Colonic Transit Research Articles

Glucagon-like peptide-1 receptor agonists significantly affect the quality of bowel preparation for colonoscopy.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) affect gastrointestinal motility, slowing gastric emptying and colonic transit. GLP-1RAs have an impact on gastric residue before endoscopy, but only limited data are available regarding its effect on the adequacy of colonic preparation. We investigated the association between GLP-1RA use and inadequate bowel preparation (IBP) for colonoscopy. We performed a multicenter retrospective study with GLP-1RA cases matched with controls (using propensity scores for age, sex, diabetes mellitus [DM], obesity, and co-morbidities). Data on demographics, medication use, procedural indications, and colonoscopy findings were collected. IBP ("poor preparation" on Aronchik scale or Boston Bowel preparation scale <5) was the primary outcome. 4876 patients treated with GLP-1RAs were included in the analysis and compared with 4876 controls selected from 333 648 patients without GLP-1RA use. Among the GLP-1RA patients, 10% (n = 487) had IBP compared with 197 (4%) of the control group (P<0.001). Subgroup analysis showed a higher rate of IBP among diabetic patients treated with GLP-1RA (284/2364 [12%]) than among diabetic patients without GLP-1RA treatment (118/2364 [5%]; P<0.001). Additionally, 203/2512 nondiabetic patients treated with GLP-1RAs had IBP (8%) compared with 79 of the nondiabetic non-GLP-1RA group (3%; P<0.001). On multivariate analysis, diabetes and GLP-1RA use were both found to be independent risk factors for IBP (odds ratio [OR] 1.4 and OR 2.7, respectively; both P<0.001). Our findings highlight the necessity for special attention and tailored recommendations for both diabetic and nondiabetic patients treated with GLP-1RAs in terms of colonic preparation prior to colonoscopy.

Molecular Thumbprints: Biological Signatures That Measure Loss of Identity.

Each life is challenged to adapt to an ever-changing environment with integrity-simply put, to maintain identity. We hypothesize that this mission statement of adaptive homeostasis is particularly poignant in an adaptive response, like inflammation. A maladaptive response of unresolved inflammation can seed chronic disease over a lifetime. We propose the concept of a molecular thumbprint: a biological signature of loss of identity as a measure of incomplete return to homeostasis after an inflammatory response. Over time, personal molecular thumbprints can measure dynamic and precise trajectories to chronic inflammatory diseases and further loss of self to cancer. Why is this important? Because the phenotypes and molecular signatures of established complex inflammatory diseases are a far cry from the root of the complex problem, let alone the initial seed. Understanding the science behind key germinating seeds of disease helps to identify molecular factors of susceptibility, resilience, and early dietary or drug intervention. We pilot this hypothesis in a rat colitis model that is well-established for understanding molecular mechanisms of colonic health, disease, and transition of colitis to cancer.

S2232 Delayed Gastric Emptying, but not Colonic Transit, Is Associated With SIBO Defined By Breath Test and Aspirate

S2232 Delayed Gastric Emptying, but not Colonic Transit, Is Associated With SIBO Defined By Breath Test and Aspirate

Gastrointestinal Dysmotility, Autonomic Function and Small Intestinal Bacterial Overgrowth Among People with Well-Controlled HIV.

