The prevalence and impact of psychiatric comorbidities on hospitalized inflammatory bowel disease patients in the United States: insights from the National Inpatient Sample from 2009-2018.

Background: Patients with inflammatory bowel disease (IBD) are at increased risk of anxiety and mood disorders. This study examines the temporal trends and clinical impact of anxiety and mood disorder diagnoses in hospitalized IBD patients in the United States during a 10-year period. Methods: Using the National Inpatient Sample from 2009-2018, all IBD-related discharges in adults were analyzed. Primary outcomes were the prevalence and temporal trends of mood disorder and anxiety diagnoses for IBD-related admissions. The impact of the psychiatric comorbidities on clinical outcomes was also evaluated. Results: A total of 1,718,736 IBD-related discharged were identified. A diagnosis of anxiety or a mood disorder was found to have a prevalence of 16.44% and 18.97%, respectively, amongst IBD-related admissions. The prevalence of anxiety disorders amongst hospitalized IBD patients increased significantly (from 12.13% to 20.26%), whereas the prevalence of mood disorders did not (17.46% and 18.9%). IBD admissions with psychiatric comorbidities had lower rates of IBD-related complications or mortality during hospitalization compared to IBD admissions without comorbid psychiatric diagnoses. This population, however, was more likely to experience certain comorbidities such as Clostridioides difficile, pneumonia, and venous thromboembolism, as well as a longer hospitalization. Conclusions: The prevalence of comorbid anxiety among hospitalized IBD patients in the United States matches or exceeds the prevalence of anxiety in the general hospitalized population. Given its association with more in-hospital complications and a longer hospital stay, it is important to further understand how psychological screening and mental health services can improve the management of hospitalized IBD patients.

Comparison of Disease Phenotypes and Clinical Characteristics Among South Asian and White Patients with Inflammatory Bowel Disease at a Tertiary Referral Center.

BACKGROUND: The prevalence and clinical features of inflammatory bowel disease (IBD) vary among different racial and ethnic groups. The aim of this study was to compare the clinical and phenotypic features of Crohn's disease (CD) and ulcerative colitis (UC) in South Asian patients living in the United States with those of a white cohort. METHODS: The demographic, clinical, and phenotypic characteristics of 73 South Asian patients (31 CD and 42 UC) who presented initially to our tertiary referral center from 2012 to 2016 and had subsequent follow-up were retrospectively compared with those of 408 consecutive white patients (245 CD and 163 UC). RESULTS: South Asian IBD patients were significantly more likely to have UC (58.0% vs 40.0%; P = 0.005) than white patients. South Asians with CD were less likely to have a family history of IBD (9.7% vs 26.9%; P = 0.037) and required fewer CD-related surgeries (22.5% vs 46.1; P = 0.012). South Asians were also less likely to be active or former smokers in both the CD (P = 0.004) and UC (P = 0.020) groups. South Asians with UC had a higher incidence of Clostridium difficile infection compared with white patients (19.0% vs 8.6%; P = 0.050). CONCLUSIONS: A cohort of South Asian patients with IBD were more likely to have UC and had differing family and tobacco risk factors, requirements for surgery, and Clostridium difficile infection rates as compared with white patients.

Effect of Long-Term Mesalamine Therapy on Cancer-Associated Gene Expression in Colonic Mucosa of Patients with Ulcerative Colitis.

