Figure - available from: BioMed Research International
This content is subject to copyright. Terms and conditions apply.
CD pathogenesis and autophagy: susceptible CD genes ATG16L1, NOD2, and IRGM are proteins critical for the autophagy process. (a) The process of mammalian autophagy is divided into the following principal steps: initiation, elongation, closure, maturation, and degradation. (b) At the bacterial entry site NOD2 activated by MDP recruit ATG16L1 to the plasma membrane. Follow the assembling of the ATG5-ATG12 complex, stabilized by ATG16L1, that facilitates the formation of an autophagosome around the invading bacterium. (c) IRGM, another autophagy-related gene, could be involved in the final steps of the degradation step.
Source publication
Crohn's disease is a complex disease in which genome, microbiome, and environment interact to produce the immunological background of the disease. Disease in childhood is more extensive and characterized by a rapid progression, leading to severe repercussions in the course of the disorder. Several genetic variations have been associated with an inc...
Similar publications
Mitochondria are key organelles involved in energy production, functioning as the metabolic hubs of cells. Recent findings emphasize the emerging role of the mitochondrion as a key intracellular signaling platform regulating innate immune and inflammatory responses. Several mitochondrial proteins and mitochondrial reactive oxygen species have emerg...
Citations
... Notably, in patients with Crohn's disease (CD), there was a significant elevation in the presence of adherent-invasive E. coli, indicating that pathogens could influence intestinal permeability, the composition of the gut microbiota and ultimately contribute to intestinal inflammation (Ahmed et al., 2016). The pathophysiology of IBD is multifactorial, involving complex interactions among genetics (Marcuzzi et al., 2013), environment (Leone et al., 2013), microbiome (Manichanh et al., 2012;Wang et al., 2014), immunity (Kaistha and Levine, 2014) and potential other risk factors. ...
Objective
Gastric and intestinal diseases possess distinct characteristics although they are interconnected. The primary objective of this study was to investigate the pathogenesis of gastrointestinal diseases through different analyses of clinical characteristics, serum immunology, and gut microbiota in patients with gastrointestinal diseases.
Methods
We collected serum samples from 89 patients with gastrointestinal diseases and 9 healthy controls for immunological assessment, stool samples for DNA extraction, library construction, sequencing, as well as clinical data for subsequent analysis.
Results
Regarding clinical characteristics, there were significant differences between the disease group and the healthy control (HC) group, particularly in terms of age, cancer antigen 125 (CA125), cancer antigen 199 (CA199), alpha-fetoprotein (AFP), total bilirubin (TBIL) and indirect bilirubin (IBIL). The intestinal disease (ID) group exhibited the highest IL-6 level, which significantly differed from the stomach disease (SD) group (p < 0.05). In comparing the HC with the ID groups, significant differences in abundance were detected across 46 species. The HC group displayed a greater abundance of Clostridiales, Clostridia, Firmicutes, Bifidobacterium, Bifidobacteriaceae, Bifidobacteriales, Actinobacteria, Veillonellaceae, Longum, Copri, Megamonas and Callidus than other species. Similarly, when comparing the HC with the SD groups, significant differences in abundance were identified among 49 species, with only one species that the Lachnospiraceae in the HC group exhibited a higher abundance than others. Furthermore, certain clinical characteristics, such as CA125, CA199, glucose (Glu), creatine kinase-MB (CKMB) and interleukin-22 (IL-22), displayed positive correlations with enriched gut species in the ID and SD groups, while exhibiting a negative correlation with the HC group.
Conclusion
The disturbance in human gut microbiota is intimately associated with the development and progression of gastrointestinal diseases. Moreover, the gut microbiota in the HC group was found more diverse than that in the ID and SD groups, and there were significant differences in microbial species among the three groups at different classification levels. Notably, a correlation was identified between specific clinical characteristics (e.g., CA125, CA199, Glu, CKMB and IL-22) and gut microbiota among patients with gastrointestinal diseases.
... In our work, all cases of CD are negative for BRAF. Marcuzzi et al., (2013) studied genetic changes in CD and detected no BRAF expression. It is not from the susceptibility mutated genes. ...
Objectives:
To evaluate DNA ploidy and S-phase fraction (SPF) in non-Lynch colonic adenocarcinoma, ulcerative colitis (UC), Crohn disease (CD) which are known as risk factors, and colitis. We correlated ploidy and SPF with tumor grading, staging and BRAF expression.