Gastrointestinal dysfunction, including microbiome changes and increased translocation across a compromised gastrointestinal barrier plays a role in the chronic inflammation experienced by people with HIV (PWH). It is unknown whether autonomic neuropathy (AN) may contribute to these mechanisms by altering gastrointestinal motility. This is a cross-sectional study of 100 PWH and 89 controls. All participants underwent assessment of gastrointestinal transit times using a wireless motility capsule (WMC). All PWH and a subset of controls also underwent: a standardized battery of autonomic function tests summarized as the Modified Composite Autonomic Severity Score (MCASS) and its adrenergic, cardiovagal and sudomotor sub-scores, breath testing for small intestinal bacterial overgrowth (SIBO), and the Patient Assessment of Upper Gastrointestinal Disorders Symptoms (PAGI-SYM) and Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaires. PWH displayed shorter gastric emptying times (GET) and longer small bowel and colonic transit times (SBTT, CTT) compared to controls. Among PWH, GET was associated with PAGI-SYM score. The MCASS and its sudomotor sub-score (reflecting peripheral sympathetic function) were associated with SBTT but not GET or CTT. PWH with prolonged SBTT (>6h) were more likely to have SIBO. Gastrointestinal motility is altered in PWH. This study provides preliminary evidence that changes in autonomic function may influence SBTT in PWH and that prolonged SBTT may contribute to the development of SIBO. Future studies are needed to more fully elucidate the pathophysiologic links between HIV-associated AN, altered gastrointestinal motility, the gastrointestinal microbiome, chronic inflammation, and resulting morbidity and mortality among PWH.

Impact of physical activity on gastrointestinal health and prevention and treatment of common gastrointestinal diseases: Irritable Bowel Syndrome and Inflammatory Bowel Diseases

Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Diseases (IBD), among them Crohn's disease and ulcerative colitis, are common chronic diseases affecting a growing group of patients. Physical activity (PA) is an important part of a healthy lifestyle. The aim of the study was to critically evaluate current knowledge of impact of PA on gastrointestinal (GI) health and prevention and treatment of some most common GI tract diseases, such as IBS and IBD. The comprehensive research of literature available on PubMed, Google Scholar, ResearchGate and Springer Link was performed. PA improves function of GI by increasing colon transit and bowel movements. These mechanisms contribute to reducing the risk of colorectal cancer and, to varying degrees depending on location, other digestive-system cancers. There is a potential association between PA and the more health-beneficial gut microbiota, but more research in this area is needed. Sedentary lifestyle seems to be a risk factor for IBD, while physical activity seems to be a protective factor only for Crohn disease. Altough, PA contributes to improvement of quality of life and reduction of stress in patients with IBD, futher conclusions on the effect of PA on the course of ulcerative colitis and Crohn disease still require expanded research. Available literature suggests that physical activity prevents obesity, a proven risk factor for worsening the course of the disease, and osteoporosis, an important complication of glucocorticosteroid therapy. Despite evidence of a sedentary lifestyle as a risk factor for IBS, there is still a lack of studies examining the impact of physical activity as a protective factor. the number of RCTs examining the effect of PA on the course of IBS remains insufficient, and studies conducted should take into account the various symptoms of IBS.

Clinical manifestations and quality of life in patients with different types of idiopathic megabowel

AIM: to compare the clinical and diagnostic features and quality of life in patients with different types of idiopathic megabowel. PATIENTS AND METHODS: 157 patients with idiopathic megacolon/megarectum, confirmed by barium enema, were divided on 3 groups: 1) distal idiopathic megabowel (megarectum ± distal third of sigmoid colon dilatation); 2) idiopathic megacolon (variable extent of colon dilatation with a normal size rectum); 3) idiopathic megabowel (megarectum ± variable extent of colon dilatation). Hirschsprung’s disease was excluded in all patients based on complex of clinical features, barium enema and anorectal manometry results and (if needed) rectal Swenson’s biopsy. RESULTS: the cohort included 70 (44.6 %) patients with distal idiopathic megabowel, 50 (31.8 %) patients with idiopathic megacolon and 37 (23.6 %) patients with idiopathic megabowel. Wexner constipation scale rate, rate of integral parameters “abdominal discomfort” and “defecation difficulties”, summary assessment of quality of life by IBSQOL questionnaire did not differ between groups (p &gt; 0.05). At the same time patients with distal idiopathic megabowel were statistically significant younger (p &lt; 0.01), had significant higher rate of faecal incontinence due to faecal impaction overflow (p &lt; 0.01), had less often bowel movement. Also these patients had significant higher rate of distal contrast retention (p &lt; 0.01) during gut transit test, but their colonic transit time was slight faster (p = 0.04).In multivariate analysis both megarectum (OR = 25.42; 95 % CI 5.01–128.92) and insufficiency of anal sphincter (OR = 4.71; 95 % CI 1.38–16.14) were independent predictors of faecal incontinence. The surgical treatment was performed most often in idiopathic megacolon group (p &lt; 0.01), mainly due to colon volvulus. The most patients with distal idiopathic megabowel (97.1 %) were successfully maintained with a conservative treatment. CONCLUSION: there was not substantial difference in clinical features and quality of life in patients with different types of idiopathic megabowel, except of significant higher rate of faecal incontinence and less often bowel movement in distal idiopathic megabowel group. Faecal incontinence in these patients is linked disturbance rather intestinal, than anal component of continence. The necessity in surgical treatment was rising most often in cases of idiopathic megacolon. The conservative treatment was quite effective in most patients with distal idiopathic megabowel.

