Colon Volume by Computed Tomography and Scintigraphic Colonic Transit in Constipated Patients With or Without Redundant Colon.

Redundant colon, also referred to as "dolichocolon," is an anatomical variant associated with elongation and redundancy thought to be associated with constipation, abdominal pain, and distention.1,2 Diagnosis requires radiological visualization of the non-dilated colon in situ via barium enema or abdominopelvic computed tomography (CT). Colonic redundancy is based on 3 criteria: sigmoid loop displaced cranially relative to the iliac crests (type 1); transverse colon caudal to the iliac crests (type 2); and redundant loops at the hepatic or splenic flexure (type 3).2 Rarely, dolichocolon may meet all 3 criteria.2.

Comparison of biochemical, microbial and mucosal mRNA expression in bile acid diarrhoea and irritable bowel syndrome with diarrhoea.

OBJECTIVE: There are altered mucosal functions in irritable bowel syndrome with diarrhoea (IBS-D); ~30% of patients with IBS-D have abnormal bile acid (BA) metabolism (ABAM) and diarrhoea (summarised as BAD). AIM: To compare biochemical parameters, gastrointestinal and colonic transit, rectal sensation and pathobiological mechanisms in IBS-D without ABAM and in BAD (serum 7C4>52 ng/mL). DESIGN: In patients with Rome III criteria of IBS-D, we compared biochemical features, colonic transit, rectal sensation, deep genotype of five BA-related genes, ileal and colonic mucosal mRNA (differential expression (DE) analysis) and stool dysbiosis (including functional analysis of microbiome). Results in BAD were compared with IBS-D without ABAM. RESULTS: Compared with 161 patients with IBS-D without ABAM, 44 patients with BAD had significantly faster colonic transit, lower microbial alpha diversity, different compositional profile (beta diversity) and higher Firmicutes to Bacteroidetes ratio with evidence of decreased expression of bile acid thiol ligase (involved in transformation of primary to secondary BAs) and decreased sulfatases. In BAD (compared with IBS-D without ABAM), terminal ileal biopsies showed downregulation of SLC44A5 (a BA transporter), and ascending colon biopsies showed upregulation in barrier-weakening genes (CLDN2), serine protease inhibitors, immune activation, cellular differentiation and a cellular transporter (FABP6; BA binding). No DE of genes was documented in descending colon biopsies. The two groups had similar rectal sensation. CONCLUSION: Though sharing clinical symptoms with IBS-D, BAD is associated with biological differences and mechanisms that have potential to enhance diagnosis and treatment targeting barrier dysfunction, inflammatory and microbial changes.

A Randomized, Controlled Trial of Efficacy and Safety of Cannabidiol in Idiopathic and Diabetic Gastroparesis.

BACKGROUND & AIMS: Cannabis (delta-9-tetrahydrocannabinol), a nonselective cannabinoid-receptor agonist, relieves nausea and pain. Cannabidiol (CBD), a cannabinoid receptor 2 inverse agonist with central effects, also reduces gut sensation and inflammation. We compared the effects of 4 weeks of treatment with pharmaceutical CBD vs placebo in patients with idiopathic or diabetic (diabetes mellitus) gastroparesis. METHODS: We performed a randomized, double-blinded, placebo-controlled study of CBD twice daily (Epidiolex escalated to 20 mg/kg/d; Jazz Pharmaceuticals, Dublin, Ireland) in patients with nonsurgical gastroparesis with delayed gastric emptying of solids (GES). Symptoms were assessed by the Gastroparesis Cardinal Symptom Index Daily Diary. After 4 weeks of treatment, we measured GES, gastric volumes, and Ensure (Abbott Laboratories, Abbott Park, IL) satiation test (1 kcal/mL, 30 mL/min) to assess volume to comfortable fullness and maximum tolerance. Patients underwent specific FAAH and CNR1 genotyping. Statistical analysis compared 2 treatments using analysis of variance including baseline measurements and body mass index as covariates. RESULTS: Among 44 patients (32 idiopathic, 6 diabetes mellitus type 1, and 6 diabetes mellitus type 2), 5 patients did not tolerate full-dose escalation; 3 withdrew before completing 4 weeks of treatment (2 placebo, 1 CBD); 95% completed 4 weeks of treatment and diaries. Compared with placebo, CBD reduced the total Gastroparesis Cardinal Symptom Index score (P = .008), inability to finish a normal-sized meal (P = .029), number of vomiting episodes/24 hours (P = .006), and overall symptom severity (P = .034). Patients treated with CBD had a higher volume to comfortable fullness and maximum tolerance and slower GES. FAAH rs34420 genotype significantly impacted nutrient drink ingestion. The most common adverse events reported were diarrhea (14 patients), fatigue (8 patients), headache (8 patients), and nausea (7 patients). CONCLUSIONS: CBD provides symptom relief in patients with gastroparesis and improves the tolerance of liquid nutrient intake, despite slowing of GES. CLINICALTRIALS: gov NCT #03941288.

