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The mucosal gene expression in rectosigmoid mucosa (RSM) in irritable bowel syndrome with diarrhea (IBS-D) is unknown. Our objectives were, first, to study mRNA expression [by RT2 PCR of 19 genes pertaining to tight junctions, immune activation, intestinal ion transport and bile acid (BA) homeostasis] in RSM in IBS-D patients ( n = 47) and healthy controls ( n = 17) and study expression of a selected protein (PDZD3) in 10 IBS-D patients and 4 healthy controls; second, to assess RSM mRNA expression according to genotype and fecal BA excretion (high ≥2,337 μmol/48 h); and third, to determine whether genotype or mucosal mRNA expression is associated with colonic transit or BA parameters. Fold changes were corrected for false detection rate for 19 genes studied ( P < 0.00263). In RSM in IBS-D patients compared with controls, mRNA expression of GUC2AB, PDZD3, and PR2Y4 was increased, whereas CLDN1 and FN1 were decreased. One immune-related gene was upregulated (C4BP4) and one downregulated (CCL20). There was increased expression of a selected ion transport protein (PDZD3) on immunohistochemistry and Western blot in IBS-D compared with controls ( P = 0.02). There were no significant differences in mucosal mRNA in 20 IBS-D patients with high compared with 27 IBS-D patients with normal BA excretion. GPBAR1 ( P < 0.05) was associated with colonic transit. We concluded that mucosal ion transport mRNA (for several genes and PDZD3 protein) is upregulated and barrier protein mRNA downregulated in IBS-D compared with healthy controls, independent of genotype. There are no differences in gene expression in IBS-D with high compared with normal fecal BA excretion.

With the recent introduction and approval of medications directed at the treatment of opioid induced constipation (OIC) in patients with nonmalignant pain, there is increased interest and understanding of the unmet need and opportunities to enhance patient management. The high incidence of OIC is associated with rapid increase of narcotic analgesic prescriptions for nonmalignant chronic pain. This review addresses briefly the mechanisms of action of opioids that lead to OIC, the differential tolerance of gastrointestinal organs to the effects of opioids, the size and scope of the problem, the definition and outcome measures for OIC, current differential diagnosis and management algorithms, and the pharmacology and efficacy of treatments for OIC in patients with nonmalignant pain.

AbstractBackgroundTo date, genetic‐association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune‐related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk.MethodsWe conducted two independent case–control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta‐analysis which included 12 additional, earlier studies. The meta‐analysis comprised a total of 2894 patients (839 IBS‐C, 1073 IBS‐D, 502 IBS‐M), and 3138 healthy volunteers with self‐reported Caucasian ancestry.Key ResultsThe association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta‐analysis: IBS (OR 1.19, 95% CI 1.08–1.31), and IBS‐C (OR 1.24, 95% CI 1.08–1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes.Conclusions & InferencesOur meta‐analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS‐C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.

ObjectiveTo examine the association of gene variants of uncoupling proteins (UCP)‐2 and −3 with obesity and gastrointestinal (GI) traits.MethodsIn 255 overweight or obese adults, the associations of gene variants in UCP‐2 (−3474, rs659366) and UCP‐3 (rs1626521, rs2075577, rs15763) with body weight (BW) and GI traits were studied. Gene variants were genotyped by TaqMan® assay. The associations of genotypes with BW and GI traits (gastric emptying, gastric volume, satiety by buffet meal, satiation by nutrient drink test and GI hormones) were assessed using ANOVA corrected for false detection rate (FDR).ResultsA novel UCP‐3 gene variant, rs1626521, was identified; it was associated with BW (P = 0.039), waist circumference (P = 0.035), and significantly higher postprandial gastric volume (P = 0.003) and calories ingested at buffet meal (P = 0.006, both significant with FDR). In a subgroup of 11 participants, rs1626521 was also associated with reduced mitochondrial bioenergetics efficiency in skeletal muscle (P = 0.051). In an in vitro study in HEK293 cells, rs1626521 reduced UCP‐3 protein expression (P = 0.049). Associations detected between other genotypes and GI traits were nonsignificant with FDR.ConclusionsA newly identified functional variant (rs1626521) in UCP‐3 affects postprandial gastric functions and satiety and may contribute to weight gain and alter human mitochondrial function.