Additional criteria on scintigraphic testing for diagnosis of rapid colonic transit in patients with chronic diarrhea.

Colonic 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. We 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. Among 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. ∆GC identified an additional 21%-23% patients with rapid colonic transit among patients with diarrhea and normal GC24.

Evaluating the associations between dysautonomia, gastrointestinal transit, and clinical phenotype in patients with systemic sclerosis.

Our objective was to identify systemic sclerosis (SSc) patients with a high burden of autonomic symptoms and to determine whether they have a distinct clinical phenotype, gastrointestinal (GI) transit or extraintestinal features. In a prospective cohort of SSc patients with GI disease, clinical data were systematically obtained at routine visits. Dysautonomia was identified by the Composite Autonomic Symptom Score (COMPASS)-31questionnaire. GI transit was measured by whole-gut scintigraphy. Associations between total COMPASS-31 scores and clinical features, GI symptoms, and transit were evaluated. Comparisons between patients with global autonomic dysfunction [(GAD); ≥5 positive COMPASS-31 subdomains] and those with limited autonomic dysfunction [(LAD); <5 positive subdomains] were also studied. 91 patients with SSc and GI involvement were included [mean age 57, 90% female, 74% limited cutaneous disease, 83% significant GI disease (Medsger score ≥2)]. The mean COMPASS-31 score in SSc was higher than controls (38.8 vs. 7.2). 33% had GAD, 67% had LAD. Patients with GAD were more likely to have limited SSc (93% vs. 65%; p<0.01) and have sicca symptoms (100% vs. 77%; p=0.01). Gastric and colonic transit were faster in patients with GAD (p<0.05). Upper GI involvement (Medsger GI score of 1 or 2) was associated with higher total COMPASS-31 scores (p=0.02). Symptoms of global dysautonomia are seen in up to one-third of patients with SSc and GI involvement. Identifying specific clinical characteristics associated with GAD in SSc will help to identify a population that may benefit from therapies that modulate the autonomic nervous system.

Parkinson’s Disease and the faecal microbiota transplantation. Review of current knowledge

Introduction and Purpose. Parkinson’s Disease (PD) is a chronic neurodegenerative disorder caused by dopamine deficiency due to neuronal degeneration, leading to motor and non-motor symptoms. Gastrointestinal symptoms are common and often precede motor symptoms. There is increasing evidence that imbalanced gut microbiota may influence the gut-brain axis and contribute to motor and non-motor PD symptoms. Fecal microbiota transplantation (FMT) may have the potential to restore gut flora and improve PD symptoms. The study aims to explore the current knowledge on the impact of FMT on PD symptoms, acknowledging existing reviews and highlighting new studies not yet reviewed. Understanding the underlying causes of PD could lead to better treatment, diagnostics, and prevention.State of knowledge. PD patients suffer from specific gut dysbiosis which leads to imbalance in the produced pro- and anti-inflammatory substances in the intestinal lumen resulting in aggreviation of α-synuclein in gut nervous cells which may hypothetically transfer via vagal nerve to CNS causing PD. In animal research FMT showed promising results in alleviating PD symptoms. Case reports showed reduction of both motor and non-motor dysfunctions, especially in constipation. DuPont et al. showed improvements in constipation, motor deficits, overall Parkinson’s symptoms, and some non-motor disorders. Cheng et al. showed improvements in MDS-UPDRS, scores of GI tract symptoms scales, PD-related autonomic symptoms and the stool frequency. Bruggeman et al. showed better MDS-UPDRS part 3 scores and better colon transit, but no significant differencies in any other tested domains. Conclusions. As there is yet no standarized protocol for FMT, all of the past research used different techniques and showed slightly different outcomes, but all have shown that FMT have some positive effects on PD symptoms.

