Pathogenesis Of Including Inflammatory Bowel Disease Research Articles

Efficacy, Safety, and Concerns on Microbiota Modulation, Antibiotics, Probiotics, and Fecal Microbial Transplant for Inflammatory Bowel Disease and Other Gastrointestinal Conditions: Results from an International Survey.

The gut microbiota play a pivotal role in human health. Dysbiosis, alterations in microbiota composition and function, is associated with gastrointestinal disorders, including inflammatory bowel disease (IBD). This international survey aimed to assess physicians' experiences, perceptions, and practices related to microbiome modulation for gastrointestinal conditions, with a focus on IBD. Results from 142 healthcare professionals, predominantly gastroenterologists, confirmed a consensus on the relevance of the gut microbiota in IBD pathogenesis. However, the utilization of microbial composition analysis and probiotics in clinical practice was limited, primarily due to the lack of standardized guidelines and supporting evidence. Physicians held conflicting views on antibiotics, recognizing their potential for inducing remission but also causing flares in IBD. Respondents also had varying opinions on the efficacy of fecal microbiota transplantation (FMT) for different gastrointestinal conditions, with higher confidence in FMT effectiveness for irritable bowel syndrome with diarrhea, pouchitis, and ulcerative colitis. Concerns on FMT included uncertainty about effect duration, administration intervals, and conflicting evidence. Donor selection was believed to be a crucial factor in FMT outcomes. This survey highlights the need for further research and evidence-based guidelines to optimize the use of microbiome-based therapies in clinical practice. As our understanding of the gut microbiome continues to evolve, these insights will contribute to more informed and personalized approaches to managing gastrointestinal disorders.

Obesity, a challenge in the management of inflammatory bowel diseases.

Obesity, a morbid condition snowballing in the world, may cause many health issues in healthy and ill people. Many disorders are known to be influenced by obesity, mainly in a catastrophic way, including inflammatory bowel disease (IBD). Many studies sought to determine the effects that obesity prompts IBD. Some of them indicate that obesity is associated with poor outcomes. There is no consistency regarding the correlation between obesity and IBDs due to the equivocal nature of obesity and the shortage of extensive and reliable investigations. However, to a worldwide consensus, obesity has a unique disease burden and can cause poor prognosis when it accompanies other ailments. Here, we have reviewed some of the alterations and impacts that obesity may impose on the pathogenesis and clinical management of IBD. Conclusively, inflammatory processes of IBD are reinforced by obesity. Furthermore, as a two-way road, obesity can be caused by IBD. However, autoimmunity in IBD is not found to have a consistent relationship with obesity. Although, medical and surgical treatments of IBD are affected by obesity in terms of their efficacy and outcomes. The most important aspect of obesity that can influence the course of disease management is associated with significant disabilities that obesity may cause rather than a metabolic or molecular rationale.

Sialylation of CD11b/CD18 regulates Neutrophil Transepithelial Migration and Neutrophil Inflammatory function in the Intestine

Neutrophils (PMNs) are the first immune responders to infection/inflammation playing critical roles in clearing invading microbes and promoting tissue repair. However, dysregulated trafficking of PMNs across mucosal surfaces is a pathological hallmark of diseases characterized by persistent or intermittent bursts of inflammation including inflammatory bowel disease (IBD). The critical final step in PMN trafficking into mucosal lined organs (including the gut) involves transepithelial migration (TEpM). The glycoprotein CD11b/CD18 is the predominant β2 integrin mediating PMN TEpM into the intestinal lumen. Furthermore, CD11b/CD18 also regulates key PMN inflammatory effector functions that are implicated in IBD pathogenesis including superoxide release. We have previously demonstrated that specific GlcNAc and Lewis X glycan structures on CD11b/CD18 can be targeted to reduce PMN intestinal trafficking. Recent mass spectrometry analyses revealed the presence of specific sialylated glycan structures on PMN CD11b. However the role of sialylation in regulating PMN CD11b/CD18 function is not well understood. Using lectins recognizing the most common linkages of sialic acid we show that sialidase mediated removal of α2‐3 sialic acid from CD11b/CD18 occurs during PMN migration across intestinal epithelia. Furthermore, specific inhibition of sialidase activity was found to reduce PMN intestinal migration in vitro and in vivo. In addition to limiting PMN intestinal trafficking, sialidase inhibition also reduced key PMN effector functions including degranulation and superoxide release. Finally, we demonstrate that sialidase inhibition impedes PMN CD11b activation and blocks downstream β2 integrin signaling mediated by Spleen tyrosine kinase (Syk). Therefore α2‐3 sialylated glycans on CD11b/CD18 represent novel targets for ameliorating PMN mediated intestinal tissue damage and reducing mucosal inflammation in IBD.

