Systematic review: bile acids and intestinal inflammation-luminal aggressors or regulators of mucosal defence?

BACKGROUND: Inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis (UC), are chronic conditions attributed to an aberrant immune response to luminal triggers. Recently, published work suggests a pathogenic role for bile acids in this context. AIM: To perform a systematic review of studies investigating the role of bile acids in intestinal inflammation and present potentially relevant clinical implications. METHODS: Pubmed search for English language articles published up to May 2015. Terms used were: 'bile', 'bile acid', 'barrier', 'small bowel injury', 'Crohn's' and 'colitis'. RESULTS: Experimental studies support a variable role for bile acids in intestinal barrier homoeostasis. This may be attributed to different physicochemical properties, variable effects on epithelia and immune cells via bile acids-specific receptors, or through a cross-talk with the gut microbiome. A reduction in the bile acids pool, with lower concentrations of secondary forms, has been recognised for some time in Crohn's disease and associated to ileal dysfunction and bile acids malabsorption. Recent work suggests that these changes, including an increase in sulphated forms, are related to inflammatory activity in both Crohn's disease and UC. The detrimental effects of 'western diet' elements such as emulsifiers and fat, which have been implicated in the development of the current IBD and obesity epidemics, may also be bile acid-mediated. CONCLUSIONS: Although there are only a few observational clinical studies to support an interaction, in vivo human and animal studies support an association between bile acids metabolism, the gut microbiome and intestinal inflammation. This may well prove to have significant diagnostic and therapeutic implications.

Randomised clinical trial: A liquid multi-strain probiotic vs. placebo in the irritable bowel syndrome--a 12 week double-blind study.

BACKGROUND: The importance of interactions between the host and gut microbiota in the pathogenesis of irritable bowel syndrome (IBS) is becoming increasingly apparent. Probiotics offer a potential new treatment for IBS, but current results are conflicting, largely as a result of poorly designed trials and nonstandardisation of outcome measures. AIM: To assess the efficacy of a liquid, multi-strain probiotic (Symprove) in IBS. METHODS: A single-centre, randomised, double-blind, placebo-controlled trial of adult patients with symptomatic IBS. Patients received 12 weeks of treatment with the probiotic or placebo (1 mL/kg/day). The primary efficacy measure was the difference in change in the IBS symptom severity score (IBS-SSS) between probiotic vs. placebo at week 12. Secondary outcome measures included change in the IBS quality of life (IBS-QOL) score and change in the IBS-SSS symptom component scores. RESULTS: A total of 186 patients were randomised and 152 patients completed the study. The mean change in IBS-SSS was -63.3 probiotic vs. -28.3 placebo. The mean difference in the IBS-SSS was statistically significant [-35.0 (95% CI; -62.03, -7.87); P = 0.01]. There was no significant improvement in the IBS-QOL. No serious adverse events were reported. CONCLUSIONS: The multi-strain probiotic was associated with a statistically significant improvement in overall symptom severity in patients with IBS, and was well tolerated. These results suggest this probiotic confers benefit in IBS and deserves further investigation (ISRCTN identifier: 77512412).

Increased diverticular complications with nonsteriodal anti-inflammatory drugs and other medications: a systematic review and meta-analysis.

AIM: Complications of colonic diverticula, perforation and bleeding are a source of morbidity and mortality. A variety of drugs have been implicated in these complications. We present a systemic review and meta-analysis of the literature to assess the importance of this relationship. METHOD: A systematic review of articles in PubMed, Cochrane Reviews, Embase and Google Scholar was undertaken in February 2013. An initial literature search yielded 2916 results that were assessed for study design and topicality. Twenty-three articles were included in the review. A qualitative data synthesis was conducted using forest plots of studies comparing single medication with complications. RESULTS: Individual studies demonstrated the odds of perforation and abscess formation with nonsteridal anti-inflammatory drugs (NSAIDs) (1.46-10.30), aspirin (0.66-2.40), steroids (2.17-31.90) and opioids (1.80-4.51) and the odds of bleeding with NSAIDs (2.01-12.60), paracetamol (0-3.75), aspirin (1.14-3.70) and steroids (0.57-5.40). Pooled data showed significantly increased odds of perforation and abscess formation with NSAIDs (OR = 2.49), steroids (OR = 9.08) and opioids (OR = 2.52). They also showed increased odds of diverticular bleeding from NSAIDs (OR = 2.69), aspirin (OR = 3.24) and calcium-channel blockers (OR = 2.50). Most studies did not describe the duration or dosage of medication used and did not systematically describe the severity of diverticular complications. CONCLUSION: Various common medications are implicated in complications of diverticular disease.

