Slc26a3 (DRA) in the Gut: Expression, Function, Regulation, Role in Infectious Diarrhea and Inflammatory Bowel Disease

2020 ◽  
Author(s):  
Qin Yu
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Current Knowledge ◽  
Cloning And Expression ◽  
Intestinal Epithelial ◽  
Infectious Diarrhea ◽  
Luminal Membrane ◽  
Inflammatory Bowel ◽  
Future Therapy

Abstract Background The transport of transepithelial Cl- and HCO3- is crucial for the function of the intestinal epithelium and maintains the acid-based homeostasis. Slc26a3 (DRA), as a key chloride-bicarbonate exchanger protein in the intestinal epithelial luminal membrane, participates in the electroneutral NaCl absorption of intestine, together with Na+/H+ exchangers. Increasing recent evidence supports the essential role of decreased DRA function or expression in infectious diarrhea and inflammatory bowel disease (IBD). Method In this review, we give an overview of the current knowledge of Slc26a3, including its cloning and expression, function, roles in infectious diarrhea and IBD, and mechanisms of actions. A better understanding of the physiological and pathophysiological relevance of Slc26a3 in infectious diarrhea and IBD may reveal novel targets for future therapy. Conclusion Understanding the physiological function, regulatory interactions, and the potential mechanisms of Slc26a3 in the pathophysiology of infectious diarrhea and IBD will define novel therapeutic approaches in future.

scholarly journals Thymus leukemia antigen controls intraepithelial lymphocyte function and inflammatory bowel disease

2008 ◽  
Vol 105 (46) ◽  
pp. 17931-17936 ◽  
Author(s):  
Danyvid Olivares-Villagómez ◽  
Yanice V. Mendez-Fernandez ◽  
Vrajesh V. Parekh ◽  
Saif Lalani ◽  
Tiffaney L. Vincent ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Genetic Model ◽  
Critical Role ◽  
Intraepithelial Lymphocytes ◽  
Lymphocyte Function ◽  
Intestinal Epithelial ◽  
Inflammatory Bowel

Intestinal intraepithelial lymphocytes (IEL) bear a partially activated phenotype that permits them to rapidly respond to antigenic insults. However, this phenotype also implies that IEL must be highly controlled to prevent misdirected immune reactions. It has been suggested that IEL are regulated through the interaction of the CD8αα homodimer with the thymus leukemia (TL) antigen expressed by intestinal epithelial cells. We have generated and characterized mice genetically-deficient in TL expression. Our findings show that TL expression has a critical role in maintaining IEL effector functions. Also, TL deficiency accelerated colitis in a genetic model of inflammatory bowel disease. These findings reveal an important regulatory role of TL in controlling IEL function and intestinal inflammation.

scholarly journals A4 THE CIRCADIAN TIMING OF INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 4-5
Author(s):  
Z Taleb ◽  
K Stokes ◽  
H Wang ◽  
S M Collins ◽  
W I Khan ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Circadian Clock ◽  
Bowel Disease ◽  
Mutant Mice ◽  
Intestinal Epithelial ◽  
Wild Type ◽  
Colon Tissue ◽  
Rhythmic Expression ◽  
Inflammatory Bowel

