Hyperhomocysteinemia as a potential contributor of colorectal cancer development in inflammatory bowel diseases: A review

Homocysteine is an amino acid generated metabolically by the S-adenosylmethionine-dependent transmethylation pathway. In addition to being a well-known independent risk factor for coronary heart disease, is also a risk factor for cancer. Patients suffering from inflammatory bowel diseases(IBD) including ulcerative colitis and Crohn’s disease are at increased risk of developing colorectal cancer in comparison to healthy individuals. Furthermore, the risk of hyperhomocysteinaemia is significantly higher in IBD patients when compared with controls. In the present article, we review the mechanisms in which hyperhomocysteinemia may contribute to increased risk of colorectal cancer in IBD patients.     

Inflammatory bowel disease associated neoplasia: A surgeon's perspective

Inflammatory bowel disease(IBD) is associated with increased risk of colorectal cancer(CRC). The risk is known to increase with longer duration of the disease, family history of CRC, and history of primary sclerosing cholangitis. The diagnosis of the neoplastic changes associated with IBD is difficult owing to the heterogeneous endoscopic appearance and interobserver variability of the pathological diagnosis. Screening and surveillance guidelines have been established which aim for early detection of neoplasia. Several surgical options are available for the treatment of IBD-associated neoplasia. Patients' morbidities, risk factors for CRC, degree and the extent of neoplasia must be considered in choosing the surgical treatment. A multidisciplinary team including the surgeon, gastroenterologist, pathologist, and the patient who has a clear understanding of the nature of their disease is needed to optimize outcomes.     

Neurotensin receptor 1 overexpression in inflammatory bowel diseases and colitis-associated neoplasia

AIM: To explore the association of neurotensin receptor 1 (NTSR1) with inflammatory bowel diseases (IBD) and colitis-associated neoplasia. METHODS: NTSR1 was detected by immunohistochemistry in clinical samples of colonic mucosa with IBD colitis, colitis-associated raised low-grade dysplasia (LGD) including dysplasia-associated lesions or masses (DALMs, n = 18) and adenoma-like dysplastic polyps (ALDPs, n = 4), colitis-associated high-grade dysplasia (HGD, n = 11) and colitis-associated colorectal carcinoma (CACRC, n = 13), sporadic colorectal adenomatous polyp (SAP, n = 17), and sporadic colorectal carcinoma (SCRC, n = 12). The immunoreactivity of NTSR1 was semiquantitated (as negative, 1+, 2+, and 3+) and compared among different conditions.RESULTS: NTSR1 was not detected in normal mucosa but was expressed similarly in both active and inactive colitis. LGD showed a significantly stronger expression as compared with non-dysplastic colitic mucosa, with significantly more cases showing > 2+ intensity (68.75% in LGD vs 32.26% in nondysplastic mucosa, P = 0.001). However, no significant difference existed between DALMs and ALDPs. CACRC and HGD showed a further stronger expression, with significantly more cases showing 3+ intensity than that in LGD (61.54% vs 12.50% for CACRC vs LGD, P = 0.022; 58.33% vs 12.50% for CACRC/HGD vs LGD, P = 0.015). No significant difference existed between colitis-associated and non-colitic sporadic neoplasia. CONCLUSION: NTSR1 in colonic epithelial cells is overexpressed in IBD, in a stepwise fashion with sequential progress from inflammation to dysplasia and carcinoma.     