Methods:
All studied adenocarcinomas have intact mismatch repair genes as proved by immunohistochemistry. All were assessed for ploidy by automated image-based DNA cytometry and histograms were drawn. Immunostaining by anti-BRAF V600E was performed. Diagnostic laparoscopy (DL) was done as a preliminary step for staging GI cancers.
Results:
there is significant difference in DNA ploidy between groups; 77.5% and 17.5% of aneuploid cases are adenocarcinoma and UC. Groups are compared in terms of 2C, 4C, above 4C DNA content and SPF and significant difference is principally found between adenocarcinoma group and others. In adenocarcinomas, DNA ploidy is significantly correlated with tumor staging and grading. Regarding BRAF expression, there is significant difference between groups; all adenocarcinomas, 83.33% of UC were positive, while all cases of colitis, bilharzial colitis, CD were negative. There is significant relation between BRAF and SPF among all diploid cases including adenocarcinoma, and among non-neoplastic diploid cases. There is direct significant relation between BRAF intensity and adenocarcinoma staging. There is no significant difference between BRAF and ploidy among UC cases, although 75% of aneuploid UC are positive. DL helps in GI cancer staging. Routine laparoscopy before laparotomy, especially in cancers which have equivocal operability helps to avoid unnecessary laparotomies.
Conclusion:
Based on significant difference in ploidy between adenocarcinoma and UC and between SPF and ploidy, assessment of ploidy by DNA cytometry for UC and other colitis could therefore predict impending malignant transformation before development of colonic dysplasia. Also measuring SPF in adenocarcinoma helps to select patients who could greatly benefit from chemotherapy. DL has vital role in staging GI cancers.
... For example, genetic mutations associated with CD include polymorphisms for the Nucleotide Oligomerization Domain Containing 2 (NOD2/ CARD15), Immunity-elated GTPase family M (IRGM), and autophagy-related 16 Like 1 (ATG16L1). 238 Studies have shown that gut microbiota are highly associated with the development of IBD. Mechanistically, microbiota dysbiosis is linked to IBD through its impact on inflammation as well as the intestinal barrier. ...
The role of microbiota in health and diseases is being highlighted by numerous studies since its discovery. Depending on the localized regions, microbiota can be classified into gut, oral, respiratory, and skin microbiota. The microbial communities are in symbiosis with the host, contributing to homeostasis and regulating immune function. However, microbiota dysbiosis can lead to dysregulation of bodily functions and diseases including cardiovascular diseases (CVDs), cancers, respiratory diseases, etc. In this review, we discuss the current knowledge of how microbiota links to host health or pathogenesis. We first summarize the research of microbiota in healthy conditions, including the gut-brain axis, colonization resistance and immune modulation. Then, we highlight the pathogenesis of microbiota dysbiosis in disease development and progression, primarily associated with dysregulation of community composition, modulation of host immune response, and induction of chronic inflammation. Finally, we introduce the clinical approaches that utilize microbiota for disease treatment, such as microbiota modulation and fecal microbial transplantation.
... Autophagy is a cellular degradation process in which cellular proteins and organelles are sequestered in double membrane vesicles known as autophagosomes, delivered to lysosomes, and digested by lysosomal hydrolases [30][31][32]. Autophagy plays an important role in cellular homeostasis, and it is involved in a number of human diseases [33][34][35]. ...
Previous study demonstrates that intracerebral hemorrhage (ICH) promotes microglia activation and inflammation. However, the exact mechanism of microglia activation induced by ICH is not clear. In this experiment, microglia autophagy was examined using electron microscopy, conversion of light chain 3(LC3), and monodansylcadaverine (MDC) staining to detect autophagic vacuoles. We found that ICH induced microglia autophagy and activation. The suppression of autophagy using either pharmacologic inhibitors (3-methyladenine, bafilomycin A1) or RNA interference in essential autophagy genes (BECN1 and ATG5) decreased the microglia activation and inflammation in ICH. Moreover, autophagy inhibitors reduced brain damage in ICH. In conclusion, these data indicate that ICH contributes to microglia autophagic activation through BECN1 and ATG5 and provide the therapeutical strategy for ICH.
