newer interventions, such as vaccination, FMT, dietary remediation and gut microbiome regulation, that will become more relevant as existing therapeutic options expire. Revisiting the MAP theory as a potential infectious cause of CD, rather than the prevailing concept of an "aberrant immune response" will require expanding the current therapeutic programme to include potential new alternatives, and combinations of existing treatments. To advance research on MAP in humans, it is essential for microbiologists and medical scientists to microscopically detect CWDM and to biologically amplify the growth by directed culture.

Investigation of Crohn's Disease by Immunohistochemistry Technique in Iraqi Patients

Crohn's disease (CD) is one of the most common IBD types. CD necessitates an erratic immune response. Previous research has shown that inflammation of the intestines is elevated or continues due to inappropriate immune responses that result from the relationships between environmental factors, intestinal microbiota, and genetic factors. Induces intense transmural inflammation. This study aimed to investigate (i) CD detection by Histopathology and Immunohistochemistry (IHC) Markers that are Mycobacterium avium subspecies paratuberculosis MAP antibody and TWEAK/Fn14 antibody and their association with CD. (ii) Prove or disprove the hypothesis of MAP as a potential cause of CD. Tissue biopsies of 30 cases with a recognized diagnosis of CD and 20 cases as control presented without disease symptoms were collected. They are 20 males and 10 females for patients, and 13 males and 7 females for control with ages ranging from 9-55(±34.78) years. From 2019 - 2020, Biopsies were collected from Medical City Hospitals in Baghdad. One tissue section has been stained by the Hematoxylin & Eosin (H&E) for histopathology examinations. IHC stained the other two sections to the markers mentioned earlier in the IHC technique. The results of IHC for MAP showed a highly significant relationship in the ileal tissues of patients with disease CD with varying degrees according to the intensity of the immune reaction, which represents the intensity of the color, which is distributed between weak, moderate and strong, according to the (Aperio image Scope) program. Where it was 10% weak, 43.33% medium, and 46.67% strong. The P-value for patients vs. control was 0.0052 and 0.0001, respectively (P-value 0 ≤ 0.01). The result of IHC proves the hypothesis of MAP as a potential cause of CD. The other effects of IHC staining for TWEAK/Fn14 marker showed a highly significant relationship in the ileal tissues of patients with Crohn's Disease with varying degrees according to the intensity of the immune reaction, according to the Aperio image Scope program. It was 10% weak, 36.67% medium, and 53.33% strong. P-value for patients vs control were 0.0003 and 0.0001, respectively (P-value 0 ≤ 0.01).

Identification of immune infiltration and cuproptosis-related subgroups in Crohn's disease.

Crohn's disease (CD) is a type of heterogeneous, dysfunctional immune-mediated intestinal chronic and recurrent inflammation caused by a variety of etiologies. Cuproptosis is a newly discovered form of programmed cell death that seems to contribute to the advancement of a variety of illnesses. Consequently, the major purpose of our research was to examine the role of cuproptosis-related genes in CD. We obtained two CD datasets from the gene expression omnibus (GEO) database, and immune cell infiltration was created to investigate immune cell dysregulation in CD. Based on differentially expressed genes (DEGs) and the cuproptosis gene set, differentially expressed genes of cuproptosis (CuDEGs) were found. Then, candidate hub cuproptosis-associated genes were found using machine learning methods. Subsequently, using 437 CD samples, we explored two distinct subclusters based on hub cuproptosis-related genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, Gene set variation analysis (GSVA) and immune infiltration analysis studies were also used to assess the distinct roles of the subclusters. Overall, 25 CuDEGs were identified, including ABCB6, BACE1, FDX1, GLS, LIAS, MT1M, PDHA1, etc. And most CuDEGs were expressed at lower levels in CD samples and were negatively related to immune cell infiltration. Through the machine learning algorithms, a seven gene cuproptosis-signature was identified and two cuproptosis-related subclusters were defined. Cluster-specific differentially expressed genes were found only in one cluster, and functional analysis revealed that they were involved in several immune response processes. And the results of GSVA showed positive significant enrichment in immune-related pathways in cluster A, while positive significant enrichment in metabolic pathways in cluster B. In addition, an immune infiltration study indicated substantial variation in immunity across different groups. Immunological scores were higher and immune infiltration was more prevalent in Cluster A. According to the current research, the cuproptosis phenomenon occurs in CD and is correlated with immune cell infiltration and metabolic activity. This information indicates that cuproptosis may promote CD progression by inducing immunological response and metabolic dysfunction. This research has opened new avenues for investigating the causes of CD and developing potential therapeutic targets for the disease.