The influence of tramadol on bowel function: A randomised, placebo-controlled trial.

Tramadol is a weak opioid used to treat moderate pain. Stronger opioids inhibit gastrointestinal function, but little is known about the gastrointestinal effects of tramadol. Our aim was to investigate if tramadol causes opioid-induced bowel dysfunction (OIBD). Twenty healthy male participants (mean age 24 [range 20-31] years) were included. Tramadol (extended-release formulation, 200 mg/day) or placebo was administered for 10days in two study periods separated by 3weeks. Gastrointestinal transit times and segmental volume, motility and water content were investigated with the 3D-transit system and magnetic resonance imaging. Bowel movements and gastrointestinal symptoms were recorded daily. Tramadol prolonged colonic transit time (34 h vs. 25 h, p< 0.001) and increased small bowel motility (p< 0.01) and water content (p= 0.002) compared to placebo. Across all days of treatment, tramadol reduced the number of mean daily bowel movements (p= 0.001) and increased mean stool consistency (p= 0.006). Gastrointestinal symptom scores increased with tramadol (indigestion: +358%, p= 0.01; constipation: +475%, p= 0.01). Additionally, more participants fulfilled the diagnostic criteria for constipation after tramadol treatment compared to placebo (40% vs. 0%, p< 0.001). This study showed that tramadol treatment is associated with OIBD, and management of constipation and other bowel symptoms should, therefore, be prioritised when treating pain patients with tramadol.

Whole Gut Transit Scintigraphy for the Assessment of Patients with Symptoms of Chronic Constipation

IntroductionWhole gut transit scintigraphy (WGTS) can detect delayed colonic transit (CT), different types of CT delays, and assess upper GI tract transit.AimTo delineate the frequency of different types of CT patterns in patients with chronic constipation (CC), determine the relationship between these CT patterns and upper GI tract transit abnormalities, and assess how symptoms relate to different colonic transit patterns.MethodsRetrospective review of patients who had WGTS for CC. Patients completed a modified PAGI-SYM questionnaire to assess symptoms. Patients ingested a standard solid (Tc-99m egg sandwich)–liquid (In-111 water) meal to assess solid meal gastric emptying (GE), liquid GE, small bowel transit (SBT), and geometric center of colonic activity at 24, 48, and 72h.ResultsOne hundred and eighty six patients underwent WGTS. Main symptoms were constipation (41%), nausea (24%), and bloating (22%). CT assessment showed 32% of patients had normal transit, 31% colonic inertia (CI), 28% functional rectosigmoid obstruction (FRS0), and 9% generalized slow colonic transit (GSCT). GE was delayed in 36%; more commonly in CI and FRSO. SBT was delayed in 19%; more commonly in GSCT and CI. Patients with CI had less bowel movements per week whereas patients with normal CT had more bm/week.ConclusionsIn this series of patients with symptomatic constipation, WGTS assessment showed delayed colonic transit in 68% of patients, with 31% having colonic inertia, 28% a functional rectosigmoid obstruction pattern, and 9% generalized delay in colonic transit. Abnormalities in GE and SBT were present in 36 and 19%. WGTS is helpful to document delayed colonic transit (CT), assess the pattern of the delay in CT, and determine if there are upper GI transit abnormalities.

