Omega-3 fatty acids and inflammatory bowel diseases - a systematic review.

BACKGROUND & AIM: Despite their well known anti-inflammatory actions, the clinical usefulness of omega-3 PUFA in inflammatory bowel disease is controversial. We aimed to systematically review the available data on the performance of omega-3 PUFA as therapeutic agents in these patients. METHODS: Electronic databases were systematically searched for RCT of fish oil or omega-3 PUFA therapy in both active and inactive ulcerative colitis or Crohn's disease, without limitation on either the length of therapy or the form it was given, including nutritional supplements and enteral formula diets. Eligible articles were assessed for methodological quality on the basis of the adequacy of the randomisation process, concealment of allocation, blinding of intervention and outcome, possible biases, and completeness of follow-up. The five-point Oxford quality score was calculated. RESULTS: A total of 19 RCT were finally selected for this review. Overall, available data do not allow to support the use of omega-3 PUFA supplementation for the treatment of both active and inactive inflammatory bowel disease. Negative results are quite consistent in trials assessing the use of omega-3 PUFA to maintain disease remission, particularly ulcerative colitis, and to a lesser extent Crohn's disease. Trials on their use in active disease do not allow to draw firm conclusions mainly because the heterogeneity of design (ulcerative colitis) or their short number (Crohn's disease). In most trials, the appropriateness of the selected placebo is questionable. CONCLUSION: The present systematic review does not allow to make firm recommendations about the usefulness of omega-3 PUFA in inflammatory bowel disease.

Bacteria and spontaneous experimental colitis: immunological changes.

BACKGROUND: Intestinal commensal flora seems to be a requisite for both human and experimental intestinal inflammation. Our aim was to assess the immunological changes in the colon of IL-10(-/-) mice depending on the environmental conditions. MATERIALS AND METHODS: Twelve wild-type (WT) and 24 IL-10(-/-) 4-week-old mice were kept under specific pathogen-free (SPF) conditions for 4 weeks. Half of them were transferred to a conventional environment. Mice were sacrificed at 12 weeks of age, and the incidence and severity of colitis was assessed. Intraepithelial (IEL) and lamina propria (LPL) lymphocytes were assessed for phenotype and apoptosis by flow cytometry. Toll-like receptors 2 (TLR2) and TLR9 expression was assessed by real-time PCR. Immunohistochemical analyses for cell apoptosis, TLR2 and MyD88 were also performed. RESULTS: IL-10(-/-) mice shifted to conventional conditions showed a greater incidence (66% vs. 50%) and severity of colitis than animals kept under SPF conditions (P = 0·009). The number of CD3+ IEL was higher and their apoptosis rate lower in IL-10(-/-) than in their WT counterparts, regardless of the environment. In LPL, however, these differences were only observed in mice shifted to conventional conditions. TLR2 expression was significantly increased in SPF-housed IL-10(-/-) mice when compared to WT controls. Immunohistochemistry demonstrated the loss of TLR2 and MyD88 in damaged areas. CONCLUSIONS: In SPF conditions, IL-10 deficiency appears to be compensated by an increased epithelial TLR2 expression, thus resulting in a milder colonic damage. However, in conventional conditions, this compensatory mechanism would be exceeded inducing a more severe colonic damage with activation of LPL immune cells.

Therapeutic effect of antisecretory factor-rich egg yolk on the late phases of 2,4,6-trinitrobenzenesulphonic acid colitis in mice.

Antisecretory factor (AF) is expressed in all tissues of mammals, inhibits intestinal hypersecretion and has anti-inflammatory properties as well. Endogenous AF synthesis may be stimulated by feeding hydrothermally processed cereals. Alternatively, freeze-dried egg yolk can be used as a source of exogenous AF. Several reports have suggested that AF from freeze-dried egg yolk may be useful in inflammatory bowel disease. We assessed the effect of freeze-dried, AF-rich egg yolk intake on 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis. Balb/c mice were randomised to receive (1) AF in sterile drinking-water (4 g/l, n 38) and (2) sterile drinking-water alone (vehicle, n 38) from TNBS or saline administration onwards. Different subsets of mice were killed at weeks 1-3 after TNBS or saline administration. Macroscopic and microscopic damage was assessed in colonic specimens. Eicosanoid and cytokine production was evaluated in supernatants of 24 h-incubated colonic explants. Myeloperoxidase activity was measured in frozen colonic samples, while apoptosis was assessed in paraffined samples by the in situ oligoligation method. AF-treated mice showed a milder colonic damage compared with the vehicle group, which became statistically significant at week 3. This was accompanied by decreased IL-2, IL-1 and leukotriene B4 production at weeks 2 and 3, as well as increased interferon-γ at week 1, in AF-treated mice compared with vehicle-treated mice. AF-treated mice had significantly increased counts of apoptotic cells in the lamina propria at weeks 1 and 2 post-TNBS. In conclusion, the administration of AF-rich egg yolk has a therapeutic effect in the late phases of TNBS colitis in Balb/c mice.

