Camilleri, Michael

ABSTRACT Background Bile acid (BA) malabsorption (BAM) is a common cause of chronic diarrhoea and may occur in some patients due to abnormalities of the gut microbiota. Effects of probiotics on faecal secretory BAs, particularly the primary BA, chenodeoxycholic acid, are unclear. Aim/Methods We conducted a randomized, double‐blind, placebo‐controlled trial of the De Simone formulation 8‐strain probiotic in 24 patients previously diagnosed with BAM. Patients were randomized to 3 weeks of the probiotic (900 billion bacteria) or placebo (maltose), both administered three times daily. Symptoms, serum 7 α C4, faecal primary BAs, intestinal permeability by 13 C‐mannitol‐lactulose test (0.1 and 1 g of the sugars respectively) over 24 h, faecal short chain fatty acids (SCFA), microbiome, and metabolome were assessed at baseline and post‐intervention. Results Data from 22 patients were included. Probiotic supplementation was associated with a significant decrease in % faecal primary BAs (chenodeoxycholic acid and cholic acid) with median change from baseline −5.7 [IQR −10.3, 0.9]% compared to 9.8 [IQR 0.2, 20.6]% on placebo ( p = 0.012). The faecal microbiome was significantly different in the probiotic group after intervention, driven by probiotic‐specific species. There were no significant differences in symptoms, intestinal permeability, or SCFA. However, there was a numerical difference in the changes from baseline in 0‐2 h 13 C‐mannitol excretion −1.9 [−13.9, 4.2] mg for the probiotic and 1.0 (−0.5, 12.7) mg for placebo ( p = 0.084). Conclusions The De Simone formulation probiotic induced significant microbiome and metabolome changes in patients with BAM, ultimately leading to a decrease in % faecal primary BAs and possible reduction in intestinal permeability. Clinical Trials.gov registration NCT #06609148, January 2, 2025.

Importance Gastroparesis is a condition of delayed gastric emptying in the absence of gastric outlet obstruction. Based on a 2018 US administrative health insurance claims database study, prevalence of definite gastroparesis (with documented delayed gastric emptying) was 21.5 per 100 000 persons. Observations Gastroparesis, which is caused by reduced contractions of the distal stomach or abnormal pyloric relaxation, is more common among females than males (ratio, 2:1-4:1) and typically causes nausea, vomiting, early satiety, bloating, and abdominal pain or discomfort. In a large US epidemiological study involving 82.6 million patients, the most common causes of gastroparesis were type 2 diabetes (51.7%), postsurgical effects (15%), medication-induced (11.8%), idiopathic (11.3%), type 1 diabetes (5.7%), and other (4.5%). Other risk factors include neurological disorders (eg, Parkinson disease), hypothyroidism, amyloidosis, connective tissue disorders (eg, scleroderma), and viral infections (eg, norovirus, cytomegalovirus, Epstein-Barr virus, SARS-CoV-2). The 2022 American College of Gastroenterology and the 2025 American Gastroenterological Association (AGA) guidelines define the criterion standard diagnostic test for gastroparesis as gastric emptying scintigraphy with more than 10% gastric retention at 4 hours in patients with symptoms of gastroparesis without mechanical obstruction based on upper endoscopy or abdominal imaging such as computed tomographic (CT) scan. The carbon 13 spirulina stable isotope breath test is also approved for diagnosing gastroparesis by the US Food and Drug Administration. Based on the percentage of gastric retention at 4 hours, gastroparesis is categorized in the 2022 AGA clinical practice update as mild (10%-15%), moderate (16%-35%), or severe (>35%). Treatment includes discontinuation of medications that delay gastric emptying such as opioids, cannabis, anticholinergics, and glucagon-like peptide-1 receptor agonists and for patients with diabetes, optimizing glycemic control. First-line therapies according to the AGA 2022 clinical practice update are a small particle diet (food that is blended or chopped into small pieces) that is low in fat and nondigestible fiber and antiemetics (eg, serotonin 5-hydroxytryptamine 3 [5-HT 3 ] receptor antagonists, histamine H 1 receptor antagonists) for mild gastroparesis; antiemetics and prokinetics (metoclopramide, erythromycin) for moderate gastroparesis, and liquid diet or jejunal enteral feeding for severe gastroparesis. Severe refractory gastroparesis may be treated with gastric peroral endoscopic myotomy (G-POEM), which involves endoscopic-guided incision of the pylorus sphincter muscle, or gastric electrical simulation, in which an implanted neurostimulator sends electrical pulses to the stomach muscle. Conclusions and Relevance Gastroparesis is a condition of delayed gastric emptying without gastric outlet obstruction that is diagnosed based on a gastric emptying study. First-line treatments include a small particle diet and antiemetics and prokinetics. Severe refractory gastroparesis may be treated with procedures such as G-POEM or gastric electrical simulation.

