Deborah Rhoten

Phenotypic Variation of Colonic Motor Functions in Chronic Constipation

BACKGROUND & AIMS Colonic motor disturbances in chronic constipation (CC) are heterogeneous and incompletely understood; the relationship between colonic transit and motor activity is unclear. We sought to characterize the phenotypic variability in chronic constipation. METHODS Fasting and postprandial colonic tone and phasic activity and pressure-volume relationships were assessed by a barostat manometric assembly in 35 healthy women and 111 women with CC who had normal colon transit (NTC; n = 25), slow transit (STC; n = 19), and defecatory disorders with normal (DD-normal; n = 34) or slow transit (DD-slow; n = 33). Logistic regression models assessed whether motor parameters could discriminate among these groups. Among CC, phenotypes were characterized by principal components analysis of these measurements. RESULTS Compared with 10th percentile values in healthy subjects, fasting and/or postprandial colonic tone and/or compliance were reduced in 40% with NTC, 47% with STC, 53% with DD-normal, and 42% with DD-slow transit. Compared with healthy subjects, compliance was reduced (P <or= .05) in isolated STC and DD but not in NTC. Four principal components accounted for 85% of the total variation among patients: factors 1 and 2 were predominantly weighted by fasting and postprandial colonic phasic activity and tone, respectively; factor 3 by postprandial high-amplitude propagated contractions; and factor 4 by postprandial tonic response. CONCLUSIONS Fasting and/or postprandial colonic tone are reduced, reflecting motor dysfunctions, even in NTC. Colonic motor assessments allow chronic constipation to be characterized into phenotypes. Further studies are needed to evaluate the relationship among these phenotypes, enteric neuropathology, and response to treatment in CC.

Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndrome-diarrhea

OBJECTIVES:Approximately 25% of patients with irritable bowel syndrome-diarrhea (IBS-D) have increased total fecal bile acids (BA) and serum C4 (surrogate for BA synthesis). BA synthesis-related genes (KLB and FGFR4) are associated with colonic transit (CT) in IBS-D. Our aims were: (i) to compare phenotype and pathophysiology in IBS-D patients with increased or normal fecal excretion or synthesis of BA; and (ii) to explore association of variations in two candidate bile-acid synthesis genes (KLB and FGFR4) in these two subgroups of IBS-D.METHODS:A total of 64 IBS-D patients underwent on one occasion: fasting serum C4 and FGF19, total fecal fat and BA excretion, CT, intestinal and colonic permeability, and candidate genotyping (rs17618244 (KLB), rs351855 (FGFR4)). Colonic sensation and tone were measured in 47 of the IBS-D patients. IBS-D subgroups were identified by fecal BA >2,337 mM per 48 h or by serum C4 >47.1 ng/ml.RESULTS:IBS-D patients with fecal BA >2,337 mM per 48 h (19/54) had significantly greater body mass index, fecal fat, percent chenodeoxycholic acid (CDCA) in feces, and intestinal permeability, and borderline increased CT (P=0.13). Those IBS-D patients with serum C4 >47.1 ng/ml (13/54) had increased total fecal BA excretion and borderline increased colonic permeability. Variants in genes involved in feedback regulation of BA synthesis (KLB, P=0.06 and FGFR4, P=0.09) were potentially associated with the subgroup with elevated serum C4.CONCLUSIONS:IBS-D with increased BA excretion or synthesis is associated with significant pathophysiological changes relative to patients with normal BA profile. BA diarrhea is identified more effectively with total fecal BA than with serum C4.

Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea

Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0-2 h for SB and 8-24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxons rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability (P < 0.001), a borderline increase in colonic permeability (P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients.

A randomised, placebo‐controlled trial comparing the effects of tapentadol and oxycodone on gastrointestinal and colonic transit in healthy humans

Tapentadol is a mu‐opioid receptor agonist and norepinephrine reuptake inhibitor. In clinical trials, tapentadol provided somatic pain relief comparable to mu‐opioids such as oxycodone, with significantly less gastrointestinal adverse effects. The acute effects of tapentadol on gastrointestinal and colonic transit are unclear.

