The Natural History of Chronic Unexplained Gastrointestinal Disorders and Gastroesophageal Reflux During 20 Years: A US Population-Based Study.

OBJECTIVE: To explore the natural history of chronic unexplained gastrointestinal (GI) symptoms and to determine the longitudinal trends of prevalence during a 20-year period in a single US community. METHODS: Between January 1, 1990, and December 31, 2009, valid self-report questionnaires of GI symptoms were mailed to randomly selected cohorts of a community. The study used respondents who answered questions on 1 or more of 3 surveys (initial, 1990-1992; second, 2003-2004; and third, 2008-2009). The trends of prevalence of GI symptoms over time were analyzed in responders who completed 3 surveys, and the natural history or transition was evaluated. RESULTS: The overall prevalence of major symptom groupings including gastroesophageal reflux disease was consistent among residents in a community on 3 survey time points (1990-1992, 2003-2004, and 2008-2009). The transitions of GI symptoms were common in 228 patients who responded to all 3 surveys; only 29% had the same symptom category in 3 surveys; otherwise, symptoms changed over time, resolving, recurring, or transitioning to another disorder. Observed proportions of symptom transitions were significantly different from expected during 20 years (P<.001). Higher non-GI somatic symptom scores were significantly associated with both symptom transitions (odds ratio, 3.9; 95% CI, 1.38 to 10.77) and having sustained symptoms (odds ratio, 12.7; 95% CI, 4.62 to 34.90). CONCLUSION: The overall population prevalence of chronic unexplained GI symptoms is stable, but in individuals, transitions seem to be the rule. As these various GI syndromes appear to be so intimately interconnected, the common underlying pathogenesis may account for a major subgroup of chronic unexplained GI disorders.

Relationship between symptoms during a gastric emptying study and intestinal chemosensitivity with daily symptoms.

BACKGROUND: Non-ulcer dyspepsia (NUD) is a heterogeneous disorder, which is characterized by upper gastrointestinal symptoms and sensorimotor disturbances, including abnormal gastric emptying (GE) and increased intestinal chemosensitivity, and associated with greater plasma glucagon-like peptide-1 (GLP-1) levels during duodenal lipid infusion. However, the relationship(s) between these disturbances and daily symptoms in NUD is variable. We hypothesize that abnormal GE and symptoms during a GE study and during duodenal lipid infusion are associated with the severity of daily symptoms and that GLP-1 mediates symptoms during duodenal lipid infusion in NUD. METHODS: Gastric emptying of solids, symptoms during the GE study and duodenal lipid infusion, and daily gastrointestinal symptoms (2 week diary) were measured in 24 healthy controls and 40 NUD patients. During duodenal lipid infusion, participants received the GLP-1 antagonist exendin 9-39 or placebo. KEY RESULTS: In controls and patients, GE of solids was normal in 75% and 75%, delayed in 8% and 12.5%, or rapid in 17% and 12.5%, respectively. No controls but 26 patients (65%) had severe symptoms during the GE study. During lipid infusion, gastrointestinal symptoms were greater (P = .001) in patients and not affected by exendin. Symptoms during GE study and lipid infusion accounted for respectively 62% and 37% of variance in daily symptom severity. CONCLUSIONS: In NUD, symptoms during a GE study and to a lesser extent during lipid infusion explain the variance in daily symptoms. Intestinal chemosensitivity is not reduced by GLP-1 antagonist. Assessment of symptoms during a GE study may provide a useful biomarker for NUD in research and clinical practice.

Randomised clinical trial: pregabalin vs placebo for irritable bowel syndrome.

BACKGROUND: Pregabalin is a calcium channel α2δ ligand that modifies visceral hypersensitivity in IBS patients. Clinical data for pregabalin in IBS are lacking. AIM: To test the efficacy of pregabalin on gastrointestinal symptoms in IBS patients. METHODS: A double-blind, placebo-controlled trial was performed. Adults meeting IBS Rome III criteria with ≥3 pain attacks per month were randomised to pregabalin 225 mg vs placebo twice daily for 12 weeks. Questionnaires were completed weekly. The primary endpoint was average pain Bowel Symptom Scale (BSS) scores weeks 9-12. An intention-to-treat analysis of covariance evaluated treatment effects on quantitative endpoints, adjusting for age and gender. Adequate relief and change in pain score were assessed using a chi-squared test. RESULTS: Eighty-five patients were recruited and randomised. Sample characteristics include: mean age 39.4 (SD = 14.6); 73 (86%) female; 37 (44%) IBS-D, 29 (35%) IBS-M, 18 (21%) IBS-C. The pregabalin arm had lower average pain-BSS scores weeks 9-12 (25 vs 42, P = 0.008). Compared with placebo, the overall IBS BSS severity score was lower in the pregabalin arm (26 vs 42, P = 0.009). Differences were observed for the diarrhoea-BSS and bloating-BSS scores (P = 0.049 and 0.016, respectively). No differences between groups were seen for constipation-BSS scores. Adequate relief was not different between the two arms (46% vs 36%, P = 0.35). 63% pregabalin vs 45% placebo had a change in pain score ≥30 at week 12 from baseline (P = 0.10). Post-treatment IBS-QoL scores did not differ between groups. CONCLUSION: This trial suggests that pregabalin may be beneficial for IBS abdominal pain, bloating and diarrhoea.