To compare the effects of the κ-opioid agonist asimadoline and placebo on visceral sensation and gastrointestinal (GI) motor functions in humans, 91 healthy participants were randomized in a double-blind fashion to 0.15, 0.5, or 1.5 mg of asimadoline or placebo orally twice a day for 9 days. We assessed satiation (nutrient drink test), colonic compliance, tone, perception of colonic distension (barostat), and whole gut transit (scintigraphy). Treatment effect was assessed by analysis of covariance. Asimadoline increased nutrient drink intake ( P = 0.03). Asimadoline decreased colonic tone during fasting ( P = 0.03) without affecting postprandial colonic contraction, compliance, or transit. Gas scores in response to colonic distension were decreased with 0.5 mg of asimadoline at low levels (8 mmHg above operating pressure) of distension ( P = 0.04) but not at higher levels of distension. Asimadoline at 1.5 mg increased gas scores at 16 mmHg of distension ( P = 0.03) and pain scores at distensions of 8 and 16 mmHg ( P = 0.003 and 0.03, respectively) but not at higher levels of distension. Further studies of this compound in diseases with altered satiation or visceral sensation are warranted.

This study evaluated the effects of serotonergic psychoactive agents on gastrointestinal functions in healthy human subjects. Participants received one of four regimens in a randomized, double-blind manner: buspirone, a 5-HT 1A receptor agonist (10 mg twice daily); paroxetine, a selective serotonin reuptake inhibitor (20 mg daily); venlafaxine-XR, a selective serotonin and norepinephrine reuptake inhibitor (75 mg daily); or placebo for 11 days. Physiological testing performed on days 8–11included scintigraphic assessment of gastrointestinal and colonic transit, the nutrient drink test, and assessment of the postprandial change in gastric volume. Fifty-one healthy adults (40 females, 11 males) participated in this study. No effects on gastric emptying or colonic transit were identified with any agent. Small bowel transit of a solid meal was accelerated by paroxetine. Buspirone decreased postprandial aggregate symptom and nausea scores. Venlafaxine-XR increased the postprandial change in gastric volume. Buspirone, paroxetine, and venlafaxine-XR affect upper gastrointestinal functions in healthy humans. These data support the need for clinical and physiological studies of these agents in functional gastrointestinal disorders.

To determine if enteral delivery of glucose influences splanchnic glucose metabolism, 10 subjects were studied when glucose was either infused into the duodenum at a rate of 22 μmol · kg −1 · min −1 and supplemental glucose given intravenously or when all glucose was infused intravenously while saline was infused intraduodenally. Hormone secretion was inhibited with somatostatin, and glucose (∼8.5 mmol/l) and insulin (∼450 pmol/l) were maintained at constant but elevated levels. Intravenously infused [6,6- 2 H 2 ]glucose was used to trace the systemic appearance of intraduodenally infused [3- 3 H]glucose, whereas UDP-glucose flux (an index of hepatic glycogen synthesis) was measured using the acetaminophen glucuronide method. Despite differences in the route of glucose delivery, glucose production (3.5 ± 1.0 vs. 3.3 ± 1.0 μmol · kg −1 · min −1 ) and glucose disappearance (78.9 ± 5.7 vs. 85.0 ± 7.2 μmol · kg −1 · min −1 ) were comparable on intraduodenal and intravenous study days. Initial splanchnic glucose extraction (17.5 ± 4.4 vs. 14.5 ± 2.9%) and hepatic UDP-glucose flux (9.0 ± 2.0 vs. 10.3 ± 1.5 μmol · kg −1 · min −1 ) also did not differ on the intraduodenal and intravenous study days. These data argue against the existence of an “enteric” factor that directly (i.e., independently of circulating hormone concentrations) enhances splanchnic glucose uptake or hepatic glycogen synthesis in nondiabetic humans.

AbstractBackgroundOpioids are effective for acute and chronic pain conditions, but their use is associated with often difficult‐to‐manage constipation and other gastrointestinal (GI) effects due to effects on peripheral μ‐opioid receptors in the gut. The mechanism of opioid‐induced constipation (OIC) differs from that of functional constipation (FC), and OIC may not respond as well to most first‐line treatments for FC. The impact of OIC on quality of life (QoL) induces some patients to decrease or stop their opioid therapy to relieve or avoid constipation.PurposeAt a roundtable meeting on OIC, a working group developed a consensus definition for OIC diagnosis across disciplines and reviewed current OIC treatments and the potential of treatments in development. By consensus, OIC is defined as follows: ‘A change when initiating opioid therapy from baseline bowel habits that is characterized by any of the following: reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool consistency’. The working group noted the prior validation of a patient response outcome and end point for clinical trials and recommended future efforts to create treatment guidelines and QoL measures specific for OIC. Details from the working group's discussion and consensus recommendations for patient care and research are presented in this article.