BACKGROUND: The role of 5-aminosalicylic acid (5-ASA or mesalamine) in the prevention of colorectal cancer in ulcerative colitis (UC) patients was reported, but the effect on molecular targets in UC colon mucosa is unknown. AIM: This observational study evaluates gene expression levels of 5-ASA targets using serial colon biopsy specimens from UC patients undergoing long-term 5-ASA therapy. METHODS: Transcript levels were compared between colonoscopic biopsy specimens collected from 62 patients at initial and final follow-up colonoscopy at 2-6 years. All patients had mild-to-moderate UC and were undergoing long-term 5-ASA maintenance. Stepwise multiple linear regression analyses were performed to correlate changes in transcript levels with therapeutic response (Mayo clinical score endoscopy and DAI and/or Nancy histopathology score) and nonclinical variables. RESULTS: The transcript levels of colorectal carcinogenesis-associated known 5-ASA target genes were significantly reduced after prolonged 5-ASA therapy (P < 0.005-0.03). Multiple linear regression models predicted significant association between transcript levels of Ki-67, NF-kB (p65), PPARγ, COX-2 and IL-8, CDC25A, and CXCL10 with duration of drug (5-ASA) exposure (P ≤ 0.05). Ki-67, NF-kB (p65), and CXCL10 transcripts were also correlated with reduced endoscopy sub-score (P ≤ 0.05). COX-2, IL-8, CDC25A, and TNF transcripts strongly correlated with DAI sub-scores (P ≤ 0.05). Only COX-2 and IL-8 transcript levels correlated (P ≤ 0.05) with Nancy histological score. CONCLUSION: This study provides molecular evidence of changes in carcinogenesis-related targets/pathways in colon tissue during long-term 5-ASA maintenance therapy that may contribute to the observed chemopreventive effects of 5-ASA in UC patients.

Posterior Reversible Encephalopathy Syndrome following Ustekinumab Induction for Crohn's Disease.

Biological agents are frequently used in the management of inflammatory bowel disease, and it is important to understand the potential adverse effects of these therapies. Ustekinumab is a human monoclonal antibody that interferes with interleukin-12 and -23 cytokine signaling and is approved for the treatment of moderate to severe Crohn's disease. We report 2 cases of neurological adverse events, one of which is consistent with posterior reversible encephalopathy syndrome (PRES), in the setting of ustekinumab therapy for Crohn's disease. The first patient had a seizure and classic neuroimaging features of PRES following induction with ustekinumab. The second patient presented with acute encephalopathy and atypical imaging findings concerning for PRES after ustekinumab induction. Both patients recovered fully following cessation of ustekinumab therapy. PRES associated with ustekinumab is uncommon, but must be a consideration in Crohn's disease patients receiving this therapy who present with focal neurological symptoms or change in mentation.

Auto-inflammatory diseases in ileal pouch patients with NOD2/CARD15 mutations.

Pouchitis is common in ulcerative colitis patients undergoing total proctocolectomy with ileal pouch-anal anastomosis, and chronic antibiotic-refractory pouchitis occurs in a subgroup of the patients. Auto-inflammatory diseases are characterized by systemic inflammation, manifesting as periodic fever, rash, arthritis, and serositis. We describe two cases with ulcerative colitis and an ileal pouch, who presented with extra-intestinal manifestations and genetic features atypical for inflammatory bowel disease alone. Case 1 had a spectrum of clinical manifestations including refractory pouchitis, intermittent fevers, polyarthralgia, and pericarditis. Case 2 presented with oral ulcers, migratory oligoarthritis, and periodic papular rash. Genetic testing in both cases revealed mutations of the NOD2/CARD15 gene, including the IVS8(+158) mutation commonly detected among patients with NOD2-associated auto-inflammatory disease. Both of the patients demonstrated clinical improvement of these diverse systemic complaints following treatment with immunosuppressive and anti-inflammatory therapies.

Autoimmune features are associated with chronic antibiotic-refractory pouchitis.

BACKGROUND: Chronic antibiotic-refractory pouchitis (CARP) occurs more frequently in patients with ileal pouch-anal anastomosis (IPAA) with concomitant autoimmune disorders. The aim of this study was to assess the overlap between dysregulated immune features in patients with IPAA and their association with CARP. METHODS: We identified 150 symptomatic patients with IPAA who met inclusion criteria, including measurement of select autoimmune serology. Demographic and clinical variables were compared between patients with and without CARP. RESULTS: Autoimmune thyroid disease was more frequent among patients with CARP. The frequency of primary sclerosing cholangitis (16.7% versus 5.3%; P = 0.04) and serum positivity for microsomal antibody (25% versus 6.1%, P = 0.003) were significantly greater in patients with CARP compared with non-CARP patients, respectively. Increased tissue infiltration by IgG4-expressing plasma cells was detected in 17 of 31 patients (54.8%) in the CARP group as compared with 10/67 (14.9%) in the non-CARP group (P = 0.0001). Forty-seven percent of patients in the CARP group versus 22.8% in the non-CARP group had at least 2 immune features (P = 0.019). Among patients with IgG4 histology, 87% of patients in the CARP group versus 60% in the non-CARP group had at least 1 immune marker (P = 0.004). On multivariate analysis, microsomal antibody expression (odds ratio, 6.8; 95% confidence interval, 1.3-42.6; P = 0.02) and increased IgG4-expressing plasma cells tissue infiltration (odds ratio, 9.6; 95% confidence interval, 3.2-32.6, P = 0.0001) were risk factors for CARP. CONCLUSIONS: There is marked overlap of certain immune markers in patients with pouch dysfunction, especially those with CARP. Microsomal antibody expression and elevated IgG4-positive plasma cell infiltration were independent risk factors for CARP.