Comparison of Gas-sensing Capsule With Wireless Motility Capsule in Motility Disorder Patients.

Motility disorders are prevalent, often leading to disrupted regional or whole gut transit times. In this study, we conducted a comparative analysis between the wireless motility capsule and an innovative gas-sensing capsule to evaluate regional and whole gut transit times in individuals with diagnosed motility disorders. We prospectively enrolled 48 patients (34 women) diagnosed with functional dyspepsia and/or functional constipation according to Rome IV criteria. Patients ingested the capsules in tandem. We assessed the agreement between transit times recorded by both devices using Spearman correlation and Bland-Altman analysis. Additionally, diagnostic concordance between the capsules were evaluated using confusion matrices. We observed a significant correlation between the wireless motility capsule and the gas-sensing capsule for gastric emptying time (r = 0.79, P < 0.001) and colonic transit time (r = 0.66, P < 0.001). The gas-sensing capsule exhibited a sensitivity of 0.83, specificity of 0.96, and accuracy of 0.94 when using the standard cutoff for delayed gastric emptying (5 hours). Similarly, when applying the cutoff value for delayed colonic transit (> 59 hours), the gas-sensing capsule demonstrated a sensitivity of 0.79, specificity of 0.84, and accuracy of 0.82. Importantly, the gas-sensing capsule was well-tolerated, and no serious adverse events were reported during the study. Our findings underscore the gas-sensing capsule's suitability as a dependable tool for assessing regional and whole gut transit times. It represents a promising alternative to the wireless motility capsule for evaluating patients with suspected motility disorders.

Intestinal Methanogen Overgrowth (IMO) Is Associated with Delayed Small Bowel and Colonic Transit Time (TT) on the Wireless Motility Capsule (WMC).

Methanogens are associated with gut dysmotility in animal models but have not been robustly studied in humans. The WMC assesses regional transit time (TT) and pH in the GI tract. To study the segmental TT and pH among patients with SIBO or IMO utilizing WMC. We conducted a retrospective study of 207 patients who underwent a glucose or lactulose breath test (BT) and WMC from 2010 to 2022. Diagnosis of SIBO and IMO were based on the 2017 North American consensus criteria. TT and pH were extracted from WMC recordings. We tested for differences in means of continuous variables and frequencies of categorical variables using two-sample t tests, Wilcoxon Rank Sum test, Chi-square, and Fisher exact tests. We used R version 3.3.1 (2016-06-21) for all statistical analyses. A total of 196 patients met criteria, mean age 47.4years and 155 (79.1%) females. Of the 86 (43.9%) patients with a positive BT, 42 (58.3%) had IMO only (meeting only CH4 criteria) and 30 (34.9%) met both H2 and CH4 criteria. Colonic TT was longer in patients with a positive BT compared to negative patients (40h:29min vs 28h:51min, p = 0.028). Small bowel TT and colonic TT were longer in patients with IMO compared to negative patients (SBTT: 5h:15min vs 4h:32min, p = 0.021; CTT: 44h:23min vs 28h:51min, p = 0.030). There were no significant differences in segmental pH compared to negative patients. To our knowledge, this is the largest study of patients who have undergone both BT and WMC. A positive BT was associated with delayed CTT, while having IMO only was associated with both delayed CTT and SBTT, but neither with pH. Future investigation is needed to elucidate whether changes in intestinal microbiota affect gut transit.