Bile acid diarrhea - as bad as it gets?

PURPOSE OF REVIEW: Bile acid diarrhea (BAD) is a common but under-recognized gastrointestinal condition that manifests with increased stool frequency and urgency, and a looser stool consistency. The aim of this review is to present recent advances in the pathophysiology, mechanisms, manifestations, diagnosis, and treatment of BAD. RECENT FINDINGS: Patients with BAD have evidence of accelerated colonic transit, increased gut mucosal permeability, altered stool microbiome composition, and decreased quality of life. Single, random stool measurements of bile acids, alone or in combination with fasting serum 7-alpha-hydroxy-4-cholesten-3-one, have shown good sensitivity and specificity for the diagnosis of BAD. Novel therapeutic approaches include farnesoid X receptor agonists and glucagon-like peptide 1 agonists. SUMMARY: Recent research has led to a better understanding of the pathophysiology and mechanisms of BAD, which might pave the way towards more targeted treatment strategies for BAD. Newer, more affordable, and easier diagnostic methods facilitate the diagnosis of BAD.

Factors associated with successful weight loss after liraglutide treatment for obesity.

AIM: To identify patient factors, including gastrointestinal functions, that are predictive or associated with weight loss in response to once-daily 3 mg liraglutide administered subcutaneously (SQ) or placebo in obesity. METHODS: One hundred and thirty-six obese adults (87% female) were randomized in a placebo-controlled, 16-week trial of liraglutide, escalated to 3 mg administered SQ daily. Gastrointestinal functions were measured at baseline and 16 weeks: gastric emptying of solids (GET1/2 ); fasting and postprandial gastric volumes; kcal ingested during ad libitum buffet meal and the nutrient drink test. GET1/2 was also measured at 5 weeks. A multiple variable regression model examined variables associated with weight loss of more than 4 kg at 16 weeks. A parsimonious model using backward selection identified the final model. RESULTS: Weight loss of more than 4 kg at 16 weeks occurred in 71% of liraglutide- and 16% of placebo-treated patients. In all participants combined, parameters univariately associated with a weight loss of more than 4 kg were GET1/2 at 5 and 16 weeks, weight loss at 5 weeks and kcal intake during the buffet meal at 16 weeks. The final parsimonious model (area under the receiver operator characteristics [AUROC] curve = 0.832) identified that factors associated with more than 4-kg weight loss were GET1/2 at 5 weeks (OR = 2.505; 95% CI: 1.57-3.997) per 50 minutes and kcal intake during ad libitum meal at 16 weeks (OR = 0.721; 95% CI: 0.602-0.864) per 100 kcal. Among only the 60 liraglutide-treated subjects, kcal intake at 16 weeks was associated with 4-kg weight loss (AUROC = 0.757). CONCLUSIONS: Slower GET1/2 and weight loss at 5 weeks predicted a weight loss of more than 4 kg at 16 weeks in all participants. Among liraglutide-treated adults, weight loss of more than 4 kg was associated with ad libitum meal kcal intake at 16 weeks.

Comprehensive characterization of antral and pyloric contractions by high resolution manometry: applied physiology in suspected gastroparesis.

