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SummaryBackgroundIrritable bowel syndrome (IBS) patients often experience meal‐associated symptoms. However, the underlying mechanisms are unclear.AimTo determine small intestinal mechanisms of lipid‐induced symptoms and rectal hypersensitivity in IBSMethodsWe recruited 26 IBS patients (12 IBS‐C, 14 IBS‐D) and 15 healthy volunteers (HV). In vivo permeability was assessed using saccharide excretion assay. Rectal sensitivity was assessed using a barostat before and after small bowel lipid infusion; symptoms were assessed throughout. Next, an extended upper endoscopy with probe‐based confocal laser endomicroscopy (pCLE) was performed with changes induced by lipids. Duodenal and jejunal mucosal biopsies were obtained for transcriptomics.ResultsFollowing lipid infusion, a higher proportion of HV than IBS patients reported no pain, no nausea, no fullness and no urgency (P < 0.05 for all). In a model adjusted for sex and anxiety, IBS‐C and IBS‐D patients had lower thresholds for first rectal sensation (P = 0.0007) and pain (P = 0.004) than HV. In vivo small intestinal permeability and mean pCLE scores were similar between IBS patients and HV. Post‐lipid, pCLE scores were higher than pre‐lipid but were not different between groups. Baseline duodenal transient receptor potential vanilloid (TRPV) 1 and 3 expression was increased in IBS‐D, and TRPV3 in IBS‐C. Duodenal TRPV1 expression correlated with abdominal pain (r = 0.51, FDR = 0.01), and inversely with first rectal sensation (r = −0.48, FDR = 0.01) and pain (r = −0.41, FDR = 0.02) thresholds.ConclusionLipid infusion elicits a greater symptom response in IBS patients than HV, which is associated with small intestinal expression of TRPV channels. TRPV‐mediated small intestinal chemosensitivity may mediate post‐meal symptoms in IBS.

AbstractObjectiveSatiety, defined as the duration of the sensation of fullness, is usually measured by validated visual analog scales (VAS) for appetite. Gastric function plays a key role in food intake regulation. However, the association between gastric emptying (GE) and VAS appetite is unknown.MethodsIn this cross‐sectional study, 134 participants (mean [SEM] age = 39 [0.8] years, mean [SEM] BMI = 38 [0.5] kg/m2, 67% females) completed simultaneous measurements of GE and VAS appetite. After a 320‐kcal meal, GE was measured by scintigraphy and appetite by validated 100‐mm VAS for 240 minutes. Satiation was defined as calories consumed to terminate meal and was measured by an ad libitum meal. GE, VAS, and ad libitum meal tests were measured on the same day. Percent of meal retention in the stomach, VAS area under curve (AUC0‐240 min), and overall appetite score (OAS) were calculated. Pearson correlation (ρ) determined the association of GE with VAS appetite and satiation. Appetite components were also analyzed by quartiles based on GE120 min.ResultsGE120 min was correlated with sensation of VAS hungerAUC(0‐240 min) (ρ = 0.24, p = 0.004), fullnessAUC(0‐240 min) (ρ = 0.16, p = 0.05), and OASAUC(0‐240 min) (ρ = 0.20, p = 0.02). Patients with rapid GE120 min had a mean increase in VAS hungerAUC(0‐240 min) by 32 mm/min (15.62%, p = 0.03) compared with normal/slow GE120 min.ConclusionsGE is associated with the sensations of appetite, and rapid GE is associated with increased appetite, which may contribute to weight gain.

ObjectiveLittle is known about the predictors of response to obesity interventions.MethodsIn 450 participants with obesity, body composition, resting energy expenditure, satiety, satiation, eating behavior, affect, and physical activity were measured by validated studies and questionnaires. These variables were used to classify obesity phenotypes. Subsequently, in a 12‐month, pragmatic, real‐world trial performed in a weight management center, 312 patients were randomly assigned to phenotype‐guided treatment or non‐phenotype‐guided treatment with antiobesity medications: phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide. The primary outcome was weight loss at 12 months.ResultsFour phenotypes of obesity were identified in 383 of 450 participants (85%): hungry brain (abnormal satiation), emotional hunger (hedonic eating), hungry gut (abnormal satiety), and slow burn (decreased metabolic rate). In 15% of participants, no phenotype was identified. Two or more phenotypes were identified in 27% of patients. In the pragmatic clinical trial, the phenotype‐guided approach was associated with 1.75‐fold greater weight loss after 12 months with mean weight loss of 15.9% compared with 9.0% in the non‐phenotype‐guided group (difference −6.9% [95% CI −9.4% to −4.5%], P < 0.001), and the proportion of patients who lost >10% at 12 months was 79% in the phenotype‐guided group compared with 34% with non‐phenotype‐guided treatment group.ConclusionsBiological and behavioral phenotypes elucidate human obesity heterogeneity and can be targeted pharmacologically to enhance weight loss.

