Factors Determining Colorectal Cancer: The Role of the Intestinal Microbiota.

The gastrointestinal tract, in particular the colon, holds a complex community of microorganisms, which are essential for maintaining homeostasis. However, in recent years, many studies have implicated microbiota in the development of colorectal cancer (CRC), with this disease considered a major cause of death in the western world. The mechanisms underlying bacterial contribution in its development are complex and are not yet fully understood. However, there is increasing evidence showing a connection between intestinal microbiota and CRC. Intestinal microorganisms cause the onset and progression of CRC using different mechanisms, such as the induction of a chronic inflammation state, the biosynthesis of genotoxins that interfere with cell cycle regulation, the production of toxic metabolites, or heterocyclic amine activation of pro-diet carcinogenic compounds. Despite these advances, additional studies in humans and animal models will further decipher the relationship between microbiota and CRC, and aid in developing alternate therapies based on microbiota manipulation.

Quercetin ameliorates dysregulation of lipid metabolism genes via the PI3K/AKT pathway in a diet-induced mouse model of nonalcoholic fatty liver disease.

SCOPE: Flavonoids and related compounds seem to have favorable effects on nonalcoholic fatty liver disease (NAFLD) progression, although the exact mechanisms implicated are poorly understood. In this study, we aimed to investigate the effect of the flanovol quercetin on gene expression deregulation involved in the development of NAFLD, as well as the possible implication of phosphatidylinositol 3-kinase (PI3K)/AKT pathway modulation. METHODS AND RESULTS: We used an in vivo model based on methionine- and choline-deficient (MCD) diet-fed mice and an in vitro model consisting of Huh7 cells incubated with MCD medium. MCD-fed mice showed classical pathophysiological characteristics of nonalcoholic steatohepatitis, associated with altered transcriptional regulation of fatty acid uptake- and trafficking-related gene expression, with increased lipoperoxidation. PI3K/AKT pathway was activated by MCD and triggered gene deregulation causing either activation or inhibition of all studied genes as demonstrated through cell incubation with the PI3K-inhibitor LY294002. Treatment with quercetin reduced AKT phosphorylation, and oxidative/nitrosative stress, inflammation and lipid metabolism-related genes displayed a tendency to normalize in both in vivo and in vitro models. CONCLUSION: These results place quercetin as a potential therapeutic strategy for preventing NAFLD progression by attenuating gene expression deregulation, at least in part through PI3K/AKT pathway inactivation.

Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C.

NAFLD (non-alcoholic fatty liver disease) is one of the most frequent chronic liver diseases worldwide. The metabolic factors associated with NAFLD are also determinants of liver disease progression in chronic HCV (hepatitis C virus) infection. It has been reported that, besides inducing hepatic fatty acid biosynthesis, LXR (liver X receptor) regulates a set of inflammatory genes. We aimed to evaluate the hepatic expression of LXRα and its lipogenic and inflammatory targets in 43 patients with NAFLD, 44 with chronic HCV infection and in 22 with histologically normal liver. Real-time PCR and Western blot analysis were used to determine hepatic expression levels of LXRα and related lipogenic and inflammatory mediators in the study population. We found that the LXRα gene and its lipogenic targets PPAR-γ (peroxisome-proliferator-activated receptor-γ), SREBP (sterol-regulatory-element-binding protein)-1c, SREBP-2 and FAS (fatty acid synthase) were overexpressed in the liver of NAFLD and HCV patients who had steatosis. Moreover, up-regulation of inflammatory genes, such as TNF (tumour necrosis factor)-α, IL (interleukin)-6, OPN (osteopontin), iNOS (inducible NO synthase), COX (cyclo-oxygenase)-2 and SOCS (suppressors of cytokine signalling)-3, was observed in NAFLD and HCV patients. Interestingly, TNF-α, IL-6 and osteopontin gene expression was lower in patients with steatohepatitis than in those with steatosis. In conclusion, hepatic expression of LXRα and its related lipogenic and inflammatory genes is abnormally increased in NAFLD and HCV patients with steatosis, suggesting a potential role of LXRα in the pathogenesis of hepatic steatosis in these chronic liver diseases.

Primary liver carcinoid tumour with a Zollinger Ellison syndrome - an unusual diagnosis: a case report.

Carcinoids are neuroendocrine tumours which may secrete hormones like gastrin, insulin, ACTH, etc. Liver is a common site for metastasis of carcinoid origin and an unusual site for a primary carcinoid tumour to arise.We present the case of a 51-year-old Caucasian man with diarrhoea, weight loss, duodenum ulcers and a liver mass in ultrasonography. A primary hepatic carcinoid tumour with a Zollinger Ellison syndrome was diagnosed. Surgery resection was performed and the patient remained free of symptoms two years after, with normalisation of gastrin levels.Primary hepatic carcinoid tumour represents an uncommon diagnosis, based on radiological and pathological features. The exclusion of different primary locations is necessary. Once associated with a Zollinger Ellison syndrome, diagnose may be more complicated and challenging since only 7 cases of hepatic carcinoids with gastrin secretion were reported in medical literature.A review of medical literature is performed and diagnoses tools that should be used for an accurate diagnosis and available treatment approaches are commented here.

Influence of insulin resistance and adipokines in the grade of steatosis of nonalcoholic fatty liver disease.