GI Dysfunctions in Diabetic Gastroenteropathy, Their Relationships With Symptoms, and Effects of a GLP-1 Antagonist.

CONTEXT: Delayed gastric emptying (GE) is common but often asymptomatic in diabetes. The relationship between symptoms, glycemia, and neurohormonal functions, including glucagonlike peptide 1 (GLP-1), are unclear. OBJECTIVES: To assess whether GE disturbances, symptoms during a GE study, and symptoms during enteral lipid infusion explain daily symptoms and whether GLP-1 mediates symptoms during enteral lipid infusion. DESIGN: In this randomized controlled trial, GE, enteral lipid infusion, gastrointestinal (GI) symptoms during these assessments, autonomic functions, glycosylated hemoglobin (HbA1c), and daily GI symptoms (2-week Gastroparesis Cardinal Symptom Index diary) were evaluated. During enteral lipid infusion, participants received the GLP-1 antagonist exendin 9-39 or placebo. SETTING: Single tertiary referral center. PARTICIPANTS: 24 healthy controls and 40 patients with diabetic gastroenteropathy. MAIN OUTCOME MEASURES: GE, symptoms during enteral lipid infusion, and the effect of exendin 9-39 on the latter. RESULTS: In patients, GE was normal (55%), delayed (33%), or rapid (12%). During lipid infusion, GI symptoms tended to be greater (P = 0.06) in patients with diabetes mellitus (DM) than controls; exendin 9-39 did not affect symptoms. The HbA1c was inversely correlated with the mean symptom score during the GE study (r = -0.46, P = 0.003) and lipid infusion (r = -0.47, P < 0.01). GE and symptoms during GE study accounted for 40% and 32%, respectively, of the variance in daily symptom severity and quality of life. CONCLUSIONS: In DM gastroenteropathy, GE and symptoms during a GE study explain daily symptoms. Symptoms during enteral lipid infusion were borderline increased but not reduced by a GLP-1 antagonist.

Aging, Obesity, and the Incidence of Diverticulitis: A Population-Based Study.

OBJECTIVE: To understand why the population-based incidence of diverticulitis has increased over time, we studied temporal changes in age, body mass index (BMI), and diverticulitis in Olmsted County, Minnesota. PARTICIPANTS AND METHODS: We compared the BMIs of 2967 patients with diverticulitis and 9795 people without diverticulitis from January 1, 1980, through December 31, 2007. Because BMI is a surrogate for adipose tissue, computed tomographic estimations of abdominal fat content were compared between 381 diverticulitis cases and 381 age- and sex-matched controls. RESULTS: Between 1980 and 2007, the prevalence of obesity increased from 12% to 49% in the population and from 19% to 40% in patients with diverticulitis (P<.001 for both). Temporal trends in age, BMI, and the increased incidence of diverticulitis in people with normal BMI accounted for 48%, 47%, and 20%, respectively, of corresponding trends in diverticulitis. The secular decline in the proportion of people with normal BMI was partly offset by an increased incidence of diverticulitis in such people. In the case-control study, BMI was greater in cases than in controls (P=.001). However, after incorporating abdominal visceral (odds ratio [OR], 2.4; 95% CI, 1.6-3.7) and subcutaneous (OR, 2.9; 95% CI, 1.7-5.2) fat content (both associated with diverticulitis), BMI was associated with lower risk (OR, 0.8; 95% CI, 0.7-0.8) of diverticulitis. CONCLUSION: Aging, increasing obesity, and the increased incidence of diverticulitis in people with normal BMI account for the temporal increase in diverticulitis. Rather than BMI per se, increased abdominal visceral and subcutaneous fat are independently associated with diverticulitis. The incidence of diverticulitis, which is among the most common gastrointestinal diagnoses in hospitalized patients, has increased markedly since 2000. This study suggests that aging, increasing obesity, and the increased incidence of diverticulitis in people with normal BMI account for the temporal increase in diverticulitis.