In vivo human studies evaluated concurrently the volume of the stomach during fasting and after a solid and liquid meal using a new SPECT-based method. Although fasting gastric volumes did not impact the rates of gastric emptying, both postprandial and accommodation volumes of the whole and proximal stomach were significantly correlated with gastric emptying. Larger stomach volumes were associated with slower gastric emptying.

SummaryBackgroundIn primary bile acid diarrhoea, feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired.AimsTo evaluate the safety, mechanisms and efficacy of negative feedback by FXR activation with tropifexor, a non‐bile acid FXR agonist, in patients with primary bile acid diarrhoea.MethodsIn this double‐blind, multicentre, randomised, cross‐over study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of two treatment periods. Primary objectives included tropifexor safety and tolerability, and on stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers and gastrointestinal transit.ResultsTwenty patients (tropifexor 60 µg/placebo [N = 10]; placebo/tropifexor 60 µg [N = 10]) were enrolled. Adverse event rates were lower with tropifexor vs placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. There were no significant differences in stool frequency, stool form or loperamide use between treatments. Tropifexor increased FGF19 and decreased 7α‐hydroxy‐4‐cholesten‐3‐one (C4) levels for up to 8 h. Plasma tropifexor concentrations peaked at 5 hours post‐dose on days 1 and 12. At day 12, tropifexor caused reduction in peak total bile acid concentration (33%, P = 0.032) and exposure (36%, P = 0.005). Moreover, tropifexor showed a significant increase in ascending colon half‐emptying time (P = 0.036).ConclusionsTropifexor 60 µg once daily had acceptable safety and tolerability. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with primary bile acid diarrhoea.ClinicalTrials.gov number: NCT02713243.

Buffet meal intake was inversely related to the ability to resist the urge to overeat. Factors associated with ingestive behavior significantly correlated with satiety and gastric accommodation. Gastric capacity during fasting is associated with calorie intake to the point of comfortable fullness; factors associated with ingestive behavior are associated with satiety and gastric accommodation.

AbstractBackgroundColonic transit measurement [geometric center (GC) at 24 and 48 hours] identifies slow transit constipation (STC) in patients with chronic constipation.AimTo evaluate the utility of the difference between GC24 and GC48 (Δ48‐24) to identify STC in adults with chronic constipation.MethodsWe reviewed medical records of 250 patients, aged 18‐75 years, who underwent colonic transit by scintigraphy during 1994‐2019 for investigation of chronic constipation. Data collected included demographics, medical and surgical histories, and anorectal manometry. We used colonic transit from 220 healthy controls to identify the 5th percentile for diagnosing STC: 1.3 at 24 hours, and 1.9 at 48 hours. In addition, the 5th percentile for Δ48‐24 was 0.38 for females and 0.29 for males. Data are reported as median and IQR [Q1, Q3]).Key resultsAmong the 250 patients [median age 42.5 years (IQR 30.75, 56), 84% female], based on GC24 < 1.3, 52 (20.8%) had STC (3 males, 49 females); and based on GC48 < 1.9, 28(11.2%) had STC (3 males, 25 females). Colonic transit was normal in 74.8%. In the groups with normal GC24 and GC48, Δ48‐24 identified an additional 32(15.1%) of 212 female patients and 4 (10.5%) of 38 male patients with slow progression of colonic transit between 24 and 48 hours. Among these 36 patients with abnormal Δ48‐24, 13(36.1%) had evidence of rectal evacuation disorder.Conclusions & InferencesΔ48‐24 measurement on scintigraphic colonic transit can identify an additional 9.2% of STC in patients with constipation without rectal evacuation disorder and can help individualize treatment of chronic constipation.