A Randomized Trial of 5-Hydroxytryptamine4–Receptor Agonist, YKP10811, on Colonic Transit and Bowel Function in Functional Constipation

BACKGROUND & AIMS YKP10811, a selective agonist of the serotonin 5-hydroxytryptamine-4 receptor, increases gastrointestinal (GI) motility. We investigated the safety and effects of YKP10811 on GI and colonic transit and bowel movements (BMs) in patients with functional constipation in a randomized, double-blind, placebo-controlled study. METHODS Patients with functional constipation, based on the Rome III criteria, were assigned randomly to groups given YKP10811 10 mg (n = 15), 20 mg (n = 16), 30 mg (n = 15), or placebo (n = 11) daily for 8 days. Transit of solids was measured by validated scintigraphy at baseline and on days 7 to 9. Patients kept diaries on days 1 to 9, recording time to first BM, number of BMs/day, and stool consistency (based on the Bristol Stool Form Scale). To evaluate safety, we collected data on adverse events and clinical laboratory test and electrocardiograms results. The primary efficacy end points were determined from an intent-to-treat analysis assessing colonic transit at 24 hours and the half-time (t1/2) of gastric emptying, using analysis of covariance models. Secondary efficacy end points included measures of colonic transit (geometric center at 4 and 24 hours), small-bowel transit (based on colon filling at 6 hours), t1/2 of ascending colon emptying, and bowel functions. We used the Dunnett test to compare the effects of each dose with placebo. A per-protocol analysis (PPA) assessed the t1/2 of gastric emptying and time to first BM using proportional hazards models. RESULTS Fifty-five participants completed the study. YKP10811 was associated with a significant acceleration in colon filling at 6 hours (P < .05), t1/2 of ascending colon emptying, and colonic transit at 24 and 48 hours, as well as increased stool consistency over 8 days (based on intent-to-treat analysis). In general, the 10-mg and 20-mg doses were the most effective in accelerating colonic transit. No serious adverse events were observed. CONCLUSIONS YKP10811, a selective agonist of the serotonin receptor 5-hydroxytryptamine-4, accelerates GI and colonic transit and improves bowel functions in patients with functional constipation, compared with placebo. ClinicalTrial.Gov: NCT01523184.

Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers

Synthetic human ghrelin accelerates gastric emptying, reduces gastric accommodation, and results in numerical increases in postprandial symptom scores. The ghrelin receptor agonist, relamorelin, accelerates gastric emptying in patients with diabetic gastroparesis.

Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial

OBJECTIVE: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose‐related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC). METHODS: Two‐dose NGM282 (1 and 6 mg, subcutaneously daily), parallel‐group, randomized, placebocontrolled, 14‐day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1). Statistical analysis: overall ANCOVA at &agr; = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (&agr; = 0.008). RESULTS: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose‐related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056). CONCLUSION: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

Effects of naloxegol on whole gut transit in opioid-naïve healthy subjects receiving codeine: A randomized, controlled trial

Nausea, vomiting, and constipation (OIC) are common adverse effects of acute or chronic opioid use. Naloxegol (25 mg) is an approved peripherally active mu‐opiate opioid receptor antagonist.