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, placebo-controlled, 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 α = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (α = 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 Amitriptyline and Escitalopram on Sleep and Mood in Patients With Functional Dyspepsia.

BACKGROUND & AIMS: Tricyclic antidepressants are effective in reducing symptoms of functional dyspepsia (FD). We performed a post hoc analysis of data from a previous randomized clinical trial to determine whether the benefits of an antidepressant on gastrointestinal symptoms in patients with FD were mediated by improving sleep or reducing anxiety. We explored the relationships between psychological measures, quality of sleep, and relief of symptoms. METHODS: We analyzed data from a multicenter, double-blind trial that evaluated the efficacy of antidepressants on symptoms of FD, from October 2006 through October 2012. Patients (n = 292) were randomly assigned to groups given 50 mg amitriptyline, 10 mg escitalopram, or placebo for 12 weeks. During the study, participants completed the following validated psychological questionnaires: Symptom Check List 90, Symptom Somatic Checklist, Hospital Anxiety Depression Scale, Profile of Mood States, State Trait Anxiety Inventory, and Pittsburgh Sleep Quality Index at baseline and 12 weeks following treatment. RESULTS: Baseline scores for the psychological and sleep measures were similar among groups; after 12 weeks there were no significant differences in scores among groups. Baseline mean global Pittsburgh Sleep Quality Index scores indicated poor sleep quality in all groups at baseline and after 12 weeks. Overall, antidepressants affected sleep duration scores: patients given amitriptyline had lower (better) scores than patients given placebo or escitalopram (P = .019). In all groups, responders had decreased anxiety and improvements in some sleep components. CONCLUSIONS: In a post hoc analysis of data from a clinical trial that evaluated the effects of antidepressants in patients with FD, amitriptyline was found to reduce symptoms of FD, but its mechanism is unlikely to involve reductions in psychological distress. The drug may modestly improve sleep. Clinicaltrials.gov no: NCT00248651.

Identification and validation of functional gastrointestinal disorder subtypes using latent class analysis: a population-based study.

OBJECTIVE: Attempts to categorize distinct functional gastrointestinal disorders based on reported symptoms continue but symptoms frequently overlap. The study objective was to use latent class analysis (LCA) which accommodates both continuous and discrete manifest variables to determine mutually exclusive subgroup assignments of a population-based sample using gastrointestinal symptom and patient data. MATERIALS AND METHODS: A validated bowel disease questionnaire and somatic symptom questionnaire were mailed to an age and gender stratified randomly selected community sample. Responses to the symptom questions were dichotomized as frequent vs. infrequent based on Rome IV criteria. A LCA model was developed using a calibration subset and the results applied to the validation subset. RESULTS: There were 3831 total respondents (48%) with 3425 having complete data. The LCA algorithm was run for each of 10 (random) splits of the dataset and 2-6 latent classes were specified. Using the values of Akaike's Information Criterion coefficient c to determine fit of the data, 4 latent classes yielded better values resulting in four subgroups: 'asymptomatic,' 'upper' abdominal symptoms, 'lower' abdominal symptoms, and 'mixed' (upper and lower abdomen). CONCLUSIONS: Latent class analysis identified 4 groups based on symptoms. This approach resulted in differentiation by anatomical region rather than the Rome IV classification of symptoms.

Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo-controlled pilot trial.

