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The objectives of this review on ‘leaky gut’ for clinicians are to discuss the components of the intestinal barrier, the diverse measurements of intestinal permeability, their perturbation in non-inflammatory ‘stressed states’ and the impact of treatment with dietary factors. Information on ‘healthy’ or ‘leaky’ gut in the public domain requires confirmation before endorsing dietary exclusions, replacement with non-irritating foods (such as fermented foods) or use of supplements to repair the damage. The intestinal barrier includes surface mucus, epithelial layer and immune defences. Epithelial permeability results from increased paracellular transport, apoptosis or transcellular permeability. Barrier function can be tested in vivo using orally administered probe molecules or in vitro using mucosal biopsies from humans, exposing the colonic mucosa from rats or mice or cell layers to extracts of colonic mucosa or stool from human patients. Assessment of intestinal barrier requires measurements beyond the epithelial layer. ‘Stress’ disorders such as endurance exercise, non-steroidal anti-inflammatory drugs administration, pregnancy and surfactants (such as bile acids and dietary factors such as emulsifiers) increase permeability. Dietary factors can reverse intestinal leakiness and mucosal damage in the ‘stress’ disorders. Whereas inflammatory or ulcerating intestinal diseases result in leaky gut, no such disease can be cured by simply normalising intestinal barrier function. It is still unproven that restoring barrier function can ameliorate clinical manifestations in GI or systemic diseases. Clinicians should be aware of the potential of barrier dysfunction in GI diseases and of the barrier as a target for future therapy.

Objectives: To determine patient preference for treating opioid-induced constipation (OIC) using naloxegol or polyethylene glycol (PEG) 3350 in patients receiving opioids for noncancer pain. Methods: This crossover study included two 2-week active treatment periods, each preceded by a 1-week washout period (NCT03060512). Individuals with baseline Bowel Function Index scores ≥30 were randomized to 1 of 2 treatment sequences (naloxegol/PEG 3350 or PEG 3350/naloxegol). Patient preference (primary end point) was measured at the end of the second treatment period. Results: Of 276 patients randomized, 246 completed both treatment periods and reported preference (per protocol). Similar proportions of patients reported overall preference for naloxegol (50.4%) or PEG 3350 (48.0%; P = 0.92); 1.6% reported no preference. Medication characteristics influencing preference were similar for both treatments, except convenience and working quickly, which were strong influences of preference for higher proportions of patients preferring naloxegol (69.9% and 39.0%, respectively) vs those preferring PEG 3350 (29.9% and 27.4%, respectively). Patients aged <50 years or receiving laxatives within the previous 2 weeks generally preferred naloxegol. Changes from baseline in overall Bowel Function Index and Patient Global Impression of Change scores were similar between treatments, but analyses according to treatment preference revealed clinical improvement aligned with reported preference. Safety profiles were generally consistent with known medication profiles. Conclusions: Almost equal proportions of patients with OIC reported similar preference for daily naloxegol or PEG 3350 treatment, and their preference was generally supported by clinically relevant and measurable improvements in OIC symptoms.

INTRODUCTION: Aquaporin (AQP) channels are involved in regulating fluid homeostasis in the colon. Several AQP channels were detected in human colon epithelial cells. In a previous study, rats fed 1% (wt/wt) sodium cholate had increased AQP3, 7, and 8 levels, suggesting AQP involvement in bile acid diarrhea (BAD). Our aim was to compare AQP expressions in rectosigmoid mucosal (RSM) biopsies from patients with irritable bowel syndrome–diarrhea (IBS-D) (divided into those with normal or high fecal BA excretion) and in patients with IBS-constipation (IBS-C) compared with healthy controls. METHODS: In RSM biopsies from 44 patients with IBS-D (with normal (<) or high (>2,337 μmol/48 hours (BAD)) fecal BA excretion), 10 patients with IBS-C, and 17 healthy controls, we measured expressions of AQP1, 3, 7, and 8, with RT-PCR (housekeeper gene GAPDH ). We analyzed RNA for expression by RT 2 -PCR assays, with expression calculated using 2 −ΔΔCT -based fold-change. Comparisons of IBS groups were corrected for false detection rate (Bonferroni correction for 12 comparisons; P < 0.0042). AQP protein measurements on biopsies from 3 healthy controls, 3 patients with IBS-D, and 3 patients with BAD were performed by western blots (GAPDH housekeeping protein). RESULTS: In RSM from patients with IBS-D (but not IBS-C), mRNA expression of AQP3 was decreased, and AQP7 and 8 were increased relative to controls. Fold differences were not different in IBS-D with or without BAD. Western blots confirmed increased expression of AQP7 and 8 and decreased AQP3 proteins in biopsies from patients with IBS-D compared with controls. CONCLUSIONS: Increased AQP7 and 8 and decreased AQP3 expressions in RSM suggest that further studies on AQPs' potential role in the pathophysiology of diarrhea in IBS-D are warranted.

