Diverticular disease: update on pathophysiology, classification and management.

Colonic diverticulosis is prevalent, affecting approximately 70% of the western population by 80 years of age. Incidence is rapidly increasing in younger age groups. Between 10% and 25% of those with diverticular disease (DD) will experience acute diverticulitis. A further 15% will develop complications including abscess, bleeding and perforation. Such complications are associated with significant morbidity and mortality and constitute a worldwide health burden. Furthermore, chronic symptoms associated with DD are difficult to manage and present a further significant healthcare burden. The pathophysiology of DD is complex due to multifactorial contributing factors. These include diet, colonic wall structure, intestinal motility and genetic predispositions. Thus, targeted preventative measures have proved difficult to establish. Recently, commonly held conceptions on DD have been challenged. This review explores the latest understanding on pathophysiology, risk factors, classification and treatment options.

Faecal metabolite deficit, gut inflammation and diet in Parkinson's disease: Integrative analysis indicates inflammatory response syndrome.

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.

Faecal calprotectin is a surrogate marker of biliary inflammation in primary sclerosing cholangitis associated inflammatory bowel disease.

Objective: Faecal 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. Methods: We 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). Results: A strong correlation was seen between fCAL and UCEIS in UC (r=0.821, 95% CI (0.585 to 0.929), p<0.0001). In PSC-IBD, the correlation was weaker (r=0.596, 95% CI (0.195 to 0.8260), p=0.006). PSC-IBD patients with endoscopically quiescent colitis (UCEIS: 0-1) had higher fCAL than patients with UC (279 µg/g, IQR (68-601) vs 30 µg/g, IQR (14-107), p=0.015). This was associated with higher risk of biliary complications like need for antibiotics or instrumentation (HR 16.39, 95% CI (2.98 to 90.25)) rather than colitis flares (follow-up: 12 months). Calprotectin measured in faeces correlated positively with biliary calprotectin (r=0.898, p=0.0024). Conclusion: fCAL is a surrogate marker for biliary inflammation in PSC-IBD. Trial registration number: NCT02543021.

Daily life difficulties among patients with ulcerative colitis in Japan and the United Kingdom: A comparative study.

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.

Self-Reported Medication Adherence Among Patients with Ulcerative Colitis in Japan and the United Kingdom: A Secondary Analysis for Cross-Cultural Comparison.

Purpose: 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.

A 4-strain probiotic supplement influences gut microbiota composition and gut wall function in patients with ulcerative colitis.

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.

Role of Helicobacters in Neuropsychiatric Disease: A Systematic Review in Idiopathic Parkinsonism.

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.

Distinctive Pathophysiology Underlying Constipation in Parkinson's Disease: Implications for Cognitive Inefficiency.

Depression is associated with constipation within and outside Parkinson'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.

Validation of the English version of the difficulty of life scale for patients with ulcerative colitis.

OBJECTIVE: Patients with ulcerative colitis have abdominal symptoms that affect their quality of life in multiple ways. The difficulty of life scale was developed in Japan to measure these patients' degree of daily difficulties. We aimed to assess this scale for English-speaking patients and to evaluate its validity and reliability. METHODS: The original Japanese version of the difficulty of life scale was translated into English and administered to 100 consecutive outpatients with ulcerative colitis at a university hospital in London. Medical information was obtained from participants' medical records. Factor validity, construct validity using the Short Inflammatory Bowel Disease Questionnaire, known group validity with clinically different groups, internal consistency and test-retest reliability were analyzed statistically. RESULTS: Three factors were extracted by exploratory factor analysis, as in the original scale. The construct validity was supported by the association between the Difficulty of Life Scale and Short Inflammatory Bowel Disease Questionnaire scores (Pearson's correlation coefficient: 0.73-0.83). Patients with visible bleeding or who were prescribed corticosteroids reported significantly greater difficulty than did those without them, demonstrating a significant effect size. The scaling success rate was acceptable. Internal consistency was confirmed (Cronbach's alpha: 0.68-0.89). The intraclass correlation coefficients were >0.75, thus confirming the test-retest reliability. CONCLUSION: The English version of the difficulty of life scale is a reliable and valid disease-specific scale for ulcerative colitis. It can be used to communicate the challenge of daily living between patients with this long-term condition and health care providers.

Drug-Induced Small Bowel Injury: a Challenging and Often Forgotten Clinical Condition.

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Helicobacter suis Is Associated With Mortality in Parkinson's Disease.