Regulatory T cells in inflammatory bowel diseases and colorectal cancer

Regulatory T cells (T_regs) are key elements in immunological self-tolerance. The number of T_regs may alter in both peripheral blood and in colonic mucosa during pathological circumstances. The local cellular, microbiological and cytokine milieu affect immunophenotype and function of T_regs. Forkhead box P3+ T_regs function shows altered properties in inflammatory bowel diseases (IBDs). This alteration of T_regs function can furthermore be observed between Crohn’s disease and ulcerative colitis, which may have both clinical and therapeutical consequences. Chronic mucosal inflammation may also influence T_regs function, which together with the intestinal bacterial flora seem to have a supporting role in colitis-associated colorectal carcinogenesis. T_regs have a crucial role in the immunoevasion of cancer cells in sporadic colorectal cancer. Furthermore, their number and phenotype correlate closely with the clinical outcome of the disease, even if their contribution to carcinogenesis has previously been controversial. Despite knowledge of the clinical relationship between IBD and colitis-associated colon cancer, and the growing number of immunological aspects encompassing sporadic colorectal carcinogenesis, the molecular and cellular links amongst T_regs, regulation of the inflammation, and cancer development are still not well understood. In this paper, we aimed to review the current data surrounding the role of T_regs in the pathogenesis of IBD, colitis-associated colon cancer and sporadic colorectal cancer.     

Cancer in inflammatory bowel disease

Patients with long-standing inflammatory bowel disease （IBD） have an increased risk of developing colorectal cancer （CRC）. Many of the molecular alterations responsible for sporadic colorectal cancer, namely chromosomal instability, microsatellite instability, and hypermethylation, also play a role in colitis-associated colon carcinogenesis. Colon cancer risk in inflammatory bowel disease increases with longer duration of colitis, greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. Chemoprevention includes aminosalicylates, ursodeox, ycholic acid, and possibly folic acid and statins. To reduce CRC mortality in IBD, colonoscopic surveillance with random biopsies remains the major way to detect early mucosal dysplasia. When dysplasia is confirmed, proctocolectomy is considered for these patients. Patients with small intestinal Crohn＇s disease are at increased risk of small bowel adenocarcinoma. Ulcerative colitis patients with total proctocolectomy and ileal pouch anal- anastomosis have a rather low risk of dysplasia in the ileal pouch, but the anal transition zone should be monitored periodically. Other extra intestinal cancers, such as hepatobiliary and hematopoietic cancer, have shown variable incidence rates. New endoscopic and molecular screening approaches may further refine our current surveillance guidelines and our understanding of the natural history of dysplasia.     

Survival after inflammatory bowel disease-associated colorectal cancer in the Colon Cancer Family Registry

AIM: To investigate the survival of individuals with colorectal cancer (CRC) with inflammatory bowel disease (IBD-associated CRC) compared to that of individuals without IBD diagnosed with CRC. METHODS: Epidemiologic, clinical, and follow-up data were obtained from the Colon Cancer Family Registry (Colon CFR). IBD-associated cases were identified from self-report of physician diagnosis. For a subset of participants, medical records were examined to confirm self-report of IBD. Cox proportional hazards regression was applied to estimate adjusted hazard ratios (aHR) and 95%CI of mortality, comparing IBD-associated to non-IBD-associated CRC, adjusted for age at CRC diagnosis, sex, Colon CFR phase, and number of prior endoscopies. Following imputation to complete CRC stage information, adjustment for CRC stage was examined. RESULTS: A total of 7202 CRC cases, including 250 cases of IBD-associated CRC, were analyzed. Over a twelve year follow-up period following CRC diagnosis, 2013 and 74 deaths occurred among non-IBD associated CRC and IBD-associated CRC patients, respectively. The difference in survival between IBD-associated and non-IBD CRC cases was not statistically significant (aHR = 1.08; 95%CI: 0.85-1.36). However, the assumption of proportional hazards necessary for valid inference from Cox regression was not met over the entire follow-up period, and we therefore limited analyses to within five years after CRC diagnosis when the assumption of proportional hazards was met. Over this period, there was evidence of worse prognosis for IBD-associated CRC (aHR = 1.36; 95%CI: 1.05-1.76). Results were similar when adjusted for CRC stage, or restricted to IBD confirmed in medical records. CONCLUSION: These results support the hypothesis that IBD-associated CRC has a worse prognosis than non-IBD-associated CRC.     