Clostridium difficile infection in the postcolectomy patient.

Clostridium difficile infection (CDI) after total colectomy has been increasingly recognized over the past decade. C. difficile enteritis (CDE) is a rare occurrence, whereas C. difficile pouchitis (CDP) has been reported in approximately 10% of symptomatic patients seen at a referral center for pouch dysfunction. Similar to colonic CDI in the general population, antibiotic use and comorbid diseases may be risk factors for CDE. In contrast, the postoperative use of antibiotics does not seem to be associated with CDP, whereas male gender, recent hospitalization, and presurgery antibiotic use were shown to be risk factors for CDP. C. difficile is capable of colonizing all intestinal sites, including the ileal pouch. Similarities with the colon at physiological and cellular levels may contribute to the susceptibility of the ileal pouch to CDI. Postcolectomy CDI likely represents a disease spectrum from asymptomatic colonization to severe symptomatic infection. CDI should be considered in ostomy patients with fever and increased ileostomy output and in ileal pouch patients with a change in "normal" symptom pattern or chronic antibiotic-refractory pouchitis. Sensitive and specific methods for detection of CDI are available, and endoscopy is useful in evaluating the patient with suspected CDE or CDP, although pseudomembranes are typically absent. Vancomycin is used as the first-line therapy for CDP and may be warranted for patients with inflammatory bowel disease with CDE. Fecal microbiota transplantation has found its use in the management of severe or antibiotic refractory CDP, but this approach requires evaluation for the management of refractory CDE.

Risk factors and management of refractory or recurrent clostridium difficile infection in ileal pouch patients.

BACKGROUND: Clostridium difficile infection (CDI) is increasingly recognized in patients with ulcerative colitis with ileal pouch-anal anastomosis (IPAA). The aim of this study was to identify clinical risk factors for treatment-refractory or recurrent CDI in patients with IPAA. METHODS: We identified patients with IPAA for underlying ulcerative colitis and a positive polymerase chain reaction stool test for C. difficile at the Center for Ileal Pouch Disorders during the period from October 2010 to November 2013. Demographic clinical variables were compared between the refractory or recurrent CDI and nonrecurrent CDI groups. RESULTS: Patients with IPAA with refractory or recurrent symptoms (refractory/recurrent CDI, the study group, N = 19) were compared with patients with a single antibiotic-responsive episode of ileal pouch CDI (nonrecurrent CDI, the control group, N = 21). The frequency of pouchitis before the index CDI was similar in the study and control groups (63.2% versus 66.7%, P = 0.82). Postoperative mechanical abnormalities occurred in 16 patients (84.2%) in the study group versus 7 patients (33.3%) in the control group (P = 0.0008). There were no differences between the two groups regarding hospitalization, non-C. difficile antibiotic use, the use of gastric acid-reducing therapy, or immunosuppressives before or after the index CDI. Six of 15 patients (40.0%) in the study group versus 1 of 15 patients (7.1%) in the control group had a low serum level of IgG1 (P = 0.031). CONCLUSIONS: Refractory or recurrent disease is common in patients with ileal pouch with CDI. The presence of postsurgery mechanical intestinal complications or low serum immunoglobulin level may be risk factors for refractory or recurrent CDI in this patient population.

Clostridium difficile infection in patients with ileal pouches.

