Lupianez‐Merly, Camille

INTRODUCTION: Indomethacin is often used experimentally to induce intestinal hyperpermeability, enabling evaluation of interventions targeting barrier function. METHODS: We conducted a randomized, double-blind, placebo-controlled study (NCT05538247) in healthy volunteers to assess whether a supplement could mitigate indomethacin-induced hyperpermeability. Participants received 150 mg/d of indomethacin for 6 days, either before or during placebo/supplement administration. Permeability was measured using 13 C-mannitol and lactulose urinary excretion. RESULTS: Contrary to expectations, indomethacin failed to increase 13 C-mannitol excretion in either group. No meaningful elevations in serum (zonulin, claudins) or fecal (calprotectin) biomarkers were observed. DISCUSSION: Our findings suggest that the expected increase in intestinal permeability after indomethacin administration may not be consistently observed in healthy volunteers. These results highlight the need to carefully consider the reproducibility and sensitivity of this model in future clinical studies aiming to investigate gut barrier function.

ABSTRACT Background Bile acid diarrhoea, a common cause of diarrhoea‐predominant irritable bowel syndrome, has a similar prevalence to coeliac disease and inflammatory bowel diseases. The mainstay of treatment is bile acid sequestrants (BAS). The effectiveness of using bile acid‐targeted therapies remains unclear. Aim To compare BAS with placebo for bile acid diarrhoea. Methods We conducted a systematic review and meta‐analysis of randomised controlled trials comparing BAS to placebo using a comprehensive search of databases from inception to 8/1/2023. Inclusion required unequivocal diagnosis using serum or faecal biochemical parameters, or 75 SeHCAT. Co‐primary endpoints were ≥ 30% improvement in bowel movement consistency and frequency averaged over 7 days. Adverse effects were also summarised. Results Database search resulted in 1152 citations; 1 additional study was added. Ultimately, 6 trials (5 parallel arm, 1 crossover) involving 182 participants evaluated the effectiveness of BAS over 1–8 weeks. Participants were between the third and seventh decades of life and mostly female. The risk of bias was low except in one parallel and one crossover trial. Meta‐analysis of parallel‐design trials of sequestrants only showed a clinically significant reduction in stool consistency and frequency with pooled relative risks of 1.50 (95% CI: 1.14–1.96) and 2.80 (95% CI: 1.68–4.67), respectively. There was no observable heterogeneity ( I 2 = 0%), and the certainty of evidence was moderate. There was no statistically significant difference in adverse effects. Conclusions This study quantifies the significant and rapid improvement in both stool consistency and frequency with BAS in patients with objective diagnosis of bile acid diarrhoea. Sequestrants also appear well tolerated.

INTRODUCTION: Altered intestinal permeability (IP) is implicated in multiple gastrointestinal and systemic disease conditions; an experimental model of perturbed IP in healthy subjects is needed. Traditional approaches to perturbing IP include use of nonsteroidal anti-inflammatory drugs. METHODS: We conducted a single-center, randomized, placebo-controlled pilot study of dose-related effects of castor oil (CO) (and its ingredient ricinoleic acid) at 750, 1,500, or 3,000 mg daily doses on IP. Permeability was assessed using validated 13 C-mannitol and lactulose urine excretion at 0–2, 8–24, and 0–24 hours after oral administration. RESULTS: Permeability analysis across all groups demonstrated significant difference among the groups for 0–2 hours 13 C-mannitol, 0–24 hours 13 C-mannitol, and borderline significant difference for 2–8 hours 13 C-mannitol ( P = 0.060) and 0–24 hours lactulose ( P = 0.056). Direct comparison of 3,000 mg CO vs placebo ( t test) demonstrated higher excretion of 13 C-mannitol and lactulose at 0–2, and 0–24 hours, and lactulose at 2–8 hours. DISCUSSION: CO may perturb small intestinal and colonic permeability in healthy adults.