Mediterranean-Like Dietary Pattern Associations With Gut Microbiome Composition and Subclinical Gastrointestinal Inflammation

Case-control studies have shown that patients with Crohn's disease (CD) have a microbial composition different from healthy individuals. Although the causes of CD are unknown, epidemiologic studies suggest that diet is an important contributor to CD risk, potentially via modulation of bacterial composition and gut inflammation. We hypothesized that long-term dietary clusters (DCs) are associated with gut microbiome compositions and gut inflammation. Our objectives were to identify dietary patterns and assess whether they are associated with alterations in specific gut microbial compositions and subclinical levels of gut inflammation in a cohort of healthy first-degree relatives (FDRs) of patients with CD. As part of the Genetic, Environmental, Microbial (GEM) Project, we recruited a cohort of 2289 healthy FDRs of patients with CD. Individuals provided stool samples and answered a validated food frequency questionnaire reflecting their habitual diet during the year before sample collection. Unsupervised analysis identified 3 dietary and 3 microbial composition clusters. DC3, resembling the Mediterranean diet, was strongly associated with a defined microbial composition, with an increased abundance of fiber-degrading bacteria, such as Ruminococcus, as well as taxa such as Faecalibacterium. The DC3 diet was also significantly associated with lower levels of subclinical gut inflammation, defined by fecal calprotectin, compared with other dietary patterns. No significant associations were found between individual food items and fecal calprotectin, suggesting that long-term dietary patterns rather than individual food items contribute to subclinical gut inflammation. Additionally, mediation analysis demonstrated that DC3 had a direct effect on subclinical inflammation that was partially mediated by the microbiota. Overall, these results indicated that Mediterranean-like dietary patterns are associated with microbiome and lower intestinal inflammation. This study will help guide future dietary strategies that affect microbial composition and host gut inflammation to prevent diseases.

Role of mesenteric component in Crohn's disease: A friend or foe?

Crohn’s disease (CD) is a complex and relapsing gastrointestinal disease with mesenteric alterations. The mesenteric neural, vascular, and endocrine systems actively take part in the gut dysbiosis-adaptive immunity-mesentery-body axis, and this axis has been proven to be bidirectional. The abnormalities of morphology and function of the mesenteric component are associated with intestinal inflammation and disease progress of CD via responses to afferent signals, neuropeptides, lymphatic drainage, adipokines, and functional cytokines. The hypertrophy of mesenteric adipose tissue plays important roles in the pathogenesis of CD by secreting large amounts of adipokines and representing a rich source of proinflammatory or profibrotic cytokines. The vascular alteration, including angiogenesis and lymphangiogenesis, is concomitant in the disease course of CD. Of note, the enlarged and obstructed lymphatic vessels, which have been described in CD patients, are likely related to the early onset submucosa edema and being a cause of CD. The function of mesenteric lymphatics is influenced by endocrine of mesenteric nerves and adipocytes. Meanwhile, the structure of the mesenteric lymphatic vessels in hypertrophic mesenteric adipose tissue is mispatterned and ruptured, which can lead to lymph leakage. Leaky lymph factors can in turn stimulate adipose tissue to proliferate and effectively elicit an immune response. The identification of the role of mesentery and the crosstalk between mesenteric tissues in intestinal inflammation may shed light on understanding the underlying mechanism of CD and help explore new therapeutic targets.

Cytoskeletal Organization and Cell Polarity in the Pathogenesis of Crohn's Disease.

Crohn's disease (CD) is a type of inflammatory bowel disease (IBD) and affects diverse segments of the entire gastrointestinal tract. Although the underlying causes of CD are not completely known, it is believed that disruption of the intestinal barrier and cell polarity may contribute to pathogenesis. The formation of the intestinal epithelial barrier, which is mainly regulated by cytoskeletal modulations, and apico-basal cell polarity are two major and mutually dependent features of the intestinal epithelial layer. As this layer serves as an important barrier between the external environment and the internal milieu, the defect can start an inflammatory cascade by failing to block the entrance of luminal pathogens and lead to CD. In this review, we highlight the factors and impact of intestinal barrier function and cell polarity in the natural history of CD. The discussion in the present review further strengthens the new challenge in facilitating the development of viable pharmacological targets.

Characterization of Crohn disease in X-linked inhibitor of apoptosis–deficient male patients and female symptomatic carriers

Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP, including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)-mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations.

Crohn's Disease Clinical Network and Cohort (CONNECT) Study: The First Step Toward Nationwide Multicenter Research of Crohn's Disease in Korea.

Crohn's Disease Clinical Network and Cohort (CONNECT) Study: The First Step Toward Nationwide Multicenter Research of Crohn's Disease in Korea.