Abstract Background The circadian clock is a highly conserved molecular pacemaker found in nearly every cell of the body. It consists of the genes BMAL1 and CLOCK that positively regulate CRY and PER, their negative regulators, resulting in a transcription/translation feedback loop that has a 24 hour cycle. This core clock mechanism drives the rhythmic expression of over 40% of the genome in a tissue-specific manner and therefore imposes 24 hour rhythms on many physiological processes. Shift work, which causes disruptions to the natural 24 hour physiological rhythms, has been shown to lead to an increased incidence of inflammatory bowel disease (IBD). Aims This study aims to characterize daily rhythms in inflammation and regeneration of the colon upon induction of acute colitis. We also aim to investigate the intestinal epithelial-specific effects of circadian clock disruption on overall disease progression. We hypothesize that the absence of a functional circadian clock eliminates proliferation rhythms of intestinal epithelial cells and disrupts the rhythms of inflammatory cytokines, thereby increasing the pathogenesis of IBD. Methods We tested the role of the clock in IBD using BMAL1+/+ (wild type) and BMAL1-/- (null mutant) mice. We also investigated the effects of the circadian clock specific to intestinal epithelial tissue using Vil+/+;BMAL1flox/flox (control) and VilCre/+;BMAL1flox/flox (conditional intestinal epithelial mutant) mice. Dextran Sulfate Sodium (DSS) was applied to induce acute colitis. Results We observed significantly decreased survival of BMAL1 circadian clock mutant mice when given colitis. A histology analysis indicates increased lesioning and overall inflammation in BMAL1-/- colon tissue. Disease activity and cytokine analyses reveal time-dependent severity in inflammatory response that is worse in BMAL1-/- mice. To test the circadian rhythms in intestinal regeneration of mice with IBD, we performed a 24 hour analysis comparing epithelial cell proliferation and cell death in colon tissue. We observed rhythmic expression of phosphor-histone H3 (a mitosis marker) in wild type mice which is eliminated in the BMAL1-/- lacking a circadian clock. Cell death which was measured by caspase 3 did not exhibit any differences between genotypes. Based on these results, we conclude that the loss of clock function leads to impaired regeneration during IBD, in part due to decreased and arrhythmic cell proliferation. Preliminary results in our VilCre/+;BMAL1flox/flox conditional intestinal epithelial mutant mice indicate that some of these effects may be epithelial-specific. Conclusions Our results support a critical role of the circadian clock in inflammatory bowel disease development. These data highlight that the circadian clock affects the regenerative abilities of intestinal epithelial cells. Funding Agencies CIHRChron’s and Colitis Canada, Ontario, University of Windsor

scholarly journals Alteration of Gut Microbiota in Inflammatory Bowel Disease (IBD): Cause or Consequence? IBD Treatment Targeting the Gut Microbiome

Pathogens ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 126 ◽  
Author(s):  
Israr Khan ◽  
Naeem Ullah ◽  
Lajia Zha ◽  
Yanrui Bai ◽  
Ashiq Khan ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Gut Microbiota ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Current Knowledge ◽  
Pathological Condition ◽  
Gut Flora ◽  
Core Microbiome ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is a chronic complex inflammatory gut pathological condition, examples of which include Crohn’s disease (CD) and ulcerative colitis (UC), which is associated with significant morbidity. Although the etiology of IBD is unknown, gut microbiota alteration (dysbiosis) is considered a novel factor involved in the pathogenesis of IBD. The gut microbiota acts as a metabolic organ and contributes to human health by performing various physiological functions; deviation in the gut flora composition is involved in various disease pathologies, including IBD. This review aims to summarize the current knowledge of gut microbiota alteration in IBD and how this contributes to intestinal inflammation, as well as explore the potential role of gut microbiota-based treatment approaches for the prevention and treatment of IBD. The current literature has clearly demonstrated a perturbation of the gut microbiota in IBD patients and mice colitis models, but a clear causal link of cause and effect has not yet been presented. In addition, gut microbiota-based therapeutic approaches have also shown good evidence of their effects in the amelioration of colitis in animal models (mice) and IBD patients, which indicates that gut flora might be a new promising therapeutic target for the treatment of IBD. However, insufficient data and confusing results from previous studies have led to a failure to define a core microbiome associated with IBD and the hidden mechanism of pathogenesis, which suggests that well-designed randomized control trials and mouse models are required for further research. In addition, a better understanding of this ecosystem will also determine the role of prebiotics and probiotics as therapeutic agents in the management of IBD.

scholarly journals Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention

2021 ◽  
Vol 12 ◽  
Author(s):  
Marianna Lucafò ◽  
Debora Curci ◽  
Martina Franzin ◽  
Giuliana Decorti ◽  
Gabriele Stocco
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Inflammatory Process ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
Pharmacological Prevention ◽  
Increased Risk ◽  
Inflammatory Bowel

Increased risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients has been attributed to long-standing chronic inflammation, with the contribution of genetic alterations and environmental factors such as the microbiota. Moreover, accumulating data indicate that IBD-associated CRC (IBD-CRC) may initiate and develop through a pathway of tumorigenesis distinct from that of sporadic CRC. This mini-review summarizes the current knowledge of IBD-CRC, focusing on the main mechanisms underlying its pathogenesis, and on the important role of immunomodulators and biologics used to treat IBD patients in interfering with the inflammatory process involved in carcinogenesis.

scholarly journals Temporal induction of intestinal epithelial hypoxia-inducible factor-2α is sufficient to drive colitis

