Crohn's disease is an inflammatory bowel disease that is characterized by chronic inflammation of any part of the gastrointestinal tract, has a progressive and destructive course and is increasing in ...incidence worldwide. Several factors have been implicated in the cause of Crohn's disease, including a dysregulated immune system, an altered microbiota, genetic susceptibility and environmental factors, but the cause of the disease remains unknown. The onset of the disease at a young age in most cases necessitates prompt but long-term treatment to prevent disease flares and disease progression with intestinal complications. Thus, earlier, more aggressive treatment with biologic therapies or novel small molecules could profoundly change the natural history of the disease and decrease complications and the need for hospitalization and surgery. Although less invasive biomarkers are in development, diagnosis still relies on endoscopy and histological assessment of biopsy specimens. Crohn's disease is a complex disease, and treatment should be personalized to address the underlying pathogenetic mechanism. In the future, disease management might rely on severity scores that incorporate prognostic factors, bowel damage assessment and non-invasive close monitoring of disease activity to reduce the severity of complications.
Introduction: For 30 years, 5-aminosalicylic acid (5-ASA) has been the backbone of therapeutic management in patients with ulcerative colitis (UC). In the biologic era, it still remains the treatment ...of choice in mild-to-moderate UC. Positioning of this therapeutic class in moderate-to-severe UC is less clear.
Areas covered: Several studies demonstrated the ability of 5-ASA to induce endoscopic remission to a similar extent as anti-TNF therapy on the moderate segment of UC. Histologic remission is achieved after induction in up to 45% of patients treated with topical 5-ASA and 30% with oral formulations. Aminosalicylates offer a favorable safety profile compared to that of immunomodulators and biologics. High-dose 5-ASA therapy may be a valuable option for patients with moderately active disease, and physicians should weigh the pros and cons of this strategy in selected patients. Whether aminosalicylates should be continued in combination with thiopurines or biologic therapy remains under debate.
Expert opinion: In the era of biologics, aminosalicylates remain the first-line therapy in patients with mild UC, and have to be considered in case of moderate UC, given their favorable risk-benefit profile. We suggest that 5-ASA should be used in moderate patients without poor prognostic factors, while biologics should be preferred otherwise.
Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract, characterized by a dysregulated innate and adaptive immune response to gut microbiota that contributes to the ...perpetuation of intestinal inflammatory processes. The Interleukin (IL) 23/IL17 axis has been reported to play a key role in UC pathogenesis promoting Th17 cells and cytokines-related immune response. Recently, the blockade of IL23/IL17 pathways has been raised enormous interest in the treatment o several chronic inflammatory disorders. In this review, we summarize the emerging results from clinical trials that evoked both promise and discouragement in IL23/IL17 axis in the treatment of UC. Targeting IL23 p40 through Ustekinumab results safe and effective to induce and maintain clinical remission, low inflammatory indexes, mucosal healing, and a better quality of life. Studies targeting IL23 p19 through Mirikizumab, Risankizumab, Brazikumab and Guselkumab are still ongoing. To date, no clinical studies targeting IL17 pathway are ongoing in UC. IL-17 targeting is thought to have a context-dependent biological effect, based on whether cytokine is selectively targeted or if its function is dampened by the upstream block of IL23.
Colorectal cancer (CRC) ranks as the second among the causes of tumor death worldwide, with an estimation of 1.9 million new cases in 2020 and more than 900,000 deaths. This rate might increase by ...60% over the next 10 years. These data are unacceptable considering that CRC could be successfully treated if diagnosed in the early stages. A high-fat diet promotes the hepatic synthesis of bile acids (BAs) increasing their delivery to the colonic lumen and numerous scientific reports correlate BAs, especially secondary BAs, with CRC incidence. We reviewed the physicochemical and biological characteristics of BAs, focusing on the major pathways involved in CRC risk and progression. We specifically pointed out the role of BAs as signaling molecules and the tangled relationships among their nuclear and membrane receptors with the big bang of molecular and cellular events that trigger CRC occurrence.
Necroptosis is a programmed form of non-apoptotic cell death that requires the kinase activity of the receptor interacting protein kinase 3 (RIPK3). Although in vitro data suggests that cancer cells ...lacking expression of RIPK3 are invasive, the physiological role of RIPK3 in a disease-relevant setting remains unknown. Here we provide evidence that RIPK3 has a critical role in suppressing colorectal cancer (CRC). RIPK3-deficient mice were highly susceptible to colitis-associated CRC and exhibited greater production of pro-inflammatory mediators and tumor promoting factors. Tumorigenesis in RIPK3-deficiency resulted from uncontrolled activation of NF-κB, STAT3, AKT and Wnt-β-catenin signaling pathways that enhanced the ability of intestinal epithelial cells (IECs) to aberrantly proliferate in the face of the sustained inflammatory microenvironment and promote CRC. We found that RIPK3 expression is reduced in tumors from patients with inflammatory bowel diseases, and further confirmed that expression of RIPK3 is downregulated in human CRC and correlated with cancer progression. Thus, our results reveal that the necroptosis adaptor RIPK3 has key anti-inflammatory and anti-tumoral functions in the intestine, and define RIPK3 as a novel colon tumor suppressor.
