Background Abnormalities of colonic motility were reported in relatively small studies of patients with lower functional gastrointestinal disorders (FGID) including irritable bowel syndrome (IBS). ...The influence of gender and body mass on the observed motor pathophysiology is unclear. We sought to compare colonic transit in patients within different lower FGID subgroups and healthy controls, controlling for gender and BMI, and to determine whether BMI independently influences colonic motility.
Methods We evaluated a scintigraphic gastrointestinal and colonic transit database of 287 lower FGID patients associated with constipation (IBS‐C, or functional constipation, n = 118), diarrhoea (IBS‐D or functional diarrhoea, n = 139) or mixed bowel function (IBS‐M, n = 30) and 170 healthy controls. We measured colon filling at 6 h (CF 6 h), and overall colonic transit at 8, 24 and 48 h.
Key Results Colon filling at 6 h did not differentiate health from FGID. Colonic transit was abnormal at 24 h (GC24 of <1.50 or >3.86) in 29.7% of all lower FGID patients. There was a significant overall association between colonic transit and subject group (healthy controls and FGID subgroups) at 8 (P = 0.01), 24 (P < 0.001) and 48 h (P < 0.001) in particular for those with diarrhoea or constipation at 24 and 48 h (P < 0.05), even after adjusting for age, gender and BMI. In addition, BMI was associated with colonic transit after adjusting for age, gender and subject group.
Conclusions & Inferences Abnormal transit is documented non‐invasively with scintigraphy in 30% of lower FGID patients; transit measurement may help document pathophysiology and inform selection of therapy in lower FGID.
The aim of this study was to assess pathophysiology in irritable bowel syndrome (IBS).
A total of 122 IBS patients (3 male) and 41 healthy females underwent the following: questionnaires (symptoms, ...psychology), autonomic function, gut transit, gastric volumes, satiation, rectal compliance, and sensation (thresholds and pain ratings) testing. Proportions of patients with abnormal (<10th and >90th percentiles) motor or sensory functions according to bowel symptoms (constipation C, diarrhea D, mixed M),) pain/bloat, and number of primary symptoms were estimated.
IBS subgroups (C, D, M) were similar in age, gastric and small-bowel transit, satiation, gastric volumes, rectal compliance, sensory thresholds, and pain ratings. IBS was associated with body mass index, somatic symptoms, and anxiety and depression scores. Significant associations were observed with colonic transit (IBS-C P = .078 and IBS-D P < .05 at 24 h; IBS-D P < .01 and IBS-M P = .056 at 48 h): 32% of IBS patients had abnormal colonic transit: 20.5% at 24 hours and 11.5% at 48 hours. Overall, 20.5% of IBS patients had increased sensation to distensions: hypersensitivity (<10th percentile thresholds) in 7.6%, and hyperalgesia (pain sensation ratings to distension >90th percentile for ratings in health) in 13%. Conversely, 16.5% of IBS patients had reduced rectal sensation. Pain greater than 6 times per year and bloating were not associated significantly with motor, satiation, or sensory functions. Endorsing 1 to 2 or 3 to 4 primary IBS symptoms were associated with abnormal transit and sensation in IBS.
In tertiary referral (predominantly female) patients with IBS, colonic transit (32%) is the most prevalent physiologic abnormality; 21% had increased and 17% had decreased rectal pain sensations. Comprehensive physiologic assessment may help optimize management in IBS.
Background The inter‐ and intra‐subject variations of scintigraphy, which are used to identify colonic transit disturbances in irritable bowel syndrome (IBS), are unclear. The relationship between ...colonic transit and bowel functions is incompletely understood.
To assess inter‐ and intra‐subject variations of scintigraphic colonic transit measurements in 86 IBS patients and 17 healthy subjects and to quantify the relationship between colonic transit and bowel symptoms in 147 IBS patients and 46 healthy subjects.
Methods Data from participants with multiple colonic transit measurements were analysed. Primary end points were colonic filling at 6 h (CF6h) and geometric center (GC) at 24 and 48 h for colonic transit. Bowel functions were assessed by daily stool diaries.
Key Results Inter‐ and intra‐subject variations were greater for small intestinal than colonic transit. Overall, inter‐ and intra‐subject variations were relatively narrow for colonic transit (both GC24h and GC48h, with lower COV at 48 h); there was little intra‐subject variation in health and IBS‐constipation over a period of ≤3 weeks and over 2.0 years (median, range 0.1, 11.0 years). Significant intra‐individual differences in GC24h were observed only in IBS‐D patients. Colonic transit was significantly associated with stool form (accounting for 19–27% of the variance), frequency (19%), and ease of stool passage (12%).
Conclusions & Inferences Despite inter‐subject variation in scintigraphic colonic transit results, the intra‐subject measurements are reproducible over time in healthy volunteers and patients with IBS; significant changes in colonic transit at 24 h were observed only in IBS‐D. Colonic transit is associated with stool form, frequency and ease of passage.