BACKGROUND: Liraglutide, a long-acting GLP-1 receptor agonist, is approved for treatment of obesity; however, the mechanisms of action of liraglutide are incompletely understood. We compared effects of liraglutide versus placebo on gastric motor functions, satiation, satiety, and weight in obese individuals over 16 weeks. METHODS: We did a randomised, double-blind, placebo-controlled pilot trial at a single centre (Mayo Clinic, Rochester, MN, USA). Participants were randomly allocated (1:1) by a computer generated randomisation schedule with no stratification to receive subcutaneous liraglutide (3·0 mg) or placebo, with standardised nutritional and behavioural counselling. Allocation was concealed from participants and study investigators. Otherwise healthy, local residents aged 18-65 years with body-mass index (BMI) 30 kg/m2 or higher were included. Liraglutide or placebo was escalated by 0·6 mg/day each week for 5 weeks and continued until week 16. The primary outcome was change in gastric emptying (delay relative to baseline) of solids T1/2 (time taken for half the radiolabelled meal to empty from the stomach), measured at 5 weeks and 16 weeks in all patients who received at least one dose of study drug, with missing data imputed. Secondary outcomes included weight loss at weeks 5 and 16, satiation (volume to fullness and maximum tolerated volume), satiety, and fasting and postprandial gastric volumes at 16 weeks. This trial is registered with ClinicalTrials.gov, number NCT02647944, and is closed to new participants. FINDINGS: Between Dec 18, 2015, and Sept 1, 2016, 40 adults were enrolled and randomly allocated (19 to the liraglutide group; 21 to the placebo group). Compared with placebo, liraglutide delayed gastric emptying of solids at 5 weeks (median 70 min [IQR 32 to 151] vs 4 min [-21 to 18]; p<0·0001) and 16 weeks (30·5 min [-11 to 54] vs -1 min [-19 to 7]; p=0·025). There was also significantly greater weight loss in the liraglutide group than in the placebo group (at 5 weeks: median 3·7 kg [IQR 2·8 to 4·8] vs 0·6 kg [-0·3 to 1·4], p<0·0001; at 16 weeks: 5·3 kg [5·2 to 6·8] vs 2·5 kg [0·1 to 4·2], p=0·0009). Satiation, as assessed by maximum tolerated volume at 16 weeks, was lower in the liraglutide group (median 750 mL [IQR 651 to 908]) compared with the placebo group (1126 mL [944-1185]; p=0·054). No significant differences were noted between groups in terms of volume to fullness, satiety, or fasting and postprandial gastric volumes at week 16. Post-hoc analysis showed that the T1/2 of gastric emptying of solids at 5 weeks correlated with change in weight loss at week 16 with liraglutide (Rs 0·567, p=0·018). Nausea was the most common adverse event in the liraglutide group (12 of 19) compared with placebo (four of 21). INTERPRETATION: Effects of liraglutide on weight loss are associated with delay in gastric emptying of solids; measurement of gastric emptying (eg, at 5 weeks of treatment) may be a biomarker of responsiveness and may help to select individuals for prolonged treatment with this class of drug. FUNDING: US National Institutes of Health grant R56-DK67071.

Relationship of gastric emptying or accommodation with satiation, satiety, and postprandial symptoms in health.

The contributions of gastric emptying (GE) and gastric accommodation (GA) to satiation, satiety, and postprandial symptoms remain unclear. We aimed to evaluate the relationships between GA or GE with satiation, satiety, and postprandial symptoms in healthy overweight or obese volunteers (total n = 285, 73% women, mean BMI 33.5 kg/m2): 26 prospectively studied obese, otherwise healthy participants and 259 healthy subjects with previous similar GI testing. We assessed GE of solids, gastric volumes, calorie intake at buffet meal, and satiation by measuring volume to comfortable fullness (VTF) and maximum tolerated volume (MTV) by using Ensure nutrient drink test (30 ml/min) and symptoms 30 min after MTV. Relationships between GE or GA with satiety, satiation, and symptoms were analyzed using Spearman rank (rs ) and Pearson (R) linear correlation coefficients. We found a higher VTF during satiation test correlated with a higher calorie intake at ad libitum buffet meal (rs = 0.535, P < 0.001). There was a significant inverse correlation between gastric half-emptying time (GE T1/2) and VTF (rs = -0.317, P < 0.001) and the calorie intake at buffet meal (rs = -0.329, P < 0.001), and an inverse correlation between GE Tlag and GE25% emptied with VTF (rs = -0.273, P < 0.001 and rs = -0.248, P < 0.001, respectively). GE T1/2 was significantly associated with satiation (MTV, R = -0.234, P < 0.0001), nausea (R = 0.145, P = 0.023), pain (R = 0.149, P = 0.012), and higher aggregate symptom score (R = 0.132, P = 0.026). There was no significant correlation between GA and satiation, satiety, postprandial symptoms, or GE. We concluded that GE of solids, rather than GA, is associated with postprandial symptoms, satiation, and satiety in healthy participants.NEW & NOTEWORTHY A higher volume to comfortable fullness postprandially correlated with a higher calorie intake at ad libitum buffet meal. Gastric emptying of solids is correlated to satiation (volume to fullness and maximum tolerated volume) and satiety (the calorie intake at buffet meal) and symptoms of nausea, pain, and aggregate symptom score after a fully satiating meal. There was no significant correlation between gastric accommodation and either satiation or satiety indices, postprandial symptoms, or gastric emptying.

