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A lack of biomarkers that detect drug-induced liver injury (DILI) accurately continues to hinder early- and late-stage drug development and remains a challenge in clinical practice. The Innovative Medicines Initiative’s TransBioLine consortium comprising academic and industry partners is developing a prospective repository of deeply phenotyped cases and controls with biological samples during liver injury progression to facilitate biomarker discovery, evaluation, validation and qualification.In a nested case–control design, patients who meet one of these criteria, alanine transaminase (ALT) ≥ 5 × the upper limit of normal (ULN), alkaline phosphatase ≥ 2 × ULN or ALT ≥ 3 ULN with total bilirubin > 2 × ULN, are enrolled. After completed clinical investigations, Roussel Uclaf Causality Assessment and expert panel review are used to adjudicate episodes as DILI or alternative liver diseases (acute non-DILI controls). Two blood samples are taken: at recruitment and follow-up. Sample size is as follows: 300 cases of DILI and 130 acute non-DILI controls. Additional cross-sectional cohorts (1 visit) are as follows: Healthy volunteers (n = 120), controls with chronic alcohol-related or non-alcoholic fatty liver disease (n = 100 each) and patients with psoriasis or rheumatoid arthritis (n = 100, 50 treated with methotrexate) are enrolled. Candidate biomarkers prioritised for evaluation include osteopontin, glutamate dehydrogenase, cytokeratin-18 (full length and caspase cleaved), macrophage-colony-stimulating factor 1 receptor and high mobility group protein B1 as well as bile acids, sphingolipids and microRNAs. The TransBioLine project is enabling biomarker discovery and validation that could improve detection, diagnostic accuracy and prognostication of DILI in premarketing clinical trials and for clinical healthcare application.

Background: Feeding triggers inter-related gastrointestinal (GI) motor, peptide and appetite responses. These are rarely studied together due to methodological limitations. Recent MRI advances allow pan-intestinal, non-invasive assessment of motility in the undisturbed gut. This study aimed to develop a methodology to assess pan-intestinal motility and transit in a single session using MRI and compare imaging findings to GI peptide responses to a test meal and symptoms in a healthy volunteer cohort. Methods: Fifteen healthy volunteers (29.3±2.7years and BMI 20.1±1.2Kg/m2) underwent baseline and postprandial MRI scans, symptom questionnaires and blood sampling (for subsequent GI peptide analysis, Glucagon-like peptide-1 (GLP-1), Polypeptide YY (PYY), Cholecystokinin (CCK)) at intervals for 270min following a 400g soup meal (204kcal, Heinz, UK). Gastric volume, gall bladder volume, small bowel water content, small bowel motility and whole gut transit were measured from the MRI scans. Key Results: (mean±SEM) Small bowel motility index increased from fasting 39±3 arbitrary units (a.u.) to a maximum of 87±7a.u. immediately after feeding. PYY increased from fasting 98±10pg/ml to 149±14pg/ml at 30min and GLP-1 from fasting 15±3µg/ml to 22±4µg/ml. CCK increased from fasting 0.40±0.06pmol/ml to 0.94±0.1pmol/ml. Gastric volumes declined with a T1/2 of 46±5min and the gallbladder contracted from a fasting volume of 19±2ml to 12±2ml. Small bowel water content increased from 39±2ml to 51±2ml postprandial. Fullness VAS score increased from 9±5mm to 41±6mm at 30min postprandial. Conclusions and Inferences: The test meal challenge was effective in inducing a change in MRI motility end-points which will improve understanding of the pathophysiological postprandial GI response.

Background: Poorly absorbed, fermentable carbohydrates can provoke irritable bowel syndrome (IBS) symptoms by escaping absorption in the small bowel and being rapidly fermented in the colon in some susceptible subjects. IBS patients are often anxious and stressed and stress accelerates small bowel transit which may exacerbate malabsorption. Objective: In this study we investigated the effect of intravenous injection of corticotrophin releasing factor (CRF) on fructose malabsorption and the resulting volume of water in the small bowel. Design: We performed a randomised, placebo controlled, cross-over study of CRF versus saline injection in 11 male and 10 female healthy subjects, examining the effect on the malabsorption of a 40 g fructose test meal and its transit through the gut which was assessed by serial Magnetic Resonance imaging (MRI) and breath hydrogen measurement. Orocaecal transit was assessed using the lactose-ureide C13 breath test and the adrenal response to CRF assessed by serial salivary cortisol measurements. Results: (Mean ± SD) CRF injection caused a significant rise in salivary cortisol which lasted 135 minutes. Small bowel water content (SBWC) rose from baseline, peaking at 45 minutes after fructose ingestion while breath hydrogen peaked later at 75 minutes. The area under the curve (AUC) for SBWC from -15 - 135 minutes was significantly lower after CRF versus saline (mean difference [95% CI] 7433 [275, 14591] mL.min, P = 0.04). Ascending colon volume rose after CRF, significantly more for male volunteers than female (P = 0.025). Conclusions: CRF constricts the small bowel and increases fructose malabsorption as shown by increased ascending colon volumes. This mechanism may help to explain the increased sensitivity of some stressed individuals to fructose malabsorption. This trial was registered at ClinicalTrials.gov as NCT01763281

