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Background: Gut-brain axis is widely implicated in the pathophysiology of Parkinson's disease (PD). We take an integrated approach to considering the gut as a target for disease-modifying intervention, using continuous measurements of disease facets irrespective of diagnostic divide. Methods: We characterised 77 participants with diagnosed-PD, 113 without, by dietary/exogenous substance intake, faecal metabolome, intestinal inflammation, serum cytokines/chemokines, clinical phenotype including colonic transit time. Complete-linkage hierarchical cluster analysis of metabolites discriminant for PD-status was performed. Results: Longer colonic transit was linked to deficits in faecal short-chain-fatty acids outside PD, to a ‘tryptophan-containing metabolite cluster’ overall. Phenotypic cluster analysis aggregated colonic transit with brady/hypokinesia, tremor, sleep disorder and dysosmia, each individually associated with tryptophan-cluster deficit. Overall, a faster pulse was associated with deficits in a metabolite cluster including benzoic acid and an imidazole-ring compound (anti-fungals) and vitamin B3 (anti-inflammatory) and with higher serum CCL20 (chemotactic for lymphocytes/dendritic cells towards mucosal epithelium). The faster pulse in PD was irrespective of postural hypotension. The benzoic acid-cluster deficit was linked to (well-recognised) lower caffeine and alcohol intakes, tryptophan-cluster deficit to higher maltose intake. Free-sugar intake was increased in PD, maltose intake being 63% higher (p = .001). Faecal calprotectin was 44% (95% CI 5%, 98%) greater in PD [p = .001, adjusted for proton-pump inhibitors (p = .001)], with 16% of PD-probands exceeding a cut-point for clinically significant inflammation compatible with inflammatory bowel disease. Higher maltose intake was associated with exceeding this calprotectin cut-point. Conclusions: Emerging picture is of (i) clinical phenotype being described by deficits in microbial metabolites essential to gut health; (ii) intestinal inflammation; (iii) a systemic inflammatory response syndrome.

The difficulty of life scale (DLS) instrument is used to measure specific life problems in patients with ulcerative colitis (UC). Importantly, health care providers should consider the characteristics of the country in which they support patients with UC. This cross-cultural comparison study investigated DLS among patients with UC in Japan and the United Kingdom (UK). Outpatients attending one hospital in London and one in Osaka were included. We collected patient information using the DLS questionnaire, which comprises 18 items in three domains. Mean differences between Japan and the UK were compared for the total score and each domain of the DLS. Variables with P.05 in univariate analysis were entered into a multiple regression model. We included 142 patients from Japan and 100 patients from the UK in the analysis. Univariate results showed that UK patients had more difficulties than Japanese patients in all three domains. Multivariate results showed that only "decline of vitality or vigor" showed significantly lower difficulty scores in Japanese patients. Having four or more bowel movements per day, visible bleeding, and being a homemaker or unemployed were significantly associated with greater difficulty according to the DLS total score. The level of daily life difficulties assessed using the DLS was greater among patients in the UK than among Japanese patients. This comparative study between patients with UC in Japan and the UK demonstrated certain country-related features for domain 3, "decline of vitality or vigor," of the DLS. The reasons why UK patients felt greater decline in vitality or vigor may be that these patients may have symptoms other than bowel symptoms; also, Japanese patients are more hesitant to express discomfort. The findings of this study might lead to a better understanding of culturally sensitive perceptions of daily life difficulties in UC.

ObjectiveFaecal calprotectin (fCAL) is an established marker of intestinal inflammation in inflammatory bowel disease (IBD). Disproportionally high fCAL levels, for the severity of intestinal inflammation, have been previously observed in primary sclerosing cholangitis associated IBD (PSC-IBD). The aim of this study was to test the hypothesis that fCAL is a marker of biliary injury in PSC-IBD.MethodsWe used two cohorts: (1) post hoc analysis of a colonoscopic surveillance study allowing correlation of fCAL to endoscopic severity as measured by the ulcerative colitis endoscopic index of severity (UCEIS) in PSC-IBD (n=20) and ulcerative colitis (UC, n=20) and (2) prospective recruitment of patients attending for endoscopic retrograde cholangiopancreatography allowed the correlation of fCAL to biliary calprotectin (n=8).ResultsA strong correlation was seen between fCAL and UCEIS in UC (r=0.821, 95% CI (0.585 to 0.929), pConclusionfCAL is a surrogate marker for biliary inflammation in PSC-IBD.Trial registration numberNCT02543021.