Polymorphisms of 5-HTT LPR and GNß3 825C>T and Response to Antidepressant Treatment in Functional Dyspepsia: A Study from The Functional Dyspepsia Treatment Trial.

OBJECTIVES: The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNß3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNß3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy. METHODS: Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNß3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods. RESULTS: GNß3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy-Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNß3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43). CONCLUSIONS: GNß3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.

High-resolution Anorectal Manometry for Identifying Defecatory Disorders and Rectal Structural Abnormalities in Women.

BACKGROUND & AIMS: Contrary to conventional wisdom, the rectoanal gradient during evacuation is negative in many healthy people, undermining the utility of anorectal high-resolution manometry (HRM) for diagnosing defecatory disorders. We aimed to compare HRM and magnetic resonance imaging (MRI) for assessing rectal evacuation and structural abnormalities. METHODS: We performed a retrospective analysis of 118 patients (all female; 51 with constipation, 48 with fecal incontinence, and 19 with rectal prolapse; age, 53 ± 1 years) assessed by HRM, the rectal balloon expulsion test (BET), and MRI at Mayo Clinic, Rochester, Minnesota, from February 2011 through March 2013. Thirty healthy asymptomatic women (age, 37 ± 2 years) served as controls. We used principal components analysis of HRM variables to identify rectoanal pressure patterns associated with rectal prolapse and phenotypes of patients with prolapse. RESULTS: Compared with patients with normal findings from the rectal BET, patients with an abnormal BET had lower median rectal pressure (36 vs 22 mm Hg, P = .002), a more negative median rectoanal gradient (-6 vs -29 mm Hg, P = .006) during evacuation, and a lower proportion of evacuation on the basis of MRI analysis (median of 40% vs 80%, P < .0001). A score derived from rectal pressure and anorectal descent during evacuation and a patulous anal canal was associated (P = .005) with large rectoceles (3 cm or larger). A principal component (PC) logistic model discriminated between patients with and without prolapse with 96% accuracy. Among patients with prolapse, there were 2 phenotypes, which were characterized by high (PC1) or low (PC2) anal pressures at rest and squeeze along with higher rectal and anal pressures (PC1) or a higher rectoanal gradient during evacuation (PC2). CONCLUSIONS: In a retrospective analysis of patients assessed by HRM, measurements of rectal evacuation by anorectal HRM, BET, and MRI were correlated. HRM alone and together with anorectal descent during evacuation may identify rectal prolapse and large rectoceles, respectively, and also identify unique phenotypes of rectal prolapse.

Colonic Transit and Bile Acid Synthesis or Excretion in Patients With Irritable Bowel Syndrome-Diarrhea Without Bile Acid Malabsorption.

BACKGROUND AND AIMS: Bile acids (BAs) are passively absorbed to a different extent along the mammalian colon, so that levels are lower in the feces than in proximal colon. Our aim was to explore associations among total, primary, and secretory BA in stool and colonic transit in patients with irritable bowel syndrome-diarrhea (IBS-D) without overt BA malabsorption (BAM). METHODS: In a cross-sectional observational study of 116 patients with IBS-D recruited from local communities in Minnesota, we measured total and individual main fecal BA excretion, fecal fat and fecal weight over 48 hours, fasting serum levels of C4 (surrogate for BA synthesis), and overall colonic transit by scintigraphy (geometric center at 24 hours and 48 hours). Patients without overt BAM were assigned to groups based on total fecal BA level below 2337 µmol/48 hours (n = 86) or serum levels of C4 below 47.1 ng/mL (n = 91). We used Spearman correlations to test study hypotheses with correction for 14 correlations tested (P < .0036). Data from 30 healthy volunteers were used as control subjects. RESULTS: Patients with IBS-D who had increased or normal total BA excretion in stool or BA synthesis had higher stool proportions of primary BAs (especially chenodeoxycholate), compared with healthy control subjects. In patients with IBS-D without overt BAM (normal 48-hour total fecal BA or serum C4), there were significant positive correlations between total fecal BA, fecal primary and secretory BA, fecal weight, and increased geometric center at 24 and 48 hours (P < .0036). Normal and slightly increased levels of total fecal BA have greatest effects on colonic transit at 48 hours. CONCLUSIONS: In the absence of overt BAM, the total, primary, and secretory BAs in stool contribute to the acceleration of colonic transit and fecal weight in the diarrhea of patients with IBS-D.

Low Risk of Pneumonia From Pneumocystis jirovecii Infection in Patients With Inflammatory Bowel Disease Receiving Immune Suppression.