Clostridium difficile (C. difficile) infection (CDI) following total proctocolectomy and ileal pouch-anal anastomosis has been increasingly recognized over the past 5 years. CDI of the ileal pouch has been recognized in ∼10% of symptomatic patients seen at a tertiary referral center for pouch dysfunction. In contrast to colonic CDI in the general population or in patients with inflammatory bowel disease, postoperative antibiotic exposure and the use of immunosuppressive agents or proton pump inhibitors do not appear to be associated with CDI of the pouch. Male gender, recent hospitalization, and presurgery antibiotic use were shown to be risk factors for ileal pouch CDI. The ileal pouch may be susceptible to CDI owing to similarities with the colon at physiological and structural levels. Postcolectomy CDI likely represents a spectrum of disease processes, varying from asymptomatic colonization to severe symptomatic infection. CDI should be considered in any patient with an ileal pouch presenting with a change in "normal" symptom pattern or treatment-refractory disease. Sensitive and specific methods for the detection of CDI are available, and pouchoscopy is a valuable tool in the evaluation of the patient with symptomatic CDI of the pouch. At a referral center for pouch dysfunction, vancomycin is used as the first-line therapy for ileal pouch CDI. Fecal microbiota transplantation may find use in the management of severe or antibiotic refractory CDI-related pouchitis.

The association between autoimmunity and pouchitis.

: Restorative proctocolectomy with ileal pouch-anal anastomosis is commonly used in the management of ulcerative colitis. Inflammation of the ileal pouch reservoir, or pouchitis, is a common complication of ileal pouch-anal anastomosis that is incompletely understood. Risk factors including nonsmoker status and primary sclerosing cholangitis have been linked with pouchitis development, but the etiopathogenesis of pouchitis remains poorly defined. Pouchitis is more commonly a complication of ileal pouch-anal anastomosis performed in patients with ulcerative colitis, and similar to ulcerative colitis, chronic pouchitis is associated with extraintestinal manifestations and other diseases of immune origin, suggesting overlap in the disease pathogenesis. It is becoming apparent that pouchitis encompasses clinically distinct subtypes based on the response or lack of response to antibiotic therapy. There is also emerging evidence of the role of autoimmunity in a subgroup of patients with pouchitis, including patients with concurrent primary sclerosing cholangitis, seropositivity for immunoglobulin G4, or infiltration of immunoglobulin G4-expressing plasma cells in the pouch mucosa. The identification of underlying autoimmunity may have important clinical implications in the diagnosis, subclassification, and management of pouchitis.

Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice.

Ogg1 DNA repair enzyme recognizes and excises oxidative stress-caused 8-hydroxyl-deoxyguanosine (8-OHdG) from GC base-pairs. Ogg1 knockout mice are phenotypically normal, but exhibit elevated levels of 8-OHdG in nuclear and mitochondrial DNA, as well as moderately elevated mutagenesis and spontaneous lung tumors and UV-induced skin tumors. To elucidate the mechanistic role of inflammation-caused oxidative stress in carcinogenesis, the development of chronic ulcerative colitis (UC)-induced carcinoma in Ogg1 knockout mice was studied using a dextran sulfate sodium (DSS)-induced UC model without the use of a carcinogen. Ogg1 (-/-), Ogg1 (+/-), and wild type C57BL/6 mice were subjected to long-term, cyclic DSS treatment to induce chronic UC and carcinogenesis. In wild type C57BL/6 control mice after 15 cycles of DSS treatment, colorectal adenocarcinoma incidence was 24.1% (7/29 mice), with a tumor volume of 27.9 +/- 5.2 mm(3). Ogg1 (-/-) mice showed significantly increased adenocarcinoma development in the colon with a tumor incidence of 57.1% (12 of 21 mice, P < 0.05) and a tumor volume of 35.1 +/- 6.1 mm(3). Ogg1 mice (+/-) also exhibited significantly increased tumor development in the colon with a tumor incidence of 50.0% (13/26 mice) and a tumor volume of 29.1 +/- 7.2 mm(3). Histopathologic analyses revealed that colorectal tumors were well-differentiated tubular adenocarcinomas or mucinous carcinoma and adjacent colonic mucosa showed mild to moderate chronic UC. Using immunohistochemical approaches, Ogg1 (-/-) and (+/-) mice exhibited similar numbers and staining intensities of macrophages in UC areas as seen in Ogg1 (+/+) mice, but markedly increased numbers and staining intensities of 8-OHdG positive inflammatory and epithelial cells. These results provide important evidence on the relationship between inflammation-caused oxidative stress, DNA repair enzyme Ogg1, and carcinogenesis.