Opium tincture has anti-propulsive effects in patients with chronic diarrhea: a randomized, placebo-controlled, and cross-over trial

Objective Chronic diarrhea affects approximately 5% of the population. Opioids inhibit gastrointestinal motility, and opium tincture has shown anti-propulsive effects in healthy, but no controlled studies of its clinical efficacy exist. We aimed to investigate the anti-propulsive and central nervous system (CNS) effects of opium tincture in patients with chronic diarrhea. Materials and methods The study was a randomized, double-blinded, placebo-controlled, cross-over trial in subjects with chronic diarrhea refractory to standard treatment. Participants received opium tincture or placebo during two intervention periods, each lasting seven days. Bowel movements were recorded daily, and gastrointestinal transit time was investigated with the wireless motility capsule system. Gastrointestinal symptoms, health-related quality of life, and CNS effects (pupil size, reaction time, memory, and general cognition) were also investigated, along with signs of addiction. Results Eleven subjects (mean age: 45 ± 17 years, 46% males) with a median of 4.7 daily bowel movements were included. The number of daily bowel movements was reduced during opium tincture treatment to 2.3 (p = 0.045), but not placebo (3.0, p = 0.09). Opium tincture prolonged the colonic transit time compared to placebo (17 h vs. 12 h, p < 0.001). In both treatment arms, there were no changes in self-reported gastrointestinal symptoms, health-related quality of life, or CNS effects, and no indication of addiction was present. Conclusion Opium tincture induced anti-propulsive effects in patients with chronic diarrhea refractory to standard treatment. This indicates that opium tincture is a relevant treatment strategy for selected patients with chronic diarrhea. Moreover, no evidence of opioid-induced sedation or addiction was found. Trial Registration Number: NCT05690321 (registered 2023-01-10)

MoPill a novel gastrointestinal positioning system (GPS): New technology to navigate the alimentary tract highway.

Evaluation of gut motility in clinical practice is currently limited. A novel medical system (MoPill™) consisting of a capsule that wirelessly transmits radiofrequency signals to assess motility via 3D location, was used to conduct this study. The objectives were to: (1) confirm the safety of the MoPill™ system; (2) compare the 3D location transmitted by the capsule to its location captured by abdominal x-rays; 3 determine gastric emptying (GE), whole gut transit time (WGTT) and segmental transit times. The MoPill™ system consists of an electronic capsule (2 × 1.2 cm), eight color-coded adhesive sensors (6 × 5.5 cm), a recorder (15 × 11 × 2 cm), and software on a laptop. Four sensors were applied to the abdomen and four to the back. Healthy subjects who had fasted overnight ingested a 250-calorie protein bar, 17 oz. of water, followed by an activated capsule. No further caloric contents were permitted for the next 5 h. At 1, 5, and 24 h (if the capsule had not been expelled), upright abdominal X-rays (AP and lateral) were obtained to assess the location of the capsule, which was compared to the gastrointestinal positioning system (GPS) location determined by the MoPill™ system. Identification of the capsule's anatomical location by the MoPill™ system was based on (1) the 3D (x, y, z) location; (2) time; (3) trajectory (e.g., going up the right side of the body signified ascending colon); (4) frequency of contractions (e.g., 3 cycles/min for the stomach); and (5) milestone relationship (e.g., pyloric passage must follow the end of gastric contractions). GE was determined first by the end of the 3 cycles/min rhythmic movement of the stomach and then again by pyloric expulsion on 3D location. Small intestine transit was taken as the duration from pyloric expulsion to arrival in the cecum. Colon transit time was determined by calculating the duration from 3D arrival in the cecum to passage of the capsule out of the body (i.e., loss of signal accompanying a bowel movement). Ten healthy subjects (five women; mean age 34; mean BMI 24) were enrolled, and nine provided reliable data. The variation between the x-ray and the estimated (i.e., identified by the MoPill™ system) location of the capsule was within an average of 3.5 cm (range 0.9-9.4 cm). The mean GE was 3.1 h. The small intestine's mean transit time was 4.3 h. The mean colonic transit time was 17.6 h. There were no adverse events recorded during the study. MoPill™ is a novel gastrointestinal positional system that accurately identifies the location of a capsule compared to an X-ray. MoPill™ system also recognizes GE, small bowel, colonic, and WGTT as well as segmental gut location and movement characteristics. MoPill™ offers the potential for new insights into GI motility disorders not attainable by current modalities.