AbstractBackgroundColonic transit (CT) measured by validated scintigraphy using 111In‐labeled activated charcoal particles is summarized using geometric center (GC) of isotopic distribution in four colonic regions and stool at 24 and 48 h. Diagnosis of rapid CT is currently based on GC24 ≥4.4 in females and >4.7 in males, which lack sensitivity. Our aim was to evaluate, in patients with chronic diarrhea with normal CT by GC24 and GC48, the diagnostic utility of CT change (∆GC) relative to sex‐matched normal values.MethodsWe evaluated two adult patient cohorts: 701 clinical patients (1994–2023) with chronic diarrhea and 76 research participants with irritable bowel syndrome with diarrhea (N = 63) or bile acid diarrhea (BAD, N = 13). Results of ∆GC were compared to 220 healthy controls' 95th percentiles (%ile) (≥2.0 females and ≥2.2 males). In the research cohort, we also analyzed (Spearman correlation) colonic ∆GC with ascending colon emptying T1/2 (AC T1/2), average stool frequency and consistency based on a daily diary, total fecal bile acid (BA) concentration, and % primary BA in a single stool sample.Key ResultsAmong 701 clinical patients with normal GC24, 160 (22.3%) had rapid CT based on ∆GC 95th %ile in health. Among 76 research participants, an additional 20.6% IBS‐D and 23% BAD had rapid CT ∆GC. Younger age and absence of diabetes mellitus were predictive of rapid ∆GC. ∆GC significantly correlated with AC T1/2 and with fecal BA.Conclusions & Inferences∆GC identified an additional 21%–23% patients with rapid colonic transit among patients with diarrhea and normal GC24.

SummaryBackgroundObesity has reached epidemic proportions, with >40% of the US population affected. Although traditionally managed by lifestyle modification, and less frequently by bariatric therapies, there are significant pharmacological advancements.AimsTo conduct a narrative review of the neurohormonal and physiological understanding of weight gain and obesity, and the development, clinical testing, indications, expected clinical outcomes, and associated risks of current FDA‐approved and upcoming anti‐obesity medications (AOMs).MethodsWe conducted a comprehensive review in PubMed for articles on pathophysiology and complications of obesity, including terms ‘neurohormonal’, ‘obesity’, ‘incretin’, and ‘weight loss’. Next, we searched for clinical trial data of all FDA‐approved AOMs, including both the generic and trade names of orlistat, phentermine/topiramate, bupropion/naltrexone, liraglutide, and semaglutide. Additional searches were conducted for tirzepatide and retatrutide ‐ medications expecting regulatory approval. Searches included combinations of terms related to mechanism of action, indications, side effects, risks, and future directions.ResultsWe reviewed the pathophysiology of obesity, including specific role of incretins and glucagon. Clinical data supporting the use of various FDA‐approved medications for weight loss are presented, including placebo‐controlled or, when available, head‐to‐head trials. Beneficial metabolic effects, including impact on liver disease, adverse effects and risks of medications are discussed, including altered gastrointestinal motility and risk for periprocedural aspiration.ConclusionAOMs have established efficacy and effectiveness for weight loss even beyond 52 weeks. Further pharmacological options, such as dual and triple incretins, are probable forthcoming additions to clinical practice for combating obesity and its metabolic consequences such as metabolic dysfunction‐associated steatotic liver disease.

Agonists targeting the receptors of incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, have been well established for the treatment of type 2 diabetes mellitus. There is increasing awareness that gastroenterologists and hepatologists should be treating obesity when patients present to their clinics. In addition, gastroenterologists and hepatologists should be aware of the effects of these classes of medications prescribed by other providers. Therefore, given the widespread use of incretin agonists for obesity treatment and weight loss, it is important to recognize their effects in the gastrointestinal tract, which could constitute significant benefits in weight loss and cardiometabolic benefits, but can be associated with adverse effects that constitute a potential barrier to their use, particularly at higher doses. Multiple studies reviewed in this article document the diverse effects of these drugs on the glucagon-like peptide-1 receptors that are widely expressed in the human body, including the nervous system modulating appetite, the gastrointestinal tract modifying gastric emptying, and lipid metabolism regulation leading to reduction in fat deposition. The objective of this review is to summarize the mechanism of action of incretin receptor agonists, their effects in the gastrointestinal tract, and implications in clinical practice, particularly in the practice of gastroenterology, endoscopy, and surgery.