Bile acids are carcinogens causing mutations leading to colorectal cancer (CRC). Higher total bile acid concentrations in the serum of patients with primary biliary cholangitis (PBC), compared to healthy controls, have been reported in previous studies. However, the association between PBC and the risk for CRC remains controversial. We investigated the association between PBC and the development of colonic polyps leading to CRC overall in this study.

The study enrolled 1,936,512 individuals from the Longitudinal Health Insurance Database spanning 2000 to 2017 for cohort analysis. Individuals assigned to ICD-9-CM and ICD-10-CM codes representing PBC were incorporated. A 1:4 control cohort was randomly selected. After adjusting for CRC risk factors using Cox regression analysis, we calculated the hazard ratios for developing colon polyps and CRC in PBC patients compared to the general population.

Within the study cohort, consisting of 2024 individuals meeting the inclusion criteria, 199 patients developed colon polyps or CRC. In contrast, among the 8096 individuals in the comparison cohort, 650 cases of colon polyps or CRC were observed during the 17-year-follow-up period. According to Cox regression analysis, the adjusted hazard ratio indicated that the risk was 1.678 times higher in the PBC group compared to the comparison group.

This population-based retrospective cohort study identified a 1.68-fold increased risk of colon polyps and CRC in patients with PBC, suggesting a potential association with colonic neoplasia. Further research is warranted to evaluate the role of endoscopic surveillance in patients with PBC.

The gut microbiota (GM), the set of microorganisms that colonizes our intestinal tract, can undergo many changes, some of which are age related. Several studies have shown the importance of maintaining a healthy GM for a good quality of life. In the elderly, maintaining a good GM may become a real defense against infection by pathogens, such as C. difficile. In addition to the GM, bile acids (BAs) have been shown to provide an additional defense mechanism against the proliferation of pathogenic bacteria and to regulate bacterial colonization of the gut. BAs are molecules produced in the host liver and secreted with the bile into the digestive tract, and they are necessary for the digestion of dietary lipids. In the gut, host-produced BAs are metabolized by commensal bacteria to secondary BAs. In general GM and host organisms interact in many ways. This review examines the relationship between GM, BAs, aging, and possible new approaches such as dietary interventions, administration of ursodesoxycholic acid/tauroursodesoxycholic acid (UDCA/TUDCA), and probiotics to enrich the microbial consortia of the GM in the elderly and achieve a eubiotic state necessary for maintaining good health. The presence of Firmicutes and Actinobacteria together with adequate levels of secondary BAs would provide protection and improve the frailty state in the elderly. In fact, an increase in secondary BAs has been observed in centenarians who have reached old age without serious health issues, which may justify their active role in achieving longevity.

Background: Inflammatory bowel diseases (IBDs) have been associated with a higher risk of colorectal cancer (CRC) development and chronic colonic inflammation seems to have a critical role in the pathogenesis of CRC in patients suffering from IBD. In respect to that, surveillance colonoscopy at regular intervals is recommended in patients with colitis. Objective: This review aims to explore the chemopreventive potential of a range of agents, including mesalazine, thiopurines, anti-TNF agents, statins, ursodeoxycholic acid, aspirin, folic acid, and nutraceuticals. Results: These agents target inflammation, oxidative stress, and oncogenic pathways, thereby offering the potential to reduce the risk of CRC in patients with IBD. Anti-TNF agents, such as infliximab and adalimumab, not only reduce colonic inflammation, but also play a protective role against CRC by lessening the carcinogenic effects associated with prolonged inflammatory processes. Furthermore, mesalazine and thiopurines have demonstrated established efficacy, while newer biologics, including interleukin inhibitors, show promising advancements. Although nutraceuticals and dietary interventions require further clinical validation, they offer additional possibilities for non-pharmacological prevention. Conclusion: Despite progress, knowledge gaps persist regarding the long-term safety, optimal dosing, and combined use of these agents. A significant reduction in the incidence of CRC in patients with IBD could be achieved by advancing chemoprevention and personalizing strategies.

The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti-programmed cell death protein 1 (anti-PD-1) immunotherapy. Furthermore, different BAs regulated CD8+ T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

The diagnostics of colorectal cancer (CRC) and precancerous lesions in the colon is one of the most urgent matters to be considered for the modern protocols of complex examination, recommended for use from the age of 45 years, and including both instrumental and laboratory methods of research: Colonoscopy, CT colonography, flexible sigmoidoscopy, fecal occult blood test, fecal immunohistochemistry test and stool DNA test Nevertheless, the removal of those precancerous lesions does not solve the issue, and, apart from the regular endoscopic monitoring of patients who are at a high risk of developing CRC, the pharmacological treatment of certain key pathogenic mechanisms leading to the development of CRC is required. The present review to discusses the function of β-catenin in the transformation of precancerous colorectal lesions into CRC, when collaborating with PI3K/AKT/mTOR signaling pathway and other mechanisms. The existing methods for the early diagnostics and prevention of discovered anomalies are described and categorized. The analysis of the approaches to chemoprophylaxis of CRC, depending on the results of endoscopic, morphological and molecular-genetic tests, is presented.

Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.