2019 ◽  
Vol 317 (2) ◽  
pp. G98-G107 ◽  
Author(s):  
Sumeet Solanki ◽  
Samantha N. Devenport ◽  
Sadeesh K. Ramakrishnan ◽  
Yatrik M. Shah
Keyword(s):  
Inflammatory Bowel Disease ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Intestinal Epithelial Cells ◽  
Hypoxia Inducible Factor ◽  
Intestinal Epithelial ◽  
Inflammatory Bowel

Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1α and HIF-2α (endothelial PAS domain protein 1, EPAS1) play important, but opposing, roles in its pathogenesis. While activation of HIF-1α decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2α exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2α in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2α led to massive intestinal inflammation and decreased survival. As oxygen homeostasis and HIFs are critical in embryonic development, it is not clear whether the observed intestinal inflammatory response was secondary to developmental defects. To address this question, the present study used a mouse model to temporally modulate expression of intestinal epithelial HIF-2α to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2α in intestinal epithelial cells in adult mice increased expression of proinflammatory mediators; however, no decrease in survival was observed. Furthermore, in an acute model of colitis, activation of HIF-2α was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2α mediates inflammatory response and demonstrates that activation of HIF-2α is sufficient to exacerbate colitis.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestinal tract. Hypoxia and activation of its downstream transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are notable features of IBD. HIF-1α has well-characterized protective roles in IBD; however, the role of HIF-2α has been less studied. Using novel HIF-2α mouse models, we show that activation of HIF-2α in intestinal epithelial cells is sufficient to exacerbate colitis.

scholarly journals Proteomics and Lipidomics in Inflammatory Bowel Disease Research: From Mechanistic Insights to Biomarker Identification

2018 ◽  
Vol 19 (9) ◽  
pp. 2775 ◽  
Author(s):  
Bjoern Titz ◽  
Raffaella Gadaleta ◽  
Giuseppe Lo Sasso ◽  
Ashraf Elamin ◽  
Kim Ekroos ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Continuous Monitoring ◽  
Biomarker Discovery ◽  
Treatment Options ◽  
Intestinal Epithelial ◽  
Future Studies ◽  
Targeted Treatments ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) represents a group of progressive disorders characterized by recurrent chronic inflammation of the gut. Ulcerative colitis and Crohn′s disease are the major manifestations of IBD. While our understanding of IBD has progressed in recent years, its etiology is far from being fully understood, resulting in suboptimal treatment options. Complementing other biological endpoints, bioanalytical “omics” methods that quantify many biomolecules simultaneously have great potential in the dissection of the complex pathogenesis of IBD. In this review, we focus on the rapidly evolving proteomics and lipidomics technologies and their broad applicability to IBD studies; these range from investigations of immune-regulatory mechanisms and biomarker discovery to studies dissecting host–microbiome interactions and the role of intestinal epithelial cells. Future studies can leverage recent advances, including improved analytical methodologies, additional relevant sample types, and integrative multi-omics analyses. Proteomics and lipidomics could effectively accelerate the development of novel targeted treatments and the discovery of complementary biomarkers, enabling continuous monitoring of the treatment response of individual patients; this may allow further refinement of treatment and, ultimately, facilitate a personalized medicine approach to IBD.

The Diverse Roles of the IL-36 Family in Gastrointestinal Inflammation and Resolution

2020 ◽  
Author(s):  
Gemma Leon ◽  
Seamus Hussey ◽  
Patrick T Walsh
Keyword(s):  
Inflammatory Bowel Disease ◽  
Intestinal Mucosa ◽  
Significant Influence ◽  
Clinical Setting ◽  
Bowel Disease ◽  
Current Knowledge ◽  
Family Members ◽  
Inflammatory Bowel ◽  
Gastrointestinal Inflammation

Abstract The interleukin (IL)-36 family is a member of the IL-1 superfamily of cytokines and, in common with other IL-1 family members, has been shown to exhibit pleiotropic effects in homeostasis and inflammation. Although the important role these cytokines play in the skin has been widely reported, recent evidence suggests that IL-36 family members are expressed and can also exert significant influence at the intestinal mucosa. In this review, we summarize current knowledge surrounding the role of the IL-36 in the intestines. In particular, we examine its likely dichotomous role as a mediator of both inflammation and resolution, highlighting its overlapping roles in innate and adaptive inflammation at the mucosa and its contribution to pathophysiology of inflammatory bowel disease. We also summarize the complexities of targeting this cytokine family in a clinical setting.