Transcriptomic and Metabolomic Correlates of Increased Colonic Permeability in Postinfection Irritable Bowel Syndrome

Background and aimPost-infection irritable bowel syndrome (PI-IBS) is well-known epidemiologically; however, its physiological and molecular characteristics are not well studied. We aimed to determine the physiological phenotypes, colonic transcriptome, fecal microbiome, and metabolome in PI-IBS. MethodsFifty-one Rome III Campylobacter PI-IBS patients and 39 healthy volunteers (HV) were enrolled. Participants completed questionnaires, in vivo intestinal permeability, gastrointestinal transit, and rectal sensation. Fecal samples were collected for shotgun metagenomics, untargeted metabolomics, and sigmoid colonic biopsies for bulk RNAseq. Differential gene expression, differences in microbiota composition and metabolite abundance were determined. Gene and metabolite clusters were identified via weighted gene correlation network analysis and correlations with clinical and physiological parameters determined. ResultsPI-IBS (59% F, 46±2 yrs.) and HV (64% F, 42±2 yrs.) demographics were comparable. Mean IBS-symptom severity score was 227; 94% were non-constipation. 2-24h lactulose excretion was increased in PI-IBS, suggesting increased colonic permeability (4.4±0.5 mg vs. 2.6±0.3 mg, p=0.01). Colonic transit and sensory thresholds were similar between the two groups. Overall, expression of 2036 mucosal genes and 223 fecal metabolites were different, with changes more prominent in females. Fecal N-acetylputrescine was increased in PI-IBS and associated with colonic permeability, worse diarrhea, and negatively correlated with abundance of Collinsella aerofaciens. Histamine and N-acetyl histamine positively associated with 2-24 hr lactulose excretion. Eight weighted gene coexpression modules significantly correlated with phenotypes (sex, stool frequency, colonic permeability, transit). ConclusionsCampylobacter PI-IBS patients demonstrate higher colonic permeability which associated with changes in polyamine and histamine metabolites. Female patients demonstrated greater molecular changes.

Testing in functional constipation-What's new and what works.

Constipation is among the most common symptoms prompting a consultation with a paediatric gastroenterologist. While most patients will respond to lifestyle and dietary changes and conventional therapy, some may require diagnostic studies. To review the diagnostics studies used to evaluate children with functional constipation. There is no evidence to support the routine use of abdominal X-rays in the evaluation of paediatric constipation. Colon transit by radiopaque markers (ROM) should be indicated when medical history does not match clinical findings, to guide colon manometry (CM) performance and to discriminate between faecal incontinence from functional constipation and non-retentive faecal incontinence. Colon scintigraphy may be useful as an alternative to ROM. Lumbar spine MRI may be indicated to evaluate for spinal abnormalities. The role of defecography has not been properly evaluated in children. Anorectal manometry in children is indicated primarily to evaluate anal resting pressure, presence and quality of the recto-anal inhibitory reflex and simulated defecation manoeuvres. The CM is indicated to guide surgical interventions after failing medical therapy. The goal of these studies is to identify treatable causes of constipation. Most of these studies are designed to evaluate anatomy, transit and/or colon/rectum motility function and are primarily indicated in those who fail to respond to conventional therapy.

Algorithms or biomarkers in patients with lower DGBI?

Several organizations have proposed guidelines or clinical decision tools for the management of patients with disorders of gut-brain interactions (DGBI) affecting the lower digestive tract including irritable bowel syndrome and chronic idiopathic constipation. Such algorithms are based on sequential therapeutic trials and modifying the treatment strategy based on efficacy and adverse events. The aims of this review are to evaluate the evidence for efficacy of second- and third-line pharmacotherapies and to assess the evidence for the alternative option to manage subgroups of patients with symptoms suggestive of lower DGBI based on diagnostic tests or documented dysfunctions. The preeminent tests to identify such subgroups that present with symptoms that overlap with lower DGBI are detailed: digital rectal examination as well as anorectal manometry and balloon expulsion for evacuation disorders, detailed measurements of colonic transit, and diagnosis of bile acid diarrhea or carbohydrate malabsorption based on biochemical measurements. The review also addresses the cost implications of screening to exclude alternative diagnoses and the costs of therapy associated with the therapeutic options following an algorithmic approach to treatment from the perspective of society, insurer, or patient. Finally, the costs of the diagnostic tests to identify actionable biomarkers and the evidence of efficacy of individualized therapy based on formal diagnosis or documentation of abnormal functions are detailed in the review.