Colorectal carcinoma development in inducible nitric oxide synthase-deficient mice with dextran sulfate sodium-induced ulcerative colitis.

The overproduction of reactive oxygen and nitrogen species (RONS) may play an important role in ulcerative colitis (UC)-associated carcinogenesis. In order to study the role of nitric oxide (NO) in UC-associated colorectal carcinogenesis, the development of colorectal carcinoma was studied using the DSS-induced and iron-enhanced model of chronic UC in inducible nitric oxide synthase (iNOS)-deficient mice. Female wild-type C57BL/6 (iNOS+/+) and iNOS-/- mice were administered 1% DSS (w/v) through the drinking fluid for 15 DSS cycles and fed twofold iron-enriched diet. Colorectal inflammation and mucosal ulceration of moderate severity were observed in both iNOS+/+ and iNOS-/- mice. Similar tumor incidence and multiplicity in the colon were observed that 15 out of 23 (65.2%) iNOS+/+ mice developed colorectal tumors with a tumor multiplicity of 1.47+/-0.17 (mean+/-SE) after 15 DSS cycles, and 13 out of 19 (68.4%) iNOS-/- mice developed colorectal tumors with a tumor multiplicity of 2.08+/-0.21. Histopathologically, the tumors were confirmed to be well-differentiated adenocarcinomas. Nitrotyrosine, an indicator of peroxynitrite-caused protein modification, was detectable by immunohistochemistry in inflammatory cells and epithelial cells of the colon in iNOS+/+ and iNOS-/- mice, and no difference in staining intensity was observed between the two groups. Immunostaining for endothelial NOS (eNOS) was observed in lamina propria macrophages and colonic blood vessels, and eNOS protein levels were increased in the inflamed colon. These results show that there is no difference in UC-associated cancer development in iNOS+/+ and iNOS-/- mice, and suggest that in the absence of iNOS, other factors, such as eNOS, may play a role in nitrosative stress and UC-associated carcinogenesis in this model system.

Inhibition of chronic ulcerative colitis associated adenocarcinoma development in mice by inositol compounds.

Chronic inflammation is a well recognized risk factor for cancer and patients with long-standing ulcerative colitis (UC) are at an increased risk for colorectal carcinoma development. In order to prevent UC associated carcinogenesis, we tested the effects of inositol compounds (including inositol and hexaphosphate inositol) on UC-associated carcinogenesis in our novel mouse model. Female C57BL/6 mice were subjected to long-term, cyclic dextran sulfate sodium (DSS) treatment and fed a 2-fold iron-enriched diet. The inositol compounds were administered via the drinking fluid. In the DSS-plus-2-fold iron positive control group, colorectal adenocarcinoma incidence was 70.6% (24/34 mice) after 15 cycles of DSS treatment (1 DSS cycle=7 day DSS treatment period followed by a 10 day recovery period). Tumor multiplicity was 1.26+/-1.05 and tumor volume was 21.4+/-5.2 mm3. Adding 1% inositol, tumor incidence was statistically significantly reduced (42%, 9 of 21 mice with tumors), as was tumor multiplicity (0.5+/-0.7) and tumor volume (4.2+/-1.9 mm3). Administration of hexaphosphate inositol noticeably reduced tumor incidence (50%, 12 mice with tumors out of 24 total), tumor multiplicity (0.8+/-0.9) and tumor volume (12.3+/-4.1 mm3); however, the results were not statistically significant (P>0.05). Further mechanistic studies showed that the inhibition of UC-associated carcinogenesis by inositol compounds might relate to their function on the modulation of macrophage mediated inflammation, nitro-oxidative stress and cell proliferation in UC-associated carcinogenesis. This study indicates that inositol compounds may have the potential to serve as preventive agents for chronic inflammation-carcinogenesis.

