Citations

Background: In patients with irritable bowel syndrome with constipation (IBS-C), rapid, sustained relief from constipation and abdominal symptoms, such as pain, discomfort, and bloating, can improve quality of life. Objective: This post hoc analysis evaluates the time to constipation and abdominal symptom relief achieved with tenapanor. Design: Post hoc analysis of data pooled from three randomized placebo-controlled studies (phase IIb, T3MPO-1, and T3MPO-2) of tenapanor 50 mg twice daily in patients with IBS-C. Methods: The time to first response for complete spontaneous bowel movement (CSBM) frequency, abdominal pain, discomfort, bloating, and 3-item abdominal score (AS3) were assessed. The AS3 was derived as the average of the weekly scores for abdominal pain, discomfort, and bloating. Cumulative incidences of response over time were estimated using the Kaplan–Meier method. A Cox proportional hazards model was used to assess the effect of baseline and demographic characteristics on the time to first response. Results: Among 1372 patients with IBS-C (684 tenapanor; 688 placebo), median time to first CSBM response was 2 weeks, and median time to abdominal pain, discomfort, bloating, or AS3 response was 4–5 weeks in those treated with tenapanor, with 67.8%–76.7% achieving first response in CSBM frequency and abdominal symptoms by week 12. These time frames were shorter than those observed with the placebo (4 weeks for CSBM and 6–8 weeks for pain, discomfort, bloating, and AS3), of whom 59.1%–69.4% achieved the first response in CSBM and abdominal symptoms by week 12. Higher weekly response rates were observed with tenapanor than with placebo for all endpoints in each week of the 12-week treatment period. Conclusion: This novel post hoc analysis demonstrates that, compared with placebo, tenapanor reduces the time to first response in CSBM frequency and abdominal symptoms and consistently increases the weekly response rate during 12 weeks of treatment. Trial registration: NCT01923428; NCT02621892; NCT02686138.

AbstractBackgroundNumerous individual and environmental factors including diet may play an important role in the pathophysiology of irritable bowel syndrome (IBS). It is unclear to what degree dietary intake is affected in individuals with IBS. We aimed to perform a systematic review and meta‐analysis to summarize dietary intake of adults with IBS and to compare dietary intake between adults with IBS and non‐IBS controls.MethodsOvid MEDLINE, Embase, Cochrane, CINAHL, and Scopus were searched through February 2023 for clinical trials and observational studies measuring usual diet in adults with IBS. Pooled weighted averages were estimated for total energy, macronutrient, and micronutrient data. Mean differences (MD) in nutrient intake were estimated for adults with IBS versus non‐IBS controls using a random effects model. Heterogeneity was assessed by the inconsistency index (I2).Key ResultsSixty‐three full‐text articles were included in the review of which 29 studies included both IBS and control subjects. Nutrients not meeting the recommended intake level for any dietary reference values in the IBS population were fiber and vitamin D. Meta‐regression by female proportion was positively correlated with total fat intake and negatively correlated with carbohydrate intake. Comparisons between participants with IBS and controls showed significantly lower fiber intake in participants with IBS with high heterogeneity (MD: −1.8; 95% CI: −3.0, −0.6; I2 = 85%).Conclusions and InferencesThis review suggests that fiber and vitamin D intake is suboptimal in IBS; however, overall dietary intake does not appear to be comprised. Causes and consequences of reduced fiber in IBS deserve further study.Results of this systematic review and meta‐analysis suggest that fiber and vitamin D intake is suboptimal in IBS. However, overall intake of other macro‐ and micronutrients does not appear to be compromised. Causes and consequences of reduced fiber and Vitamin D intake in IBS deserve further study.

Background & Goals: Diet may contribute to symptoms of irritable bowel syndrome (IBS) and luminal production of putative IBS biomarkers including short-chain fatty acids (SCFAs). Study aims were to to assess relationships of habitual fiber or starch intake with fecal SCFAs in patients with IBS and healthy volunteers (HVs). Study: In 18 HVs and 30 patients with IBS (13 constipation-predominant [IBS-C] and 17 diarrhea-predominant [IBS-D]), habitual diet using a food frequency questionnaire; bowel functions using a validated bowel diary; and fecal SCFAs by HPLC-mass spectrometry were assessed. Associations of fiber and starch with SCFAs were analyzed using Spearman (r s ) and Pearson (R) correlations. Relationships between other dietary endpoints, SCFAs, and bowel functions were explored. Results: Habitual fiber or starch intakes were not significantly correlated with SCFAs or bowel functions in all participants or HVs nor with SCFAs in IBS. Starch was negatively correlated (R=−0.53; P=0.04) with complete evacuation in IBS-D. Fiber (r s =0.65; P=0.02) and starch (r s =0.56; P=0.05) were correlated with ease of passage in IBS-C. Stool form, frequency, and ease of passage were positively correlated with total SCFAs (all P<0.05), acetate (all P<0.01), propionate (all P<0.05), and butyrate (form P=0.01; ease of passage P=0.05) among all participants, but not in IBS. Complete evacuation was negatively correlated with propionate (R=−0.34; P=0.04) in all participants. Total (P=0.04) and individual SCFAs (all P<0.05) were positively correlated with stool form in HVs. Conclusions: Habitual fiber and starch intake does not influence fecal SCFAs but may influence bowel functions in IBS. Fecal SCFAs correlate with bowel functions among all participants including HVs.