The close relationship between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) provides a good opportunity to comprehend the gut-liver axis. The gut and the liver have reciprocal interactions, including how gut inflammation influences the liver through immune cells and the microbiota and how the microbiota in the gut modifies bile acids, which are produced and secreted from the liver. PSC-IBD shows distinct clinical findings from classical IBD. In addition, a distinct genetic predisposition and unique microbiota composition suggest that PSC-IBD is an independent disease entity. Understanding the pathogenesis of PSC-IBD helps to develop novel and effective therapeutic agents. Given the high risk of malignancies associated with PSC-IBD, it is critical to identify patients at high risk and implement appropriate surveillance and monitoring strategies. In this review, we provide an overview of PSC-IBD, which exemplifies the gut-liver axis.

Cholestasis is a condition characterized by decrease in bile flow due to progressive pathological states that lead to chronic cholestatic liver diseases which affect the biliary tree at the intrahepatic level and extrahepatic level. They induce complications such as cirrhosis, liver failure, malignancies, bone disease and nutritional deficiencies that merit close follow-up and specific interventions. Furthermore, as those conditions progress to liver cirrhosis, there will be an increase in mortality but also an important impact in quality of life and economic burden due to comorbidities related with liver failure. Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. With a general view of therapeutic options and their molecular targets, this review addresses the pathophysiology of cholangiopathies. The objective is to provide clinicians with an overview of the safety and efficacy of the treatment of cholangiopathies based on the current evidence.

Accumulating evidence has suggested that curcumin may protect against cerebral ischemia-reperfusion injury (CIRI). However, biological mechanisms vary across studies, limiting the clinical applicability of these findings. We performed a meta-analysis on publications evaluating curcumin administration in rat models of CIRI. Furthermore, we sought to test the hypothesis that curcumin alleviates CIRI through diminishing oxidation and inflammation. We searched PubMed, Embase, Web of Science, and Cochrane from the starting date of each database to May 2022 for experimental rat studies exploring the use of curcumin after ischemia reperfusion. Included articles were assessed for bias using SYRCLE's risk of bias tool. Data were aggregated by a random effects model. Curcumin administration significantly reduced neurological deficit score (20 studies; pooled mean difference [MD] = -1.57; 95% CI, -1.78 to -1.36, P < .00001), infarct volume (18 studies; pooled MD = -17.56%; 95% CI, -20.92% to -14.20%; P < 0.00001), and brain water content (8 studies, pooled MD = -11.29%, 95% CI: -16.48%, -6.11%, P < .00001). Compared with control, the levels of superoxide dismutase, glutathione, and glutathione peroxidase were significantly higher, whereas the levels of reactive oxygen species, malondialdehyde, interleukin-1β, interleukin-6, interleukin-8, and nuclear factor kappa B were significantly lower (P < .05). Subgroup analysis raised the possibility that intervention affections differed by curcumin's dose. To our knowledge, this is the first meta-analysis of curcumin's neuroprotection and mechanisms in rat CIRI models. Our analysis suggests the neuroprotective potential of curcumin in CIRI via antioxidant activity and anti-inflammatory effect. More research is required to further confirm the effectiveness and safety of curcumin on ischemic stroke therapy.

The association between inflammatory bowel disease and colorectal cancer is well known. Although the overall incidence of inflammatory bowel disease has declined recently, patients with this disease still have a 1.7-fold increased risk of colorectal cancer. The risk factors for developing colorectal cancer include extensive colitis, young age at diagnosis, disease duration, primary sclerosing cholangitis, chronic colonic mucosal inflammation, dysplasia lesion, and post-inflammatory polyps. In patients with inflammatory bowel disease, control of chronic inflammation and surveillance colonoscopies are important for the prevention of colorectal cancer. The 2017 guidelines from the European Crohn's and Colitis Organisation suggest that colonoscopies to screen for colorectal cancer should be performed when inflammatory bowel disease symptoms have lasted for 8 years. Current evidence supports the use of chemoprevention therapy with mesalamine to reduce the risk of colorectal cancer in patients with ulcerative colitis. Other compounds, including thiopurine, folic acid, statin, and tumor necrosis factor-α inhibitor, are controversial. Large surveillance cohort studies with longer follow-up duration are needed to evaluate the impact of drugs on colorectal cancer risks.

Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.

Inflammatory bowel disease (IBD) is characterized as chronic inflammation in the gastrointestinal tract, which includes two main subtypes, Crohn's disease and ulcerative colitis. Endoscopy combined with biopsy is the most effective way to establish IBD diagnosis and disease management. Imaging techniques have also been developed to monitor IBD. Although effective, the methods are expensive and invasive, which leads to pain and discomfort. Alternative noninvasive biomarkers are being explored as tools for IBD prognosis and disease management. This review focuses on novel biomarkers that have emerged in recent years. These serological biomarkers and microRNAs could potentially be used for disease management in IBD, thereby decreasing patient discomfort and morbidity.