The objective of this work was to study the influence of insulin resistance and adipokines on the grade of steatosis in patients with NAFLD (nonalcoholic fatty liver disease) diagnosed by liver biopsy. A sample of 24 NAFLD patients was analyzed in a cross-sectional study. All patients with a two-week weight-stabilization period before recruitment were enrolled. A liver biopsy was realized. Weight, basal glucose, insulin, insulin resistance (HOMA), total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and adipokines blood levels were measured. A nutritional evaluation (dietary intake, indirect calorimetry, and bioimpedance) was performed. The mean age was 41.6 +/- 8.7 years and the mean body mass index (BMI) 29.4 +/- 4.7. Twelve patients had a low grade of steatosis (grade 1 of the Brunt classification) and 12 patients had a high grade of steatosis (grade 2 or 3). Only HOMA was higher in patients with a high grade of steatosis (1.4 +/- 0.5 vs. 2.8 +/- 1.7 units; P < 0.05). Anthropometric data and dietary intake were similar for both groups. Blood levels of adiponectin were higher in patients with a low grade of steatosis (37.7 +/- 22.5 vs. 24.2 +/- 33 ng mL(-1); P < 0.05). Blood levels of resistin were higher in patients with a high grade of steatosis (2.36 +/- 0.6 vs. 2.8 +/- 0.6 mg mL(-1); P < 0.05), without differences in TNF-alpha or leptin levels. In logistic regression analysis, the HOMA-IR remained in the model, with an odds ratio to develop high grade of steatosis of 7.8 (95% CI: 1.8-75) with each 1 unit of HOMA-IR adjusted by age, sex, BMI, and dietary intake. This study demonstrates that insulin resistance determined with the HOMA model is associated with a high grade of steatosis in patients with NAFLD.

Quality of life in patients with functional dyspepsia: a prospective 1-year follow-up study in Spanish patients.

BACKGROUND AND AIMS: The natural history of functional dyspepsia is not well known. We prospectively assess the quality of life and severity of symptoms in a group of Spanish patients with functional dyspepsia. PATIENTS AND METHODS: One hundred and twelve consecutive patients with functional dyspepsia, according to Rome II criteria, were prospectively followed up for 1 year. All patients completed symptom (Dyspepsia Questionnaire and the Gastrointestinal Symptoms Rating Scale) and quality of life [the Psychological General Well-Being (PGWB) Index and the General Health Questionnaire (GHQ)] questionnaires every 3 months. Only free antacid consumption was permitted during the study period. RESULTS: The group was made up of 81 women and 31 men with a mean age of 45 +/- 17 years; 66% of patients were infected with Helicobacter pylori, and ulcer-like dyspepsia (53%) was the predominant subgroup. At baseline, quality of life scores were low (PGWB, 87.1 +/- 17.6 and GHQ, 20.6 +/- 11.8), but these values gradually improved during the year of follow-up (PGWB, 107.7 +/- 1.1 and GHQ, 8.9 +/- 0.4). Digestive symptoms also decreased. In the multivariate analysis, the anxiety score on the PGWB index (Wald, 5.2; P = 0.02) and smoking status (Wald, 4.3; P = 0.04) were predictors of end quality of life. At baseline, patients with a high level of anxiety had a very reduced quality of life, although their symptom scores were similar to other patients. CONCLUSION: Quality of life is reduced in patients with functional dyspepsia. Some improvement in quality of life together with a decrease in the severity of symptom scores was seen during the 1 year of follow-up. We believe that both the reassurance of negative endoscopy and the scheduling of visits to the doctor favourably influence the quality of life.

Human recombinant anti-transglutaminase antibody testing is useful in the diagnosis of silent coeliac disease in a selected group of at-risk patients.

BACKGROUND: Functional dyspepsia, unexplained chronic hypertransaminasaemia (CHT) and hepatitis C virus (HCV) are common gastrointestinal situations that have been related to coeliac disease. Antibodies to tissue transglutaminase (tTG) have been claimed recently to be highly effective as a screening method for coeliac disease. AIM: To assess the prevalence of coeliac disease by means of detection of antibodies against human tTG in the above-mentioned groups of patients. PATIENTS AND METHODS: A control group consisted of 165 normal blood donors. Patient groups comprised 90 CHT patients, 102 HCV patients and 92 functional dyspepsia patients. All patients were tested for anti-tTG (immunoglobulin A, IgA) antibodies. Anti-endomysium (IgA) antibodies (AEA) and antigliadin (IgA) antibodies (AGA) and antigliadin (immunoglobulin G, IgG) antibodies (AGG) were also tested. When anti-tTG or AEA was positive, a duodenal biopsy was recommended. RESULTS: One of 165 blood donors, three of 92 functional dyspepsia patients, four of 90 CHT patients and none of 102 HCV patients were positive for anti-tTG antibodies. In the anti-tTG-positive group, all but one were AEA-positive. There were no AEA- or AGA IgA-positives that revealed a negative anti-tTG test. Duodenal biopsy confirmed a diagnosis of coeliac disease in all the cases. Statistically significant differences were found between the controls and the functional dyspepsia group and between the controls and the CHT group, but not between the controls and the HCV group. CONCLUSIONS: Both CHT and functional dyspepsia may represent a true oligosymptomatic form of coeliac disease. In such conditions, the detection of anti-tTG antibodies is useful as a screening method. Coeliac disease is not an autoimmune manifestation of HCV, so screening for coeliac disease in HCV patients cannot be recommended.