Gut microbiota,inflammatory bowel disease and colorectal cancer

The gut microbiota is a complex community of microorganisms that inhabit the digestive tracts of humans, living in symbiosis with the host. Dysbiosis, characterized by an imbalance between the beneficial and opportunistic gut microbiota, is associated with several gastrointestinal disorders, such as irritable bowel syndrome (IBS); inflammatory bowel disease (IBD), represented by ulcerative colitis and Crohn’s disease; and colorectal cancer (CRC). Dysbiosis can disrupt the mucosal barrier, resulting in perpetuation of inflammation and carcinogenesis. The increase in some specific groups of harmful bacteria, such as Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF), has been associated with chronic tissue inflammation and the release of pro-inflammatory and carcinogenic mediators, increasing the chance of developing CRC, following the inflammation-dysplasia-cancer sequence in IBD patients. Therefore, the aim of the present review was to analyze the correlation between changes in the gut microbiota and the development and maintenance of IBD, CRC, and IBD-associated CRC. Patients with IBD and CRC have shown reduced bacterial diversity and abundance compared to healthy individuals, with enrichment of Firmicute sand Bacteroidetes. Specific bacteria are also associated with the onset and progression of CRC, such as Fusobacterium nucleatum, E. coli, Enterococcus faecalis, Streptococcus gallolyticus, and ETBF. Future research can evaluate the advantages of modulating the gut microbiota as preventive measures in CRC high-risk patients, directly affecting the prognosis of the disease and the quality of life of patients.     

What＇s new about inflammatory bowel diseases in 2011

Inflammatory bowel diseases （IBD） are chronic disorders of the intestine with increasing incidence in Europe, Northern America and asiatic countries such as china. Thus, we have putted together these topic highlight articles to give insights into the current understanding of IBD pathogenesis, diagnostics and treatment.     

Secondary causes of inflammatory bowel diseases

Inflammatory bowel diseases(IBD), conventionally consist of Crohn's disease(CD) and ulcerative colitis. They occur in individuals with high risk genotype for the disease in the setting of appropriate environmental factors. The pathogenesis of IBD involves a dysregulated autoimmune response to gut dysbiosis, which in turn is triggered due to exposure to various inciting environmental factors. But there is no clearly defined etiology of IBD and this type of disease is termed as "idiopathic IBD", "classic IBD", or "primary IBD". We reviewed the current medical literature and found that certain etiological factors may be responsible for the development of IBD or IBD-like conditions, and we consider this form of de novo IBD as "secondary IBD". Currently known factors that are potentially responsible for giving rise to secondary IBD are medications; bowel altering surgeries and transplantation of organs, stem cells or fecal microbiome. Medications associated with the development of secondary IBD include; immunomodulators, anti-tumor necrosis factor alpha agents, anti-interleukin agents, interferons, immune stimulating agents and checkpoint inhibitors. Colectomy can in some cases give rise to de novo CD, pouchitis of the ileal pouch, or postcolectomy enteritis syndrome. After solid organ transplantation or hematopoietic stem cell transplantation, the recipient may develop de novo IBD or IBD flare. Fecal microbiota transplantation has been widely used to treat patients suffering from recurrent Clostridium difficile infection but can also causes IBD flares.     

Qualitative and quantitative analyses of the bifidobacterial microbiota in the colonic mucosa of patients with colorectal cancer, diverticulitis and inflammatory bowel disease