Bile acids (BAs) can regulate their own metabolism and transport as well as other key aspects of metabolic homeostasis via dedicated (nuclear and G protein-coupled) receptors. Disrupted BA transport and homeostasis results in the development of cholestatic disorders and contributes to a wide range of liver diseases, including nonalcoholic fatty liver disease and hepatocellular and cholangiocellular carcinoma. Furthermore, impaired BA homeostasis can also affect the intestine, contributing to the pathogenesis of irritable bowel syndrome, inflammatory bowel disease, and colorectal and oesophageal cancer. Here, we provide a summary of the role of BAs and their disrupted homeostasis in the development of gastrointestinal and hepatic disorders and present novel insights on how targeting BA pathways might contribute to novel treatment strategies for these disorders.

Due to the increased incidence of colorectal cancer in inflammatory bowel diseases (IBDs), the value of chemoprevention for this patient group has been repeatedly debated in the past decade. This review describes available evidence and the current recommendations for chemoprevention in national and international guidelines IBD guidelines.

5-Aminosalicylic acid (5-ASA) compounds are the preferred therapeutic option for mild to moderate ulcerative colitis (UC). Aside from the known anti-inflammatory effects, their chemopreventive abilities have been described in vitro and in vivo. Pooling the increasing number of retrospective and population-based clinical studies over the last 15 years, 7 consecutive meta-analyses revealed partially conflicting results for the chemopreventive efficacy of 5-ASA, and thus, not all IBD guidelines currently recommend chemoprevention with mesalamine compounds. Accumulating evidence for decreasing the colorectal cancer (CRC) risk in support of thiopurines more recently shows a protective effect. This effect seems solely mediated by control of intestinal inflammation since, for this drug class, another mechanistic interference in IBD-associated CRC pathogenesis is not known. The results regarding chemopreventive efficacy for ursodeoxycholic acid or folic acid are equivocal, and the use of these medications to prevent CRC is not firmly established. Like UC, the risk of CRC is also significantly increased in patients with Crohn's disease (CD), especially Crohn's colitis. However, no published studies exclusively assess the effects of surveillance on the early detection of cancer or CRC chemoprevention in CD patients. In meta-analyses, which predominantly included UC patients, 5-ASA or thiopurines were not beneficial in small CD subgroups. The level of evidence for anti-TNFα agents, anti-integrin (e.g., vedolizumab), or anti-IL-12/IL-23 agents (e.g., ustekinumab) and Janus kinase inhibitors is currently too low or nonexistent to use them solely for chemoprevention in UC or CD patients.

Intestinal inflammation is one of the main risk factors for developing CRC in IBD, and all drugs that induce and maintain mucosal healing most likely also decrease the IBD-associated CRC risk. Thus, a therapeutic strategy of adding a 5-ASA therapy to a successfully mucosal healing-inducing therapy, for example, with a biologic or a small molecule merely to prevent CRC appears to be obsolete.

Inflammatory bowel disease (IBD) may show a wide range of extraintestinal manifestations. In this context, liver involvement is a focal point for both an adequate management of the disease and its prognosis, due to possible serious comorbidity. The association between IBD and primary sclerosing cholangitis is the most known example. This association is relevant because it implies an increased risk of both colorectal cancer and cholangiocarcinoma. Additionally, drugs such as thiopurines or biologic agents can cause drug-induced liver damage; therefore, this event should be considered when planning IBD treatment. Additionally, particular consideration should be given to the evidence that IBD patients may have concomitant chronic viral hepatitis, such as hepatitis B and hepatitis C. Chronic immunosuppressive regimens may cause a hepatitis flare or reactivation of a healthy carrier state, therefore careful monitoring of these patients is necessary. Finally, the spread of obesity has involved even IBD patients, thus increasing the risk of non-alcoholic fatty liver disease, which has already proven to be more common in IBD patients than in the non-IBD population. This phenomenon is considered an emerging issue, as it will become the leading cause of liver cirrhosis.

Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). Current guidelines recommend frequent surveillance colonoscopies for patients with at least left-sided ulcerative colitis, or Crohn's disease involving more than 30% of the colon. Surveillance allows for early detection and treatment of colorectal dysplasia and cancer. The first colonoscopy should be performed 8 to 10 years after onset of disease symptoms. European and British guidelines employ a risk-stratification algorithm that assigns patients to surveillance intervals of one, three or five years, whereas American guidelines recommend to perform surveillance every 1 to 3 years based on the (combined) presence of risk factors. Patients with concomitant primary sclerosing cholangitis are at an additionally increased risk, and should undergo annual surveillance starting immediately after the diagnosis. The current practice of surveillance is based on limited evidence, is resource intensive and cannot preclude the occurrence of interval carcinomas. Fortunately, advances in endoscopic techniques for mucosal visualisation, along with better control of inflammation, have resulted in a declining incidence of CRC in patients with IBD. Furthermore, advanced endoscopic resection techniques can be expected to result in a shift from surgical to endoscopic management of dysplastic lesions. In this review, we provide an up-to-date overview of colitis-associated CRC pathophysiology, epidemiology, surveillance practices, and management of dysplasia.