Ustekinumab for the Treatment of Crohn‘s Disease

Crohn's disease (CD) results from a pathological immune response to luminal antigens in genetically predisposed individuals. Since the causes of CD are complex and only partially understood, treatment is based on the empiric use of anti-inflammatory drugs. Although multiple therapies for CD currently exist, a substantial proportion of patients are unresponsive to conventional agents. Approximately a third of patients fail treatment with TNF antagonists, and up to 40% of patients who initially benefit subsequently lose response. Accordingly, new approaches are required. Ustekinumab, a fully human IgG1-κ monoclonal antibody to the p40 subunit shared by IL-12 and IL-23, has emerged as a promising new treatment for both psoriasis and CD. This article reviews the available data regarding the mechanism of action, pharmacokinetics, efficacy and safety of ustekinumab in CD.

P076 A gene expression outlier strategy towards identifying molecular causes of Crohn's disease

P076 A gene expression outlier strategy towards identifying molecular causes of Crohn's disease

Role ofATG16L,NOD2andIL23Rin Crohn’s disease pathogenesis

Inflammatory bowel disease is a group of diseases that includes Crohn's disease (CD) and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mouth to the anus. Although there are gross pathological and histological similarities between CD and Johne's disease of cattle, the cause of CD remains controversial. It is vital to understand fully the cause of this disease because it affects approximately 500,000 people in North America and Europe. It ranges from 27 to 48 cases per 100,000 people. There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the patients. Regardless of the environmental trigger, there is strong evidence that a genetic disposition is a major key in acquiring CD. Many studies have proven the link between mutations in the ATG16L, NOD2/CARD15, IBD5, CTLA4, TNFSF15 and IL23R genes, and CD. The purpose of this review is to examine all genetic aspects and theories of CD, including up to date multiple population studies performed worldwide.

Role of defective autophagia and the intestinal flora in Crohn disease

The precise mechanisms underlying the development of Crohn disease (CD) remain controversial, but sufficient data have been collected to suggest that an uncontrolled immune response within the intestinal mucosa leads to inflammation in a genetically susceptible host. Although lack of mucosal regulatory T cells causes colitis in humans and experimental rodents, patients with CD have more rather than less regulatory activity in the intestine, apparently excluding defects in tolerance as the cause of CD. Genome-wide association studies have identified many gene variants that confer susceptibility and which seem associated to diminished functioning of especially innate immunity. In apparent agreement, CD patients are impaired with respect to innate immune responses and controlling bacterial flora in the intestine. Furthermore, severe genetic deficiencies in innate immunity, like e.g., lack of NADP oxidase activity or diminished function of the Wiskott Aldrich syndrome protein are associated with colitis in mice and men, and are often mistakenly diagnosed as CD. Thus we favor the view that the primary defect in CD is a lack in innate immunity, causing second tier immunological defenses to combat otherwise easily controlled bacterial breaches of the mucosal barrier.

Mycobacterium avium paratuberculosis and the etiology of Crohn's disease: a review of the controversy from the clinician's perspective.

Mycobacterium avium paratuberculosis (MAP) is an obligate intracellular organism that has frequently been associated with Crohn's disease (CD). Because CD is a chronic inflammatory condition, many researchers have speculated that an infectious agent must be the cause of CD. MAP has often been proposed to be one such agent; however, despite considerable research, the evidence remains inconclusive. Higher levels of MAP have been found in the tissues and blood of CD patients than in controls, forming the foundation for much of the research into the role of MAP in CD and the primary argument in support of a causative role for MAP in CD. MAP is a slow-growing and fastidious organism that is difficult to grow in culture and, therefore, challenging to detect in patients. As a result, there has been variability in the results of studies attempting to detect the presence of MAP in CD patients, and considerable controversy over whether this organism has a causative role in the etiology of CD. Two main hypotheses exist with respect to the role of MAP in CD. The first is that MAP is a principal cause of CD, while the second is that MAP is more prevalent because of the immune dysfunction seen in CD but does not play a causative role. Clinicians are often faced with questions regarding the role of this organism and the need to treat it. The present article attempts to provide an overview of the controversy including the nature of the mycobacterium, the difficulty in detecting it, the use of antimycobacterial agents to treat it and the effect of immunosuppressive agents - all from a clinician's perspective. Although the role of MAP in CD remains controversial and an area of considerable research, it is currently only of academic interest because there is no clinically useful test to identify the presence of the organism, and no evidence to support the use of antibiotics to eradicate it for the treatment of CD.

Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn’s disease

The hypothesis postulating that Mycobacterium avium paratuberculosis (MAP) is the cause of Crohn's disease (CD) has been circulating for many years. Advances in molecular techniques, such as polymerase chain reaction and culture methods, have enabled researchers to demonstrate that there is an association between MAP and CD. Recently, genome-wide association studies have identified novel susceptibility genes for CD, which are critical for generation of an adaptive immune response that is protective against intracellular pathogens, including M. tuberculosis infection. However, the role of MAP as a cause of CD suffered a setback with the report that administration of antimycobacterial therapy failed to lead to a sustained response in CD patients. Accordingly, this review sought neither to confirm nor refute this, but instead to survey recent literature on the role of MAP in CD.