Gp130 Signaling in NOD2-Driven Crohn’s Disease: A Key Player in Fibrosis and a Novel Target for Refractory Patients

Gp130 Signaling in NOD2-Driven Crohn’s Disease: A Key Player in Fibrosis and a Novel Target for Refractory Patients

Lactic Acid Bacteria Isolated From Korean Kimchi Activate the Vitamin D Receptor–autophagy Signaling Pathways

Probiotic lactic acid bacteria (LAB) have been used in the anti-inflammation and anti-infection process of various diseases, including inflammatory bowel disease (IBD). Vitamin D receptor (VDR) plays an essential role in pathogenesis of IBD and infectious diseases. Previous studies have demonstrated that the human VDR gene is a key host factor to shape gut microbiome. Furthermore, intestinal epithelial VDR conditional knockout (VDRΔIEC) leads to dysbiosis. Low expressions of VDR is associated with impaired autophagy, accompanied by a reduction of ATG16L1 and LC3B. The purpose of this study is to investigate probiotic effects and mechanism in modulating the VDR-autophagy pathways. Five LAB strains were isolated from Korean kimchi. Conditional medium (CM) from these strains was used to treat a human cell line HCT116 or intestinal organoids to measure the expression of VDR and autophagy. Mouse embryonic fibroblast (MEF) cells with or without VDR were used to investigate the dependence on the VDR signaling. To test the role of LAB in anti-inflammation, VDR+/+ organoids were treated with 121-CM before infection with Salmonella enterica serovar Enteritidis. In vivo, the role of LAB in regulating VDR-autophagy signaling was examined using LAB 121-CM orally administrated to VDRLoxp and VDRΔIEC mice. The LAB-CM-treated groups showed higher mRNA expression of VDR and its target genes cathelicidin compared with the control group. LAB treatment also enhanced expressions of Beclin-1 and ATG16L1 and changed the ratio of LC3B I and II, indicating the activation of autophagic responses. Furthermore, 121-CM treatment before Salmonella enterica serovar Enteritidis infection dramatically increased VDR and ATG16L1 and inhibited the inflammation. Administration of 121-CM to VDRLoxp and VDRΔIEC mice for 12 and 24 hours resulted in an increase of VDR and LC3B II:I ratio. Furthermore, we identified that probiotic proteins P40 and P75 in the LAB-CM contributed to the anti-inflammatory function by increasing VDR. Probiotic LAB exert anti-inflammation activity and induces autophagy. These effects depend on the VDR expression. Our data highlight the beneficial effects of these 5 LAB strains isolated from food in anti-infection and anti-inflammation.

Dual immune functions of IL-33 in inflammatory bowel disease.

Interleukin-33 (IL-33) has emerged as a critical regulator in a variety of diseases, including inflammatory bowel disease (IBD). IL-33 can be produced by various tissues and cells, and typically induces Th2-type immune responses via binding to the receptor ST2. In addition, accumulated data have shown that IL-33 also plays a modulatory role in the function of regulatory T cells (Tregs), B cells, and innate immune cells such as macrophages and innate lymphoid cells (ILCs). IBD, including Crohn's disease and ulcerative colitis, are characterized by aberrant immunological responses leading to intestinal tissue injury and destruction. Although IL-33 expression is increased in IBD patients and correlates with the patients' disease activity index, mechanistic studies to date have demonstrated both pathogenic and protective roles in animal models of experimental colitis. In this review, we will summarize the roles and mechanisms of IL-33 in IBD, which is essential to understand the pathogenesis of IBD and determine potential therapies.

Epigenetics in Gastrointestinal Health and Disease: Spotlight on DNA Methylation in the Intestinal Epithelium.