Linked ContentThis article is linked to Rotondo et al and Masuy papers. To view these articles, visit https://doi.org/10.1111/apt.15195 and https://doi.org/10.1111/apt.15242.

Objective Over half of patients with IBS have either diarrhoea (IBS-D) or a mixed stool pattern (IBS-M). The relative efficacy of licenced pharmacological therapies is unclear in the absence of head-to-head trials. We conducted a network meta-analysis to resolve this uncertainty. Design We searched MEDLINE, Embase, Embase Classic, the Cochrane central register of controlled trials, and Clinicaltrials.gov through January 2019 to identify randomised controlled trials (RCTs) assessing the efficacy of licenced pharmacological therapies (alosetron, eluxadoline, ramosetron and rifaximin) in adults with IBS-D or IBS-M. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all pharmacological therapies were reported as a pooled relative risk with 95% CIs to summarise the effect of each comparison tested. Treatments were ranked according to their p score. Results We identified 18 eligible RCTs (seven alosetron, five ramosetron, two rifaximin and four eluxadoline), containing 9844 patients. All were superior to placebo for the treatment of IBS-D or IBS-M at 12 weeks, according to the Food and Drug Administration (FDA)-recommended endpoint for trials in IBS. Alosetron 1 mg twice daily was ranked first for efficacy, based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms of IBS and effect on stool consistency. Ramosetron 2.5µg once daily was ranked first for effect on abdominal pain. Total numbers of adverse events were significantly greater with alosetron 1 mg twice daily and ramosetron 2.5µg once daily, compared with placebo. Rifaximin 550 mg three times daily ranked first for safety. Constipation was significantly more common with all drugs, except rifaximin 550 mg three times daily. Conclusion In a network meta-analysis of RCTs of pharmacological therapies for IBS-D and IBS-M, we found all drugs to be superior to placebo, but alosetron and ramosetron appeared to be the most effective.

AbstractObjectiveTo compare estimates of gastric accommodation (GA) with single photon emission computed tomography (SPECT) to measurements based on intragastric meal distribution immediately post‐meal ingestion (IMD0).MethodsWe evaluated 108 diabetics with upper gastrointestinal (UGI) symptoms who had undergone gastric emptying of solids (GE) by scintigraphy and GA measurements by SPECT. Immediately after ingestion of a 99mTc‐labeled egg meal (time 0), we estimated IMD0 as radioactive counts or area of the proximal half of the stomach on two‐dimensional images. Gastric volume (GV) during fasting and after 300 mL Ensure® was measured by SPECT to quantify accommodation volume (AV) or postprandial to fasting volume ratio (GVR). From the measured proximal gastric area, we estimated the volume of proximal stomach (4/3 × π × r3). We performed regression analyses to assess relationships between IMD0 and GA (AV) and GVR.ResultsThere was a significant correlation between area and radioactivity counts in the proximal stomach (r = 0.67, P < 0.001); however, there was considerable interpersonal variation [bias 0.20 (95% CI −0.07, 0.47)]. There were no significant correlations between total GV or AV or VR by SPECT and measurements using IMD0: proximal gastric counts, area, and estimated volume as continuous variables of dichotomized patient groups, based on published cutoff values. There were no significant differences in total gastric area or the IMD0 parameters (% area or % radioactive counts) between those with and without UGI symptoms except for fullness and satiety.ConclusionsIntragastric meal distribution immediately post‐meal ingestion is not significantly correlated with GA measurement by SPECT.