scholarly journals The Multifaceted Role of Serotonin in Intestinal Homeostasis

2021 ◽  
Vol 22 (17) ◽  
pp. 9487
Author(s):  
Nienke Koopman ◽  
Drosos Katsavelis ◽  
Anne S. ten Hove ◽  
Stanley Brul ◽  
Wouter J. de Jonge ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Current Knowledge ◽  
Bacterial Species ◽  
Disease Course ◽  
Intestinal Homeostasis ◽  
Wide Range ◽  
Range Of Functions ◽  
Inflammatory Bowel

The monoamine serotonin, 5-hydroxytryptamine (5-HT), is a remarkable molecule with conserved production in prokaryotes and eukaryotes and a wide range of functions. In the gastrointestinal tract, enterochromaffin cells are the most important source for 5-HT production. Some intestinal bacterial species are also able to produce 5-HT. Besides its role as a neurotransmitter, 5-HT acts on immune cells to regulate their activation. Several lines of evidence indicate that intestinal 5-HT signaling is altered in patients with inflammatory bowel disease. In this review, we discuss the current knowledge on the production, secretion, and signaling of 5-HT in the intestine. We present an inventory of intestinal immune and epithelial cells that respond to 5-HT and describe the effects of these signaling processes on intestinal homeostasis. Further, we detail the mechanisms by which 5-HT could affect inflammatory bowel disease course and describe the effects of interventions that target intestinal 5-HT signaling.

scholarly journals Emerging Comorbidities in Inflammatory Bowel Disease: Eating Disorders, Alcohol and Narcotics Misuse

2021 ◽  
Vol 10 (19) ◽  
pp. 4623
Author(s):  
Paweł Kuźnicki ◽  
Katarzyna Neubauer
Keyword(s):  
Inflammatory Bowel Disease ◽  
Eating Disorders ◽  
Bowel Disease ◽  
Current Knowledge ◽  
Wide Spectrum ◽  
Systemic Disease ◽  
Alcohol And Drugs ◽  
Inflammatory Bowel ◽  
Established Role

Inflammatory bowel disease (IBD) is a chronic and potentially devastating condition of the digestive tract which is exemplified by increasing prevalence worldwide, byzantine pathogenesis with a poorly defined role of the environmental factors, and complex clinical demonstration. As a systemic disease, IBD may progress with a wide spectrum of extraintestinal manifestations (EMs) and comorbidities affecting different organs and systems, from anaemia, undernutrition, and cancer to those which are often neglected like anxiety and depression. Evolving IBD epidemiology and changing environment are reflected by an expanding list of IBD-related comorbidities. In contrast to the well-established role of smoking the connection between alcohol and IBD is still debatable on many levels, from pathogenesis to complications. Furthermore, little is known about narcotics use in IBD patients, even if there are obvious factors that may predispose them to narcotics as well as alcohol misuse. Last but not least, the question arises what is the prevalence of eating disorders in IBD. In our paper, we aimed to discuss the current knowledge on alcohol and drugs misuse and eating disorders as emerging extraintestinal comorbidities in IBD.

scholarly journals Stromal Cells in the Pathogenesis of Inflammatory Bowel Disease

2020 ◽  
Vol 14 (7) ◽  
pp. 995-1009 ◽  
Author(s):  
M C Barnhoorn ◽  
S K Hakuno ◽  
R S Bruckner ◽  
G Rogler ◽  
L J A C Hawinkels ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Stromal Cells ◽  
Bowel Disease ◽  
Immune Cell ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Clinical Settings ◽  
Intestinal Epithelial ◽  
Stromal Compartment ◽  
Inflammatory Bowel

Abstract Up till now, research on inflammatory bowel disease [IBD] has mainly been focused on the immune cells present in the gastrointestinal tract. However, recent insights indicate that stromal cells also play an important and significant role in IBD pathogenesis. Stromal cells in the intestines regulate both intestinal epithelial and immune cell homeostasis. Different subsets of stromal cells have been found to play a role in other inflammatory diseases [e.g. rheumatoid arthritis], and these various stromal subsets now appear to carry out also specific functions in the inflamed gut in IBD. Novel potential therapies for IBD utilize, as well as target, these pathogenic stromal cells. Injection of mesenchymal stromal cells [MSCs] into fistula tracts of Crohn’s disease patients is already approved and used in clinical settings. In this review we discuss the current knowledge of the role of stromal cells in IBD pathogenesis. We further outline recent attempts to modify the stromal compartment in IBD with agents that target or replace the pathogenic stroma.

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