Aki Kawakami,1,2 Makoto Tanaka,2 Lee Meng Choong,1 Reiko Kunisaki,3 Shin Maeda,4 Ingvar Bjarnason,1 Bu’Hussain Hayee1 1Department of Gastroenterology, King’s College Hospital, London, UK; 2Department of Critical and Invasive-Palliative Care Nursing, Graduate School of Health Care Sciences, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Japan; 3Inflammatory Bowel Disease Center, Yokohama City University Medical Center, Yokohama, Japan; 4Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, JapanCorrespondence: Makoto Tanaka, Department of Critical and Invasive-Palliative Care Nursing, Graduate School of Health Care Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan, Tel +81-3-5803-4507, Fax +81-3-5803-4507, Email tanaka.cc@tmd.ac.jpPurpose: Non-adherence to medication was reported by 28% of Japanese patients with ulcerative colitis, but in the United Kingdom, patients with inflammatory bowel disease have lower medication adherence, which increases clinical relapse risk. The objective of this study was to compare medication adherence among patients with ulcerative colitis in Japan with previously reported results and patients in the United Kingdom.Patients and Methods: This cross-cultural comparison study investigated medication adherence among 100 ulcerative colitis patients in the United Kingdom and 432 ulcerative colitis patients in Japan. Adherence was assessed using The Morisky Medication Adherence Scale-8 questionnaire. Patient clinical features were collected from medical records and the questionnaire. Distribution of responses for each item, questionnaire total score, difference in ratio for each item between Japanese and UK patients, and difference in percentage of low/medium/high adherence between Japanese and UK patients were compared.Results: The proportion of low/medium or high adherence was significantly different between countries (42.6% and 7.4% [Japan] vs 24.0% and 76.0% [United Kingdom]; p< 0.01). Significantly more Japanese patients reported taking medication correctly the day before the questionnaire compared with UK patients.Conclusion: UK patients were more likely to not take medication when they felt their symptoms were under control compared with Japanese patients. UK patients perceived it was more difficult to remember to take the medication than Japanese patients. This study highlights culturally sensitive medication-taking behaviors in Japanese and UK patients with ulcerative colitis.Keywords: cross-cultural comparison, self-management, race, inflammatory bowel disease

Background There is considerable interest in the possible importance of the gut microflora in the pathophysiology of the inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn’s disease (CD). Probiotics offer a potential adjuvant treatment in these patients by modifying the intestinal milieu, but reports of their efficacy are conflicting. Aims To assess the efficacy of a multi-strain probiotic (Symprove™, Symprove Ltd, Farnham, United Kingdom) in quality of life issues and intestinal inflammation in patients with asymptomatic UC and CD. Methods A single-centre, randomised, double-blind, placebo-controlled trial of adult patients with asymptomatic IBD. Patients received 4 weeks of treatment with the probiotic or placebo (1 ml/kg/day). The primary efficacy measure was the difference in change in the IBD Quality of Life Questionnaire results (QOL) between probiotic vs. placebo at week 4. Secondary outcome measures included analyses of the change in laboratory findings, including faecal calprotectin (FCAL). Results Over 500 patients were recruited to the study and 81 and 61 patients with UC and CD, respectively were randomised and completed the study. There were no significant differences in IBD-QOL scores between placebo and the probiotic groups. Similarly, there were no significant changes observed in the laboratory data. However, the differences in FCAL between patients with UC before and after probiotics versus placebo approached statistical significance with a p value of 0.076. Post-hoc analyses showed that the FCAL levels were significantly (p

Interest in an aetiopathogenic role for Helicobacter in neuropsychiatric diseases started with idiopathic parkinsonism (IP), where the cardinal signs can be assessed objectively. This systematic review, using an EMBASE database search, addresses Oxford Centre for Evidence-Based Medicine based questions on the inter-relationship of Helicobacter and IP, the benefits of eradicating Helicobacter in IP and the outcome of not treating. The search strategy was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines: 21 of 204 articles met the inclusion criteria. The results show that the assumption that any benefit of Helicobacter eradication results from improved levodopa bioavailability is unjustified. The inter-relationship between Helicobacter and IP is well-established. H. pylori virulence markers (associated with autoimmunity and immune tolerance) influence the risk, severity and progression of IP. The birth cohort effect for virulence marker antibodies, seen in controls, is obliterated in IP, suggesting causality. Successful H. pylori eradication in IP is disease-modifying (even in anti-parkinsonian treatment-naïve patients) but not preventive. Hypokinesia regresses with eradication and overall motor severity lessens. Eradication may influence gastrointestinal microbiota adversely, unlocking the next stage in the natural history, the development of rigidity. Failed eradication worsens hypokinesia, as does the presence/persistence of H. pylori at molecular level only. Adequate prognostic assessment of the consequences of not treating Helicobacter, for IP, is prevented by a short follow-up. We conclude that Helicobacter is a pathophysiological driver of IP.

Depression is associated with constipation within and outside Parkinson&rsquo, s disease (PD). Since inefficient cognitive-processing (bradyphrenia) features in PD and an enterokinetic agent improved cognitive performance in healthy individuals, bradyphrenia may be associated with constipation. We aim to define the archetypical bowel function of PD, and its association with cognition, mood, and motor features within and outside PD. We assessed colonic transit time (oral radio-opaque markers over 6 days), bowel function and psychometric questionnaires and measures of PD facets, including bradyphrenia, in 58 participants with diagnosed PD, and 71 without (controls). The best abdominal X-ray (day 7) predictors of PD status were total retained marker count and transverse colon segmental delay. However, Rome functional constipation status complemented segmental delay better, giving good specificity (85%) but low sensitivity (56%). Transverse colon marker count appeared to be age-associated only in PD. In PD, those correctly classified by bowel dysfunction had higher depression scores (p = 0.02) and longer cognitive-processing times than the misclassified (p = 0.05). Controls misclassified as PD by bowel dysfunction had higher depression and anxiety scores than the correctly classified (p = 0.002 and 0.003, respectively), but not slower cognitive processing. Measures of motor features were independent of sub-classification by bowel function in PD and in controls. In conclusion, constipation in PD has distinct localized pathophysiology, and is associated with bradyphrenia.