... IFN-γ, which is known to be essential for mammalian host defense against intracellular pathogens, was a central factor in the common network at 3 and 6 weeks p.i. (Fig 5). Interferon-inducible protein-encoding genes (Gbp, Irgm) together with IFN-γ were up-regulated in this network and may also play a role in the innate immune response by regulating autophagy against intracellular pathogens [45,58]. In particular, IRGM proteins help trigger autophagy in cells infected with mycobacteria, and several polymorphisms in or near IRGM have been associated with an increased risk of developing Crohn's disease [58][59][60]. ...
... Interferon-inducible protein-encoding genes (Gbp, Irgm) together with IFN-γ were up-regulated in this network and may also play a role in the innate immune response by regulating autophagy against intracellular pathogens [45,58]. In particular, IRGM proteins help trigger autophagy in cells infected with mycobacteria, and several polymorphisms in or near IRGM have been associated with an increased risk of developing Crohn's disease [58][59][60]. In accordance with the down-regulation of Hla-doa, Hla-dob, and Hla-dmb, MHC class II gene expression was downregulated in MAP-infected mice at 3 and 6 weeks p.i. ...
Paratuberculosis or Johne’s disease is a chronic granulomatous enteropathy in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP) infection. In the present study, we examined the host response to MAP infection in spleens of mice in order to investigate the host immunopathology accompanying host-pathogen interaction. Transcriptional profiles of the MAP-infected mice at 3 and 6 weeks p.i. showed severe histopathological changes, whereas those at 12 weeks p.i. displayed reduced lesion severity in the spleen and liver. MAP-infected mice at 3 and 6 weeks p.i. showed up-regulation of interferon-related genes, scavenger receptor, and complement components, suggesting an initial innate immune reaction, such as macrophage activation, bactericidal activity, and macrophage invasion of MAP. Concurrently, MAP-infected mice at 3 and 6 weeks p.i. were also suggested to express M2 macrophage phenotype with up-regulation of Mrc1, and Marco and down-regulation of MHC class II, Ccr7, and Irf5, and canonical pathways related to the T cell response including ICOS-ICOSL signaling in T helper cells, calcium-induced T lymphocyte apoptosis, and CD28 signaling in T helper cell. These results provide information which furthers the understanding of the immunopathologic response to MAP infection in mice, thereby providing insights valuable for research into the pathogenesis for MAP infection.
... The intrinsic differences in DC-stimulating properties of bacteria associated with the airway microbiota are very similar to what has been observed in the gut. Many studies have observed imbalances or dysbioses in the GI microbiomes of Crohn's disease patients [39], and preclinical models have demonstrated that commensal bacteria from the healthy gut, for example, Bacteroides fragilis, stimulate CD4 T cells to differentiate into Treg. In contrast, pathogenic segmented filamentous bacteria and Helicobacter hepaticus were found to be potent inducers of Th17 and Th1 cells. ...
Chronic obstructive pulmonary disease (COPD) is characterized by sustained inflammation of the airways, leading to destruction of lung tissue and declining pulmonary function. Although smoking is the most obvious risk factor for COPD, only about 20% of smokers develop COPD and smoking cessation does not reverse progression of COPD, indicating that while smoking is an important cause or initiating factor, it is not the only driver of ongoing chronic inflammation and disease progression in COPD patients. We hypothesize that smoking-induced changes in lung microbiota, epithelial integrity and epigenetic control of gene expression result in autoantigen induction and perturbed immune regulation in genetically vunerable individuals. In our view, COPD patients may be stratified according to their immunological and inflammatory status related to specific changes in the lung microbiota (innate and adaptive immunity), presence of autoantigens (adaptive immunity: Th1-B-cell axis) and epigenetic modifications (inflammation and structural changes).
... 19,20 Loss of function variants of the NOD2 gene have been associated with increased susceptibility to Crohn's disease, especially small bowel disease. 18,[21][22][23] Other loci involved with increased susceptibility to Crohn's disease include IBD5,3,6 on chromosomes 5, 6, and 19, respectively. 20,24 Another genetically defined process which can contribute to susceptibility to Crohn's disease is that of autophagy. ...
... 22 ATG16L1 is essential for autophagy, and the coding mutation T300A is associated with an increased risk of Crohn's disease. 22 The search for a microbial trigger for Crohn's disease has been carried out along two pathways -either a specific transmissible agent, or a dysbiosis involving the gastrointestinal microbial milieu. Dysbiosis refers to the breakdown of balance between commensal bacteria and harmful bacteria in the gut. ...