BACKGROUND & AIMS: Use of immunosuppressants and inflammatory bowel disease (IBD) may increase the risk of pneumonia caused by Pneumocystis jirovecii (PJP). We assessed the risk of PJP in a population-based cohort of patients with IBD treated with corticosteroids, immune-suppressive medications, and biologics. METHODS: We performed a population-based cohort study of residents of Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 427) or ulcerative colitis (n = 510) from 1970 through 2011. Records of patients were reviewed to identify all episodes of immunosuppressive therapies and concomitant PJP prophylaxis through February 2016. We reviewed charts to identify cases of PJP, cross-referenced with the Rochester Epidemiology Project database (using diagnostic codes for PJP) and the Mayo Clinic and Olmsted Medical Center databases. The primary outcome was risk of PJP associated with the use of corticosteroids, immune-suppressive medications, and biologics by patients with IBD. RESULTS: Our analysis included 937 patients and 6066 patient-years of follow-up evaluation (median, 14.8 y per patient). Medications used included corticosteroids (520 patients; 55.5%; 555.4 patient-years of exposure), immunosuppressants (304 patients; 32.4%; 1555.7 patient-years of exposure), and biologics (193 patients; 20.5%; 670 patient-years of exposure). Double therapy (corticosteroids and either immunosuppressants and biologics) was used by 236 patients (25.2%), with 173 patient-years of exposure. Triple therapy (corticosteroids, immunosuppressants, and biologics) was used by 70 patients (7.5%) with 18.9 patient-years of exposure. There were 3 cases of PJP, conferring a risk of 0.2 (95% CI, 0.01-1.0) to corticosteroids, 0.1 (95% CI, 0.02-0.5) cases per 100 patient-years of exposure to immunosuppressants, 0.3 (95% CI, 0.04-1.1) cases per 100 patient-years of exposure to biologics, 0.6 (95% CI, 0.01-3.2) cases per 100 patient-years of exposure to double therapy, and 0 (95% CI, 0.0-19.5) cases per 100 patient-years of exposure to triple therapy. Primary prophylaxis for PJP was prescribed to 37 patients, for a total of 24.9 patient-years of exposure. CONCLUSIONS: In a population-based cohort of patients with IBD treated with corticosteroids, immunosuppressants, and biologics, there were only 3 cases of PJP, despite the uncommon use of PJP prophylaxis. Routine administration of PJP prophylaxis in these patients may not be warranted, although it should be considered for high-risk groups, such as patients receiving triple therapy.

Effects of Rifaximin on Transit, Permeability, Fecal Microbiome, and Organic Acid Excretion in Irritable Bowel Syndrome.

OBJECTIVES: Rifaximin relieves irritable bowel syndrome (IBS) symptoms, bloating, abdominal pain, and loose or watery stools. Our objective was to investigate digestive functions in rifaximin-treated IBS patients. METHODS: In a randomized, double-blind, placebo-controlled, parallel-group study, we compared the effects of rifaximin, 550 mg t.i.d., and placebo for 14 days in nonconstipated IBS and no evidence of small intestinal bacterial overgrowth (SIBO). All subjects completed baseline and on-treatment evaluation of colonic transit by scintigraphy, mucosal permeability by lactulose-mannitol excretion, and fecal microbiome, bile acids, and short chain fatty acids measured on random stool sample. Overall comparison of primary response measures between treatment groups was assessed using intention-to-treat analysis of covariance (ANCOVA, with baseline value as covariate). RESULTS: There were no significant effects of treatment on bowel symptoms, small bowel or colonic permeability, or colonic transit at 24 h. Rifaximin was associated with acceleration of ascending colon emptying (14.9±2.6 h placebo; 6.9±0.9 h rifaximin; P=0.033) and overall colonic transit at 48 h (geometric center 4.0±0.3 h placebo; 4.7±0.2 h rifaximin; P=0.046); however, rifaximin did not significantly alter total fecal bile acids per g of stool or proportion of individual bile acids or acetate, propionate, or butyrate in stool. Microbiome studies showed strong associations within subjects, modest associations with time across subjects, and a small but significant association of microbial richness with treatment arm (rifaximin vs. treatment). CONCLUSIONS: In nonconstipated IBS without documented SIBO, rifaximin treatment is associated with acceleration of colonic transit and changes in microbial richness; the mechanism for reported symptomatic benefit requires further investigation.

Cumulative Length of Bowel Resection in a Population-Based Cohort of Patients With Crohn's Disease.