Symprove, a multi-strain probiotic, has been shown to exert a mild anti-inflammatory effect in patients with ulcerative colitis (UC). We examined stool samples from 3 patients with UC in order to create microbiotas in an in-vitro gut model. The effects of Symprove on bacterial diversity and metabolic activity in the microbiotas was evaluated over 48 h. In addition, the influence of probiotic dosing on epithelial tight-junction integrity, production of inflammatory markers and wound healing were evaluated in cell culture models. The relative proportions of the main bacterial phyla in UC patients differed from those of healthy subjects studied previously; levels of Firmicutes were lowered and levels of Bacteroidetes were raised. Addition of Symprove changed the bacterial composition in the microbiotas over a 48 h period. Several other factors generally implicated in good gut health changed after dosing with probiotic; production of short chain fatty acids (SCFAs) and lactate was stimulated, levels of anti-inflammatory cytokines (IL-6, IL-10) increased, levels of pro-inflammatory cytokines and chemokines (MCP-1 and IL-8) decreased, epithelial tight junction integrity improved and wound healing occurred faster than a control. The results imply it is not the simple addition of probiotic bacteria that improves gut health. Rather, the probiotic bacteria generate lactate, which then stimulates growth of commensal gut bacteria, raising SCFA levels (particularly butyrate). The increased butyrate concentration positively influences inflammation response and time of wound healing.

Objectives Formulations of over the counter (OTC) NSAIDs differ substantially, but information is lacking on whether this alters their gastrointestinal profiles. To assess disintegration and dissolution rates and pharmacokinetics of four preparations of OTC ibuprofen and relate these with spontaneously reported gastrointestinal adverse events. Methods Disintegration and dissolution rates of ibuprofen tablets as (a) acid, (b) sodium salt, (c) lysine salt, and (d) as a liquid gelatine capsule were assessed. Pharmacokinetic data gastrointestinal and spontaneously reported adverse events arising from global sales were obtained from files from Reckitt Benckiser. Key findings Disintegration at low pH was progressively shorter for the preparations from a-to-d with formation of correspondingly smaller ibuprofen crystals, while dissolution was consistently poor. Dissolution at a neutral pH was least rapid for the liquid gelatine capsule. Pharmacokinetic data showed a shorter tmax and a higher Cmax for preparations b–d as compared with ibuprofen acid. Spontaneously reported abdominal symptoms were rare with the liquid gelatine preparation. Conclusions The formulations of OTC ibuprofen differ in their disintegration and dissolution properties, pharmacokinetic profiles and apparent gastrointestinal tolerability. Spontaneously reported abdominal symptoms were five times lower with the liquid gelatine capsule as compared with ibuprofen acid despite a 30% increase in Cmax.

Most drugs are given by the oral route. Oral intake allows direct contact between the drug and the entire GI tract mucosa, exposing it to potential topical damage until absorption. Medication-induced GI symptoms and lesions are therefore commonly encountered in clinical practice. This review will examine the most common drugs or classes of drugs affecting small bowel function and/or structure. Since non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medicines, NSAID enteropathy is highly prevalent and brings about considerable morbidity. Antimicrobials and proton-pump inhibitors profoundly modify intestinal microbiota, affecting gut sensory and motor functions, while other drugs (like iron and gold derivatives) impair intestinal permeability. Olmesartan (and likely ACE inhibitors) induce villous atrophy and consequent malabsorption. Mycophenolate mofetil, cancer chemotherapeutic agents, and immune checkpoint inhibitors cause intestinal inflammation, abdominal pain, and diarrhea. Potassium chloride supplements may induce small bowel ulceration, stenosis, and perforation while the cotraceptive pill and anticoagulants are associated with intestinal ischemia and spontaneous intramural hematoma, respectively. In clinical practice, a deep knowledge of clinical pharmacology and toxicology and a high degree of suspicion of drug-related adverse events are mandatory. Only then, the practicing physician will be able to diagnose medication-induced small bowel lesions correctly and will implement the best strategies to treat them.

Introduction Delay in diagnosis of colorectal cancer (CRC) is associated with worse outcomes. Although studies have shown the incidence of CRC missed at endoscopy to be 2.5%-7.7% (Morris et al., 2014), there are additional non-endoscopic factors that may lead to delays. This study aimed to identify all factors leading to a delayed diagnosis, including endoscopic “misses”. Methods All patients diagnosed with CRC at Kings College Hospital, London between 2011 – 2018 were included. We identified patients seen in an outpatient clinic or underwent endoscopy within 36 months preceding diagnosis. ‘Delayed’ cancers were grouped into ‘clinical factors’ and ‘technical factors’. ‘Clinical factors’ included the subset of post-colonoscopy colorectal cancers (PCCRC). The Joint Advisory Group on GI endoscopy (JAG) have defined PCCRC as being cancers diagnosed within 36 months of an endoscopy. Results 797 cases of CRC were diagnosed in the study period and 60(7.5%) were seen in the preceding 36 months. 46 patients (5.8%) were determined to have a delayed diagnosis, of which 24(52.2%) were diagnosed within 1 year of initial investigation. 38 delayed diagnoses were due to clinical factors: PCCRC (n=23), incomplete endoscopy (n=2), inadequate investigation (n=7), missed on rigid sigmoidoscopy (n=1) and incomplete bowel preparation (n=5) with an average delay of 172 days. 8 delays were caused by technical factors: Incomplete follow up (n=4), delayed investigation (n=2), histology not reviewed (n=1), missed on CT (n=1). The rate of missed cancer in the 2WW, Bowel Cancer Screening and Routine referral pathways was 4.8% (n=14), 5.1% (n=8), 7.3% (n=28) respectively. The incidence of missed cancer in the right colon was significantly higher (p=0.068, 95% CI 0.9–.57). Further interrogation showed the highest incidence in the hepatic flexure (10.5%), splenic flexure (9.4%), caecum (7.5%), and anal canal (6.5%). 91.3% of PCCRCs versus 47.8% of other missed cancers identified another pathology at the initial endoscopy which was documented on the report (p=0.003, 95% Confidence interval 2.1–0.6). A delay in diagnosis was not associated with more advanced TNM staging or K-ras mutations. Conclusions Our rate of missed cancers is equivalent to that published in the literature, with the majority of missed cancers due to PCCRC. Delays in diagnosis are related to avoidable factors, such as improving the quality of bowel prep or ensuring further investigations in patients with incomplete endoscopies. Endoscopists should also be aware of the increased miss rate in specific locations. Non-cancer pathology identified at endoscopy is also associated with missed cancer, so endoscopists should be careful to maintain a careful examination for concomitant cancers.