AbstractBackgroundIn two phase 3 trials, elobixibat, a locally acting ileal bile acid transporter inhibitor, resolved constipation and was well tolerated in Japanese patients with chronic constipation. We analyzed the efficacy, safety, and impact on quality of life (QOL) of elobixibat in patients with symptomatically more severe constipation in the two phase 3 trials.MethodsThis post hoc analysis of elobixibat treatment outcomes included data from a 2‐week, randomized, placebo‐controlled, phase 3 trial (10 mg/d), and a 52‐week, open‐label trial (5‐15 mg/d) in subgroups with severe constipation defined as ≤2 spontaneous bowel movements (SBMs) and ≤3 Bristol Stool Form Scale score during the second week of the 2‐week run‐in period. We also analyzed the rates of abdominal pain, diarrhea, and QOL in subgroups according to sex, presence of constipation‐predominant irritable bowel syndrome (IBS‐C) and side effects.Key ResultsIn patients with severe constipation, there was significant improvement in the 10 mg elobixibat group compared to the placebo group in change in SBMs from baseline at week 1 (primary endpoint) of the 2‐week trial. The differences between groups were reduced in patients with more severe constipation. Increasing the dose to 15 mg was effective for more severe constipation in improving the number of SBMs per week in the 52‐week trial. Overall, elobixibat was well tolerated and improved QOL scores, irrespective of gender, presence of IBS‐C or side effects.Conclusions & InferencesElobixibat is effective for symptomatically severe constipation, is well tolerated and improves QOL, irrespective of potentially confounding patient characteristics.

SummaryBackgroundBiomarkers in irritable bowel syndrome (IBS) may guide targeted therapy in this multifactorial disease. It has been suggested that 75% accuracy and cost <$500 categorise biomarkers as cost‐effective.AimTo identify differences in faecal bile acids, faecal fat and fasting serum C4 (7a‐hydroxy‐4‐cholesten‐3‐one) and fibroblast growth factor 19 (FGF19) among patients with IBS‐D, IBS‐C and healthy controls and to determine accurate, cost‐effective biomarkers for clinically relevant diarrhoea and constipation.MethodsWe assessed daily stool frequency and consistency (Bristol Stool Form Scale) from validated bowel diaries, 48 hours total and individual faecal bile acids, 48 hours faecal fat and weight, fasting serum C4 and FGF19, and colonic transit by scintigraphy from healthy volunteers (HV) and patients with IBS‐D and IBS‐C (Rome III criteria). We utilised multivariate logistic regression to determine biomarkers of clinically significant diarrhoea or constipation based on stool frequency, consistency and weight.ResultsAmong the 126 HV (44M/82F, 37.5 ± 10.9 years [SD]), 64 IBS‐D (5M/59F, 41.9 ± 12.2 years), and 30 IBS‐C (0M/30F, 44.6 ± 10 years) patients, there were significant differences between all groups in stool weight, frequency, and consistency; in addition, there were differences in colonic transit at 48 hours, faecal fat, and total and individual faecal bile acids between IBS‐D and IBS‐C. Reduced total and primary faecal bile acids and increased faecal lithocholic acid were significant predictors of decreased faecal weight, frequency and consistency with AUC > 0.82 (sensitivity >76%, specificity >72%). Total and primary faecal bile acids and faecal fat were significant predictors of increased stool weight, frequency and consistency with AUC > 0.71 (sensitivity >55%, specificity >74%).The faecal parameters had a 11.5 positive likelihood ratio in predicting elevated faecal weight.ConclusionsFaecal bile acids and faecal fat are cost‐effective and accurate biomarkers associated with significant bowel dysfunction among IBS‐D and IBS‐C patients.

AbstractBackgroundThe purpose of this study was to evaluate the measurement properties of the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index‐Daily Diary, a patient‐reported outcome instrument developed to meet US FDA recommendations for a symptom‐based clinical trial endpoint in gastroparesis. The ANMS GCSI‐DD assesses nausea, early satiety, postprandial fullness, and upper abdominal pain on a severity score from none (0) to very severe (4) and number of vomiting episodes during the past 24 hours. The composite score includes the first four symptoms, the core symptom score includes all five symptoms.MethodsSeventy‐one patients diagnosed with idiopathic or diabetic gastroparesis were recruited for a four‐week observational study. Patients completed the ANMS GCSI‐DD at home between Baseline and Week 4. Statistical analyses included confirmatory factor analysis, item response theory analysis, internal consistency, test‐retest reliability, and construct and known‐groups validity.Key ResultsUnidimensionality for the composite and core symptom scores was supported, and items exhibited good fit. Internal consistency (Cronbach's alpha =0.85 and 0.83) and test‐retest reliability were 0.89 and 0.88, for composite and core symptom scores, respectively. Convergent validity was supported by strong correlations with patient‐reported and clinician measures. Baseline and Week 4 scores differed for three measures used to define disease severity status (P < 0.0001), supporting known‐groups validity.Conclusions & InferencesThe ANMS GCSI‐DD has excellent reliability and validity, supporting its use to assess symptom‐based endpoints in gastroparesis clinical studies. Further analyses will be conducted using clinical trial data to ascertain treatment responsiveness and define a responder.