Partial replacement of dietary (n-6) fatty acids with medium-chain triglycerides decreases the incidence of spontaneous colitis in interleukin-10-deficient mice.

Enteral nutrition has a primary therapeutic effect in active Crohn's disease. It is unknown which nutrient(s) account for this action, but a role for both the amount and type of dietary fat has been postulated. Some clinical and experimental data suggest that medium-chain triglycerides (MCT) may reduce intestinal inflammation. We aimed to assess the effect of replacing part of the dietary fat with MCT on the incidence and severity of colitis in interleukin (IL)-10(-/-) mice under specific pathogen-free conditions. Twenty-four IL-10(-/-) 4-wk-old mice were randomized to receive a control diet based on sunflower oil [(n-6) fatty acids (FA)] and an experimental isocaloric, isonitrogenous diet with 50% sunflower and 50% coconut oil (MCT diet). When the mice were 12 wk old, they were killed and the colon was examined for the presence of colitis, lymphocyte subpopulations and apoptosis, ex vivo cytokine production in supernatant of colon explants, toll-like receptor (TLR)-2 and TLR-9 mRNA, and FA profile in colonic tissue homogenates. Colitis incidence was lower in the IL-10(-/-) mice fed the MCT diet (1/12) than in the mice fed the control diet (8/12; P = 0.03). The histological damage score was also lower in the former (P < 0.0005). Feeding the MCT diet resulted in fewer total and apoptotic intraepithelial CD3+ and lamina propria CD3+CD4+ lymphocytes, as well as downregulated production of IL-6 and interferon-gamma, and reduced TLR-9 mRNA. We conclude that partial replacement of dietary (n-6) FA with MCT decreases the incidence of colitis in a model of spontaneous intestinal inflammation and provide experimental arguments for a possible primary therapeutic effect of MCT in human Crohn's disease.

Prospective, observational, cross-sectional study of intestinal infections among acutely active inflammatory bowel disease patients.

BACKGROUND: Intestinal infections have been claimed to precipitate or aggravate flares of inflammatory bowel disease (IBD). The reported incidence of such infections among IBD patients varies between 9 and 13%, but only a few prospective studies have been conducted. AIMS: To evaluate the incidence of intestinal infections by enteropathogens in patients with active IBD, their impact on clinical outcome, and to identify associated risk factors. PATIENTS AND METHODS: Consecutive patients admitted because of a relapse or suspected onset of IBD were prospectively included. At admittance, stool samples for culture, examination for intestinal parasites, and cytotoxin assay for Clostridium difficile were collected. Baseline clinical characteristics, potential risk factors for gastrointestinal infections, and clinical outcome were recorded. RESULTS: Ninety-nine episodes were included. Six intestinal infections were diagnosed in 6 patients (5 ulcerative colitis, 1 ileocolonic Crohn's disease), Campylobacter jejuni being the most frequent isolated microbe (n = 5). None of the patients with intestinal infection needed surgery, but two of them required second-line therapies. CONCLUSIONS: Gastrointestinal infections among IBD patients do not exceed 10% and occur mostly in patients with extensive involvement of the colon. Infection by enteropathogenic bacteria does not appear to be associated with a poorer clinical outcome of the IBD flare.

Impact of azathioprine on the prevention of postoperative Crohn's disease recurrence: results of a prospective, observational, long-term follow-up study.

BACKGROUND: Postoperative recurrence (PR) occurs early after intestinal resection in >75% of Crohn's disease (CD) patients. No well-established strategy for long-term PR prevention is available. The aim was to prospectively evaluate the long-term endoscopic and clinical outcomes of postoperative CD on maintenance treatment with azathioprine (AZA), especially in patients who developed endoscopic lesions confined to the ileocolic anastomosis. METHODS: Long-term AZA therapy (2-2.5 mg/kg/day) was initiated immediately after surgery in 56 consecutive patients who underwent a curative intestinal resection. Clinical and biological assessments every 3 months, as well as yearly endoscopic evaluation, were performed until the end of the study or clinical PR (CPR). RESULTS: Thirty-seven patients (70%) showed mucosal lesions at endoscopy after a median of 12 months (range 12-60); however, in 15 of these patients lesions were confined to the anastomosis and only 6 showed endoscopic progression, but none of them developed CPR. Among the remaining 22 patients with endoscopic PR (EPR), 23% suffered a CPR during follow-up. Thirty percent of patients remained free of EPR after a median follow-up of 33 months (range 12-84). The cumulative probability of EPR was 44%, 53%, 69%, and 82%, at 1, 2, 3, and 5 years, respectively. No predictive factors of EPR were found. CONCLUSIONS: Early postoperative use of AZA seems to delay EPR development in comparison to historical series or placebo groups in randomized controlled trials. Although usually considered as endoscopic recurrence, those lesions confined to the ileocolonic anastomosis are not likely to progress or to become symptomatic in the short term.