Introduction Delay in diagnosis of Upper Gastrointestinal (UGI) cancer may lead to worse patient outcomes. Several studies have published experience of post endoscopy cancers, with rates ranging between 4.6% – 21.6% in Western studies (Mennon and Trudgil, 2014). Our study aimed to identify the incidence of a delay in diagnosis of UGI cancer, investigating the underlying cause, including endoscopic ‘misses’. This will identify reversible factors, which may improve our patient outcomes. Methods A retrospective analysis was undertaken on all patients diagnosed with UGI cancer at King’s College Hospital (KCH) between 2011 – 2018 inclusive. Patients who were seen by a gastroenterologist, GI surgeon or had an endoscopy within the last 36 months were screened. Each case was discussed to determine whether a delay had occurred, or a cancer had been missed on endoscopy. Any delay in diagnosis was investigated to identify a root cause. Results 276 patients were diagnosed with UGI cancer in the time period, with 28 (11.3%) seen in the last 36 months. In 16 of these cases (5.8%) a delay in diagnosis was identified (mean 187 days, range - 21–1,106). In 11 cases (4.0%) the delay was less than 12 months. The factor leading to a delay in diagnosis were: post-endoscopy cancer (n=10), inadequate investigation (n=3) and delayed investigation (n=3). The missed cancer rate was 3.9% (n=5) in the 2 week wait (2WW) pathway versus 7.5% (n=11) in the routine referral pathway. This may reflect patients being referred on a routine pathway due to reassurance from investigations in the preceding year. The post endoscopy cancer rate in the oesophagus, stomach and duodenum were 6.5% (n=9), 6.4% (n=6) and 2.3% (n=1) respectively. The highest rate by individual location was 18.2% (n=2) in the upper third of the oesophagus. 40% of post endoscopy cancers showed an alternate diagnosis at initial endoscopy; Gastritis/Oesophagitis (n=4), Hiatus hernia (n=2), Schatzki ring (n=1). This group also showed a higher TNM staging compared to the background population; pT 3.30 vs. 2.85 (p=0.16, z = 1.41), pN 2.00 vs. 1.12 (p=0.17, z = 2.37), although this did not reach statistical significance. Conclusion We have a low rate of delay in diagnosis of our UGI cancers, but it is associated with a higher TNM stage which could impact patient prognosis. A large number of cancers were missed on endoscopy, in particular in the upper third of the oesophagus. Endoscopists should take care to obtain clear views on extubation. A large proportion of patients re-present within one year of endoscopy, so clinicians should re-investigate if there are persistent symptoms.

Background/Aim: Transanal endoscopic microsurgery (TEMS) is emerging as an alternative treatment for rectal cancer Stage I. There remains a risk of local recurrence. The Aim of the study was to study the effect of biomarkers in local recurrence for Stage I rectal cancer following TEMS plus or minus radiotherapy. Materials and Methods: This is a case-control study where we compared ten early rectal cancers that had recurred, against 19 cases with no recurrence, total 29 patients (age=28.25-86.87, mean age=67.92 years, SD=14.91, Male, N=18, Female, N=11). All patients underwent TEMS for radiological Stage I rectal cancer (yT1N0M0 or yT2N0M0) established with a combination of magnetic resonance imaging (MRI) and endorectal ultrasound. We prospectively collected all data on tumor histology, morphological features, as well as follow-up parameters. Molecular analysis was performed to identify their status on BRAF, KRAS, p16 O6-methylguanine-DNA methyltransferase (MGMT) and β-catenin. Results: Out of 29 specimens analyzed, 19 were KRAS wild type (65.9%) and ten mutant (34.5%). Recurrence of the tumor was noted in 10 cases (34.5%) of which 60% were pT1 (N=6) and 40% pT2 (N=4). There was a statistically significant association between KRAS mutant status and local recurrence (N=6, p=0.037). P16 expression greater than 5% (mean=10.8%, min=0, max=95) is linked with earlier recurrence within 11.70 months (N=7, p=0.004). Membranous β-catenin expression (N=12, 48%) was also related to KRAS mutant status (p=0.006) but not with survival (p>0.05). BRAF gene was found to be wild type in all cases tested (N=23). Conclusion: KRAS/p16/β-catenin could be used as a combined biomarker for prediction of local recurrence and stratification of the risk for further surgery.