AIM： To characterize the bifidobacterial microbiota of the colonic mucosa in patients with colon cancer, inflammatory bowel disease or diverticulitis.
METHODS： A sample of the distal colonic mucosa was taken during surgery from a total of 34 patients, twenty-one with diagnosed colorectal cancer, nine with diverticulitis and four with inflammatory bowel disease, requiring surgery for their condition. Bacterial DNA was extracted from the resected mucosal samples and bifidobacterial mucosa-associated microbiota was qualitatively and quantitatively determined by means of qualitative and quantitative PCR.
RESULTS： Bifidobacteria were found in 100% of the samples from patients with diverticulitis or IBD and a 76% of those suffering colon cancer. The species B. Iongum and B. bifidum were the most widely found, followed by B. animalis, B. catenulatum and B. adolescentis. B. breve, B. dentium and B. angulatum were not detected in any sample. A significantly higher occurrence of B. Iongum was observed in patients with diverticulitis than in those with colon cancer or IBD （100%, 62% and 75%, respectively, P 〈 0.05）. Similar results were obtained for B, animalis （56%, 0% and 25%, P 〈 0.05）, while B. adolescentis was only found in the mucosa from patients with colon cancer （5 out of 21, 24%）. At the quantitative level, patients with colon cancer or IBD showed lower counts of total Bifidobacterium （4.94 and 5.91 vs 6.96 log Cells/sample, respectively, P 〈 0.05） and of the species B. longum （4.05 and 4.79 vs 6.76, P 〈 0.05） than those with diverticulitis.
CONCLUSION： Aberrancies in mucosa associated microbiota are present in different intestinal diseases. This may indicate a role of the microbiota in the pathogenesis of these diseases.     

Relationship between methylation and colonic inflammation in inflammatory bowel disease

AIM:To investigate the relationship between the methylation status in the SLIT2 and TGFB2 promoters and colonic inflammation in inflammatory bowel disease patients.METHODS:We evaluated the methylation status of 2genes(SLIT2 and TGFB2)in 226 biopsies taken from62 colonoscopies of 38 patients(29 ulcerative colitis and 9 Crohn’s colitis)using methylation-specific melting curve analysis.The relationships between methylation status and clinical,biological,endoscopic and histological activities were evaluated.Twenty-three of the 38patients had a second colonoscopy and were included in a longitudinal analysis.Numerical results were given as the means±SD of the sample and range,except when specified.Student t analysis,U Mann Whitney and ANOVA factor were used to compare the means.Qualitative results were based on theχ2 test.RESULTS:SLIT2 methylation was more frequent in samples with endoscopic activity than with endoscopic remission(55%vs 18%,P<0.001).SLIT2 methylation was also higher in samples with acute inflammation(56.5%)than in samples with chronic(24%)or absent inflammation(15%)(P<0.001).For TGFB2methylation,the correlation was only significant with endoscopic activity.Methylation was higher in the distal colon for both genes(P<0.001 for SLIT2 and P=0.022for TGFB2).In the multivariate analysis,only inflammation status(and not disease duration or extension)was independently associated with SLIT2 methylation[OR=6.6(95%CI:1.65-27.36),P=0.009].In the longitudinal analysis,the maintenance of endoscopic remission was protective for methylation.CONCLUSION:Endoscopic and histological inflammation are predictive for SLIT2 methylation.     

Etiology of the inflammatory bowel diseases

Inflammatory bowel diseases (IBD) are complex disorders. While the exact etiology of these diseases remains unknown, recent progress in the epidemiology and genetics of IBD has clearly demonstrated both environmental and genetic factors to play a role in the development of the disease, and it is expected that some risk factors are common for both Crohn's disease (CD) and ulcerative colitis (UC). The environmental factor(s) are associated with the Western way of life in the second half of the twentieth century. Cigarette smoking is presently the best known environmental factor. However, the effect of tobacco is opposite in CD and UC. A familial history of IBD is the most important risk factor for developing the disease, suggesting a genetic predisposition to IBD. This hypothesis has recently been confirmed by the localization of at least two susceptibility loci on chromosomes 12 and 16. These genes seem to play a role in both CD and UC. They must now to be identified. Accepted: 14 December 1998     

Endoscopic evaluation for colon cancer and dysplasia in patients with inflammatory bowel disease

Certain patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer, and surveillance is recommended to detect dysplasia and early neoplasia. Endoscopic techniques that screen large mucosal surface areas for potential areas of interest that have been studied in IBD surveillance include dye-based surface chromoendoscopy with methylene blue or indigo carmine, dye-less chromoendoscopy including narrow-band imaging, i-scan, Fujinon intelligent chromoendoscopy, and autofluorescence imaging. Literature to date supports the use of surface chromoendoscopy with either methylene blue or indigo carmine to maximize dysplasia detection. Characterization of detected lesions may be further enhanced with optical biopsy technology, including confocal laser endomicroscopy and endocystoscopy, that allows in vivo histologic diagnosis that may guide both diagnosis and therapy of detected dysplastic lesions. Current and future endoscopic approaches for optimizing screening and surveillance of colon cancer and dysplasia in patients with IBD are reviewed.     