Effect of the administration of fermentable and non-fermentable dietary fibre on intestinal bacterial translocation in ascitic cirrhotic rats.

BACKGROUND: Bacterial infections are frequent in cirrhosis. Experimental studies suggest a pathogenic role of intestinal bacterial translocation in them. Both fermentable and non-fermentable fibre avoided intestinal bacterial translocation (IBT) in animal models of gut starvation and critical illness. AIM: To assess the effect of fermentable (pectin) or non-fermentable (lignin) fibre on IBT in ascitic cirrhotic rats. METHODS: Thirty-six rats induced to cirrhosis with oral CCl4 were randomized (6 weeks after the first CCl4 dose) to receive rat chow+5% lignin (LIG, n=13), rat chow+5% pectin (PEC, n=13), or rat chow only (CON, n=10). Once ascites developed, animals were laparotomized and samples of mesenteric lymph nodes (MLN), ascitic fluid, portal and peripheral blood and liver, were obtained for culture. RESULTS: IBT rate was: LIG=5/13, PEC=4/13, CON=5/10 (P=N.S.). The median amount of translocated bacteria in rats with IBT was lower in the PEC group (2 x 10(2) CFU/g MLN), than in LIG (10(5) CFU/g MLN) and CON (10(4) CFU/g MLN) groups (P<0.05). All other samples were sterile except for a portal blood sample (Enterococcus faecalis) of the LIG group. CONCLUSIONS: IBT incidence is not decreased by either pectin or lignin in ascitic cirrhotic rats, but pectin supplementation reduces the amount of translocated bacteria.

[Use of complementary and alternative medicine and drug abuse in patients with inflammatory bowel disease]. / Utilización de medicinas alternativas y consumo de drogas por pacientes con enfermedad inflamatoria intestinal.

BACKGROUND AND OBJECTIVE: The use of complementary and alternative medicine (CAM) is increasing in last years. Studies performed out of Spain have reported rates of CAM use of 40-50% among IBD patients. There are no available data on drug abuse among IBD patients. The aims of our study were to evaluate the rate and associate factors of CAM use and drug abuse among Spanish IBD patients. PATIENTS AND METHOD: Anonymous, structured questionnaire, administered to consecutive patients with IBD of at least 2 years of duration, seen in a IBD outpatient clinic. RESULTS: Twenty-six per cent of the 214 included patients reported having used CAM. No associated factors were found, although patients with ulcerative colitis tended to a higher rate of CAM use. Ten per cent of patients admitted to consume drugs, mainly cannabis derivatives. Younger age and college and universitary degree were the only factors associated to cannabis consumption. CONCLUSIONS: The rate of CAM use in IBD patients from a Spanish referral centre is lower than those described in other countries. About 10% of IBD patients consume cannabis, but only one third of them inform their physician about it.

[Acute appendicitis in inactive extensive ulcerative colitis]. / Apendicitis aguda en colitis ulcerosa extensa e inactiva.

Appendectomy is associated with a reduced risk of developing ulcerative colitis (UC). In addition, there may be appendicular involvement in UC in patients with extensive or even left-sided disease. However, no data are available on the incidence, clinical presentation and outcome of acute appendicitis in patients previously diagnosed with UC. The impact of appendectomy in this subset of patients also remains to be determined. We describe 2 cases of acute appendicitis in the setting of inactive extensive ulcerative colitis and compare their histologic features with those of the surgical specimens of 2 further UC patients colectomized for refractory and extensive disease.

Pernicious anaemia in triplets. A case report and literature review.

Pernicious anemia is the most common cause of vitamin B12 deficiency in adults. This entity is associated with chronic atrophic gastritis. We report a case of pernicious anaemia in triplets. We also report a fourth case of cobalamin deficiency with antibodies against intrinsic factor and anti parietal cell antigen negative antibodies in a sibling. The present article reviews the pediatric presentation of pernicious anemia and highlights the possible existence of familial aggregation. Furthermore, the need for systematic familial screening and the usefulness of an endoscopic follow-up program in patients with pernicious anemia are evaluated.