Aspirin is in many ways a non- steroidal anti-inflammatory drug (NSAID) prototype. Similar to conventional NSAIDs the gastric side effects of aspirin are well studied. However its potential adverse effects on the small and large intestine are less well known and under- researched. Experimental studies support a pathogenic pathway leading to NSAID enteropathy involving the topical effects on the intestinal barrier (mucous layer, enterocytes) that lead to dysfunction and increased intestinal permeability followed by increased exposure to luminal triggers and acute inflammation. Although aspirin has a toxic effect in vitro, enteral or parenteral administration in vivo, in animal models, did not result to intestinal injury. In man, experimental studies have revealed changes in intestinal permeability similar to conventional NSAIDs but of lesser magnitude. The clinical implication of these changes though is not known. Population studies have associated aspirin use with occult gastrointestinal bleeding from the small or large bowel although the magnitude of this risk is difficult to estimate but certainly small. Associations to colitis flare-ups have been made in case reports and retrospective cohort studies but low dose aspirin appears safe. Complications of diverticular disease may also be more frequent with aspirin use.

Background: Primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (AISC) are related, but distinct chronic liver diseases. PSC is associated with a high prevalence of ulcerative colitis while the intestinal inflammation associated with AISC is less well characterised. Aims: To assess and contrast aspects of intestinal inflammation in patients with AISC and PSC and compare the clinical features with those of patients with ulcerative colitis and Crohn's disease. Methods: 23 and 22 patients with AISC and PSC, respectively, underwent review of colonoscopy and biopsy findings, capsule enteroscopy and assessment of clinical and inflammatory (faecal calprotectin) disease activity, which was compared with that of patients with ulcerative colitis and Crohn's disease (n = 55 each). Findings: Five and 6 patients with AISC and PSC, respectively, had normal colonoscopy and faecal calprotectin levels of 34.4 ± 8.3 and 39.7 ± 8.4 μg/g, respectively (normal 0.05) between patients with intestinal inflammation in AISC (588 ± 549 μg/g), PSC (421 ± 351 μg/g), ulcerative colitis (501 ± 656 μg/g) or Crohn's disease (476 ± 571 μg/g). Capsule enteroscopy showed that 7 of 18 (39%) (p

BACKGROUND Assessment of diverticular disease (DD) is routinely undertaken by colonoscopy and computed tomography (CT) scan. Improvements in high-frequency ultrasound have enabled evaluation of the colon wall structure in detail. Our objective was to assess ultrasound in measuring colonic wall thickness in DD. METHODS High-frequency 20-MHz ultrasound was undertaken to measure individual layer and total colonic wall thickness. Case patients had symptomatic DD. Control patients underwent colonoscopy for other reasons. Select patients also underwent abdominal CT scan. RESULTS Thirty-three patients underwent colonoscopic ultrasound, 18 with sigmoid diverticula and 15 control patients.Total wall thickness was greater in patients with DD, 5.69 mm (1.68) versus 2.61 mm (1.29, P

Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the gastrointestinal tract, causing widespread morbidity and mortality. Although mechanisms of damage involve the activities of prostaglandin-endoperoxide synthase 1 (PTGS1 or COX1) and PTGS1 (COX2), other factors are involved. We review mechanisms of gastrointestinal damage induction by NSAIDs, via COX-mediated and COX-independent processes. NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the gastrointestinal barrier. The resulting increase in intestinal permeability leads to low-grade inflammation. NSAID's inhibition of COX enzymes, along with luminal aggressors, results in erosions and ulcers, with potential complications of bleeding, protein loss, stricture formation, and perforation. We propose a model for NSAID-induced damage to the gastrointestinal tract that includes these complex, interacting, and inter-dependent factors. This model highlights the obstacles for the development of safer NSAIDs. [Abstract copyright: Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.]

This chapter reviews the history of development of noninvasive techniques for assessing intestinal permeability in humans, to outline the practical aspects of testing, and to draw attention to ways to localize the observed changes. With the introduction of nonmetabolized disaccharides as test substances it became practically possible to assess intestinal permeability noninvasively in humans. The term permeability has become synonymous with assessing the intestinal barrier function. Assessment of upper gastrointestinal permeability may be possible to assess the gastric side effects of alcohol selectively by using a sucrose permeation test which has been validated in relation to the gastric toxicity of NSAIDs. The chapter outlines some recent developments in intestinal function testing which represents an advance on preexisting tests in respect to sensitivity and specificity. NSAIDs increase intestinal permeability within 12 h of ingestion. The permeability changes occur in the period during drug absorption when the enterocytes are exposed to the highest concentration of the drugs.

Diverticular disease is a significant burden on healthcare systems that is managed, surgically or medically, mainly as an emergency or acute condition. There are no standardized treatment recommendations for symptomatic uncomplicated disease. We hypothesized that a probiotic would reduce abdominal pain in such patients. We conducted a single-center, double-blind, placebo-controlled trial of probiotic treatment (Symprove) in adult patients with moderate-to-severe chronic, non-acute symptomatic diverticular disease. 143 patients were randomized to receive 1 mL/kg/day of probiotic liquid (N = 72) or placebo (N = 71) daily for 3 months. The primary endpoint was abdominal pain severity. Secondary endpoints consisted of the change in the frequency of eight abdominal symptoms and the level of intestinal inflammation (fecal calprotectin). 120 patients completed the trial. Abdominal pain score, the primary end point, decreased in both groups, but no significant difference between the groups was found (P = 0.11). In relation to placebo, the probiotic significantly decreased the frequency of four of the eight secondary endpoints: constipation, diarrhea, mucorrhea, and back pain (P

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.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.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.Various common medications are implicated in complications of diverticular disease.