Significantly higher frequency of Helicobacter suis in patients with idiopathic parkinsonism than in control patients.

BACKGROUND: There is increased proportional mortality from Parkinson's disease amongst livestock farmers. The hypokinesia of Parkinson's disease has been linked to Helicobacter pylori. H. suis is the most common zoonotic helicobacter in man. AIM: To compare the frequency of H. suis, relative to H. pylori, in gastric biopsies of patients with idiopathic parkinsonism (IP) and controls from gastroenterology services. METHODS: DNA extracts, archived at a Helicobacter Reference Laboratory, from IP patient and gastroenterology service biopsies were examined anonymously for H. suis, using species-specific RT-PCR. RESULTS: Relative risk of having H. suis in 60 IP patients compared with 256 controls was 10 times greater than that of having H. pylori. In patients with IP and controls, respectively, frequencies of H. suis were 27 (exact binomial 95% C.I. 15, 38) and 2 (0, 3)%, and of H. pylori, 28 (17, 40) and 16 (12, 21)%. Excess of H. suis in IP held when only the antral or corporal biopsy was considered. Of 16 IP patients with H. suis, 11 were from 19 with proven H. pylori eradication, 3 from 17 pre-H. pylori eradication, 2 from 24 H. pylori culture/PCR-negative. Frequency was different between groups (P = 0.001), greatest where H. pylori had been eradicated. Even without known exposure to anti-H. pylori therapy, H. suis was more frequent in IP patients (5/41) than in controls (1/155) (P = 0.002). Partial multilocus sequence typing confirmed that strains from IP patients (6) and control (1) differed from RT-PCR standard strain. CONCLUSIONS: Greater frequency of H. suis in idiopathic parkinsonism appears exaggerated following H. pylori eradication. Multilocus sequence testing comparison with porcine strains may clarify whether transmission is from pigs/porcine products or of human-adapted, H. suis-like, bacteria.

High-frequency mini-probe ultrasound as a useful adjunct in the management of patients with malignant colorectal polyps.

AIM: Colorectal polyps with a focus of malignancy, identified postpolypectomy, pose a management challenge of whether endoscopic treatment is adequate or whether further surgical resection is required. This study assessed 12- and 20-MHz colonoscopic ultrasound to evaluate the presence of residual disease and local lymph nodes. METHOD: Consecutive cases of all colorectal polyps with a focus of malignancy were included. Colonoscopic high-frequency ultrasound was performed (20-MHz mini-probes for residual polyps and 12-MHz ultrasound for local lymph nodes) in the region of previous polypectomy. Biopsies were taken of the polypectomy site if any abnormalities were seen. RESULTS: Twenty-one malignant polyps (sigmoid, n = 10; rectum, n = 8; transverse colon, n = 1; ascending colon, n = 1; and caecum, n = 1) were identified. All were invasive adenocarcinomas; 12 were intramucosal and nine were submucosal (seven sm1 lesions in the upper third of the submucosa; and two sm2 lesions in the middle third of the submucosa). Excision was histologically complete in 12 patients, four had involved margins and histology was uncertain in five owing to diathermy artefacts. Further colonoscopy revealed a residual abnormality in eight patients. The 12- and 20-MHz ultrasound imaging revealed mucosal irregularity with normal bowel-wall layers and no lymph-node involvement, with normal histology. High-frequency ultrasound was normal in the remaining 13 patients. At the time of writing, 15 (72%) of the 21 patients were disease free without further surgery. Six of the 21 patients underwent surgery, despite normal high-frequency ultrasound findings, because of submucosal invasion (sm1 or sm2) and uncertain completeness of resection. The specimens were free of cancer in all six patients. CONCLUSION: High-frequency ultrasound is feasible for the assessment of colorectal malignant polyps.