Epigenetics can be defined as stable, potentially heritable changes in cellular phenotype caused by mechanisms other than alterations in the underlying DNA sequence. DNA methylation is amongst the most intensely studied epigenetic mechanisms and has been shown to play a major role in regulating fundamental aspects of cell biology including cellular differentiation, organ development, and cell type-specific gene expression. Importantly, it is becoming increasingly clear that epigenetic mechanisms operate at the interface between the genetic code and our environment and are able to mediate environmental changes into stable phenotypic alterations. Given existing evidence supporting the important effects of environmental factors (e.g., diet, nutrition, and infections) on human health, epigenetic mechanisms provide a plausible mechanistic framework for the development of many multifactorial diseases including inflammatory bowel disease (IBD). Impaired function of the intestinal epithelium has been implicated in IBD pathogenesis, yet underlying mechanisms remain ill defined. The work of our group focuses on investigating the role of DNA methylation in regulating cellular function of the human intestinal epithelium during gastrointestinal health and IBD. In addition to performing an analysis of primary human intestinal epithelium, we utilize human intestinal organoid culture systems allowing us to perform functional analysis in a patient-derived ex vivo model.

Host-microbial Cross-talk in Inflammatory Bowel Disease.

A vast community of commensal microorganisms, commonly referred to as the gut microbiota, colonizes the gastrointestinal tract (GI). The involvement of the gut microbiota in the maintenance of the gut ecosystem is two-fold: it educates host immune cells and protects the host from pathogens. However, when healthy microbial composition and function are disrupted (dysbiosis), the dysbiotic gut microbiota can trigger the initiation and development of various GI diseases, including inflammatory bowel disease (IBD). IBD, primarily includes ulcerative colitis (UC) and Crohn's disease (CD), is a major global public health problem affecting over 1 million patients in the United States alone. Accumulating evidence suggests that various environmental and genetic factors contribute to the pathogenesis of IBD. In particular, the gut microbiota is a key factor associated with the triggering and presentation of disease. Gut dysbiosis in patients with IBD is defined as a reduction of beneficial commensal bacteria and an enrichment of potentially harmful commensal bacteria (pathobionts). However, as of now it is largely unknown whether gut dysbiosis is a cause or a consequence of IBD. Recent technological advances have made it possible to address this question and investigate the functional impact of dysbiotic microbiota on IBD. In this review, we will discuss the recent advances in the field, focusing on host-microbial cross-talk in IBD.

Neuroimmunomodulation in the Gut: Focus on Inflammatory Bowel Disease.

Intestinal immunity is finely regulated by several concomitant and overlapping mechanisms, in order to efficiently sense external stimuli and mount an adequate response of either tolerance or defense. In this context, a complex interplay between immune and nonimmune cells is responsible for the maintenance of normal homeostasis. However, in certain conditions, the disruption of such an intricate network may result in intestinal inflammation, including inflammatory bowel disease (IBD). IBD is believed to result from a combination of genetic and environmental factors acting in concert with an inappropriate immune response, which in turn interacts with nonimmune cells, including nervous system components. Currently, evidence shows that the interaction between the immune and the nervous system is bidirectional and plays a critical role in the regulation of intestinal inflammation. Recently, the maintenance of intestinal homeostasis has been shown to be under the reciprocal control of the microbiota by immune mechanisms, whereas intestinal microorganisms can modulate mucosal immunity. Therefore, in addition to presenting the mechanisms underlying the interaction between immune and nervous systems in the gut, here we discuss the role of the microbiota also in the regulation of neuroimmune crosstalk involved in intestinal homeostasis and inflammation, with potential implications to IBD pathogenesis.

Role of high-mobility group box 1 protein in inflammatory bowel disease

High-mobility group box 1 (HMGB1) protein is a nuclear non-histone DNA-binding protein. It is released into the extracellular milieu and mediates inflammatory responses, which contribute to the pathogenesis of numerous inflammatory diseases, including inflammatory bowel disease (IBD). An online search was performed in PubMed and Web of Science databases for articles providing evidence on the role of HMGB1 in IBD. HMGB1 plays an important role in IBD pathogenesis. Application of HMGB1 antagonists reduced inflammatory reactions and ameliorated colitis in rodent models, which may provide new insights into the diagnosis and treatment of IBD.