Collagenous duodeno-ileo-colitis with transient IgG deficiency preceded by Yersinia enterocolitica intestinal infection: case report and review of literature.

A case-report of a man with chronic diarrhoea is presented. After an unsuccessful treatment of an intestinal yersioniosis, the diagnosis of collagenous intestinal disease affecting duodenum, ileum and colon was made. In addition, a IgG transient deficiency was observed. The literature about gastrointestinal involvement, concomintant infection by Yersinia and IgG deficiency in collagenous colitis is reviewed.

Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is the commonest form of inherited colorectal cancer. Whereas it has been known that mismatch repair gene mutations are the underlying cause of HNPCC, an undetermined number of patients do not have these alterations. The main objectives of this study were to assess the relevance of clinically defined HNPCC patients without characteristic mutator pathway alterations and to identify their specific features. EXPERIMENTAL DESIGN: This was a prospective, population-based, cohort that included 1,309 newly diagnosed colorectal cancer patients. Demographic, clinical, pathologic data and tumor DNA from probands as well as a detailed family history were collected. Microsatellite analysis and MLH1, MSH2, and MSH6 immunohistochemistry were done. Germ line MLH1 and MSH2 mutational analysis was done in all patients with evidence of MMR alterations. RESULTS: Twenty-five patients (1.9%) fulfilled Amsterdam criteria of HNPCC but 15 (60%) of them did not have microsatellite instability and showed normal expression of MMR proteins. These patients presented mostly left-sided tumors without lymphocytic infiltrate; they were older, had fewer family members affected with colorectal or endometrial cancers, and more often fulfilled Amsterdam II criteria than HNPCC patients with microsatellite instability. Like unstable HNPCC patients, this group without mutator pathway alterations had a significant percentage of synchronous and metachronous adenomatous polyps and cancers. CONCLUSIONS: We define an important group of HNPCC families with specific features, no evidence of mismatch repair deficiency, and an autosomal dominant trait with a lesser penetrance than HNPCC with deficiency.

Absorption and transport of dietary long-chain fatty acids in cirrhosis: a stable-isotope-tracing study.

BACKGROUND: In rats, 30-70% of dietary fatty acids (FAs) are absorbed through the portal vein. Whether this occurs in humans is unknown, but it may occur in persons with cirrhosis, who show a blunted chylomicronemic response to dietary fat without significant steatorrhea. OBJECTIVE: The objective was to investigate whether portal FA absorption occurs in humans with cirrhosis. DESIGN: Six control subjects and 10 patients with (n = 5) and without (n = 5) cirrhotic ascites were fed [1-(13)C]palmitic and oleic acids in a test meal. Samples were drawn before and 30, 60, 90, 120, 240, 360, 480, and 720 min afterward for plasma [1-(13)C]-labeled FAs and breath (13)CO(2) assay. Fecal [1-(13)C]-labeled FAs were also measured. RESULTS: [1-(13)C]-Labeled FAs increased in chylomicrons in all groups, but less in ascitic cirrhotic patients, because their median area under the curve from 120 to 720 min was significantly lower than in the control subjects for labeled palmitate [520 (interquartile range: 192-1137) compared with 2862 (2674-4175) micromol . min/L] and oleate [829 (781-1263) compared with 3119 (2939-4986) micromol . min/L]. [1-(13)C]-Labeled FA enrichment of VLDL was also lower in cirrhotic patients. [1-(13)C]-Labeled FA in free FAs peaked earlier in ascitic than in nonascitic patients and control subjects, mainly for [1-(13)C]oleate, and the median area under the curve from 0 to 120 min was significantly higher in ascitic patients than in control subjects [301 (255-400) compared with 48 (34-185) micromol . min/L]. Fecal excretion of [1-(13)C]-labeled FA was negligible and not significantly different between groups. CONCLUSIONS: The low [1-(13)C]-labeled FA concentrations in chylomicrons and VLDL, without increased fecal losses, confirm previous data in cirrhotic patients with the use of an unlabeled fat load. The earlier [1-(13)C]-labeled FA appearance in free FAs supports the portal absorption of dietary fat in patients with advanced cirrhosis with spontaneous portal-systemic shunting.

Macronutrients and bioactive molecules: is there a specific role in the management of inflammatory bowel disease?