BACKGROUND & AIMS: Little is known about the cumulative extent of bowel resection among patients with Crohn's disease. METHODS: Using the resources of the Rochester Epidemiology Project, we identified a cohort of 310 incident cases of Crohn's disease from Olmsted County, Minnesota who were diagnosed between 1970 and 2004. Operative and pathology reports were reviewed for bowel resection length. Median bowel resection lengths (with interquartile range [IQR]) were calculated per resection, cumulatively, and as a rate per year of follow-up. RESULTS: One hundred forty-seven patients underwent 1 or more bowel resections. The median follow-up time per patient was 13.6 years (range, 0.2-39 years). Among the 141 patients with resection data available, 211 resections were performed (100 patients with 1 resection, 24 with 2 resections, 9 with 3 resections, 6 with 4 resections, 1 with 5 resections, and 1 patient with 7 resections). The median length of bowel resected was 40 cm (IQR, 22-65 cm) at any resection. The median cumulative length of bowel resected was 64 cm (38-93 cm) during the follow-up period. The median (IQR) rate of bowel resected was 4.2 cm total bowel annually (2.8-7.7 cm). The median length resected was highest for the first resection (52 cm; IQR, 32-71 cm). A mixed regression analysis showed that the length of the first resection was significantly greater than that of the second (P = .002), without significant differences between the second and third or subsequent resections. CONCLUSIONS: In a population-based cohort of patients with Crohn's disease, the median cumulative length of total bowel resected was 64 cm during the follow-up period; the median rate of bowel loss due to resection was 4.2 cm annually.

Chronic constipation and co-morbidities: A prospective population-based nested case-control study.

BACKGROUND: Chronic constipation (CC) is common in the community but surprisingly little is known about relevant gastro-intestinal (GI) and non-GI co-morbidities. OBJECTIVE: The purpose of this study was to assess the epidemiology of CC and in particular provide new insights into the co-morbidities linked to this condition. METHODS: In a prospective, population-based nested case-control study, a cohort of randomly selected community residents (n = 8006) were mailed a validated self-report gastrointestinal symptom questionnaire. CC was defined according to Rome III criteria. Medical records of each case and control were abstracted to identify potential CC comorbidities. RESULTS: Altogether 3831 (48%) subjects returned questionnaires; 307 met criteria for CC. Age-adjusted prevalence in females was 8.7 (95% confidence interval (CI) 7.1-10.3) and 5.1 (3.6-6.7) in males, per 100 persons. CC was not associated with most GI pathology, but the odds for constipation were increased in subjects with anal surgery relative to those without (odds ratio (OR) = 3.3, 95% CI 1.2-9.1). In those with constipation vs those without, neurological diseases including Parkinson's disease (OR = 6.5, 95% CI 2.9-14.4) and multiple sclerosis (OR = 5.5, 95% CI 1.9-15.8) showed significantly increased odds for chronic constipation, adjusting for age and gender. In addition, modestly increased odds for chronic constipation in those with angina (OR = 1.4, 95% CI 1.1-1.9) and myocardial infarction (OR = 1.5, 95% CI 1.0-2.4) were observed. CONCLUSIONS: Neurological and cardiovascular diseases are linked to constipation but in the community constipation is unlikely to account for most lower GI pathology.

Outcomes of Ultrasound-Guided Trigger Point Injection for Abdominal Wall Pain.

BACKGROUND: Abdominal wall pain (AWP) is an important cause of chronic abdominal pain. History and physical examination are critical to the diagnosis of AWP. Trigger point injection (TPI) using either a steroid or a local anesthetic or a combination of both is often used to treat AWP. AIM: To determine the efficacy of ultrasound-guided TPI and to determine the predictors of a successful response. METHODS: Patients who received ultrasound-guided TPI between July 2010 and June 2011 were surveyed. The primary outcome was determined using the Treatment Efficacy Questionnaire (TEQ). Electronic medical records were reviewed to determine patient, pain and TPI characteristics. Linear regression was used to determine the predictors of a successful response on the TEQ. RESULTS: Right upper quadrant was the most common site of AWP, and the median pain duration was 12 months. Pain was rated as >8 (1-10 scale) by 57 % and 30 % described it as an ache. Narcotic use was reported in 38 %, and 73 % had a history of at least one abdominal surgery. Forty-four of the 120 (37 %) patients met the criteria for responder on the TEQ. Compared to before treatment, 36 % reported being "significantly better" and 22 % "slightly better." Multiple linear regression analysis showed that higher somatization negatively predicted response. None of the other historical, examination or TPI characteristics were associated with response to the TPI. CONCLUSION: TPI can provide significant, long-term symptom relief in a third of patients with chronic abdominal pain attributed to AWP. Somatization was inversely related to the treatment success.