Interleukin-21 drives intestinal inflammation by bridging the adaptive and innate immune compartments (P3181)

Abstract Th17 CD4 T cells have been cast as pathogenic in the context of many autoimmune diseases, including Inflammatory Bowel Disease (IBD); however, the mechanism for this pathogenicity has yet to be elucidated. Based on the observation that IL-21 expression is increased in biopsies from patients with ulcerative colitis compared to healthy controls, we posit that IL-21 produced by Th17 cells mediates inflammation in the intestine. Using models of both spontaneous and CD4 T cell-dependent colitis, we show that a large number of IL-21-producing CD4 T cells are present in the intestines of mice with colitis and importantly, that IL-21 production is required for full disease progression. We find that although IL-21-/- CD4 T cells are unable to initiate disease, they produce elevated levels of IL-17A and IL-17F and are not selectively converted into Foxp3+ regulatory T cells, indicating that IL-21 is both crucial to the induction of colitis and surprisingly, is not acting via effects on the activation and differentiation of T cells. In direct support of this idea, IL-21R-/- CD4 T cells are capable of inducing disease unlike their IL-21-/- counterparts. In fact, our data demonstrate that IL-21 has an impact on the innate lymphoid cell compartment, which has previously been implicated in IBD pathogenesis. Taken together, our data show an important and previously unrecognized role for IL-21 that links CD4 T cells to innate lymphoid cells in the induction of chronic intestinal inflammation.

Pharmacological Control of Autophagy: Therapeutic Perspectives in Inflammatory Bowel Disease and Colorectal Cancer

Autophagy, an intracellular process involved in removing and recycling cellular components, plays a major role in growth, development, and responses to stress and pathogens. Autophagy is compromised in many human diseases, including inflammatory bowel disease (IBD) and colorectal cancer (CRC). Autophagy malfunction is associated to an alteration of both innate and adaptative immune responses, defects in bacterial clearance, and malfunction of goblet and Paneth cells; all these perturbations are related to IBD and CRC pathogenesis. Preclinical data show that both inhibition and induction of autophagy have significant potential to be translated into the clinic. Inhibitors of TORC1 (rapamycin and rapalogs) have proven to be effective in IBD and in many models for CRCs; however, their clinical use has produced only modest success. Second generations of mTOR inhibitors, which target its kinase domain, have been more effective. Optimal antitumor efficacy is achieved by combination of agents with different molecular targets, such as proteasome or histone deacetylase inhibitors combined with autophagy inhibitors (hydroxychloroquine) or activators (everolimus). Clinical trials in course are assaying the effect of these compounds in combination with standard treatments of CRC. This review summarizes current knowledge about the autophagic machinery and its regulation, then it explores the relevance and impact of the malfunction of autophagy on the pathogenesis of IBD and CRC, and, finally, it discusses the therapeutic potential of molecules that regulate autophagy and their use for the treatment of these two diseases.

Increased expression of fractalkine and its receptor CX3CR1 in canine inflammatory bowel disease and their possible role in recruitment of intraepithelial lymphocytes

The interaction between fractalkine/CX3CL1 and its receptor CX3CR1 has been reported to play an important role in various human inflammatory diseases, including inflammatory bowel disease (IBD) mediated by lymphocyte chemoattraction. The objective of this study was to investigate the role of fractalkine and CX3CR1 in lymphocyte migration in canine IBD. IBD was diagnosed in 34 dogs, and 19 healthy beagles were used as normal controls. We quantified intestinal mRNA and protein expression of fractalkine and CX3CR1 by real-time RT-PCR and ELISA, respectively, and examined the localization of fractalkine in canine intestine by immunohistochemistry. The expression of CX3CR1 and surface antigens on peripheral blood mononuclear cells (PBMCs) and intraepithelial lymphocytes (IELs) was analyzed by flow cytometry. Intestinal fractalkine and CX3CR1 mRNA was significantly up-regulated in IBD dogs compared with the healthy control dogs. In addition, fractalkine expression on intestinal epithelial cells was significantly increased in the intestinal mucosa of IBD dogs compared with the healthy dogs. CX3CR1+ PBMCs were significantly elevated in IBD dogs and positively correlated with the histopathological severity of IELs infiltration. These CX3CR1+ PBMCs predominantly expressed markers for cytotoxic T cells. Almost all IELs expressed CD3, and the majority of cells expressed CD8 rather than CD4, which was analogous to the CX3CR1+ PBMCs. These results suggest that the fractalkine-CX3CR1 interaction may contribute to the pathogenesis of canine IBD through migration of IELs.