High-iron diet: foe or feat in ulcerative colitis and ulcerative colitis-associated carcinogenesis.

Anemia associated with long-standing chronic inflammation and iron deficiency, and the increased risk for the development of dysplasia and carcinoma, are two of the most common complications in patients with ulcerative colitis (UC). Because of iron and nutrition deficiency, UC patients are encouraged to consume a high-protein and high-iron diet. The crucial clinical question is the effect of a high-iron diet on inflammation activity and inflammation-driven carcinogenesis. Is a high-iron diet a foe or a feat in UC and UC-associated carcinogenesis? This review updates the progress and information on (1) iron nutrition and iron-deficiency anemia in patients with UC, (2) experimental evidence of the exacerbating effect of a high-iron diet on UC and its associated carcinogenesis and the difference between a high-iron diet and parental iron supplementation, (3) the clinical efficacy of, and concerns about, oral and intravenous iron supplements in patients with inflammatory bowel disease and iron deficiency anemia, and (4) the clinical implications of long-term iron supplements and management of UC. These experimental findings from animal models provide evidence to warrant further consideration and clinical studies of iron nutrition, inflammation activity, and cancer development.

Systemic iron supplementation replenishes iron stores without enhancing colon carcinogenesis in murine models of ulcerative colitis: comparison with iron-enriched diet.

Ulcerative colitis (UC) patients frequently require iron supplementation to remedy anemia. The impact of systemic iron supplementation (intraperitoneal injection) on UC-associated carcinogenesis was assessed in mice subjected to cyclic dextran sulfate sodium (DSS) treatment and compared with dietary iron enrichment. Systemic iron supplementation, but not a twofold iron diet, remedied iron deficiency as indicated by the histochemical detection of splenic iron stores. A twofold iron diet, but not systemic iron, increased iron accumulation in colonic luminal contents, at the colonic mucosal surface, and in superficial epithelial cells. Colitis-associated colorectal tumor incidence after 15 DSS cycles was not affected by systemic iron (2/28; 7.1%) compared to nonsupplemented controls (4/28; 14.1%) but was significantly increased by the twofold iron diet (24/33; 72.7%) (P < 0.001). Mechanistic study revealed that systemic iron had no effect on DSS-induced inflammation, or colonic iNOS and COX-2 protein levels, compared to controls. Systemic iron supplementation for 16 weeks replenished splenic iron in a spontaneous colitis model (interleukin-2-deficient mice) and significantly reduced colonic inflammation compared to interleukin-2 (-/-) controls without increasing hyperplastic lesions. These results suggest that iron supplemented systemically could be used to remedy anemia in UC patients without exacerbating inflammation or enhancing colon cancer risk. These findings need to be verified in clinical studies.

Inhibition of lung carcinogenesis and effects on angiogenesis and apoptosis in A/J mice by oral administration of green tea.

Oral administration of tea (Camellia sinensis) has been shown to inhibit the formation and growth of several tumor types in animal models. The present study investigated the effects of treatment with different concentrations of green tea on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice. Two days after a single dose of NNK (100 mg/kg body weight, i.p.), the mice were given 0.1, 0.2, 0.4, and 0.6% green tea solution (1, 2, 4, and 6 g of tea solids, respectively, dissolved in 1 l of water), 0.02% caffeine, or water as the sole source of drinking fluid until the termination of the experiment. Only the treatment with 0.6% tea preparation significantly reduced lung tumor multiplicity (mean +/- SE, 6.07 +/- 0.77 vs. 8.60 +/- 0.50 tumors per mouse, P = 0.018). Treatment with 0.6% tea also inhibited angiogenesis, as indicated by the lower microvessel density (number of blood vessels/mm2) based on immunostaining for the von Willebrand factor antigen (81.9 +/- 9.5 vs. 129.4 +/- 8.2, P = 0.0018) and anti-CD31 antibody staining (465.3 +/- 61.4 vs. 657.1 +/- 43.6, P = 0.0012). Significantly lower vascular endothelial growth factor immunostaining scores were also observed in the 0.6% tea-treated group (0.98 +/- 0.17 vs. 1.43 +/- 0.07, P = 0.006). The apoptosis index was significantly higher in lung adenomas from 0.6% tea-treated mice based on morphological analysis of cell apoptosis (2.51 +/- 0.18% vs. 1.57 +/- 0.11%, P = 0.00005), and the result was further confirmed using the TUNEL method. Inhibition of angiogenesis and the induction of apoptosis by green tea may be closely related to the inhibition of pulmonary carcinogenesis.