The pathogenesis of inflammatory bowel diseases (IBDs) seems to involve a primary defect in one or more of the elements responsible for the maintenance of intestinal homeostasis and oral tolerance. ...The most important element is represented by the intestinal barrier, a complex system formed mostly by intestinal epithelial cells (IECs). IECs have an active role in producing mucus and regulating its composition; they provide a physical barrier capable of controlling antigen traffic through the intestinal mucosa. At the same time, they are able to play the role of non-professional antigen presenting cells, by processing and presenting antigens directly to the cells of the intestinal immune system. On the other hand, immune cells regulate epithelial growth and differentiation, producing a continuous bi-directional cross-talk within the barrier. Several alterations of the barrier function have been identified in IBD, starting from mucus features up to its components, from epithelial junctions up to the Toll-like receptors, and altered immune responses. It remains to be understood whether these defects are primary causes of epithelial damage or secondary effects. We review the possible role of the epithelial barrier and particularly describe the role of IECs in the pathogenesis of IBD.
Phytosterols, besides hypocholesterolemic effect, present anti-inflammatory properties. Little information is available about their efficacy in Inflammatory Bowel Disease (IBD). Therefore, we have ...evaluated the effect of a mixture of phytosterols on prevention/induction/remission in a murine experimental model of colitis. Phytosterols were administered x os before, during and after colitis induction with Dextran Sodium Sulfate (DSS) in mice. Disease Activity Index (DAI), colon length, histopathology score, 18F-FDG microPET, oxidative stress in the intestinal tissue (ileum and colon) and gallbladder ileum and colon spontaneous and carbachol (CCh) induced motility, plasma lipids and plasma, liver and biliary bile acids (BA) were evaluated. A similar longitudinal study was performed in a DSS colitis control group. Mice treated with DSS developed severe colitis as shown by DAI, colon length, histopathology score, 18F-FDG microPET, oxidative stress. Both spontaneous and induced ileal and colonic motility were severely disturbed. The same was observed with gallbladder. DSS colitis resulted in an increase in plasma cholesterol, and a modification of the BA pattern. Phytosterols feeding did not prevent colitis onset but significantly reduced the severity of the disease and improved clinical and histological remission. It had strong antioxidant effects, almost restored colon, ileal and gallbladder motility. Plasmatic levels of cholesterol were also reduced. DSS induced a modification in the BA pattern consistent with an increase in the intestinal BA deconjugating bacteria, prevented by phytosterols. Phytosterols seem a potential nutraceutical tool for gastrointestinal inflammatory diseases, combining metabolic systematic and local anti-inflammatory effects.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inflammatory Bowel Disease is lifetime chronic progressive inflammatory disease. A considerable portion of patients, do not respond or lose response or experience side effect to "traditional" ...biological treatment such as anti-tumor necrosis factor (TNF)-α agents. The concept that the blockade of T cell traffic to the gut controls inflammation has stimulated the development of new drugs which selectively targets molecules involved in controlling cell homing to the intestine. The result is the reduction of the chronic inflammatory infiltration in the gut. In this regard, anti-adhesion molecules represent a new class of drugs for patients who don't respond or lose response to traditional therapy. Moreover, some of these molecules such as vedolizumab, offer the advantage to target the delivery of a drug to the gut (gut selectivity) which could increase clinical efficacy and limit potential adverse events. In this article, we will give an overview of the current data on anti-adhesion molecules in Inflammatory Bowel Diseases.
Inflammatory bowel diseases (IBD) are chronic and progressive diseases. Long-term complications are demolitive surgery and colon-rectal cancer. A 'treat to target' strategy, in which the treatment ...aims to achieve objective outcomes, has already been introduced in the management of chronic conditions as rheumatic diseases. This approach is emerging as suitable for ulcerative colitis and Crohn's disease. Targets are predefined therapeutic goals demonstrated to prevent end-organ dysfunction. An optimization or switch of therapy is considered depending on the target's achievement, with regular monitoring.
According to the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) indications, mucosal healing and clinical remission are the main targets in IBDs. Histological remission is increasingly being considered as a novel target and has given rise to the new concept of 'disease clearance' which includes clinical, endoscopic and microscopic remission. We aim to review current evidence on the treat-to-target strategy in comparison to a stricter treat-to-clear in the IBD field.
Prospective studies on treat-to-target algorithm are sparse; a treat-to-clear approach is desirable but far from adoption in the daily practice and clinical trials. The ultimate goals of a treat-to-clear strategy differ in UC and in CD, including histological healing and transmural healing, respectively.
Intestinal fibrosis, driven by chronic inflammation in Crohn's disease, can be defined as an excessive accumulation of extracellular matrix in the affected gut segment ultimately leading to an ...impaired wound healing and cumulative tissue damage, possibly resulting in organ dysfunction, formation of stenotic lesions and necessity of surgical intervention. Despite continuous advances in developing novel treatment modalities targeting different pathways to control chronic gut inflammation in CD, no effective anti-fibrotic agents have been released, to date. Thus, a better understanding of the molecular and cellular mechanisms underlying intestinal fibrosis is key to move this area of investigation forward.
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