The effect of bioactive nutrient molecules on inflammatory response has an archetype in Inflammatory Bowel Disease. The exacerbated inflammatory response in such conditions can be nutritionally modified by 2 ways: changing the response of the host, or changing the composition of the intestinal ecosystem. Host response can be modified by changing the cell structure and function which is nutrient dependent. Nutrient deprivation will lead to a situation where there is not enough building material for cell replacement and the synthesis of mediators (enzymes, hormones, etc). However, this may occur even in a situation where there is no quantitative nutrient deprivation but only qualitative changes. In Inflammatory Bowel Disease, changes in the sources of some nutrients such as lipids or carbohydrates (CHO) can modify the inflammatory response. Lipids, by changing cell membrane composition, may modify the pattern of eicosanoid synthesis, intracellular signal transmission and activation of nuclear transcription factors, which modify the expression of some genes-that is, changing the host response. On the other hand, certain sources of carbohydrates, by undergoing anaerobic bacterial fermentation, drop the pH in the intestinal lumen favoring the growth of certain strains of bacteria which act favorably in maintaining tolerance in the bowel. In addition, as a consequence of CHO fermentation, short-chain fatty acids are produced which, especially butyrate, may act in 2 ways: by providing energy to the epithelial cells, but also as anti-inflammatory substrate-that is, modifying at least 1 of the mechanisms triggering the inflammatory response enhancement. However, it should not be forgotten that the cellular response to dietary modifications will depend on the individual genome, as has been recently observed. This may explain why some individuals do and others do not show a similar response to dietary interventions.

Combining steroids with enteral nutrition: a better therapeutic strategy for severe alcoholic hepatitis? Results of a pilot study.

BACKGROUND: Results of a previous randomized controlled trial comparing the outcome of patients with severe alcoholic hepatitis treated with total enteral nutrition (TEN) or corticosteroids suggest that these treatments act through different mechanisms and may be complementary. We report a pilot study of combined treatment with TEN and a shorter course of steroids in patients with severe alcoholic hepatitis. METHODS: Thirteen patients with severe alcoholic hepatitis were treated with systemic steroids and TEN. Steroid therapy started with 40 mg oral prednisolone daily, and was progressively tapered as soon as both serum bilirubin and prothrombin time decreased below 50% of their baseline values. TEN (2000 kcal, or 8374 kJ, daily) was administered throughout the hospital stay. Patients were followed for at least 12 months or until death. RESULTS: Tapering of prednisolone dose could be started after a mean (SD) of 15.4 (3.8) days, whereas TEN was maintained for 22 (3.8) days. TEN was tolerated in 10 of the 13 patients. The major adverse event attributable to therapy was hyperglycemia requiring insulin therapy, which occurred in 12 of 13 patients. Only two patients (15%) died during the treatment period. Another patient died within the first 2 months of follow-up. In no case was the death due to infectious complications, despite two-thirds of patients developing infections during the treatment period. Infections during follow-up occurred only in three patients. CONCLUSION: This pilot study suggests that TEN associated with a short course of steroids could be a good therapeutic strategy for severe alcoholic hepatitis. This possibility deserves investigation in a randomized controlled trial.

Development of antinuclear antibodies and its clinical impact in patients with Crohn's disease treated with chimeric monoclonal anti-TNFalpha antibodies (infliximab).

BACKGROUND: Although the efficacy of infliximab in Crohn's disease (CD) has been demonstrated, its safety profile has yet to be established. Autoimmune adverse events such as human anti-chimeric antibodies and the development of antinuclear antibodies (ANAs) have been notified, but the true incidence and clinical relevance of the latter is still unknown. OBJECTIVE: To evaluate the changes in ANA status in CD patients treated with infliximab and the clinical evolution of those who are ANA positive. METHODS: The ANA status of 36 CD patients treated with infliximab was determined at baseline and 6 weeks after the initial infliximab infusion. Patients were followed up monthly. In the case of infliximab re-treatment, ANA status was again evaluated. Twenty-eight patients (78%) were treated concomitantly with immunosuppressants. RESULTS: Eight patients (22%) were ANA positive at baseline; none developed anti-double-stranded DNA antibodies (aDNAds) at week 6. Three of them were re-treated: there were increasing ANA titres in all cases and developing aDNAds in two. Only six of 28 patients who were ANA negative at baseline changed their ANA status at week 6, but none developed aDNAds. One of them was retreated showing a further increase in ANA titre and developing aDNAds at high titre. No patient presented lupus-like syndrome. CONCLUSIONS: Only a few CD patients treated with infliximab and immunosuppressants develop ANAs. This condition is not associated with aDNAds and/or lupus-like syndrome in the majority of cases.