Introduction: Immune activation has been reported in the mucosa of irritable bowel syndrome patients with diarrhoea (IBS-D) and some small studies have suggested that Mesalazine may reduce symptoms. We performed a double blind, randomised placebo controlled trial of 2g Mesalazine twice daily versus placebo for 3 months in Rome III criteria IBS-D patients. Primary outcome was daily average stool frequency during weeks 11-12; secondary outcomes were abdominal pain, stool consistency, urgency and satisfactory relief of IBS symptoms. Methods: Participants were randomised after a 2-week baseline stool diary. All participants completed a 12-week stool diary and at the end of each week recorded the presence of “satisfactory relief of IBS symptoms”. Results: 136 patients with IBS-D (82 F, 54 M) were randomised, 10 patients withdrew from each group. Analysis by intention to treat showed the daily average stool frequency during weeks 11 and 12 were mean (SD), 2.8 (1.2) in Mesalazine and 2.7 (1.9) in placebo group with no significant group difference (95% confidence interval) 0.1 (-0.33,0.53); p=0.66. Mesalazine did not improve abdominal pain, stool consistency nor percentage with satisfactory relief compared to placebo during the last 2 weeks follow up. Conclusion: This study does not support any clinically meaningful benefit or harm of Mesalazine compared with placebo in unselected IBS with diarrhoea. More precise subtyping based on underlying disease mechanisms is needed to allow more effective targeting of treatment in IBS. (ClinicalTrials.gov number NCT01316718)

Background: Feeding triggers inter-related gastrointestinal (GI) motor, peptide and appetite responses. These are rarely studied together due to methodological limitations. Recent MRI advances allow pan-intestinal, non-invasive assessment of motility in the undisturbed gut. This study aimed to develop a methodology to assess pan-intestinal motility and transit in a single session using MRI and compare imaging findings to GI peptide responses to a test meal and symptoms in a healthy volunteer cohort. Methods: Fifteen healthy volunteers (29.3±2.7years and BMI 20.1±1.2Kg/m2) underwent baseline and postprandial MRI scans, symptom questionnaires and blood sampling (for subsequent GI peptide analysis, Glucagon-like peptide-1 (GLP-1), Polypeptide YY (PYY), Cholecystokinin (CCK)) at intervals for 270min following a 400g soup meal (204kcal, Heinz, UK). Gastric volume, gall bladder volume, small bowel water content, small bowel motility and whole gut transit were measured from the MRI scans. Key Results: (mean±SEM) Small bowel motility index increased from fasting 39±3 arbitrary units (a.u.) to a maximum of 87±7a.u. immediately after feeding. PYY increased from fasting 98±10pg/ml to 149±14pg/ml at 30min and GLP-1 from fasting 15±3µg/ml to 22±4µg/ml. CCK increased from fasting 0.40±0.06pmol/ml to 0.94±0.1pmol/ml. Gastric volumes declined with a T1/2 of 46±5min and the gallbladder contracted from a fasting volume of 19±2ml to 12±2ml. Small bowel water content increased from 39±2ml to 51±2ml postprandial. Fullness VAS score increased from 9±5mm to 41±6mm at 30min postprandial. Conclusions and Inferences: The test meal challenge was effective in inducing a change in MRI motility end-points which will improve understanding of the pathophysiological postprandial GI response.