BACKGROUND Endoscopic resection of benign colorectal polyps and early cancer is well established. Local staging is of paramount importance to ensure that local resection is feasible. Endoscopic ultrasound has been used to evaluate the depth of lesions in the rectum, but its use in the colon is limited. OBJECTIVE This prospective study aims to evaluate the accuracy of 20-MHz mini probe ultrasound before the endoscopic resection of colorectal tumors. DESIGN All patients underwent 20-MHz high-frequency mini probe ultrasound of the colorectal lesion during colonoscopic examination. The mini probes were inserted through the working channel of the colonoscope, and acoustic coupling was achieved by instilling water to completely submerge the lesion. The depth of infiltration of the colorectal tumor was identified before resection. The lesions were sent for histological examination, and the level of infiltration was compared with the preoperative ultrasound depth. SETTING This study was conducted at a tertiary referral university teaching hospital. PATIENTS Consecutive patients referred for consideration of endoscopic resection were included in the study. INTERVENTIONS All patients were subject to colonoscopic high-frequency mini probe ultrasound to evaluate the depth of lesion before local resection. MAIN OUTCOME MEASURES There were 2 outcome measures: the ultrasound depth of colorectal lesion and the histological depth. RESULTS One hundred four patients were included with a mean age of 70 years. The surgical procedures included 59 endoscopic mucosal resections, 36 transanal endoscopic microsurgeries, and 9 endoscopic submucosal dissections. The 20-MHz ultrasound correctly staged 100 of 104 lesions, an overall accuracy of 96.1%. Eighty-eight of 89 mucosal lesions and 11 of 12 submucosal lesions were correctly staged. LIMITATIONS The ultrasound examination was performed by the main author only and is therefore dependent on his experience alone. CONCLUSION Colonoscopic high-frequency mini probe ultrasound has high accuracy in determining the depth of colorectal lesion and is useful before endoscopic resection.

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.

The early identification of primary non-response to anti-TNFα therapy facilitates the timely management of patients with Crohn's disease (CD). A recent, pilot study to detect prognostic markers of early response to anti-TNFα therapy identified the two genes coding for the calprotectin subunits (S100A8, S100A9) to be among the most highly expressed gene transcripts in non-responders. This study tests the hypothesis that measurements of faecal calprotectin (FCAL) pre- and post-anti-TNFα induction can predict primary non-response.Retrospective study of 32 CD patients treated over a two-year period. Outcomes were assessed at 6 months based on clinical activity scores and the use of corticosteroids: (a) remission: Harvey-Bradshaw index (HBI) 5, off corticosteroids2 months; (b) response: drop in HBI3, off corticosteroids; (c) non-response: ΔFCAL (and ΔCRP, respectively) was calculated as (FCAL post-induction - FCAL pre-induction) × 100/FCAL pre induction.At 6 months, 23 (72%) patients had responded (median (interquartile range) HBI: 4 (3-5), FCAL: 55 (27-146)), 17 (73%) of whom were in remission [HBI: 3 (2.5-4) and FCAL: 42 (16-115)]. There was a significant difference in the ΔFCAL from baseline to post-induction in the three groups (p 0.0001). Comparing non-responders to combined response and remission groups, the AUC of ΔFCAL to predict outcome at 6 months was 0.97. Using ROC analysis, a Δ70% returned a sensitivity and specificity of 99% and 96%, respectively (likelihood ratio, LR= 23). ΔCRP did not predict 6 months outcomes.A drop in FCAL70% after induction predicts primary non-response to anti-TNFα in CD.

Data on the use of wireless capsule endoscopy (WCE) in younger children remain limited. However, this single centre study suggests that it is a relatively complication-free procedure that may be considered in younger children below 4 years of age, when small bowel pathology is suspected. We retrospectively reviewed the King's College Hospital WCE database between August 2009 and August 2011. Patients aged 4 years or younger were included in the study. Six children fulfilled the inclusion criteria. The indications for WCE were unexplained gastrointestinal tract (GIT) bleeding (n=4), chronic diarrhoea with (n=1) and without (n=1) GIT bleeding (n=1). All had an oesophagogastroduodenoscopy and an ileocolonoscopy before WCE. The mean age at the time of WCE was 2 years 6 months (range 1 year 7 months to 3 years 7 months). The mean weight at WCE was 13.3 kg (range 9–17 kg). Four children had a complete study.

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.