Negative allosteric modulation of CB1 cannabinoid receptor signaling suppresses opioid-mediated tolerance and withdrawal without blocking opioid antinociception

The direct blockade of CB1 cannabinoid receptors produces therapeutic effects as well as adverse side-effects that limit their clinical potential. CB1 negative allosteric modulators (NAMs) represent an indirect approach to decrease the affinity and/or efficacy of orthosteric cannabinoid ligands or endocannabinoids at CB1. We recently reported that GAT358, a CB1-NAM, blocked opioid-induced mesocorticolimbic dopamine release and reward via a CB1-allosteric mechanism of action. Whether a CB1-NAM dampens opioid-mediated therapeutic effects such as analgesia or alters other unwanted opioid side-effects remain unknown. Here, we characterized the effects of GAT358 on nociceptive behaviors in the presence and absence of morphine in male rats. We examined the impact of GAT358 on formalin-evoked pain behavior and Fos protein expression, a marker of neuronal activation, in the lumbar spinal cord. We also assessed the impact of GAT358 on morphine-induced slowing of colonic transit, tolerance, and withdrawal behaviors in male mice. GAT358 attenuated morphine antinociceptive tolerance without blocking acute antinociception and reduced morphine-induced slowing of colonic motility without impacting fecal boli production. GAT358 also produced antinociception in the presence and absence of morphine in the formalin model of inflammatory nociception and reduced the number of formalin-evoked Fos protein-like immunoreactive cells in the lumbar spinal cord. Finally, GAT358 mitigated the somatic signs of naloxone-precipitated, but not spontaneous, opioid withdrawal following chronic morphine dosing. Our results support the therapeutic potential of CB1-NAMs as novel drug candidates aimed at preserving opioid-mediated analgesia while preventing their unwanted side-effects. Our studies also uncover previously unrecognized antinociceptive properties associated with an arrestin-biased CB1-NAM.

Current practice in the care of children with functional constipation: What is the hold up?

For children with intractable functional constipation (FC), there are no evidence-based guidelines for subsequent evaluation and treatment. Our objective was to assess the practice patterns of a large, international cohort of pediatric gastroenterologists. We administered a survey to physicians who attended the 2nd World Congress of Pediatric Neurogastroenterology and Motility held in Columbus, Ohio (USA) in September 2023. The survey included 29 questions on diagnostic testing, nonpharmacological and pharmacological treatment, and surgical options for children with intractable FC. Ninety physicians from 18 countries completed the survey. For children with intractable FC, anorectal manometry was the most commonly used diagnostic test. North American responders were more likely than Europeans to use stimulant laxatives (97% vs. 77%, p = 0.032), prosecretory medications (69% vs. 8%, p < 0.001), and antegrade continence enemas (ACE; 83% vs. 46%, p = 0.009) for management. Europeans were more likely than North Americans to require colonic transit testing before surgery (85% vs. 30%, p < 0.001). We found major differences in management practices between Americans and the rest of the world, including use of prosecretory drugs (73% vs. 7%, p < 0.001), anal botulinum toxin injections (81% vs. 58%, p = 0.018), ACE (81% vs. 58% p = 0.018), diverting ileostomies (56% vs. 26%, p = 0.006), and colonic resections (42% vs. 16%, p = 0.012). No differences were found when respondents were compared by years of experience. Practice patterns in the evaluation and treatment of children with intractable FC differ widely among pediatric gastroenterologists from around the world. A clinical guideline regarding diagnostic testing and surgical decision-making is needed.