Gastrointestinal safety of NSAIDs and over-the-counter analgesics.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used. It is well recognised that they may adversely cause damage throughout the gastrointestinal tract and aggravate pre-existing disease. Their side effects on the upper gastrointestinal tract can be assessed by various means; each study type has different clinical connotations. Short-term use (less than 14 days) demonstrates dose-dependent damage of prescribed NSAIDs; the damage is proportional to the acidity of the drugs and not seen with Cyclooxygenase-2 (COX-2) selective inhibitors that have a pKa over 7.0. There have not been any serious outcomes, such as bleeding or perforation in these studies, and Helicobacter pylori (HP) plays no role in this damage. Long-term (3 months or more) endoscopy studies in patients show ulcer rates from 15%-35% with the various NSAIDs, but serious outcomes are exceedingly rare. Epidemiological studies show an association between NSAID intake and serious events. Ibuprofen is consistently at the lower end of toxicity rankings, whereas ketorolac and azapropazone are the worst. The risk of bleeding is increased with advancing age, presence of HP, previous history of bleeding, anticoagulant use, etc. The mega-trials show that COX-2 selective agents halve the bleeding episodes, but NSAID-induced gastric bleeding is very rare usually, less than 1 in 200 subjects taking them for a year. Seventy percent of patients develop NSAID-enteropathy, which is associated with intestinal blood and protein loss and rarely strictures. Over-the-counter (OTC) use of ibuprofen and diclofenac is associated with symptomatic gastrointestinal side effects comparable with placebo. Ibuprofen is shown to be remarkably well tolerated at OTC doses in a number of studies. There are recent studies to suggest that OTC NSAIDs should be taken on a fasting stomach, not with food as commonly advocated.

Colonoscopic high frequency mini-probe ultrasound is more accurate than conventional computed tomography in the local staging of colonic cancer.

AIM: Colonoscopic high frequency mini-probe ultrasound was compared prospectively with CT in the local staging of colonic cancer. METHOD: Consecutive patients undergoing surgical resection for colonic cancer were recruited. Preoperative 64-slice CT staging with multiplanar reconstruction was compared with colonoscopic high frequency mini-probe ultrasound using 12 MHz and 20 MHz probes. The three methods of staging (CT, 12 MHz ultrasound and 20 MHz ultrasound) were compared with the histological stage of the resected specimen. This was done using weighted kappa coefficients where weights of 0.7-0.8 were given to penalize disagreements of one level in either direction and weights of zero were given to penalize disagreements of more than one level in any direction. RESULTS: In total, 38 patients with colonic cancer were included. They were located in the sigmoid (n = 20), descending (n = 5), ascending (n = 2) and transverse colon (n = 1) and in the caecum (n = 7) and splenic (n = 2) and hepatic (n = 1) flexure. Histopathological assessment revealed seven pT1, four pT2, 25 pT3 and two pT4 cancers. In relation to the pathology the weighted kappa coefficients were 0.36 (SE = 0.14), 0.81 (SE = 0.16) and 0.81 (SE = 0.17) for CT, ultrasound 12 MHz and ultrasound 20 MHz. Histopathologically 15 (39.5%) patients were lymph node positive. The sensitivity, specificity and kappa coefficient for detection of nodal disease for CT were 80%, 47.8% and 0.25 (SE = 0.14) compared with 80%, 82.5% and 0.62 for 12 MHz ultrasound (SD = 0.14) and 23%, 90.5% and 0.15 (SD = 0.13) for 20 MHz ultrasound. CONCLUSION: Colonoscopic ultrasound is significantly more accurate than CT for T staging of colonic cancers. With respect to nodal status, 12 MHz ultrasound offers superior accuracy to CT or 20 MHz ultrasound.

Diverticular disease hospital admissions are increasing, with poor outcomes in the elderly and emergency admissions.

BACKGROUND: Diverticular disease has a changing disease pattern with limited epidemiological data. AIM: To describe diverticular disease admission rates and associated outcomes through national population study. METHODS: Data were obtained from the English 'Hospital Episode Statistics' database between 1996 and 2006. Primary outcomes examined were 30-day overall and 1-year mortality, 28-day readmission rates and extended length of stay (LOS) beyond the 75th percentile (median inpatient LOS = 6 days). Multiple logistic regression analysis was used to determine independent predictors of these outcomes. RESULTS: Between the study dates 560 281 admissions with a primary diagnosis of diverticular disease were recorded in England. The national admission rate increased from 0.56 to 1.20 per 1000 population/year. 232 047 (41.4%) were inpatient admissions and, of these, 55 519 (23.9%) were elective and 176 528 (76.1%) emergency. Surgery was undertaken in 37 767 (16.3%). The 30-day mortality was 5.1% (n = 6735) and 1-year mortality was 14.5% (n = 11 567). The 28-day readmission rate was 9.6% (n = 21 160). Increasing age, comorbidity and emergency admission were independent predictors of all primary outcomes. CONCLUSIONS: Diverticular disease admissions increased over the course of the study. Patients of increasing age, admitted as emergency and significant comorbidity should be identified, allowing management modification to optimize outcomes.