Acute Effects of a Glucagon-Like Peptide 2 Analogue, Teduglutide, on Gastrointestinal Motor Function and Permeability in Adult Patients With Short Bowel Syndrome on Home Parenteral Nutrition.

BACKGROUND: Glucagon-like peptide 2 (GLP-2) agonists decrease the need for parenteral nutrition (PN) in short bowel syndrome (SBS); mechanisms evaluated to date have focused on the intestinotrophic effect of GLP-2 agonists such as increased absorptive capacity of the remnant intestine and increased citrulline levels. Other mechanisms may also play a role in effects of GLP-2 agonists. AIM: To measure effects of a GLP-2 agonist, teduglutide (TED), compared with placebo (PLA) on gastric emptying (GE), overall gut transit, fluid balance, intestinal monosaccharide absorption, and permeability in patients with SBS on home PN (HPN). MATERIALS AND METHODS: In 8 adults with SBS on HPN, we compared daily subcutaneous TED (0.05 mg/kg) and PLA (crossover design, each treatment 7 days with a 14-day washout) on gut transit, intestinal absorption, and permeability after oral mannitol (200 mg) and lactulose (1 g), as well as stool weight and urine volume over 8 hours. Analysis used the paired t test. RESULTS: Of 8 patients, 4 were men, with a mean ± SD age of 54 ± 1 years, body mass index of 25 ± 4 kg/m2, residual small intestine of 63 ± 12 cm, and 25% ± 15% of residual colon. The overall gut transit (% emptied at 6 hours) was 53.4% ± 15% for TED vs 62.4% ± 15.2% for PLA (P = .075), with no effect on GE (P = .74). TED increased urine mannitol excretion at 0-2 hours (16.2 ± 3.6 mg TED vs 11.3 ± 2.2 mg PLA, P = .20) and 0-8 hours (32.7 ± 5.9 mg PLA vs 48.8 ± 8.9 mg TED, P = .17). There were no differences in urine lactulose excretion or lactulose/mannitol ratio (0.024 ± 0.005 TED vs 0.021 ± 0.005 PLA). Over 8 hours, TED (vs PLA) numerically reduced stool weight (mean ± SEM, 77 ± 18 g TED vs 106 ± 43 g PLA, P = .42) and increased urine volume (408.9 ± 52.2 mL TED vs 365.7 ± 57.3 mL PLA, P = .34). CONCLUSION: Seven-day TED treatment in 8 participants suggests beneficial effects on fluid balance and monosaccharide absorption, and it retarded overall gut transit with no effects on GE or mucosal permeability. Larger, longer, mechanistic studies of TED in SBS are warranted. This trial was registered at clinicaltrials.gov as NCT02099084.

Hidradenitis Suppurativa in Patients With Inflammatory Bowel Disease: A Population-Based Cohort Study in Olmsted County, Minnesota.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) may be at higher risk for hidradenitis suppurativa (HS). We studied the risk and clinical characteristics of HS in a population-based cohort of patients with IBD. METHODS: We identified all cases of HS (confirmed by biopsy and/or dermatologic evaluation) in a population-based inception cohort of Olmsted County, Minnesota, residents diagnosed with IBD between 1970 and 2004 and followed up through August 2013. We estimated the incidence rate ratio of HS in patients with IBD compared with the general population, and described the clinical characteristics, risk factors, and management of HS. RESULTS: In 679 IBD patients followed up over a median of 19.8 years, we identified 8 patients with HS (mean age, 44.4 ± 8.3 y; 7 women; 6 obese). Compared with the general population, the incidence rate ratio of HS in IBD was 8.9 (95% confidence interval, 3.6-17.5). The 10- and 30-year cumulative incidence of HS was 0.85% and 1.55%, respectively. Five patients had Crohn's disease, 4 of whom had perianal disease; of 3 patients with ulcerative colitis, 2 had undergone ileal pouch-anal anastomosis. Axillae, groin, and thighs were the most common sites of involvement. Six patients had Hurley stage 2 disease (recurrent abscesses with sinus tracts and scarring, involving widely separated areas), and required a combination of antibiotics and surgery; none of the patients were treated with anti-tumor necrosis factor-α agents. CONCLUSIONS: In this population-based study, patients with IBD were approximately 9 times more likely to develop HS than the general population, with a female predisposition.