Anemia and digestive diseases： An update for the clinician

Too often anemia is considered a rare or unimportant manifestation in inflammatory bowel disease （IBD）. However, over the last 10 years a number of studies have been conducted and the most relevant conclusions obtained are： （1） anemia is quite common in IBD; （2） although in many cases anemia parallels the clinical activity of the disease, many patients in remission have anemia, and iron, vitamin B12 and/or folic acid deficiency; （3） anemia, and also iron deficiency without anemia, have important consequences in the clinical status and quality of life of the patient; （4） oral iron can lead to gastrointestinal intolerance and failure of treatment; （5） intravenous iron is an effective and safe way to treat iron deficiency; （6） erythropoietin is needed in a significant number of cases to achieve normal hemoglobin levels. Thus, the clinician caring for IBD patients should have a comprehensive knowledge of anemia, and apply recently published guidelines in clinical practice.     

Characteristics of inflammatory bowel diseases in patients with concurrent immune-mediated inflammatory diseases

Patients with inflammatory bowel disease (IBD) are more likely to have concurrent immune-mediated inflammatory diseases (IMIDs) than those without IBD. IMIDs have been observed to alter the phenotype and outcomes of IBD in recent studies. Several studies have found that IBD patients with concurrent IMIDs may have more extensive or severe disease phenotypes, and are considered to be at increased risk of requiring biologics and IBD-related surgeries, suggesting that having multiple IMIDs is a poor prognostic factor for IBD. Furthermore, IBD patients with primary sclerosing cholangitis and Takayasu arteritis are reported to have unique endoscopic phenotypes, suggesting concurrent IMIDs can influence IBD phenotype with specific intestinal inflammatory distributions. In this review, we discuss the pathogenesis, disease phenotypes, and clinical outcomes in IBD patients with concomitant IMIDs.     

Endoscopic colorectal cancer surveillance in inflammatory bowel disease: Considerations that we must not forget

Inflammatory bowel disease (IBD), encompassing Crohn''s disease and ulcerative colitis, is a chronic immune-mediated inflammatory disease that primarily affects the gastrointestinal tract and is characterized by periods of activity and remission. The inflammatory activity of the disease involving the colon and rectum increases the risk of colorectal cancer (CRC) over the years. Although prevention strategies are evolving, regular surveillance for early detection of neoplasia as a secondary prevention strategy is paramount in the care of IBD patients. In this review article, we discuss the current evidence of the risks of developing CRC and evaluate the best available strategies for screening and surveillance, as well as future opportunities for cancer prevention.     

益生菌在炎症性肠病中的治疗进展

炎症性肠病(inflammatory bowel disease,IBD)是一种病因不明的慢性非特异性肠道炎症性疾病,包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn’s disease,CD)。许多研究显示肠道菌群的生态失调在IBD的发病中起着重要作用,而临床上相当一部分患者对常规治疗应答不佳或发生严重的不良反应,因此尝试益生菌调节肠道菌群来治疗IBD越来越受到重视。     

Methylation patterns in dysplasia in inflammatory bowel disease patients

Abstract

Background and aims: Inflammatory Bowel Disease (IBD) with colonic involvement increases colorectal cancer risk. However, the distinction between IBD related and sporadic dysplasia in IBD patients is difficult. Some data favors the importance of abnormal DNA methylation in IBD-related carcinogenesis. We aimed to define methylation patterns in patients with colonic cancer or dysplasia diagnosis following an IBD diagnosis.