Patients with primary sclerosing cholangitis (PSC) constitute 5 to 15% of patients listed for liver transplantation worldwide. Although post-transplant outcomes are favorable, recurrent PSC (rPSC) occurs in an important subset of patients, with higher prevalence rates reported with increasing time from transplant. Given its association with poor graft outcomes and risk of retransplant, effort has been made to understand rPSC, its pathophysiology, and risk factors. This review covers these facets of rPSC and focuses on implicated risk factors including pretransplant recipient characteristics, inflammatory bowel-disease-related factors, and donor-specific and transplant-specific factors. Confirming a diagnosis of rPSC requires thoughtful consideration of alternative etiologies so as to ensure confidence in diagnosis, management, subsequent risk assessment, and counseling for patients. Unfortunately, no cure exists for rPSC; however, future large-scale efforts are underway to better characterize the natural history of rPSC and its associated risk factors with hopes of identifying potential key targets for novel therapies.

Primary sclerosing cholangitis (PSC) is a progressive fibrosing cholestatic liver disease that is strongly associated with inflammatory bowel disease (IBD). PSC-associated IBD (PSC-IBD) displays a unique phenotype characterized by right-side predominant colon inflammation and increased risk of colorectal cancer compared to non-PSC-IBD. The frequent association and unique phenotype of PSC-IBD suggest distinctive underlying disease mechanisms from other chronic liver diseases or IBD alone. Multidrug resistance protein 2 knockout (Mdr2-/-) mice develop spontaneous cholestatic liver injury and fibrosis mirroring human PSC. As a novel model of PSC-IBD, we treated Mdr2-/- mice with dextran sulfate sodium (DSS) to chemically induce colitis (Mdr2-/-/DSS). Mdr2-/- mice demonstrate alterations in fecal bile acid composition and enhanced colitis susceptibility with increased colonic adhesion molecule expression, particularly mucosal addressin-cell adhesion molecule 1 (MAdCAM-1). In vitro, ursodeoxycholic acid (UDCA) co-treatment resulted in a dose dependent attenuation of TNF-α-induced endothelial MAdCAM-1 expression. In the combined Mdr2-/-/DSS model, UDCA supplementation attenuated colitis severity and downregulated intestinal MAdCAM-1 expression. These findings suggest a potential mechanistic role for alterations in bile acid signaling in modulating MAdCAM-1 expression and colitis susceptibility in cholestasis-associated colitis. Together, our findings provide a novel model and new insight into the pathogenesis and potential treatment of PSC-IBD.

Primary sclerosing cholangitis is a progressive liver disease characterized by chronic inflammation leading to liver fibrosis and cirrhosis. Even though the exact pathogenesis is still unclear, a combination of autoimmune, environmental, and ischemic factors could explain certain aspects of the disease. The most important diagnostic step is cholangiography, which can be obtained either by endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiography (MRCP as the gold standard), or percutaneous transhepatic cholangiography. It shows multifocal short biliary duct strictures leading to the "beaded" aspect. Cholangiocarcinoma and colorectal adenocarcinoma are the most feared complications in patients with Primary sclerosing cholangitis (PSC). Continuous screening consists of annual clinical, biochemical, and ultrasound assessments in asymptomatic patients and annual colonoscopy in patients with PSC and inflammatory bowel disease. In newly diagnosed patients with PSC, colonoscopy is mandatory and, if negative, then, a repeat colonoscopy should be performed in 3-5 years. The lack of efficient curative medical treatment makes invasive treatments such as liver transplant and endoscopy the mainstream for managing PSC and its complications. Until now, even though only ursodeoxycholic acid has shown a moderate clinical, biochemical, and even histological improvement, it has no significant influence on the risk of cholangiocarcinoma, liver transplant need, or death risk and it is no longer recommended in treating early PSC. Further studies are in progress to establish the effect of molecular-targeted therapies in PSC.

Introduction and aim: The aim of this study was to investigate the outcome of a paediatric onset of inflammatory bowel disease (IBD) in a cohort of subjects with primary sclerosing cholangitis (PSC) and in a matched-age population-based control group without PSC. Methods: We identified 28 IBD-PSC cases (median age at IBD diagnosis 12.5 years, 25-75th: 10-16 years) and selected three IBD controls for each case matched for age and year of IBD diagnosis. All data regarding the gastrointestinal tract and liver were collected at diagnosis and at last follow-up (median 15 years). Results: At diagnosis the prevalence of pancolitis was similar between the groups (78% and 79%, respectively p = -.30), but histologic inflammation was milder in IBD-PSC (61% vs 30%, p = .06). At last follow-up (median age 29 years) pancolitis was less frequent (6% and 33%, respectively p = .04) and the remission higher (76% and 47%, respectively p = .08) in IBD-PSC patients than in IBD patients. Panproctolectomy (32% in IBD-PSC and 34% in IBD, p = 1.0) and the rate of pouchitis (62% and 70%, respectively p = .8) were similar. Conclusions: The outcome of paediatric onset IBD in patients with PSC in adulthood seems to be comparable to those with IBD only.

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.

Inflammatory bowel diseases is associated with an increased risk for the development of colorectal cancer. However, the mechanism of immune signaling pathways linked to colitis-associated cancer (CAC) has not been fully elucidated. Tauroursodeoxycholic acid (TUDCA) exhibits anti-inflammatory and anti-cancer activities. The aim of this study is to investigate the role of TUDCA in the pathogenesis of CAC.