The role of interleukin-21 in the pathogenesis of inflammatory bowel disease (123.45)

Abstract Th17 CD4 T cells are necessary for protection against pathogens but have also been cast as pathogenic in the context of many autoimmune diseases, including Inflammatory Bowel Disease (IBD). Th17 cells produce several inflammatory cytokines, including IL-17, IL-21, IL-22, and IL-26. Although these cytokines may act in concert to induce inflammation in colitis, IL-21 is a strong candidate for further scrutiny. IL-21 expression is increased in biopsies from patients with ulcerative colitis compared to healthy controls, and recent Genome Wide Association Studies have shown an association between the locus containing IL-2/IL-21 and IBD. We have shown that IL-21 signaling is required for the full induction of IBD in a murine model of disease. While others have shown in vitro that exogenous IL-21 acts to induce IL-17 production by CD4 T cells, our in vivo data suggests that IL-21 deficient cells are capable of producing IL-17A and IL-17F to a greater degree than IL-21 competent cells during IBD. In addition, our data disputes the previous finding that IL-21 suppresses the transcription factor Foxp3 as we have shown that IL-21 deficient T-regulatory cells express equal or less Foxp3 both in vitro and in vivo during IBD. Taken together, these data indicate that IL-21 plays a role in the induction of IBD that is separate from modulating the balance between effector and regulatory T cell responses. This work highlights a previously unrecognized role for IL-21 in the pathogenesis of IBD.

Functional relevance of T helper 17 (Th17) cells and the IL-17 cytokine family in inflammatory bowel disease

The recent discovery and characterization of T helper 17 cells (Th17) and their signature cytokines (IL-17) represents a hallmark in T-cell immunobiology by providing a new distinctive pathway for the communication between adaptive and innate immunity. From the six members of the IL-17 cytokine family presently known, at least two have evident proinflammatory qualities and are involved in several chronic inflammatory disorders, including inflammatory bowel disease (IBD). IL-17A and IL-17F are abundantly found in inflamed IBD mucosa, suggesting their pivotal role in IBD. However, the precise implication of IL-17 cytokine family members in IBD pathogenesis and the mechanisms regulating their secretion are incompletely understood. Importantly, recent findings suggest that beyond IL-17 production-Th17 cells may secret a plethora of other effector cytokines such as IL-21, IL-22, and IL-9- which is in part induced by its own IL-9 production. However, the use of anti-IL-17 therapeutic strategies in experimental models of chronic inflammation results in disease-ameliorating effects suggesting their potential use in IBD patients. In this review article we discuss the latest findings on the role of Th17 cells and IL-17 family members in IBD immunopathology, as well as research perspectives.

Key role of mast cells and their major secretory products in inflammatory bowel disease.

Historically, mast cells were known as a key cell type involved in type I hypersensitivity. Until last two decades, this cell type was recognized to be widely involved in a number of non-allergic diseases including inflammatory bowel disease (IBD). Markedly increased numbers of mast cells were observed in the mucosa of the ileum and colon of patients with IBD, which was accompanied by great changes of the content in mast cells such as dramatically increased expression of TNFalpha, IL-16 and substance P. The evidence of mast cell degranulation was found in the wall of intestine from patients with IBD with immunohistochemistry technique. The highly elevated histamine and tryptase levels were detected in mucosa of patients with IBD, strongly suggesting that mast cell degranulation is involved in the pathogenesis of IBD. However, little is known of the actions of histamine, tryptase, chymase and carboxypeptidase in IBD. Over the last decade, heparin has been used to treat IBD in clinical practice. The low molecular weight heparin (LMWH) was effective as adjuvant therapy, and the patients showed good clinical and laboratory response with no serious adverse effects. The roles of PGD2, LTC4, PAF and mast cell cytokines in IBD were also discussed. Recently, a series of experiments with dispersed colon mast cells suggested there should be at least two pathways in man for mast cells to amplify their own activation-degranulation signals in an autocrine or paracrine manner. The hypothesis is that mast cell secretogogues induce mast cell degranulation, release histamine, then stimulate the adjacent mast cells or positively feedback to further stimulate its host mast cells through H1 receptor. Whereas released tryptase acts similarly to histamine, but activates mast cells through its receptor PAR-2. The connections between current anti-IBD therapies or potential therapies for IBD with mast cells were discussed, implicating further that mast cell is a key cell type that is involved in the pathogenesis of IBD. In conclusion, while pathogenesis of IBD remains unclear, the key role of mast cells in this group of diseases demonstrated in the current review implicates strongly that IBD is a mast cell associated disease. Therefore, close attentions should be paid to the role of mast cells in IBD.