ABSTRACT Objective This study aimed to evaluate relationships between delayed gastric emptying and appetite suppression during treatment with liraglutide, a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA). Methods We conducted a secondary data analysis from a 16‐week randomized, placebo‐controlled liraglutide trial in patients with obesity. We examined correlations between solid food gastric emptying and measurements of satiation and energy intake in the entire cohorts at baseline and end of treatment and separately in placebo‐ and liraglutide‐treated patients who completed the trial. We also compared appetitive measures among liraglutide‐treated participants who displayed either normal, persistently delayed, or transiently delayed emptying during treatment. Results In the entire cohorts at baseline and completion, gastric emptying correlated significantly with energy intake and, at baseline, with one parameter of satiation. Gastric emptying accounted for only 4%–6% of the variance in these appetitive measures. No such correlations were found in the placebo‐ or liraglutide‐treated groups alone. There were no differences in appetitive measures among the subgroups that displayed different gastric emptying patterns during liraglutide treatment. Conclusions Delayed gastric emptying appears to play little direct role in appetite suppression induced by liraglutide. Further research should explore whether delayed emptying or other gastrointestinal effects of other GLP‐1RAs affect appetite directly or indirectly. Trial Registration: ClinicalTrials.gov identifier: NCT02647944

ABSTRACT Background Opioids are indicated for pain that occurs with cancer and other disorders that become more prevalent with aging. The most prevalent and persistent adverse effect of opioid therapy is opioid‐induced constipation (OIC). OIC impairs patient quality of life (QoL) and leads to suboptimal pain management due to medication non‐adherence. Unlike other adverse effects, OIC persists and is not associated with pharmacological tolerance, necessitating long‐term management. Objectives The objective of this study is to evaluate current clinical strategies for OIC by comparing recommendations from American, European, and Japanese clinical guidelines. We reviewed the clinical evidence for the peripherally acting μ‐opioid receptor antagonist (PAMORA) naldemedine (the only PAMORA approved in Japan) and the rationale for early intervention in OIC. Methods The clinical guidelines and recent clinical trial data, including the COMPOSE program (phase III clinical trials of naldemedine for OIC in patients with chronic non‐cancer pain), were reviewed to establish an evidence‐based framework for the management of chronic cancer and non‐cancer pain. Results Conventional laxatives frequently provide inadequate relief as they address secondary symptoms rather than the underlying receptor‐mediated cause. PAMORAs (including naldemedine, methyl naltrexone, and naloxegol) antagonize gastrointestinal opioid receptors without compromising central analgesia. Early initiation of PAMORAs stabilizes bowel function and reduces the incidence of treatment‐related diarrhea that occurs when using conventional laxatives to treat OIC. Conclusion The 2023 Japanese guidelines advocate the proactive use of the PAMORA naldemedine as a primary treatment option. This mechanism‐based early intervention model offers a promising framework for optimizing QoL and implementing effective analgesia in an aging global population.

ABSTRACT Background Chronic megacolon is an uncommon neurogastrointestinal disorder typically characterized by a persistent increase in colonic diameter. Methods Our aim was to identify adults with medical treatment‐refractory constipation without radiographic criteria for megacolon but with increased colonic compliance (refractory constipation with colonic hypercompliance (RCCH)), and to compare the colonic compliance in 7 identified patients with “RCCH” to colonic compliance in 10 patients with chronic megacolon by radiographic criteria (i.e., megacolon) and 40 healthy volunteers. After endoscopic placement, compliance of left or transverse colon was measured using a 10‐cm‐long infinitely compliant balloon connected to an electronically controlled rigid piston barostat. The barostat inflated the balloon from 0 to 44 mmHg in 4‐mmHg steps at 30‐s intervals to measure colonic compliance (pressure‐volume relationship). Eligibility criteria for inclusion were increased colonic compliance based on a functional assessment without meeting radiographic criteria for megacolon (i.e., RCCH). In the three groups, we compared colonic volumes at intra‐balloon pressure of 8, 16, 20, 32, and 44 mmHg, the pressure at half maximum volume, and the slope of the colonic compliance curve using ANOVA on ranks and Dunn's pairwise comparison test. Other features of colonic motility were documented. Results Colonic volumes at all pressures (8‐44 mmHg) and the pressure at half maximum volume were significantly greater in patients with megacolon and RCCH than in healthy controls ( p < 0.001 for both), but compliance was not significantly different between RCCH and megacolon. Conclusion A subset of patients with medically‐refractory chronic constipation has colonic compliance similar to that of patients with megacolon.