A Major Cell Wall Lipopeptide of Mycobacterium avium subspecies paratuberculosis

Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of Johne disease in cattle and other ruminants, is proposed to be at least one of the causes of Crohn disease in humans. MAP and Mycobacterium avium subspecies avium, a closely related opportunistic environmental bacterium, share 95% of their genes and exhibit homologies of more than 99% between these genes. The identification of molecules specific for MAP is essential for understanding its pathogenicity and for development of useful diagnostic tools. The application of gas chromatography, mass spectrometry, and nuclear magnetic resonance led to the structural identification of a major cell wall lipopeptide of MAP, termed Para-LP-01, defined as C20 fatty acyl-D-Phe-N-Me-L-Val-L-Ile-L-Phe-L-Ala methyl ester. Variations of this lipopeptide with different fatty acyl moieties (C16 fatty acyl through C17, C18, C19, C21 to C22) were also identified. Besides the specificity of this lipopeptide for MAP, the presence of an N-Me-L-valine represents the first reported N-methylated amino acid within an immunogenic lipopeptide of mycobacteria. Sera from animals with Johne disease, but not sera from uninfected cattle, reacted with this lipopeptide, indicating potential biological importance.

Mycobacterium aviumsubsp.paratuberculosisInfection in a Patient with HIV, Germany

Mycobacterium avium subsp. paratuberculosis (MAP), the causative agent of Johne disease in ruminants, has been incriminated as the cause of Crohn disease in humans. We report the first case of human infection with MAP in a patient with HIV; infection was confirmed by obtaining isolates from several different specimen types.

Expression of Osteopontin (Eta-1) in Crohn Disease of the Terminal Ileum

Background: The causes of Crohn disease (CD) are still regarded as unknown, but impaired mucosal immunoregulation with activation of T-helper-1 (Th-1) cytokine responses is probably involved and may contribute to the morphological changes. We investigated a possible role of osteopontin (Opn) in the pathogenesis of CD. This glycoprotein has been suggested to be involved in the generation of Th-1-type immune responses; moreover, it carries anti-inflammatory activities. Methods: Ileal samples from CD patients--both actively inflamed and inactive areas as well as unaffected intestinal specimens from controls (normal ileum)--were investigated by Western blot analysis, immunohistochemistry and in situ hybridization. Results: In normal gut, Opn was found to be regularly expressed by plasma cells (CD 38) and a subset of lamina propria mononuclear cells (MNC) as well as by intestinal epithelial cells (IEC). In active CD, immunohistochemistry and in situ hybridization analysis revealed a loss of Opn expression by IEC adjacent to ulcerative lesions, whereas especially plasma cells (CD 38) in the vicinity of such lesions were found to express the molecule. In addition, a slight overexpression of Opn protein was found in metaplastic crypts. However, quantitative analysis of total Opn protein in the ileal mucosa of CD patients did not reveal any difference vis-à-vis control tissues. Conclusions: The constitutive expression of Opn in normal gut indicates that it is involved in intestinal immune homeostasis. Downregulation of Opn expression in IEC might favour the disintegration of the epithelial barrier. The expression of Opn in lamina propria plasma cells could contribute to disease chronification, probably by affecting cell survival.

More questions about growth hormone in Crohn disease.

More questions about growth hormone in Crohn disease.

Crohn’s Disease Uveitis: Parasitization of Vitreous Leukocytes by Mollicute-Like Organisms

Crohn's disease (CD) is an idiopathic chronic inflammatory gut disease with frequent extragut inflammatory manifestations in the eyes, orbit, lungs, joints, and skin. A bacterial cause of CD is suspected, but cultivation of a specific pathogen has not been forthcoming. Mollicute-like organisms (MLOs) were recently reported to cause human chronic ocular inflammatory disease. Inoculation of this MLO into mouse eyelids produced chronic progressive granulomatous ocular and orbital inflammatory disease. In addition, MLOs disseminated to produce similar disease in the gut, heart, and lungs. MLOs are noncultivable cell wall-deficient bacterial pathogens. Because they also pass bacteria-retaining 0.450-micron filters, they can be overlooked or confused with viruses. Because MLOs have a characteristic ultrastructural appearance, they can be identified in diseased cells with the use of a transmission electron microscope. MLOs parasitize and destroy leukocytes. They alter the nucleus, replace the cytoplasm, and destroy organelles. MLO-caused disease is treatable by certain antibiotics. This report describes MLO-parasitized vitreous lymphocytes, monocytes, and polymorphonuclear leukocytes from three patients with CD who had chronic uveitis. The results indicate that MLOs probably caused the uveitis of these patients with CD. The gut as the possible source of the MLO is suggested. Rifampin therapy of Crohn's and MLO-caused disease is discussed.