Objective To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis. Data sources We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane Central, as well as original data from authors or drug companies for the medications used for CIC. Study selection Phase IIB and phase III randomised, placebo-controlled trials (RCT) of ≥4 weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least one of four end points. Data extraction and synthesis Two investigators independently evaluated all full-text articles that met inclusion criteria and extracted data for primary and secondary end points, risk of bias and quality of evidence. Outcomes Primary end points were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary end points were change from baseline (Δ b ) in the number of SBM/week and Δ b CSBM/week. Results Twenty-one RCTs (9189 patients) met inclusion and end point criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All prespecified end points were unavailable in four polyethylene glycol studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 CSBM/week end point. No drug was superior at improving the primary end points on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary end point, Δ b in number of SBM/week. Conclusions Current drugs for CIC show similar efficacy. Bisacodyl may be superior to prescription medications for Δ b in the number of SBM/week in CIC.

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.

AbstractBackgroundA valid biomarker is ‘an indicator of normal biologic or pathogenic processes, or pharmacological responses to a therapeutic intervention’. There is no validated biomarker for irritable bowel syndrome (IBS). The aim of the study was to assess ability of three quantitative traits to identify treatable processes to discriminate between IBS‐diarrhea (IBS‐D) patients, IBS‐constipation (IBS‐C) patients and healthy volunteers (HV).MethodsIn 30 HV, 30 IBS‐C patients and 64 IBS‐D patients, we characterized bowel symptoms and quantitated pathophysiological mechanisms: bile acid (BA) synthesis (serum C4 and FGF19), fecal BA and fat, colonic transit (CT), and intestinal permeability (IP). We used multiple logistic regression and receiver‐operating characteristic (ROCAUC) to appraise three factors (fecal BA, CT, and IP) individually and in combination to identify discriminant targets for treatment in IBS.Key ResultsThere were significant associations between the three subgroups and symptoms reflecting bowel function and the quantitative traits. There were significant associations between fecal BA and CT at 48 h (r = 0.43; p < 0.001) and between fecal BA and IP (r = 0.23; p = 0.015). Individually, fecal BA and CT48 (but not IP) were significant independent predictors for distinguishing HV from IBS. In combination, they discriminated HV from IBS‐D patients (ROCAUC 0.70), HV from IBS‐C patients (ROCAUC 0.73), and IBS‐C patients from IBS‐D patients (ROCAUC 0.86). Colonic transit and fecal BA excretion together discriminate between healthy volunteers and IBS‐C patients or IBS‐D patients, or between the IBS subgroups with 75–90% specificity at 60% sensitivity.Conclusions & InferencesColonic transit and fecal BA individually and together constitute useful biomarkers to identify treatable mechanisms in IBS and to differentiate subgroups of IBS.

The pathobiology of irritable bowel syndrome (IBS) is multifaceted. We aimed to identify candidate genes predisposing to quantitative traits in IBS. In 30 healthy volunteers, 30 IBS-constipation, and 64 IBS-diarrhea patients, we measured bowel symptoms, bile acid (BA) synthesis (serum 7α-hydroxy-4-cholesten-3-one and FGF19), fecal BA and fat, colonic transit (CT by scintigraphy), and intestinal permeability (IP by 2-sugar excretion). We assessed associations of candidate genes controlling BA metabolism ( KLB rs17618244 and FGFR4 rs351855), BA receptor ( GPBAR1 rs11554825), serotonin (5-HT) reuptake ( SLC6A4 through rs4795541 which encodes for the 44-bp insert in 5HTTLPR), or immune activation ( TNFSF15 rs4263839) with three primary quantitative traits of interest: colonic transit, BA synthesis, and fecal BA excretion. There were significant associations between fecal BA and CT at 48 h ( r = 0.43; P < 0.001) and IP ( r = 0.23; P = 0.015). GPBAR1 genotype was associated with CT48 ( P = 0.003) and total fecal BA [ P = 0.030, false detection rate (FDR) P = 0.033]. Faster CT48 observed with both CC and TT GPBAR1 genotypes was due to significant interaction with G allele of KLB, which increases BA synthesis and excretion. Other univariate associations ( P < 0.05, without FDR correction) observed between GPBAR1 and symptom phenotype and gas sensation ratings support the role of GPBAR1 receptor. Associations between SLC6A4 and stool consistency, ease of passage, postprandial colonic tone, and total fecal BA excretion provide data in support of future hypothesis-testing studies. Genetic control of GPBAR1 receptor predisposing to pathobiological mechanisms in IBS provides evidence from humans in support of the importance of GPBAR1 to colonic motor and secretory functions demonstrated in animal studies.

BackgroundPatients with disorders of gastrointestinal function may undergo unnecessary treatment if misdiagnosed as motility disorders.ObjectiveTo report on clinical features, medical, surgical, and psychiatric comorbidities, and prior treatments of a patient cohort diagnosed concurrently with nonpsychogenic rumination syndrome and pelvic floor dysfunction (also termed rectal evacuation disorder).MethodsFrom a consecutive series (1994–2013) of 438 outpatients with rectal evacuation disorders in the practice of a single gastroenterologist at a tertiary care centre, 57 adolescents or adults were diagnosed with concomitant rumination syndrome. All underwent formal psychological assessment or completed validated questionnaires.ResultsAll 57 patients (95% female) fulfilled Rome III criteria for rumination syndrome; rectal evacuation disorder was confirmed by testing of anal sphincter pressures and rectal balloon evacuation. Prior to diagnosis, most patients underwent multiple medical and surgical treatments (gastrostomy, gastric fundoplication, other gastric surgery, ileostomy, colectomy) for their symptoms. Psychological comorbidity was identified in 93% of patients. Patients were managed predominantly with psychological and behavioural approaches: diaphragmatic breathing for rumination and biofeedback retraining for pelvic floor dysfunction.ConclusionsAwareness of concomitant rectal evacuation disorder and rumination syndrome and prompt identification of psychological comorbidity are keys to instituting behavioural and psychological methods to avoid unnecessary treatment.