AbstractBackgroundRapid gastric emptying, increased food intake, and alterations in gastrointestinal hormones are associated with obesity. The effect of regular physical activity (PA) on food intake, gastric emptying (GE), gastric accommodation, and gastrointestinal (GI) hormones in adults with obesity remains unclear. Our aim was to compare, at time of presentation, weight trends, eating behavior, GE, and GI hormone levels among individuals with obesity who engage in regular PA compared to those who do not.MethodsIn 270 participants with obesity, we performed validated measurements of GI phenotypes: GE of solids and liquids, gastric volume (GV) during fasting and after consumption of 200 mL Ensure®, satiety by kcal intake (T‐kcal) during a buffet meal, satiation (volume to fullness [VTF] and maximal tolerated volume [MTV]) of a liquid nutrient, and plasma levels of fasting and postprandial GLP‐1, PYY, CCK, and ghrelin. Physical Activity Stages of Change Questionnaire was used to assess whether participants were regularly PA or not.Key resultsPA was associated with lower BMI (Δ 2.01 kg/m2, P = .001) and body weight (Δ 4.42 kg, P = .0278). GE of solids (T‐50% Δ 7.54 min, P = .021) and liquids (T‐50% Δ 2.99 min, P = .029%) was significantly more rapid in physically active participants. PA was also associated with relatively higher postprandial ghrelin AUC (Δ 10.4 pg/mL, P = .015). There was no significant difference in postprandial satiation, satiety, GV, or other GI hormones (CCK, PYY, or GLP‐1) between groups.Conclusions & InferencesPhysical activity is associated with lower BMI, but faster GE and higher postprandial ghrelin levels, two factors that are also associated with obesity.

Abnormal gastric accommodation (GA) and gastric emptying contribute to pathophysiology in functional dyspepsia (FD). Secretin is a key regulator of GA in animal studies. Our aim was to study the effects of secretin on gastric motility, satiation, postprandial symptoms, and key hormones. We performed two double-blind, randomized, saline-controlled crossover trials in 10 healthy volunteers and 10 patients with FD by Rome IV criteria. We used measured GA (by validated SPECT method) after a 111In radiolabeled Ensure 300-mL meal and quantified gastric emptying for 30 min by scintigraphy. Satiation was measured by volume to fullness (VTF) and maximum tolerated volume (MTV) on an Ensure nutrient drink test and postprandial symptoms 30 min post-MTV. Fasting and postprandial GLP-1, GIP, and HPP were measured. The ages and sex distribution of healthy controls and patients with FD were similar. Compared with placebo, secretin delayed gastric emptying at 30 min in both health [−11% (−16, −4), P = 0.004]; and FD [−8% (−9, 0), P = 0.03]. Satiation (VTF and MTV), GA, and plasma levels of GLP-1, GIP, and HPP did not differ between treatment arms in health or FD. On ANCOVA analysis (adjusting for age and sex), secretin did not consistently increase postprandial symptoms in health or FD. Secretin delayed gastric emptying in both health and FD without significantly altering GA, VTF, or MTV or selected hormones. Thus, secretin receptor activation may provide a novel therapeutic mechanism for patients with FD and rapid gastric emptying. NEW & NOTEWORTHY The naturally occurring hormone secretin retards gastric emptying of solids without deleteriously affecting gastric accommodation, satiation, other upper gastrointestinal hormones, or postprandial symptoms. Given these findings, a subset of patients with rapid gastric emptying (e.g., the estimated 20% of patients with functional dyspepsia) could be candidates for treatments that stimulate a secretin receptor such as sacubitril, which inhibits neprilysin, an enzyme that degrades secretin.

Abstract Purpose Obesity is associated with alterations in appetite, gastrointestinal hormone levels and excessive fat mass. We previously published a double-blind, placebo-controlled, randomized, 16-week trial on effects of once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide on weight, satiation, and gastric functions in obese volunteers. The aim of this substudy is to compare to placebo the effects of liraglutide on appetite, taste preference, regional body fat stores, and anthropometric measurements. Methods Forty obese adults received standard instruction for weight management, monthly behavioral intervention utilizing motivational interviews, and 16-week treatment of once-daily liraglutide (escalated to 3 mg SQ daily). At baseline and 16 weeks, the following were measured: appetite and taste preferences rated every 30 min for 5 h after ingesting 300 mL Ensure®; maximal tolerated volume (MTV) with a nutrient drink test; fasting and postprandial bioactive GLP-1 (7–36) and peptide YY (PYY) levels; total and regional body fat with dual-energy X-ray absorptiometry, and waist and hip circumference. Results Thirty-five participants (17 liraglutide; 18 placebo) completed the trial. Compared to placebo group, liraglutide group had significant reductions in MTV; prospective food consumption score; desire to eat something sweet, salty, savory or fatty; and an increase in perceived fullness. Postprandial plasma levels of GLP-1 decreased and PYY levels increased with liraglutide relative to baseline. Significant reductions in total body, trunk, and upper and lower body fat without reduction in lean body mass were observed. Conclusion Liraglutide 3 mg SQ modulates appetite, taste preference, gut hormones, and regional body fat stores in adults with obesity without reduction in lean body mass.