Small intestinal function may be altered in decompensated chronic heart failure (CHF) and translocating LPS may contribute to systemic inflammation observed in CHF.We measured intestinal permeability (melibiose and rhamnose), active (3-O-methyl-d-glucose (3-OMG)) and passive (d-xylose) carrier-mediated absorption in 20 CHF patients (12 edematous and 8 non-edematous) and 8 controls by saccharide absorption technique assessing urinary recovery of orally administered sugars. We additionally measured LPS concentrations in 42 patients with decompensated heart failure and after recompensation.CHF patients had a 54% reduction of active carrier-mediated intestinal transport compared to controls (p0.0001). This reduction was strongest in edematous compared to non-edematous patients and controls (recovery in urine: 13.2±2.0% vs. 20.8±2.4% vs. 36.0 ± 3.7%, all p ≤ 0.05). Patients showed a 34% reduction of passive carrier-mediated transport, strongest in edematous patients (p=0.006). A greater impairment of active carrier-mediated transport remained significant after adjustment for non-mucosal factors in CHF (p=0.0004). Non carrier-mediated intestinal permeability was not altered. Data from 42 decompensated patients showed a decrease in LPS after recompensation (p=0.004). Edematous patients had highest blood concentrations of LPS, TNF and sTNF-R1 (p0.04). CHF patients with abnormal LPS concentrations0.50EU/mL (n=7) had the highest concentrations of TNF (7.0 ± 1.6 vs. 3.1 ± 0.3pg/mL, p0.02), and sTNF-R1 (3499 ± 52 vs. 1599±219 pg/mL, p=0.02).Active carrier-mediated intestinal transport is reduced in decompensated CHF indicating epithelial dysfunction possibly as a consequence of intestinal ischemia. Higher LPS concentrations in edematous CHF relate to inflammation. LPS decreased after recompensation. This suggests a cause/effect relationship between edematous gut wall, epithelial dysfunction and translocating LPS.

Background An association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) is well recognized. However, the disease course of IBD following liver transplantation (LT) for PSC remains ill-defined. Aims and methods We aimed to assess the impact of IBD in patients that had undergone LT for PSC to help identify risk factors for flare and to assess the impact of IBD on graft survival. Results 110 patients underwent LT for PSC (Oct 1990-Aug 2009) at King's College Hospital. 74 (67%) patients had concurrent IBD and 36 had PSC alone prior to transplant. 39 patients developed IBD (flare of IBD and de-novo) post transplant. Cumulative risk for IBD at 1-, 2-, 5- and 10-years was 16%, 24%, 38% and 72% respectively. Flare of IBD occurred in 33 patients with a mean time to flare of 30 ± 28 months. De-novo IBD occurred in 6 patients (all UC). Mean time to diagnosis was 29 ± 25 months. Multivariate cox-regression analysis identified active IBD at time of LT as a significant predictor of graft failure post LT (HR 10, CI 3-39, P = 0.001) and smoking at time of transplantation and subsequent cessation predictive of recurrent IBD post transplantation (HR 17, 2-180, P = 0.02). Conclusion In conclusion, smoking at time of LT was predictive of flare of IBD and active IBD at time of transplantation had a significant effect on graft survival. Medical therapy needs to be maximised in the pre-LT period. Patients with poorly controlled IBD refractory to medical therapy should be considered for colectomy at time of transplantation.

Objective Published and regulatory advice is to take NSAIDs with fluids and/or food irrespective whether NSAIDs are taken over the counter or long-term. The basis for this recommendation is not clear and we sought to establish the reasons for it through a search of published literature and personal files. Results Results from experimental animals show that fasting increases the gastric side effects of NSAIDs while food increases small bowel damage, but this has not been tested in humans. The possible effects of food in modifying the gastric damage caused by NSAIDs are complex, as food quantity and composition modify the responses substantially. Food usually delays peak levels of NSAIDs (and hence onset of action) without affecting total bioavailability. This may not be important when a steady state is achieved, but rapid onset of action is highly relevant for over-the-counter use of NSAIDs. The safety of over-the-counter use of ibuprofen and naproxen appears to be excellent and comparable with paracetamol. Conclusion The rapid onset of action of NSAIDs is most important during over-the-counter use, in which case it may be more appropriate to take the drugs on a fasting stomach.

The small and large intestine are one of the most common sites for the adverse action of drugs, accounting for 20-40% of all drug side effects. The most important factor in the diagnosis of drug-induced intestinal side effect is awareness. The mechanisms of damage are invariably complex, but may be due to topical effects, a known pharmacologic action of the drug on motility (for instance cholinergic/anti-cholinergic effect) and/or secretion, immune suppression and in the case of cytotoxic drug treatment a combination of many actions. The diagnosis of damage may be simple and widely recognised (NSAID-induced enteropathy resulting in bleeding, protein loss and rarely perforation and diaphragm disease), or at other times ignored (tricyclic antidepressants increasing constipation) or life threatening (docetaxene). Some associations require further research (statin and anti-retroviral associated irritable bowel symptoms). Diagnosis is traditionally made by symptom improvement on discontinuation of the drug. More lately capsule enteroscopy is used to aid diagnosis.

Summary 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.