Tu2057 Assessment of Bowel Symptoms, Colonic Transit, and the Relationship to Fecal Bile Acid (BA) Excretion in Health and Irritable Bowel Syndrome (IBS)

Background: Idiopathic bile acid malabsorption (BAM) causes chronic diarrhea and BA deficiency may cause constipation. BA supplementation and an ileal BA transporter inhibitor, elobixibat, accelerate colonic transit (CT). Rectal infusion of BA (e.g. chenodeoxycholate) induces colonic propulsive motility. Up to 50% of patients with IBS-D have accelerated CT; 20% of patients with IBS-C have delayed CT. The relationship between fecal BA excretion, CT, and bowel symptoms in IBS is unclear and may be relevant to selecting optimal therapy. Aim: To assess stool frequency (number) and consistency (form) in relation to CT and fecal BA excretion in healthy participants and patients with IBS-C and IBS-D. Methods: In a prospective study of 92 participants (31 healthy, 30 IBS-C and 31 IBS-D by Rome III criteria), we measured total and individual fecal BA and fecal fat (on 100g fat diet), overall CT by validated scintigraphy (geometric center, GC at 24 and 48h) and stool characteristics by a 14 day bowel pattern diary including Bristol stool form scale. Univariate associations between endpoints were assessed using Spearman correlation (rs). Relationships between stool characteristics, CT and fecal BA excretion were assessed using response surface multiple regression models (which included BMI as a covariate and linear, quadratic and cross product terms for the CT and BA measurements). Results: 1. There were significant univariate associations (table showing rs) between stool number and stool form and total fecal BA (including % LCA, % CDCA, and % CA), fecal fat, and GC24 and 48. 2. The response surface model for stool number (figure left panel) with total fecal BA and CT (GC24 ) explained 29% of the variation (r=0.54, p,0.001); similarly, the model for stool form (figure middle panel) with fecal BA and CT (GC24) explained 20% of the variation (r=0.45, p=0.021). Using total secretory BA (CA+DCA+CDCA), the response surface model for stool form (figure right panel) explained 23% of the variation (r=0.49, p=0.006). In these models, the relative contribution of CT was consistently greater than that for BA, with the coefficients corresponding to CT being statistically significant (p,0.05), while those for BA were borderline (e.g. p=0.073 for the coefficient for secretory BA and stool form, and p=0.227 for stool number). Conclusion: Relative to fecal BA, colonic transit is the greater determinant of stool number and stool form; increased total and secretory fecal BA enhance the effects of colon transit on stool characteristics, but are not independently significant factors. Funding:NIHDK92179

Su2067 A Pilot Pharmacogenomic Study of the Effects of Exenatide on Gastric Emptying and Weight Loss in Patients With Accelerated Gastric Emptying

injected i.p. 5 times/week to mice fed a HFD, and both body weight and food consumption were monitored weekly. At the end of the 17-week study period, magnetic resonance (MR) was used to assess fat deposition, and blood was obtained for measurements of insulin, leptin, and glucagon-like peptide-1 (GLP-1). Results: 2000 hybridoma clones were generated, with 21 positive for GIP binding, one of which yielded a mAb that effectively neutralized 1 nM of GIP. Although serum glucose levels were unchanged, the GIP mAb given i.p. nearly abolished the insulin response to GIP in the IPGTT and reduced the insulin response to oral glucose by 70%. After 17 weeks on the HFD, control mice gained 21.5±1.0 g, while mice receiving the GIP mAb gained 10.5±0.5 g, a reduction in weight gained of 46.5% (P= 0.00000007). When corrected for BW, no difference in the quantity of food consumed was detected between the 2 treatment groups. In addition, MR demonstrated that mice treated with GIP mAbs had significantly less subcutaneous (P=0.0002), omental (P=0.0005), and hepatic fat (P=0.030) than untreated animals. In response to the GIP mAb, serum insulin and leptin levels decreased from 4.3±1.1 to 1.7±0.6 ng/ml (P=0.027) and from 37.5±10.4 to 6.5±1.9 ng/ml (P=0.006), respectively, while no significant changes in serum GLP-1 levels were detected. Conclusion: Immunoneutralization of GIP in mice using a specific mAb effectively attenuates weight gain in mice fed a HFD while decreasing fat deposition. The results of these studies support the hypothesis that a reduction in GIP signaling might provide a useful method for the treatment and prevention of obesity and related disorders.