Velusetrag (TD‐5108) is a potent, selective high intrinsic activity serotonin 5‐HT4 receptor agonist. We assessed effects of Velusetrag on gastrointestinal transit and compared its pharmacokinetics ...in healthy volunteers (HV) and chronic constipation (CC) patients. Sixty HV were randomly assigned, double‐blind to placebo, 5, 15, 30 or 50 mg Velusetrag (single and 6‐day dosing). Primary endpoints were colonic transit (geometric centre at 24 h, GC24) and ascending colon emptying (ACE) T1/2 after first dose. Secondary endpoints included gastric emptying (GE) T1/2 and colonic filling at 6 h (CF6). Single dose Velusetrag significantly accelerated GC24, ACE T1/2, and CF6; 30 and 50 mg Velusetrag accelerated all three endpoints. With multiple doses, Velusetrag 30 mg accelerated GC24, and overall accelerated GE T1/2 at 15–50 mg. Pharmacokinetics studies showed dose proportionality in health, and no significant differences between health and chronic constipation with a 15 mg oral dose of Velusetrag. Stimulation of bowel function after15 mg Velusetrag was similar in CC and controls. There were no serious adverse events; notable adverse events were the predictable gastrointestinal effects such as diarrhoea or altered bowel movements. Velusetrag significantly accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing. Further studies of its potential as a gastrointestinal and colonic prokinetic are warranted.
This article reports on the analysis of an engineered Escherichia coli designed to reduce the host cell protein (HCP) burden on recombinant protein purification by column chromatography. Since ...downstream purification accounts for a major portion of production costs when using a recombinant platform, minimization of HCPs that are initially captured or otherwise interfere during chromatography will positively impact the entire purification process. Such a strategy, of course, would also require the cell line to grow, and express recombinant proteins, at levels comparable to, or better than, its parent strain. An E. coli strain with a small number of strategic deletions (LTSF06) was transformed to produce three different recombinant biologics to examine growth and expression, and with another model protein to assess growth and the effect of selectively reduced HCPs on target product capture on DEAE ion exchange medium. Cell growth levels were maintained or increased for all constructs, and a significant reduction in HCP adsorption was realized. Indeed, a breakthrough analysis indicated that as a result of reducing adsorption of particular HCPs, a 37% increase in target protein capture was observed. This increase in product capture efficiency was achieved by focusing not on HCPs that co-elute with the recombinant target, but rather on those possessing particular column adsorption and elution characteristics.
•Antimicrobial peptide fused to GFPuv expressed using engineered cell line.•Engineered cell line has comparable growth characteristics during fed batch fermentation.•DEAE column capacity increased by 38% when compared to wild type cell line as a result of deletion of 6 genes.
Summary
Aim : To investigate the effects of a probiotic formulation, VSL#3, on gastrointestinal transit and symptoms of patients with Rome II irritable bowel syndrome with predominant diarrhoea.
...Methods : Twenty‐five patients with diarrhoea‐predominant irritable bowel syndrome were randomly assigned to receive VSL#3 powder (450 billion lyophilized bacteria/day) or matching placebo twice daily for 8 weeks after a 2‐week run‐in period. Pre‐ and post‐treatment gastrointestinal transit measurements were performed in all patients. Patients recorded their bowel function and symptoms daily in a diary during the 10‐week study, which was powered to detect a 50% change in the primary colonic transit end‐point.
Results : There were no significant differences in mean gastrointestinal transit measurements, bowel function scores or satisfactory global symptom relief between the two treatment groups, pre‐ or post‐therapy. Differences in abdominal bloating scores between treatments were borderline significant (P = 0.09, analysis of covariance). Further analysis revealed that abdominal bloating was reduced (P = 0.046) with VSL#3 mean post‐ minus pre‐treatment score, − 13.7; 95% confidence interval (CI), − 2.5 to − 24.9, but not with placebo (P = 0.54) (mean post‐ minus pre‐treatment score, − 1.7; 95% CI, 7.1 to − 10.4). With the exception of changes in abdominal bloating, VSL#3 had no effect on other individual symptoms: abdominal pain, gas and urgency. All patients tolerated VSL#3 well.
Conclusion : VSL#3 appears to be promising in the relief of abdominal bloating in patients with diarrhoea‐predominant irritable bowel syndrome. This is unrelated to an alteration in gastrointestinal or colonic transit.
Background & Aims: Prucalopride (PRU) is a selective benzofuran 5-hydroxytryptamine4–receptor agonist with gastrointestinal and colonic prokinetic activities. We evaluated the effects of PRU on ...gastrointestinal and colonic transit in patients with constipation. Methods: Gastrointestinal and colonic transit were measured over 48 hours in 40 patients who fulfilled modified Rome I criteria for functional constipation. Patients had no evidence of a rectal evacuation disorder. Subjects were randomized to receive a daily dose of 2 or 4 mg PRU or placebo in a double-blind, parallel-group design. Each treatment lasted 7 days. The transit test was performed over the last 48 hours of the study. Effects on gastric emptying, small bowel transit, and colonic transit were analyzed using Kruskal–Wallis and Wilcoxon rank sum tests. Results: Of 61 patients screened, 40 were eligible and randomized. Two patients withdrew because of adverse events. PRU accelerated overall gastric emptying and small bowel transit. PRU tended to accelerate overall colonic transit with significantly faster overall colonic transit and ascending colon emptying with the 4-mg dose. Conclusions: PRU accelerates transit through the stomach, small bowel, and colon in patients with constipation unassociated with a rectal evacuation disorder.