Background & Aims Surrogate endpoints are biomarkers intended to substitute for a clinical endpoint. Are endoscopic ulcers a useful surrogate endpoint for a biological progression to clinical endpoints of ulcer complications (perforation, ulcers, and bleeds), hospital admission, or death? Methods Review of randomized trials, meta-analyses, clinical outcomes trials, and observational studies. Results No large study examined both endoscopic and clinical endpoints. Endoscopic ulcers and clinically significant ulcer complications were affected in the same direction and to about the same extent in 4 distinct circumstances: (1) by risk factors—age, previous history of symptomatic ulcer or bleeding, Helicobacter pylori, aspirin; (2) in studies of antiulcer treatments with differing modes of action, especially in relation to nonsteroidal anti-inflammatory drug toxicity, and Helicobacter pylori infection; (3) in studies evaluating ulcer complications with Cox-2 selective drugs and nonsteroidal anti-inflammatory drugs; and (4) in studies of interventions in patients with high risk of recurrent ulcer bleed needing nonsteroidal anti-inflammatory drug therapy. All study designs showed consistent and reproducible effects on gastrointestinal ulcer complications paralleling endoscopy. Conclusions Consistent and plausible findings from disparate populations and designs make endoscopic ulcers a strong candidate for surrogacy, though direct progression from endoscopic ulcers to ulcer complications cannot be demonstrated. Large outcome studies are needed to establish the power of the surrogacy, absolute risk of clinical outcomes, and to identify the totality of risks and benefits of new pharmacologic therapies.

Yoav C Metzger1, Samuel N Adler2, Ariella Bar-Gil Shitrit3, Binyamin Koslowsky4, Ingvar Bjarnason51School of Medicine, Hebrew University of Jerusalem, Israel; 2Department of Gastroenterology, Bikur Holim Hospital, Jerusalem, Israel; 3Department of Gastroenterology, Shaare Zedek Medical Center, Jerusalem, Israel; 4Department of Medicine, Hadassah Medical Organization, Jerusalem, Israel; 5Department of Gastroenterology, King’s College Hospital, London, UKBackground: Capsule endoscopy is the procedure of choice for many suspected small bowel diseases. PillCam™ small bowel (SB), has a high diagnostic yield. No improvements have been made on its optics since its introduction in 2002.Aim: To compare the diagnostic yield and quality of visualization of PillCam™ SB with that of a new small bowel endoscope (PillCam™ SB2) which has a larger angle of view and upgraded visual attributes.Methods: Twenty patients were randomized to undergo capsule enteroscopy with PillCam™ SB and PillCam™ SB2 a week apart.Results: Both procedures had a comparable diagnostic yield. However images from PillCam™ SB2 were found to be significantly better in regards of homogenous light exposure (P

The pathogenesis of nonsteroidal antiinflammatory drug (NSAID)-induced small bowel disease suggests that increased intestinal permeability is the central mechanism that translates biochemical damage to tissue damage. The purpose of this review is to summarize studies on the effect of NSAIDs to increase intestinal permeability in humans and methods for limiting this effect. A Medline search was made for papers that described measurements of increased intestinal permeability in humans. Virtually all studies agree that all conventional NSAIDs increase intestinal permeability in the human within 24 h of ingestion and that this is equally evident when they are taken long term. Various methods have been tried to limit the damage. The most promising agents are coadministration of synthetic prostaglandins, micronutrients, pre-NSAIDs, and COX-2 selective agents. However, their efficacy in preventing the development of NSAID enteropathy in the long term has not been studied in detail, and, in the case of COX-2 selective agents, small bowel damage is comparable to that which is seen with conventional NSAIDs. NSAID enteropathy is associated with significant morbidity and occasionally mortality. There are no proven effective ways of preventing this damage. Because increased intestinal permeability appears to be a central mechanism in the pathogenesis of NSAID enteropathy, it becomes a potential therapeutic target for prevention. At present there are a number of ways to limit the increased permeability, but additional studies are required to assess if this approach reduces the prevalence and severity of NSAID enteropathy.

Traditional non-steroidal anti-inflammatory drugs, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibitors control inflammation. While these drugs are formulated to reduce one of the cardinal signs of inflammation by reducing prostaglandin levels at the site of inflammation, COX-1 inhibitors induce inflammation in the stomach as well as the small bowel. The COX-2 inhibitors, a large portion of the non-steroidal anti-inflammatory drug market, provide a gastro-intestinally safer class of drugs. However, COX-2 inhibitors induce vasoconstriction via actions in renal and cardiovascular tissues. Since COX-2 inhibitors also have anticancer potential, it is worthwhile to design drug formulations that will not cause hypertension or cardiovascular damage. An attempt has thus been made in this article to formulate a hypothesis to circumvent the COX inhibitors induced inflammation and vasoconstriction through COX independent activation of calcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide found throughout the vascular and sensory nervous system.

Leukocytapheresis is a controversial nonpharmacologic treatment for IBD, in which white blood cells--the effector cells of the inflammatory process--are mechanically removed from the circulation. Current controversy centers on the uncontrolled nature of the leukocytapheresis trials performed and their use of different outcome measures in patient groups that have very variable disease activity and severity. Nonetheless, the efficacy data obtained are generally quite consistent: an excellent response (remission >80%) has been achieved in corticosteroid-naive patients with ulcerative colitis and an average remission rate of more than 50% has been achieved in patients who have steroid-dependent or refractory ulcerative colitis. Interestingly, the largest randomized, double-blind, sham-controlled study of granulocyte-monocyte apheresis in patients with moderate to severe ulcerative colitis failed to demonstrate efficacy for the induction of clinical remission or response. Regardless, leukocytapheresis seems to be remarkably safe. The precise positioning of leukocytapheresis in the treatment of ulcerative colitis is uncertain at present and will vary according to geography and patient preference for a safe, nonpharmacologic treatment. Further efficacy studies are required to assess what the optimal number and frequency of treatments is, in addition to the need for head-to-head comparisons with established drugs.