New balloon-guided technique for deep small-intestine endoscopy using standard endoscopes.

BACKGROUND AND STUDY AIMS: The advent of capsule endoscopy has opened the entire small bowel to direct inspection. The identification of pathology often requires diagnostic and therapeutic interventions. The available means today are push enteroscopy (limited to the proximal small bowel), intraoperative enteroscopy (invasive) and push-pull double-balloon enteroscopy (very effective but requires an expensive dedicated system). The aim of this study was to test the safety and efficacy of a novel push-pull technique, balloon-guided endoscopy (BGE), which can be used with standard endoscopic equipment. PATIENTS AND METHODS: Twenty patients with various disorders of the small intestine were examined by BGE. Various endoscopes were used and insertion depth was measured as is customary in double-balloon enteroscopy, by adding together the length of all the insertions of the endoscope performed during the push-pull steps. RESULTS: In 17 peroral intubations of the small bowel the average insertion depth beyond the ligament of Treitz was 1.45 m; insertion depth ranged from 0.80 m to 2.65 m. BGE advancement was deeper than in published results for push enteroscopy, though not equaling those for double-balloon enteroscopy. In the three transanal procedures the ileocecal valve was traversed and the terminal ileum intubated. No severe adverse events occurred. CONCLUSIONS: BGE is safe. BGE enables deep intubation of the small bowel beyond the ligament of Treitz utilizing standard endoscopes. Insertion depth with this technique is beyond that achieved by push enteroscopy. Further studies are needed, and technical improvements will lead to deeper insertion.

A double-blind, randomized, controlled crossover trial of glutamine supplementation in home parenteral nutrition.

OBJECTIVE: Studies suggest clinical benefit of glutamine-supplemented parenteral nutrition. The aim was to determine if the inclusion of 10 g of glutamine as part of the nitrogen source of home parenteral nutrition (HPN) reduces infectious complications. SUBJECTS/METHODS: Thirty-five patients on HPN were recruited and 22 completed the study. Patients were randomized to receive either standard HPN or glutamine-supplemented HPN. Patients were assessed at randomization, 3 and 6 months later then they were crossed over to the alternative HPN and reassessed at 3 and 6 months. Assessments included plasma amino acid concentrations, intestinal permeability and absorption, nutritional status, oral and parenteral intake, quality of life, routine biochemistry and haematology. RESULTS: No difference was seen between the groups at randomization. No difference was detected between the treatment phases for infective complications (55% in the standard treatment phase and 36% in the glutamine-supplemented phase P=0.67). There were no differences in nutritional status, intestinal permeability, plasma glutamine concentrations or quality of life. CONCLUSION: Although limited by the sample size, the study has shown that glutamine as part of the nitrogen source of parenteral nutrition can be given to patients on HPN for 6 months without any adverse effects.

Determinants of the short-term gastric damage caused by NSAIDs in man.

BACKGROUND: The short-term gastric damage seen with non-steroidal anti-inflammatory drugs (NSAIDs) in man may involve inhibition of cyclooxygenase (COX-1) and COX-2 as well as the topical irritancy, which is dependant on the acidity (pKa) and/or lipophilicity (log P(7.4)). AIM: To study the quantitative relationship between NSAID-induced short-term gastric damage, their physicochemical properties and contrasting roles of COX-1 and COX-2 inhibition. METHODS: We identified studies that allowed a qualitative comparison of the gastric injury (Lanza scores) induced by NSAIDs with their pKa and log P(7.4). Damage was correlated with gastric COX inhibition and potency to inhibit COX-1 and 2 and their COX-2/COX-1 selectivity ratio. RESULTS: The gastric damage correlates significantly with pKa (r = -0.69; P < 0.01), log P (r = -0.58, P < 0.05) and potency of the NSAIDs to inhibit COX-1 (r = -0.61, P < 0.02), but not with COX-2 inhibition or COX-2/COX-1 selectivity. CONCLUSION: Against a background of COX-1 and COX-2 inhibition, the physicochemical properties of NSAID appear to play an important role in short-term gastric damage.

The effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat.

BACKGROUND: The pathogenesis of NSAID-induced enteropathy may involve dual inhibition of the cyclooxygenase (1 and 2) and a topical effect with sequential increased intestinal permeability, development of inflammation and ulcers. It has been suggested that nitric-oxide donating drugs cause significantly less gastrointestinal injury by counteracting for NSAID-induced reductions in blood flow. AIMS: To compare the effects of AZD3582 [4-(nitroxy)butyl-(2S)-2-(6-methoxy-2-naphthyl) propanoate], and naproxen on key pathogenic steps in NSAID-enteropathy in the rat. METHODS: Single doses of AZD3582, naproxen (dose range 10-300 micromol/kg) or vehicle were given to male Sprague Dawley rats. Intestinal permeability (51CrEDTA) and intestinal inflammation (granulocyte marker protein) was quantitated and ulcer counts made. RESULTS: Intestinal permeability (all doses) and inflammation (highest dose of the drugs) increased significantly from control levels following naproxen and AZD3582 and there was no significant difference between the drugs. Median ulcer counts were, however, significantly (p < 0.01) lower with AZD3582 (4 +/- 2) than with naproxen (17 +/- 4). CONCLUSIONS: Naproxen and AZD3582 are equally associated with increased small intestinal permeability and inflammation, which is the consequence of their topical effect. The reduced small bowel ulcer counts with AZD3582 accords with the suggestion that vascular factors are the main driving force for NSAID-induced ulcer formation.

Is non-steroidal anti-inflammaory drug (NSAID) enteropathy clinically more important than NSAID gastropathy?

The side effects of conventional non-steroidal anti-inflammatory drugs (NSAIDs) on the stomach is undoubtedly a serious public health problem contributing significantly to the morbidity and mortality of patients receiving these drugs. However, the damage of NSAIDs is not confined to the stomach. Indeed the short term and long term damage of NSAIDs on the small bowel (NSAID enteropathy) is more frequent than NSAID gastropathy. Furthermore, NSAID enteropathy is associated with complications (bleeding and protein loss). While many of these are mild, the serious events (significant bleeding, perforation, obstruction, and sudden death) are frequent as that reported for NSAID gastropathy. The diagnosis of NSAID enteropathy has been greatly aided by the introduction of wireless capsule enteroscopy.

Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans.

BACKGROUND: Cyclooxygenase inhibiting nitric oxide donators (CINODs) are a new class of anti-inflammatory and analgesic drugs that may minimise gastrointestinal toxicity compared with standard non-steroidal anti-inflammatory drugs (NSAIDs) by virtue of nitric oxide donation. METHODS: A proof of concept study of the gastrointestinal safety of AZD3582, the first CINOD available for human testing, was conducted. Thirty one subjects were randomised to receive placebo, naproxen 500 mg twice daily, or its nitroxybutyl derivative AZD3582 in an equimolar dose (750 mg twice daily) for 12 days in a double blind three period crossover volunteer study. At the start and end of each dosing period, gastroduodenal injury was assessed by endoscopy and small bowel permeability by differential urinary excretion of lactulose and L-rhamnose. Pharmacokinetic profiles were assessed at steady state. RESULTS: On naproxen, the mean total number of gastroduodenal erosions was 11.5 (and one subject developed an acute ulcer) versus 4.1 on AZD3582 (p<0.0001). More than half of the subjects had no erosions on AZD3582. Differences were seen for both the stomach and duodenum. Naproxen increased intestinal permeability (lactulose:L-rhamnose ratio 0.030 before v 0.040 after treatment) whereas AZD3582 (0.029 before, 0.029 after; p=0.006 v naproxen) and placebo (0.030 before, 0.028 after; p<0.001 v naproxen) did not. The steady state bioavailability of naproxen metabolised from AZD3582 was 95% (95% confidence interval 87-101%) of that after naproxen administration. CONCLUSIONS: This human study supports animal data showing reduced gastrointestinal toxicity with the CINOD AZD3582. The potential combination of effective pain relief and gastrointestinal protection offered by AZD3582 warrants further evaluation in human clinical studies.