Introduction: Immune activation has been reported in the mucosa of irritable bowel syndrome patients with diarrhoea (IBS-D) and some small studies have suggested that Mesalazine may reduce symptoms. We performed a double blind, randomised placebo controlled trial of 2g Mesalazine twice daily versus placebo for 3 months in Rome III criteria IBS-D patients. Primary outcome was daily average stool frequency during weeks 11-12; secondary outcomes were abdominal pain, stool consistency, urgency and satisfactory relief of IBS symptoms. Methods: Participants were randomised after a 2-week baseline stool diary. All participants completed a 12-week stool diary and at the end of each week recorded the presence of “satisfactory relief of IBS symptoms”. Results: 136 patients with IBS-D (82 F, 54 M) were randomised, 10 patients withdrew from each group. Analysis by intention to treat showed the daily average stool frequency during weeks 11 and 12 were mean (SD), 2.8 (1.2) in Mesalazine and 2.7 (1.9) in placebo group with no significant group difference (95% confidence interval) 0.1 (-0.33,0.53); p=0.66. Mesalazine did not improve abdominal pain, stool consistency nor percentage with satisfactory relief compared to placebo during the last 2 weeks follow up. Conclusion: This study does not support any clinically meaningful benefit or harm of Mesalazine compared with placebo in unselected IBS with diarrhoea. More precise subtyping based on underlying disease mechanisms is needed to allow more effective targeting of treatment in IBS. (ClinicalTrials.gov number NCT01316718)

Background: Poorly absorbed, fermentable carbohydrates can provoke irritable bowel syndrome (IBS) symptoms by escaping absorption in the small bowel and being rapidly fermented in the colon in some susceptible subjects. IBS patients are often anxious and stressed and stress accelerates small bowel transit which may exacerbate malabsorption. Objective: In this study we investigated the effect of intravenous injection of corticotrophin releasing factor (CRF) on fructose malabsorption and the resulting volume of water in the small bowel. Design: We performed a randomised, placebo controlled, cross-over study of CRF versus saline injection in 11 male and 10 female healthy subjects, examining the effect on the malabsorption of a 40 g fructose test meal and its transit through the gut which was assessed by serial Magnetic Resonance imaging (MRI) and breath hydrogen measurement. Orocaecal transit was assessed using the lactose-ureide C13 breath test and the adrenal response to CRF assessed by serial salivary cortisol measurements. Results: (Mean ± SD) CRF injection caused a significant rise in salivary cortisol which lasted 135 minutes. Small bowel water content (SBWC) rose from baseline, peaking at 45 minutes after fructose ingestion while breath hydrogen peaked later at 75 minutes. The area under the curve (AUC) for SBWC from -15 - 135 minutes was significantly lower after CRF versus saline (mean difference [95% CI] 7433 [275, 14591] mL.min, P = 0.04). Ascending colon volume rose after CRF, significantly more for male volunteers than female (P = 0.025). Conclusions: CRF constricts the small bowel and increases fructose malabsorption as shown by increased ascending colon volumes. This mechanism may help to explain the increased sensitivity of some stressed individuals to fructose malabsorption. This trial was registered at ClinicalTrials.gov as NCT01763281

Background: Feeding triggers inter-related gastrointestinal (GI) motor, peptide and appetite responses. These are rarely studied together due to methodological limitations. Recent MRI advances allow pan-intestinal, non-invasive assessment of motility in the undisturbed gut. This study aimed to develop a methodology to assess pan-intestinal motility and transit in a single session using MRI and compare imaging findings to GI peptide responses to a test meal and symptoms in a healthy volunteer cohort. Methods: Fifteen healthy volunteers (29.3±2.7years and BMI 20.1±1.2Kg/m2) underwent baseline and postprandial MRI scans, symptom questionnaires and blood sampling (for subsequent GI peptide analysis, Glucagon-like peptide-1 (GLP-1), Polypeptide YY (PYY), Cholecystokinin (CCK)) at intervals for 270min following a 400g soup meal (204kcal, Heinz, UK). Gastric volume, gall bladder volume, small bowel water content, small bowel motility and whole gut transit were measured from the MRI scans. Key Results: (mean±SEM) Small bowel motility index increased from fasting 39±3 arbitrary units (a.u.) to a maximum of 87±7a.u. immediately after feeding. PYY increased from fasting 98±10pg/ml to 149±14pg/ml at 30min and GLP-1 from fasting 15±3µg/ml to 22±4µg/ml. CCK increased from fasting 0.40±0.06pmol/ml to 0.94±0.1pmol/ml. Gastric volumes declined with a T1/2 of 46±5min and the gallbladder contracted from a fasting volume of 19±2ml to 12±2ml. Small bowel water content increased from 39±2ml to 51±2ml postprandial. Fullness VAS score increased from 9±5mm to 41±6mm at 30min postprandial. Conclusions and Inferences: The test meal challenge was effective in inducing a change in MRI motility end-points which will improve understanding of the pathophysiological postprandial GI response.