Shivani Kansal,1–3 Anthony G Catto-Smith1,2 1Department of Paediatrics, University of Melbourne, 2Department of Gastroenterology, The Royal Children's Hospital Melbourne, 3Murdoch Children's Research Institute, Melbourne, VIC, Australia Abstract: There has been a dramatic increase in the incidence of Crohn's disease over the last two to three decades worldwide, which has affected both the developed world and increasingly also the developing world. Crohn's disease is a disease of youth and can have a profound effect on the growing child, both in terms of growth and skeletal health as well psychosocial maturation. Environmental risk factors appear to be crucially important, but it is not clear at present whether improved hygiene, especially in childhood, influences immunological conditioning, or whether there is a direct impact on the gut from a disturbed gut microbiota. Genetic variation appears to relate to how the host interacts with its microbiota, determining susceptibility rather than causation. The outcome is a sustained immune response, clinically presenting as a relapsing/remitting disease process. There is no current cure for Crohn's disease; treatments are designed to reduce symptoms and control inflammation, initially by inducing a remission, then trying to maintain it. Historical therapies have included 5-aminosalicylic acid-based drugs, corticosteroids, and immunomodulators. Two approaches which are gaining increasing interest are the use of exclusive enteral nutrition and biologicals. Enteral nutrition is a remarkably effective approach, though there is a limited understanding of its mechanism and difficulties in acceptance among the medical community. Biologicals are a class of drugs which specifically target molecules and pathways central to the inflammatory process; they are also very effective, but patients can develop a secondary loss of response as a result of antibodies to the biological agent. Infection and the development of secondary malignancies have provided concerns with these very potent agents and with combination therapies, but inadequately controlled disease appears to pose a bigger threat for many patients than the side effects of medications. A wide range of alternative therapies are also being explored, such as the manipulation of gut flora and pathways which might influence immune responsiveness. The marked recent increase in Crohn's disease, especially in children, has prompted a large research effort which to date has led to a better knowledge of the biology of the disease and more effective treatments. These therapies need to be used judiciously to optimize benefit and minimize side effects. Keywords: inflammatory bowel disease, ulcerative colitis, tumor necrosis factor, biologicals, microbiota, enteral nutrition
Inflammatory bowel disease (IBD) includes a spectrum of diseases from ulcerative colitis (UC) to Crohn's disease (CD). Many studies have addressed the changes in the microbiota of individuals affected by UC and CD. A decrease in biodiversity and depletion of the phyla Bacteroidetes and Firmicutes has been reported, among others. Changes in microbial composition also result in changes in the metabolites generated in the gut from microbial activity that may involve the amount of butyrate and other metabolites such as H2S being produced. Other factors such as diet, age, or medication need to be taken into consideration when studying dysbiosis associated with IBD. Diverse bacterial species have been associated specifically or non-specifically to IBD, but none of them have been demonstrated to be its ethiological agent. Recent studies also suggest that micro-eukaryotic populations may also be altered in IBD patients. Last, but not least, viruses, and specially bacteriophages, can play a role in controlling microbial populations in the gastrointestinal tract. This may affect both bacterial diversity and metabolism, but possible implications for IBD still remain to be solved. Dysbiosis in the oral microbiome associated with IBD remains an emerging field for future research.
Lysosomes degrade biological components acquired by endocytosis, the major cellular pathway for internalization of extracellular material, and macroautophagy. This chapter presents an overview of these two major degradative intracellular pathways, and highlights the emerging cross talks between them, in healthy and diseased conditions. The pathways to lysosomes include the biosynthetic transport routes, endocytic pathways, and the autophagy pathways. The central actors of the autophagy process are the ATG genes. Based on their organization in complexes and interactions, the ATG genes have been divided into many functional clusters that compose the core autophagy machinery. Cross talk between the endocytic and autophagic pathways occurs at many levels: transcriptional regulation, protein sharing, and compartmental connections. The chapter focuses on the fusion and fission events between compartments of the endolysosomal system and autophagic membranes, respectively. Lysosome-related disorders are caused by mutations in genes encoding for proteins that directly affect lysosomal functioning, including lysosomal hydrolases and lysosomal membrane proteins.