Colitis-associated cancer was induced in mice using azoxymethane and dextran sodium sulfate administration, and TUDCA's effect on tumor development was evaluated. HCT 116 and COLO 205 were treated with TUDCA or vehicle and then stimulated with tumor necrosis factor-α (TNF-α). Expression of interleukin (IL)-8 was determined by real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, and IκBα phosphorylation and degradation was evaluated by immunoblot assay. The DNA-binding activity of NF-κB was assessed by electrophoretic mobility shift assay. Cell viability assay and real-time reverse transcription-polymerase chain reaction of bcl-xL, MCL1, c-FLIP-L, and VEGF were performed.

Tauroursodeoxycholic acid significantly attenuated the development of CAC in mice. Exposure to TUDCA resulted in extensive epithelial apoptosis and reduced levels of phospho-IκB kinase in the colon. In HCT 116 cells stimulated with TNF-α, TUDCA significantly inhibited IL-8 and IL-1α expression and suppressed TNF-α-induced IκBα phosphorylation/degradation and DNA-binding activity of NF-κB. Furthermore, in both HCT 116 and COLO 205 cells, TUDCA reduced cell viability and downregulated the expression of bcl-xL, MCL1, c-FLIP-L, and VEGF.

These results demonstrated that TUDCA suppresses NF-κB signaling and ameliorates colitis-associated tumorigenesis, suggesting that TUDCA could be a potential treatment for CAC.

Primary sclerosing cholangitis (PSC) is a chronic and progressive disease of the biliary tract. PSC is strongly associated with inflammatory bowel disease (IBD), mainly with ulcerative colitis, and most PSC patients have underlying IBD. The pathophysiological interactions between IBD and PSC are unclear, although it seems that the patients with IBD and PSC have a distinct phenotype. IBD with coexisting PSC is more extensive and is characterized by milder activity compared to IBD alone. The coexistence of PSC increases the risk for colorectal cancer in IBD patients and lifelong annual surveillance colonoscopy is recommended. Also, liver transplantation (LT) for PSC may affect the course of IBD. In addition, the management of IBD after LT includes many specific problems. On the other hand, the effect of IBD on the natural history of PSC appears to be milder. However, IBD may increase the risk of postsurgical complications after LT and is a risk factor for recurrent PSC after LT. Overall, the coexistence of IBD with PSC changes the management, natural history and prognosis of both diseases.

Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic disease that is associated with inflammatory bowel disease (IBD) in approximately 70% of cases. Although the pathogenesis is still unknown for both diseases, there is increasing evidence to indicate that they share a common underlying predisposition. Herein, we review the epidemiology, diagnosis, disease pathogenesis, and specific clinical features of the PSC-IBD phenotype. Patients with PSC-IBD have a distinct IBD phenotype with an increased incidence of pancolitis, backwash ileitis, and rectal sparing. Despite often having extensive colonic involvement, these patients present with mild intestinal symptoms or are even asymptomatic, which can delay the diagnosis of IBD. Although the IBD phenotype has been well characterized in PSC patients, the natural history and disease behavior of PSC in PSC-IBD patients is less well defined. There is conflicting evidence regarding the course of IBD in PSC-IBD patients who receive liver transplantation and their risk of recurrent PSC. IBD may also be associated with an increased risk of cholangiocarcinoma in PSC patients. Overall, the PSC-IBD population has an increased risk of developing colorectal neoplasia compared to the conventional IBD population. Lifelong annual surveillance colonoscopy is currently recommended.

The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with ∼20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points.

These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate.

These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines.

These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modern management strategies while maintaining vigilance around appropriate outcomes and safety issues.

Cholestatic liver diseases (CLDs) encompass a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury and ultimately end-stage liver disease. Many patients with CLD are diagnosed between the ages of 20-50 years, a particularly productive period of life professionally, biologically and in other respects; it is not surprising, thus, that CLD is often associated with impaired health-related quality of life (HRQOL) and uncertainty regarding implications for and outcomes of pregnancy. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most prominent CLDs, both having considerable morbidity and mortality and representing major indications for liver transplantation. These disorders, as a consequence of their complications (eg ascites, hepatic osteodystrophy), associated conditions (eg inflammatory bowel disease) and symptoms (eg pruritus and fatigue), can significantly impair an array of domains of HRQOL. Here we review these impactful clinical aspects of PSC and PBC as well as the topics of fertility and pregnancy.