Introduction: Immune activation has been reported in the mucosa of irritable bowel syndrome patients with diarrhoea (IBS-D) and some small studies have suggested that Mesalazine may reduce symptoms. We performed a double blind, randomised placebo controlled trial of 2g Mesalazine twice daily versus placebo for 3 months in Rome III criteria IBS-D patients. Primary outcome was daily average stool frequency during weeks 11-12; secondary outcomes were abdominal pain, stool consistency, urgency and satisfactory relief of IBS symptoms. Methods: Participants were randomised after a 2-week baseline stool diary. All participants completed a 12-week stool diary and at the end of each week recorded the presence of “satisfactory relief of IBS symptoms”. Results: 136 patients with IBS-D (82 F, 54 M) were randomised, 10 patients withdrew from each group. Analysis by intention to treat showed the daily average stool frequency during weeks 11 and 12 were mean (SD), 2.8 (1.2) in Mesalazine and 2.7 (1.9) in placebo group with no significant group difference (95% confidence interval) 0.1 (-0.33,0.53); p=0.66. Mesalazine did not improve abdominal pain, stool consistency nor percentage with satisfactory relief compared to placebo during the last 2 weeks follow up. Conclusion: This study does not support any clinically meaningful benefit or harm of Mesalazine compared with placebo in unselected IBS with diarrhoea. More precise subtyping based on underlying disease mechanisms is needed to allow more effective targeting of treatment in IBS. (ClinicalTrials.gov number NCT01316718)

Background: Poorly absorbed, fermentable carbohydrates can provoke irritable bowel syndrome (IBS) symptoms by escaping absorption in the small bowel and being rapidly fermented in the colon in some susceptible subjects. IBS patients are often anxious and stressed and stress accelerates small bowel transit which may exacerbate malabsorption. Objective: In this study we investigated the effect of intravenous injection of corticotrophin releasing factor (CRF) on fructose malabsorption and the resulting volume of water in the small bowel. Design: We performed a randomised, placebo controlled, cross-over study of CRF versus saline injection in 11 male and 10 female healthy subjects, examining the effect on the malabsorption of a 40 g fructose test meal and its transit through the gut which was assessed by serial Magnetic Resonance imaging (MRI) and breath hydrogen measurement. Orocaecal transit was assessed using the lactose-ureide C13 breath test and the adrenal response to CRF assessed by serial salivary cortisol measurements. Results: (Mean ± SD) CRF injection caused a significant rise in salivary cortisol which lasted 135 minutes. Small bowel water content (SBWC) rose from baseline, peaking at 45 minutes after fructose ingestion while breath hydrogen peaked later at 75 minutes. The area under the curve (AUC) for SBWC from -15 - 135 minutes was significantly lower after CRF versus saline (mean difference [95% CI] 7433 [275, 14591] mL.min, P = 0.04). Ascending colon volume rose after CRF, significantly more for male volunteers than female (P = 0.025). Conclusions: CRF constricts the small bowel and increases fructose malabsorption as shown by increased ascending colon volumes. This mechanism may help to explain the increased sensitivity of some stressed individuals to fructose malabsorption. This trial was registered at ClinicalTrials.gov as NCT01763281

Background: Feeding triggers inter-related gastrointestinal (GI) motor, peptide and appetite responses. These are rarely studied together due to methodological limitations. Recent MRI advances allow pan-intestinal, non-invasive assessment of motility in the undisturbed gut. This study aimed to develop a methodology to assess pan-intestinal motility and transit in a single session using MRI and compare imaging findings to GI peptide responses to a test meal and symptoms in a healthy volunteer cohort. Methods: Fifteen healthy volunteers (29.3±2.7years and BMI 20.1±1.2Kg/m2) underwent baseline and postprandial MRI scans, symptom questionnaires and blood sampling (for subsequent GI peptide analysis, Glucagon-like peptide-1 (GLP-1), Polypeptide YY (PYY), Cholecystokinin (CCK)) at intervals for 270min following a 400g soup meal (204kcal, Heinz, UK). Gastric volume, gall bladder volume, small bowel water content, small bowel motility and whole gut transit were measured from the MRI scans. Key Results: (mean±SEM) Small bowel motility index increased from fasting 39±3 arbitrary units (a.u.) to a maximum of 87±7a.u. immediately after feeding. PYY increased from fasting 98±10pg/ml to 149±14pg/ml at 30min and GLP-1 from fasting 15±3µg/ml to 22±4µg/ml. CCK increased from fasting 0.40±0.06pmol/ml to 0.94±0.1pmol/ml. Gastric volumes declined with a T1/2 of 46±5min and the gallbladder contracted from a fasting volume of 19±2ml to 12±2ml. Small bowel water content increased from 39±2ml to 51±2ml postprandial. Fullness VAS score increased from 9±5mm to 41±6mm at 30min postprandial. Conclusions and Inferences: The test meal challenge was effective in inducing a change in MRI motility end-points which will improve understanding of the pathophysiological postprandial GI response.