Methods: Multicentric cross-sectional study-91 samples from colonic mucosa with/without dysplasia from 9 patients with IBD-related dysplasia/cancer and 26 patients with IBD and sporadic dysplasia/cancer were included. Methylation patterns of CpG islands in the promoter regions of 67 genes were studied by Methylation-specific Multiplex Ligation-dependent Probe Amplification.

Results: Mean age at IBD diagnosis: 42?±?16?years;at dysplasia diagnosis: 56?±?14?years. Twenty-ninepatients had ulcerative colitis. Twenty-five patients had at least 1 lesion endoscopically described as adenoma-like, 4 at least 1 non-adenoma like, 3 had cancer and 3 had dysplasia in flat mucosa. No patient had both adenoma-like and non-adenoma-like lesions. Patients with an IBD-related lesion were significantly younger at IBD diagnosis (p?=?.003) and at dysplasia/cancer diagnosis (p?=?.039). Promoter methylation of IGF2, RARB, ESR1, CHFR, CDH13, WT1, GATA5, WIF1genes was significantly associated to dysplasia/cancer; methylation of MSH6, TIMP3 was significantly associated to IBD-related dysplasia/cancer. Promoter methylation of MSH6, MSH3, RUNX3, CRABP1, TP73, RARB, CDH13, PAX5, WT1, THBS1, TP53, SFRP1, WIF1, APAF1, BCL2 genes was significantly associated to active IBD.

Conclusions: Methylation analysis, namely of MSH6, may contribute to the classification of dysplastic lesions in IBD– to be further tested in prospective studies.     

Colorectal cancer surveillance in inflammatory bowel disease： The search continues

Patients with inflammatory bowel disease （IBD） are at increased risk for colorectal cancer （CRC）. Risk factors for the development of CRC in the setting of IBD include disease duration, anatomic extent of disease, age at time of diagnosis, severity of inflammation, family history of colon cancer, and concomitant primary sclerosing cholangitis. The current surveillance strategy of surveillance colonoscopy with multiple random biopsies most likely reduces morbidity and mortality associated with IBD-related CRC. Unfortunately, surveillance colonoscopy also has severe limitations including high cost, sampling error at time of biopsy, and interobserver disagreement in histologically grading dysplasia. Furthermore, once dysplasia is detected there is disagreement about its management. Advances in endoscopic imaging techniques are already underway, and may potentially aid in dysplasia detection and improve overall surveillance outcomes. Management of dysplasia depends predominantly on the degree and focality of dysplasia, with the mainstay of management involving either proctocolectomy or continued colonoscopic surveillance. Lastly, continued research into additional chemopreventive agents may increase our arsenal in attempting to reduce the incidence of IBD-associated CRC.     

Vulvar and vaginal neoplasia in women with inflammatory bowel disease

Immunosuppressive drugs are the cornerstone in the treatment of inflammatory bowel disease (IBD), however they are associated with an increased risk of extra-intestinal cancer. Whether the risk for female genital tract malignancies, including vulvar and vaginal cancer, is increased is less clear.Our aim was to investigate the risk of these malignancies in IBD-patients.Histopathological data of all IBD patients with a vulvar or vaginal (pre-)cancerous lesion were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology from 1991 to 2015. Medical history was retrieved from patient records. Data from the Central Office for Statistics, the Dutch comprehensive cancer organization, and the IBDSL cohort were obtained to calculate the standardized, and age-adjusted incidence rates.Fifty-five patients met the inclusion criteria. A standardized incidence rate of 1.2(95% CI:0.8–1.7) for vulvar and vaginal carcinoma among adult female IBD was calculated, which did not significantly differ from the general population. The use of immunosuppressive therapy did not increase the occurrence of vulvovaginal malignancy, nor did it influence the recurrence rate. However, immunosuppressive drugs ever-users were on average 11 years younger at the time of their gynaecological diagnosis.Overall, our data do not support intensified screening for vulvar or vaginal malignancies in female IBD patients.