Ursodeoxycholic acid (UDCA) was reported to reduce bile acid toxicity, but the mechanisms underlying its cytoprotective effects are not fully understood. The aim of the present study was to examine the effects of UDCA on the modulation of deoxycholic acid (DCA)-induced signal transduction in oesophageal cancer cells. Nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activity was assessed using a gel shift assay. NF-κB activation and translocation was performed using an ELISA-based assay and immunofluorescence analysis. COX-2 expression was analysed by western blotting and COX-2 promoter activity was assessed by luciferase assay. DCA induced NF-κB and AP-1 DNA-binding activities in SKGT-4 and OE33 cells. UDCA pretreatment inhibited DCA-induced NF-κB and AP-1 activation and NF-κB translocation. This inhibitory effect was coupled with a blockade of IκB-α degradation and inhibition of phosphorylation of IKK-α/β and ERK1/2. Moreover, UDCA pretreatment inhibited COX-2 upregulation. Using transient transfection of the COX-2 promoter, UDCA pretreatment abrogated DCA-induced COX-2 promoter activation. In addition, UDCA protected oesophageal cells from the apoptotic effects of deoxycholate. Our findings indicate that UDCA inhibits DCA-induced signalling pathways in oesophageal cancer cells. These data indicate a possible mechanistic role for the chemopreventive actions of UDCA in oesophageal carcinogenesis.

The presence of concomitant primary sclerosing cholangitis (PSC) with inflammatory bowel disease (IBD) represents a distinct disease phenotype that carries a higher risk of colorectal cancer (CRC) than the average IBD patient. Given that liver transplantation (LT) is the only treatment that offers a survival benefit in PSC patients with hepatic dysfunction, management decisions in IBD patients' post-LT for PSC are frequently encountered. One such consideration is the risk of CRC in this immunosuppressed cohort. With most studies showing an increased risk of CRC post-LT in these IBD patients, a closer look at the associated risk factors of CRC and the adopted surveillance strategies in this subset of patients is warranted. Low-dose ursodeoxycholic acid has shown a potential chemopreventive effect in PSC-IBD patients pre-LT; however, a favorable effect remains to be seen in post-LT group. Also, further studies are necessary to assess the benefit of 5 aminosalicylate therapy. Annual surveillance colonoscopy in the post-LT period is recommended for PSC-IBD patients subset given their high risk for CRC.

Patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) have a high risk of colonic neoplasia. Neoplasia frequently develops in the proximal colon in patients with PSC. Histologic inflammation is an independent risk factor for the development of neoplasia; we investigated whether patients with UC and PSC have more subclinical disease activity than patients with UC alone.

We performed a retrospective analysis of data from 143 patients (205 examinations) with ulcerative pancolitis who were in clinical remission and treated at a tertiary medical center from May 2011 through May 2016. Endoscopic and histologic activity were compared between patients with PSC (from 36 examinations) and without PSC (from 169 examinations). Disease activity was scored per colonic segment using a modified Mayo endoscopic subscore and histologic assessment. In each colonic segment, differences in disease activity and the degree of discordance between endoscopic and histologic inflammation among UC patients with and without PSC were compared.

Patients with UC-PSC had significantly more subclinical endoscopic (odds ratio [OR], 4.21; 95% CI, 1.67-10.63) and histologic activity (OR, 5.13; 95% CI, 2.25-11.68) in the right colon, as well as greater degree of histologic than endoscopic inflammation in the proximal colon (OR, 3.14, 95% CI, 1.24-7.97), compared with patients without PSC. Patients with UC-PSC had significantly less histologic activity in the rectum on multivariate analysis (OR, 0.24; 95% CI, 0.08-0.72).

Patients with UC and PSC who are in clinical remission are significantly more likely to have endoscopic and histologic inflammation in the right colon than patients with UC without PSC. Our findings provide insight into cause of colorectal cancer in UC patients with PSC.

The regulation of reactive oxygen species (ROS) exists as a therapeutic target for cancer treatments. Previous studies have shown that ursodeoxycholic acid (UDCA) suppresses the proliferation of colon cancer cells. The aim of this study was to evaluate the effect of UDCA upon the proliferation of colon cancer cells as a direct result of the regulation of ROS.

Colon cancer cell lines (HT29 and HCT116) were treated with UDCA. The total number of cells and the number of dead cells were determined using cell counters. A fluorescein isothiocyanate-bromodeoxyuridine flow kit was used to analyze cell cycle variations. Upon exposure to UDCA, the protein levels of p27, p21, CDK2, CDK4 and CDK6 were determined using western blotting, and qRT-PCR was used to determine levels of mRNA. We preformed dichlorofluorescindiacetate (DCF-DA) staining to detect alteration of intracellular ROS using fluorescence activated cell sorting (FACS). Colon cancer stem-like cell lines were generated by tumorsphere culture and treated with UDCA for seven days. The total number of tumorspheres was determined using microscopy.

We found that UDCA reduced the total number of colon cancer cells, but did not increase the number of dead cells. UDCA inhibited the G1/S and G2/M transition phases in colon cancer cells. UDCA induced expression of cell cycle inhibitors such as p27 and p21. However, it was determined that UDCA suppressed levels of CDK2, CDK4, and CDK6. UDCA regulated intracellular ROS generation in colon cancer cells, and induced activation of Erk1/2. Finally, UDCA inhibited formation of colon cancer stem-like cells.

Our results indicate that UDCA suppresses proliferation through regulation of oxidative stress in colon cancer cells, as well as colon cancer stem-like cells.

Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer (CRC). Surveillance colonoscopy is currently recommended for patients with long-standing extensive colitis for reducing CRC risk. Chemoprevention is an attractive complementary strategy. Areas covered: Inflammation is a major determinant of CRC risk and is potentially modifiable. Reducing inflammation is supposed to reduce CRC risk. Several medications have been evaluated in this setting: 5-ASA, thiopurines, anti-TNFα agents and ursodeoxycholic acid (UCDA) in patients with associated primary sclerosing cholangitis (PSC). This review offers a critical evaluation of current evidence of the potential chemopreventive effect of such medications. Expert commentary: No randomized controlled trials have been performed and the available evidence come from observational studies. Although biological plausibility supports a chemopreventive role of the aforementioned agents, the overall evidence of efficacy is weak because of several methodological limitations of the studies. Indirect epidemiological evidence, biologic plausibility and results of meta-analyses reasonably support a potential chemopreventive effect of 5-ASA. Available evidence does not support a specific chemopreventive effect of purine analogues and anti-TNFα medications, despite their efficacy in the management of inflammatory bowel disease. Data addressing UDCA and folate supplementation are inconclusive. Limited data are available for statins.

Patients with inflammatory bowel disease are at an increased risk of colorectal cancer when compared to the general population. Chronic inflammation is thought to be the underlying cause, and medications that reduce inflammation have the potential to reduce the risk of colorectal cancer. Areas covered: After conducting a PubMed search for relevant literature, we examined several classes of medications that have been studied as potential chemopreventive agents. These include 5-aminosalicylates, thiopurines, tumor necrosis factor antagonists, ursodeoxycholic acid, NSAIDs, and statins. Expert commentary: While each class of medications has some data to support its use in chemoprevention, the majority of the evidence in each case argues against the routine use of these medications solely for a chemopreventive benefit.

Crohn disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) characterized by recurrent episodes of mucosal inflammation. This chronic mucosal inflammation has several potential consequences, one of which is the occurrence of colitis-associated colorectal cancer. Over the past decade, our understanding of the epidemiology, pathophysiology, and overall approach to diagnosing and managing colitis-associated colorectal cancer has grown considerably. In the current review article, we outline these advancements and highlight areas in need of further research. Cancer Prev Res; 9(12); 887-94. ©2016 AACR.

Although hydrophobic bile acids have been demonstrated to exhibit cytotoxic and carcinogenic effects in the colorectum, ursodeoxycholic acid (UDCA) has been investigated as a potential chemopreventive agent. Vitamin D has been shown to play a role in both bile acid metabolism and in the development of colorectal neoplasia. Using a cross-sectional design, we sought to determine whether baseline circulating concentrations of the vitamin D metabolites 25(OH)D and 1,25(OH)2D were associated with baseline fecal bile acid concentrations in a trial of UDCA for the prevention of colorectal adenoma recurrence. We also prospectively evaluated whether vitamin D metabolite concentrations modified the effect of UDCA on adenoma recurrence. After adjustment for age, sex, BMI, physical activity, and calcium intake, adequate concentrations of 25(OH)D (≥30 ng/mL) were statistically significantly associated with reduced odds for high levels of total [OR, 0.61; 95% confidence interval (CI), 0.38-0.97], and primary (OR, 0.61; 95% CI, 0.38-0.96) bile acids, as well as individually with chenodeoxycholic acid (OR, 0.39; 95% CI, 0.24-0.63) and cholic acid (OR, 0.56; 95% CI, 0.36-0.90). No significant associations were observed for 1,25(OH)2D and high versus low fecal bile acid concentrations. In addition, neither 25(OH)D nor 1,25(OH)2D modified the effect of UDCA on colorectal adenoma recurrence. In conclusion, this is the first study to demonstrate an inverse relationship between circulating levels of 25(OH)D and primary fecal bile acid concentrations. These results support prior data demonstrating that vitamin D plays a key role in bile acid metabolism, and suggest a potential mechanism of action for 25(OH)D in colorectal cancer prevention. Cancer Prev Res; 9(7); 589-97. ©2016 AACR.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that progresses to end-stage liver disease and cirrhosis. Recurrent biliary inflammation is thought to lead to dysplasia, and as such PSC confers a high risk of cholangiocarcinoma. PSC accounts for 10% of all UK liver transplants, although transplantation does not guarantee a cure with 20% recurrence in the graft. At present there are no effective medical treatment options for PSC, and trials of novel therapeutic agents are limited by the time taken to reach clinically significant endpoints with no well defined early surrogate markers for disease outcome. Moreover, PSC appears to be a heterogeneous disease with regards to disease distribution, associated inflammatory bowel disease and subsequent disease outcome, further compounding the issue. Thus existing trials have taken place in heterogeneous groups, are likely to be underpowered to detect any individual subgroups effect. The current mainstay of medical treatment is still with ursodeoxycholic acid, although there is no evidence that it alters long-term outcome. Small pilot studies of immunosuppressive agents have taken place, but despite evidence that may support studies in larger groups, these have not been conducted. Recent advances in our understanding of the disease pathogenesis may therefore pave the way for trials of novel therapeutic agents in PSC, even given the limitations described. This review explores the controversial evidence underlying current treatment strategies and discounted treatments, and explores prospective agents that may bring new hope to the treatment of PSC in the 21st century.