Delayed gastric emptying may result from diverse pathophysiological mechanisms including antral hypomotility and pylorospasm. With increasing use of gastric peroral endoscopic myotomy and preliminary evidence of efficacy, our aim was to assess the motor functions of the distal antrum and pylorus in patients with symptoms of gastroparesis using high-resolution antropyloroduodenal manometry (HR-ADM). Sixteen patients with symptoms suggestive of gastroparesis underwent HR-ADM with 13 sensors, 1 cm apart, placed across the antropyloroduodenal (APD) junction and 2 sensors, 10 cm apart, in descending and distal duodenum. The 1-h postprandial motility was quantitated as contraction frequency/minute, average amplitude, and motility index (MI). Six healthy volunteers served as controls. In the patient group, the HR-ADM identified postprandial antral hypomotility, isolated pyloric pressure waves, and tonic elevation of baseline pressure in pylorus. Patients had significantly reduced frequency of the full-hour postprandial antral contractions/minute compared with healthy volunteers [1.52 (0.97, 1.67) vs. 2.04 (1.70, 2.67), P = 0.005], as well as reduced MI [9.65 (8.29, 10.31) vs. 11.04 (10.65, 11.63), P = 0.002]. The average contraction amplitude was numerically, but not significantly reduced [51.9 (21.9, 74.9) vs. 73.0 (59.8, 82.7), P = 0.14]. Bland-Altman plots showed similar distribution of antral contraction frequency and MI during the first and second postprandial 30-min periods for both patients and controls. High-resolution ADM can characterize a variety of postprandial antral contractile and pyloric motility dysfunctions. This technique shows promise to provide guidance for the selection of optimal treatment of patients with gastroparesis.NEW & NOTEWORTHY Current selection of different treatments for patients with gastroparesis is empiric or based on trial and error, though pyloric distensibility and diameter may predict response to pyloric interventions. High-resolution antropyloroduodenal manometry (HR-ADM) can characterize a variety of postprandial antral contractile and pyloric motility dysfunctions in patients with suspected gastroparesis. HR-ADM shows promise to provide guidance for selection and individualization of treatments such as prokinetic agents or pyloric interventions for patients with gastroparesis based on documented pathophysiology.

Impact of Bile Acid Diarrhea in Patients With Diarrhea-Predominant Irritable Bowel Syndrome on Symptoms and Quality of Life.

BACKGROUND & AIMS: Bile acid diarrhea (BAD) affects approximately a quarter of patients with irritable bowel syndrome with diarrhea (IBS-D). We aimed to compare the demographics, bowel and somatic symptoms, and quality of life of patients with IBS-D, with or without BAD. METHODS: On one occasion, patients with IBS-D (positive for Rome III criteria) completed the following questionnaires: bowel disease questionnaire, Hospital Anxiety and Depression inventory, general quality of life (Symptom Checklist-90), and IBS-specific quality of life. A fasting serum C4 level higher than 52.5 ng/mL was used as a biomarker for BAD. Statistical analysis included a multiple variable logistic model to identify strong predictors of BAD in IBS-D. RESULTS: Among 219 patients (79% female) with IBS-D, 44 had BAD; the BAD group was significantly older and had a higher body mass index than the patients without BAD. Patients with BAD had more severe bowel dysfunction and impact on IBS-specific quality of life (need of toilet proximity) compared with patients with IBS-D without BAD. Patients with BAD were more likely than other IBS-D groups to receive antidiarrheals, bile acid binders, and antacid secretory agents. The severity of diarrhea and need of toilet proximity were predictors of BAD in IBS-D (P < .01). Patients with BAD were more likely to have a depression score higher than 8 on the Hospital Anxiety and Depression inventory. CONCLUSIONS: There is a greater impact on bowel and somatic symptoms and quality of life in IBS-D with BAD compared with IBS-D without BAD. Screening for BAD in IBS-D is especially relevant, with more severe and frequent diarrhea along with urgency.

New Developments in Bile Acid Diarrhea.