GASTROENTEROLOGY 2001;120:354-360
Background Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) coexist in some patients. We observed an association between Crohn’s disease (CD) candidate gene TNFSF15 and IBS ...symptom phenotype. Three genes (TLR9, IL6, and CDH1) have been associated with postinfectious (PI)‐IBS. Our aim was to preliminarily assess association between 30 susceptibility loci for CD, three genes associated with PI‐IBS, and PARM1, with colonic transit in lower functional gastrointestinal disorders (FGID).
Methods A cohort of 665 persons was assembled in previous studies. TaqMan assay was used for all single nucleotide polymorphisms (SNPs) associated with the loci of interest. Data were analyzed for univariate associations with symptoms phenotype and colonic transit (nominal P values, uncorrected) using dominant and co‐dominant genetic models.
Key Results Carriers of the rs5743836 risk allele had increased odds for IBS‐D (vs control, P = 0.02, uncorrected). Among the CD risk loci, rs7927894 (P = 0.007), rs7746082 (P = 0.011), rs2872507 (P = 0.014), together with rs5743836 (P = 0.010) were univariately associated with colonic transit at 24 or 48 h. Specific tests for genetic interactions between loci revealed potential association of genes that influence neural, barrier, or mast cell function with colonic transit.
Conclusions & Inferences Genetic variations that may influence local mucosal immune functions are univariately associated with altered colonic transit in lower FGID.
Background: The role of genetics in the phenotypic manifestations of irritable bowel syndrome (IBS) is unclear. Our aims were: (1) to compare the prevalence of polymorphisms of alpha 2 (α2) ...adrenoceptors, norepinephrine transporter, and serotonin transporter protein (soluble carrier protein member 4 (SLC6A4)) promoter in patients with lower functional gastrointestinal disorders (FGID) and in healthy controls; and (2) to test associations of these genetic variations with symptoms of IBS and high somatic symptom scores. Methods: Validated bowel and somatic symptom questionnaires characterised the phenotype: 90 with IBS constipation (IBS-C), 128 IBS diarrhoea, 38 IBS alternating bowel function, and 20 chronic abdominal pain. Logistic regression analyses assessed associations of different polymorphisms for α2 adrenoceptor and SLC6A4 with IBS or chronic abdominal pain phenotypes and high somatic score. Results: Two distinct polymorphisms independently appeared to be associated with the phenotype IBS-C: α2C Del 322–325 (odds ratio (OR) 2.48 (95% confidence interval (CI) 0.98, 6.28); p = 0.05) and α2A −1291 (C→G) (OR 1.66 (95% CI 0.94, 2.92); p = 0.08) relative to wild-type. Overall, the α2C Del 322–325 polymorphism (alone or combined with other polymorphisms) was also significantly associated with a high somatic symptom score (OR 2.2 (95% CI 1.06, 4.64); p = 0.03). Combinations of polymorphisms were also associated with high somatic scores. Conclusion: Functionally distinct α2A and α2C adrenoceptor and serotonin transporter polymorphisms are associated with constipation and high somatic symptoms in patients with lower functional gastrointestinal disorders, although the strength of the genetic contribution to the phenotype is unclear.
BACKGROUND Prucalopride (R093877) is a selective and specific 5HT4 agonist, the first of a new chemical class of benzofurans, with gastrointestinal prokinetic activities in vitro. AIMS To evaluate ...the effects of prucalopride on gastrointestinal and colonic transit. METHODS A validated scintigraphic technique was used to measure gastrointestinal and colonic transit over 48 hours in 50 healthy volunteers. For seven days, each subject received a daily dose of 0.5, 1, 2, or 4 mg prucalopride, or placebo in a double blind, randomised fashion. The transit test was performed over the last 48 hours. RESULTS There were significant accelerations of overall colonic transit at 4, 8, 24, and 48 hours (p<0.05) and proximal colonic emptying t1/2 (p<0.05). The 0.5, 2, and 4 mg doses of prucalopride were almost equally effective and accelerated colonic transit compared with placebo. Prucalopride did not significantly alter gastric emptying (p>0.5) or small bowel transit (overall p=0.12). The medication appeared to be well tolerated during the seven day treatment of healthy subjects. CONCLUSION Prucalopride accelerates colonic transit, partly by stimulating proximal colonic emptying, but does not alter gastric or small bowel transit in healthy human subjects. Prucalopride deserves further study in patients with constipation.
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