Primary sclerosing cholangitis (PSC) is a frequently progressive and fatal disease. Death from cancer occurs in a significant subset of patients with PSC. Patients with PSC have a 10 to 15 % lifetime risk of developing cholangiocarcinoma (CCA). About one third of CCAs are present in the first year after a diagnosis of PSC; the remainder are present with a frequency of about 1.5 % each year. Patients with concomitant PSC and inflammatory bowel disease (IBD) have a 4-fold higher risk of colorectal cancer (CRC) than patients with IBD alone and a 10-fold higher risk of CRC than the general population. The risk does not diminish with liver transplantation. This patient population also has a high frequency of carcinoma in gallbladder mass lesions. The risk for hepatocellular carcinoma (HCC) in the presence of cirrhosis is uncertain-two large cohort studies suggest that HCC is not as common as in other causes of cirrhosis. Although AASLD guidelines do not recommend routine screening for liver tumors in patients with PSC, we recommend MRI/MRCP and serum CA 19-9 levels in patients with PSC every 6 months to screen for CCA, HCC, pancreatic cancer, and gallbladder cancer. Screening colonoscopy at the diagnosis of PSC and surveillance colonoscopies every 1-2 years should be performed in those with PSC and IBD.

The heterogeneity and complexity of advanced cancers strongly support the rationale for an enhanced focus on molecular prevention as a priority strategy to reduce the burden of cancer. Molecular prevention encompasses traditional chemopreventive agents as well as vaccinations and therapeutic approaches to cancer-predisposing conditions. Despite challenges to the field, we now have refined insights into cancer etiology and early pathogenesis; successful risk assessment and new risk models; agents with broad preventive efficacy (eg, aspirin) in common chronic diseases, including cancer; and a successful track record of more than 10 agents approved by the US Food and Drug Administration for the treatment of precancerous lesions or cancer risk reduction. The development of molecular preventive agents does not differ significantly from the development of therapies for advanced cancers, yet it has unique challenges and special considerations given that it most often involves healthy or asymptomatic individuals. Agents, biomarkers, cohorts, overall design, and endpoints are key determinants of molecular preventive trials, as with therapeutic trials, although distinctions exist for each within the preventive setting. Progress in the development and evolution of molecular preventive agents has been steadier in some organ systems, such as breast and skin, than in others. In order for molecular prevention to be fully realized as an effective strategy, several challenges to the field must be addressed. Here, the authors provide a brief overview of the context for and special considerations of molecular prevention along with a discussion of the results from major randomized controlled trials.

Extraintestinal manifestations (EIM) in inflammatory bowel disease (IBD) are frequent and may occur before or after IBD diagnosis. EIM may impact the quality of life for patients with IBD significantly requiring specific treatment depending on the affected organ(s). They most frequently affect joints, skin, or eyes, but can also less frequently involve other organs such as liver, lungs, or pancreas. Certain EIM, such as peripheral arthritis, oral aphthous ulcers, episcleritis, or erythema nodosum, are frequently associated with active intestinal inflammation and usually improve by treatment of the intestinal activity. Other EIM, such as uveitis or ankylosing spondylitis, usually occur independent of intestinal inflammatory activity. For other not so rare EIM, such as pyoderma gangrenosum and primary sclerosing cholangitis, the association with the activity of the underlying IBD is unclear. Successful therapy of EIM is essential for improving quality of life of patients with IBD. Besides other options, tumor necrosis factor antibody therapy is an important therapy for EIM in patients with IBD.

The aim of the study was to evaluate the influence of metal [Zn(II), Cu(II), Ni(II)] complexes with ursodeoxycholic acid (UDCA) on the viability and proliferation of tumour and non-tumour cells. Cell lines established from retrovirus-transformed chicken hepatoma (LSCC-SF-Mc29) and rat sarcoma (LSR-SF-SR) as well as from human cancers of the breast (MCF-7), uterine cervix (HeLa), lung (A549) and liver (HepG2) were used as model systems. Non-tumour human embryo (Lep-3) cells were also included in some of the experiments. The investigations were carried out by the thiazolyl blue tetrazolium bromide (MTT) test, neutral red uptake cytotoxicity assay, crystal violet staining, double staining with acridine orange and propidium iodide and the colony-forming method. The results obtained revealed that: (1) UDCA and its metal complexes in the tested concentrations decreased (to a varying degree) the viability and proliferation of the treated cells in a time- and concentration-dependent manner; (2) chicken hepatoma (LSCC-SF-Mc29) cells were most sensitive to the cytotoxic and antiproliferative action of the compounds tested, followed by rat sarcoma (LSR-SF-SR) cells; (3) Cu‒UDCA and Ni‒UDCA were more effective against animal LSCC-SF-Mc29 and LSR-SF-SR cells, while Zn‒UDCA significantly decreased the viability and proliferation of human tumour cell lines; (4) applied independently, UDCA expressed lower cytotoxic/cytostatic activity as compared to metal complexes; and (5) the sensitivity of the non-tumour embryonic Lep-3 cells to the effects of UDCA and its metal complexes was comparable or even higher than those of the human tumour cells.