Helicobacter pylori has been implicated in the pathogenesis of Parkinson's disease (PD). Its eradication, in a randomized placebo-controlled trial, improved PD hypokinesia. Helicobacter species zoonosis might explain excess mortality from PD and non-Hodgkin lymphoma in livestock, but not arable, farmers. Indeed, Helicobacter is causally-associated with gastric lymphoma. We have previously shown that the relative-frequency, H. suis to H. pylori, was 10-times greater in 60 PD-patients than in 256 controls. We now go on to evaluate the pathological significance of H. suis, detected in gastric-biopsy DNA-extracts by ureA-based species-specific qPCR, validated by amplicon sequencing. The methodology had been cross-validated by a carR-based PCR. The pathological significance is put in context of H. pylori detection [urea-breath-test (UBT) with biopsy-culture, and, if negative, PCR], and the potential reservoir in pigs. Here, we explore, in these 60 PD-patients, associations of H. suis status with all-cause-mortality, and with orthostatic cardiovascular and blood profiling. H. suis had been detected in 19 of the 60 PD-patients on one or more occasion, only two (with co-existent H. pylori) being UBT positive. We found that the hazard-of-death (age-at-diagnosis- and gender-adjusted) was 12 (95% CI 1,103) times greater (likelihood-ratio test, P = 0.005) with H. suis-positivity (6/19) than with negativity (2/40: one lost to follow-up). UBT-values did not influence the hazard. H. suis-positivity was associated with lower standing mean-arterial-pressure [6 (1, 11) mmHg], H. pylori-positivity having no effect. The lower total lymphocyte count with H. pylori-positivity [-8 (-1, -14) %] was not seen with H. suis, where T-cell counts were higher [24 (2, 52) %]. Regarding the potential zoonotic reservoir in the UK, Helicobacter-like-organism frequency was determined in freshly-slaughtered pigs, nature ascertained by sequencing. Organisms immunostaining for Helicobacter, with corkscrew morphology typical of non-H. pylori Helicobacter, were seen in 47% of 111 pig-antra. We conclude that H. suis is associated with all-cause-mortality in PD and has a potential zoonotic reservoir.

A randomised, double-blind, placebo-controlled trial of a multi-strain probiotic in patients with asymptomatic ulcerative colitis and Crohn's 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 < 0.015) reduced in the UC patients receiving the probiotic as opposed to placebo. No significant changes were seen in CD. No serious adverse events were observed. CONCLUSION: This multi-strain probiotic is associated with decreased intestinal inflammation in patients with UC, but not in CD and is well tolerated. Further research is required to see if the probiotic reduces the incidence of clinical relapses in asymptomatic IBD patients.

Differing disintegration and dissolution rates, pharmacokinetic profiles and gastrointestinal tolerability of over the counter ibuprofen formulations.

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 .

Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs.

Nonsteroidal 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 cyclooxygenase [COX] 1) and PTGS1 (COX2), other factors are involved. We review the 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 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.

A randomized double-blind placebo-controlled trial of a multi-strain probiotic in treatment of symptomatic uncomplicated diverticular disease.

BACKGROUND: 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. METHODS: 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). RESULTS: 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 < 0.04). No significant differences were found in frequency of abdominal pain, PR bleeding, dysuria, and bloating. CONCLUSIONS: Multi-strain liquid probiotic did not improve abdominal pain scores significantly, but significantly improved the frequency of four other symptoms associated with chronic, non-acute symptomatic diverticular disease.

Rifaximin Reduces the Number and Severity of Intestinal Lesions Associated With Use of Nonsteroidal Anti-Inflammatory Drugs in Humans.

The intestinal microbiota might contribute to enteropathy associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs), but there have been few human studies of this association. We performed a placebo-controlled study to determine whether a delayed-release antibiotic formulation (rifaximin-extended intestinal release [EIR]) prevents the development of intestinal lesions in subjects taking daily NSAIDs. Sixty healthy volunteers (median age, 26 y; 42% female) were given the NSAID diclofenac (75 mg twice daily) plus omeprazole (20 mg once daily), and either rifaximin-EIR (400 mg) or placebo, twice daily for 14 days. Subjects were assessed by videocapsule endoscopy at baseline and after 2 weeks of treatment. The primary end point was the proportion of subjects developing at least 1 small-bowel mucosal break at week 2. Secondary end points were the change in the mean number of mucosal lesions and the number of subjects with large erosions and/or ulcers after 14 days of exposure. We detected mucosal breaks in 20% of subjects given rifaximin and in 43% of subjects given placebo (P = .05 in the post hoc sensitivity analysis). None of the subjects in the rifaximin group developed large lesions, compared with 9 subjects in the placebo group (P < .001). Our findings indicate that intestinal bacteria contribute to the development of NSAID-associated enteropathy in human beings. Clinical trial no: EudraCT 2013-000730-36.