Epigallocatechin-3-gallate is absorbed but extensively glucuronidated following oral administration to mice.

Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (Camellia sinensis), has shown cancer preventive activity in animal models. The bioavailability of EGCG in the most commonly used animal species, mice, is poorly understood. Moreover, the pharmacokinetic parameters of EGCG have not been reported previously in mice. Here we report that after administration of EGCG intravenously at 21.8 micro mol/kg or intragastrically at 163.8 micro mol/kg, the peak plasma levels of EGCG in male CF-1 mice were 2.7 +/- 0.7 and 0.28 +/- 0.08 micro mol/L, respectively. EGCG was present mainly (50-90%) as the glucuronide. The plasma bioavailability of EGCG after intragastric administration was higher than previously reported in rats (26.5 +/- 7.5% vs. 1.6 +/- 0.6%). The conjugated EGCG displayed a shorter t(1/2) (82.8-211.5 vs 804.9-1102.3 min) than unconjugated EGCG (P < 0.01, Student's t test). EGCG was present in the unconjugated form in the lung, prostate and other tissues at levels of 0.31-3.56 nmol/g after intravenous administration. Although intragastric administration resulted in lower levels in most tissues compared with intravenous administration (e.g., 0.006 +/- 0.004 vs. 2.66 +/- 1.0 nmol/g in the lung), the levels in the small intestine and colon were high at 45.2 +/- 13.5 and 7.86 +/- 2.4 nmol/g, respectively. This is the first report of the pharmacokinetic parameters of EGCG in mice. Such information provides a basis for understanding the bioavailability of EGCG in mice and should aid in understanding the cancer preventive activity of EGCG.

Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models.

The chronic inflammatory bowel disease ulcerative colitis (UC) occurs commonly in the US and other Western countries, but its etiology is unknown. An association between UC and an elevated risk for colorectal cancer is well established. UC-associated colorectal carcinogenesis is probably driven by chronic inflammation, but the mechanism is unclear. The morphological development of UC-associated cancer differs from that of its sporadic counterpart. Similarly, detailed molecular analyses have indicated that whereas many of the genetic alterations observed in sporadic colon cancers also occur in UC-associated neoplasms, the timing and frequency of those changes in the setting of UC are different. These histological and molecular signatures may very well be reflective of an inflammation-driven carcinogenesis process in UC patients. Studies in animal models of UC have helped to shed light on the mechanisms of inflammation-driven colorectal carcinogenesis. The available evidence suggests that DNA damage caused by oxidative stress in the characteristic damage-regeneration cycle is a major contributor to colorectal cancer development in UC patients. Based on this concept, iron over-nutrition is proposed as a risk factor and dietary antioxidants as protective factors for UC and associated carcinogenesis.

Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice.

Chronic ulcerative colitis (UC) patients frequently require iron supplementation to remedy anemia due to blood loss. However, the effect of iron supplementation on UC-associated carcinogenesis is unknown. In this study, the effect of an iron-enriched diet on dextran sulfate sodium-induced acute and chronic colitis in mice was assessed. In a short-term study, mice administered 1% DSS in the drinking fluid and an AIN76A diet containing increasing levels of iron exhibited dose-dependent increases in the severity of acute UC as compared to mice fed a control diet. A marked increase in iron deposition on the epithelial surface of the colon and in the inflamed areas and immunostaining for iNOS and nitrotyrosine were observed in the animals supplemented with diets containing different levels of iron. In a long-term carcinogenesis experiment, a twofold iron-enriched diet significantly increased colorectal tumor incidence (14/16, 88%) as compared with animals fed the control diet (3/16, 19%; P < 0.001). The present findings have implications for the management of human UC and suggest that dietary iron can enhance UC and its associated carcinogenesis by augmenting oxidative and nitrosative stress.