Bile acid diarrhea (BAD) is characterized by increased frequency of bowel movements, looser stool consistency, urgency, and need for proximity to toilet facilities owing to the severity of the diarrhea, when compared with or relative to irritable bowel syndrome with diarrhea. Consequently, BAD leads to decreased quality of life. The condition is often misdiagnosed as irritable bowel syndrome with diarrhea or functional diarrhea. Patients with BAD have accelerated colonic transit, increased intestinal or colonic mucosal permeability, and altered stool microbiome composition associated with reduced dehydroxylation of primary to secondary bile acids. The established diagnostic test, selenium-75 homocholic acid taurine retention, is not available in the United States. Therefore, 48-hour fecal bile acid excretion has been the gold standard for diagnosis. With recent validation of combined measurement of primary bile acids in a single, random stool in addition to fasting serum 7α-hydroxy-4-cholesten-3-one, a practical point-of-care diagnostic test will soon be available. Randomized controlled trials have documented superiority of colesevelam to placebo and, in a separate study, superiority of the glucagon-like peptide 1 agonist liraglutide compared with colesevelam. Novel experimental approaches for BAD include farnesoid X receptor agonists and fibroblast growth factor 19 analogs. This article updates information on the pathophysiology, mechanisms, manifestations, diagnosis, and treatment of BAD.

Pharmacogenetic interactions of medications administered for weight loss in adults: a systematic review and meta-analysis.

Aim: To analyze roles of single nucleotide variants (SNVs) on weight loss with US FDA-approved medications. Materials & methods: We searched the literature up until November 2022. Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were followed. Results: 14 studies were included in qualitative analysis and seven in meta-analysis. SNVs in CNR1, GLP-1R, MC4R, TCF7L2, CTRB1/2, ADIPOQ, SORCS1 and ANKK1 were evaluated relative to weight loss with glucagon-like peptide-1 agonists (13 studies) or naltrexone-bupropion (one study). CNR1 gene (rs1049353), GLP-1R gene (rs6923761, rs10305420), TCF7L2 gene (rs7903146) were associated with weight loss in at least one study involving glucagon-like peptide-1 agonist(s). The meta-analysis did not identify any consistent effect of SNVs. Conclusion: Pharmacogenetic interactions for exenatide, liraglutide, naltrexone-bupropion and weight loss were identified, but the directionality was inconsistent.

Update on the role of naldemedine in opioid-induced constipation in patients with chronic noncancer pain.

Chronic noncancer pain (CNCP) affects up to 20% of adults and can interfere with activities of daily living. Up to 4% of adults in the United States receive chronic opioid therapy and up to 57% of patients on long-term opioids for CNCP report opioid-induced constipation (OIC). OIC is essentially constipation occurring after starting opioid treatment. While laxatives are traditionally the first-line therapy for OIC, 81% of patients taking daily laxatives and opioids still reported OIC and considered that it negatively affected their quality of life. Naldemedine is a peripherally acting µ-opioid receptor antagonists (PAMORA) approved for the treatment of OIC in patients with CNCP. This article reviews the mechanism of action, efficacy, and safety of naldemedine in CNCP patients. Naldemedine improves OIC in patients with CNCP by acting as an opioid receptor antagonist in the gastrointestinal tract. It does not interfere with the analgesic properties of opioids or cause withdrawal symptoms since these effects are centrally mediated, and naldemedine does not cross the blood brain barrier. Naldemedine showed significant and sustained improvement in frequency of bowel movements, quality of life, and constipation-related symptoms. It is generally well tolerated with a higher incidence of gastrointestinal adverse events of mild or moderate severity such as diarrhea, abdominal pain, or vomiting compared to placebo. While there are no randomized, controlled trials that compare head-to-head pharmacological therapies used for treatment of OIC, network meta-analysis shows that naldemedine has an overall good benefit-risk profile compared to the other approved medications.

Pain in irritable bowel syndrome: Does anything really help?

Pain relief remains a significant challenge in the management of irritable bowel syndrome (IBS): "Does anything really help relieve the pain in patients with IBS?". Interventions aimed at pain relief in patients with IBS include diet, probiotics or antibiotics, antidepressants, antispasmodics, and drugs targeting specific gastrointestinal receptors such as opioid or histamine receptors. In the systematic review and meta-analysis published in this journal, Lambarth et al. examined the literature on the role of oral and parenteral anti-neuropathic agents in the management of pain in patients with IBS. This review article appraises their assessment of the efficacy of the anti-neuropathic agents amitriptyline, pregabalin, gabapentin, and duloxetine in the relief of abdominal pain or discomfort, and impact on overall IBS severity and quality of life. This commentary provides an update of current evidence on the efficacy of the dietary and pharmacological treatments that are available or in development, as well psychological and cognitive behavioral therapy for pain in IBS. Advances in recent years augur well for efficacious treatments that may expand the therapeutic arsenal for pain in IBS.