Abstract Bitter taste receptors (TAS2Rs) are present in extra-oral tissues, including gut endocrine cells. This study explored the presence and mechanism of action of TAS2R agonists on gut smooth muscle in vitro and investigated functional effects of intra-gastric administration of TAS2R agonists on gastric motility and satiation. TAS2Rs and taste signalling elements were expressed in smooth muscle tissue along the mouse gut and in human gastric smooth muscle cells (hGSMC). Bitter tastants induced concentration and region-dependent contractility changes in mouse intestinal muscle strips. Contractions induced by denatonium benzoate (DB) in gastric fundus were mediated via increases in intracellular Ca 2+ release and extracellular Ca 2+ -influx, partially masked by a hyperpolarizing K + -efflux. Intra-gastric administration of DB in mice induced a TAS2R-dependent delay in gastric emptying. In hGSMC, bitter compounds evoked Ca 2+ -rises and increased ERK-phosphorylation. Healthy volunteers showed an impaired fundic relaxation in response to nutrient infusion and a decreased nutrient volume tolerance and increased satiation during an oral nutrient challenge test after intra-gastric DB administration. These findings suggest a potential role for intestinal TAS2Rs as therapeutic targets to alter gastrointestinal motility and hence to interfere with hunger signalling.
Abstract Background Chronic gastroduodenal symptoms arise from heterogenous gastric motor dysfunctions. This study applied multimodal physiological testing using gastric emptying scintigraphy (GES) with intragastric meal distribution (IMD) and Gastric Alimetry® body surface gastric mapping (BSGM) to define motility and symptom associations. Methods Patients with chronic gastroduodenal symptoms underwent simultaneous supine GES and BSGM with 30 m baseline, 99mTC-labelled egg meal, and 4 h postprandial recording. IMD (ratio of counts in the proximal half of the stomach to the total gastric counts) was calculated immediately after the meal (IMD0), with <0.568 defining impaired accommodation. BSGM phenotyping followed a consensus approach, based on normative spectral reference intervals. Results Among 67 patients (84% female, median age 40, median BMI 24), median IMD0 was 0.76 (IQR 0.69-0.86) with 5 (7.5%) meeting impaired accommodation criteria. Delayed gastric emptying (n=18) was associated with higher IMD0 (median 0.9 vs 0.7, p=0.004). On BSGM, 15 patients had abnormal spectrograms (5 [7.5%] high frequency and 10 (14.9%) low rhythm stability and/or amplitude); and in these patients, higher IMD0 (proximal retention) strongly correlated to delayed BSGM meal responses (R=-0.71, p=0.003). Lower IMD, indicating antral distribution, correlated with higher gastric frequencies (R=-0.27, p=0.03). BSGM abnormalities paired with impaired accommodation were associated with worse dyspeptic symptoms. Conclusion Proximal retention of food as assessed by intragastric meal distribution correlated with delayed emptying, and in the presence of neuromuscular spectral abnormalities (abnormal frequencies or rhythms), delayed motility responses on BSGM. Patients with multiple motor abnormalities experience worse dyspeptic symptoms.
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders, affecting about 10% of the general population globally. The aim of this consensus was to develop guidelines for the management of IBS.A systematic literature search identified studies on the management of IBS. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a multidisciplinary group of clinicians and a patient.Consensus was reached on 28 of 31 statements. Irritable bowel syndrome is diagnosed based on symptoms; serological testing is suggested to exclude celiac disease, but routine testing for C-reactive protein (CRP), fecal calprotectin or food allergies is not recommended. A trial of a low fermentable oligosaccharides, disaccharides, monosaccharides, polyols (FODMAP) diet is suggested, while a gluten-free diet is not. Psyllium, but not wheat bran, supplementation may help reduce symptoms. Alternative therapies such as peppermint oil and probiotics are suggested, while herbal therapies and acupuncture are not. Cognitive behavioural therapy and hypnotherapy are suggested psychological therapies. Among the suggested or recommended pharmacological therapies are antispasmodics, certain antidepressants, eluxadoline, lubiprostone, and linaclotide. Loperamide, cholestyramine and osmotic laxatives are not recommended for overall IBS symptoms. The nature of the IBS symptoms (diarrhea-predominant or constipation-predominant) should be considered in the choice of pharmacological treatments.Patients with IBS may benefit from a multipronged, individualized approach to treatment, including dietary modifications, psychological and pharmacological therapies.
Dysphagia and non-cardiac chest pain are common referrals for esophageal motility testing. Hypertensive esophageal peristalsis, previously classified as “nutcracker esophagus,” has been re-labelled as “jackhammer esophagus” by the Chicago Classification of esophageal motility disorders (CC v3.0). Although the pathophysiology of jackhammer esophagus (JE) has yet to be elucidated, gastroesophageal acid reflux (GERD) has been implicated as a possible causative factor, based on the higher than expected incidence of GERD on patients with JE that has been seen in previous studies (43 - 47%). The aim of this present study is to determine if GERD is associated with JE when compared to symptomatic controls with normal HRM. Consecutive symptomatic patients who were referred for esophageal high-resolution manometry (HRM) studies in Calgary, AB from Nov 2013 to Sept 2018 were retrospectively analyzed. Patients with a manometric diagnosis of Jackhammer esophagus by CC v3.0 (≥ 2 hypercontractile swallows with distal contractile integral [DCI] > 8000 mmHg-s-cm) who also underwent ambulatory pH studies were compared to patients with normal HRM (controls). Groups were compared with Pearson’s chi-square testing and ANOVA as appropriate. This study was IRB approved. 20 JE patients and 82 controls who underwent both HRM and ambulatory pH testing were identified. Age and gender breakdown were similar between both groups (see Table 1). The most common presenting complaint in the JE group was dysphagia (35.0%) and in controls was heartburn (26.8%). Similar numbers of both groups were on PPI (50.0% JE, 51.2% controls). 3 (25.0%) JE patients and 14 (17.1%) controls had evidence of abnormal acid exposure on 24h ambulatory pH study (defined as DeMeester score > 14.7); this difference was not significant (p = 0.56). When abnormal acid exposure was defined as acid exposure time (AET) > 4.2%, there was no significant difference seen between both groups (p = 0.50). There were no significant differences seen between other parameters of the DeMeester score (see Table 1). Abnormal acid exposure on ambulatory pH study does not appear to be associated with JE, when compared to patients with normal HRM. This finding suggests that abnormal esophageal acid exposure is unlikely to be a causative factor for the peristaltic abnormalities seen in Jackhammer esophagus. Table 1: Demographics and GERD parameters Table 1: Demographics and GERD parameters None
Dynamic MRI defecography is a relatively new imaging protocol which can be extremely useful in identification of anatomic and functional pelvic floor dysfunction such as organ prolapse, anismus and fecal incontinence. The aim of the study is to assess for causes of Pelvic floor dysfunction on MRI and further characterize the findings based on functional or anatomical causes. Retrospective case series of all patients having from January 2017 to August 2018 at a tertiary care hospital (South Health Campus, Calgary, AB). After injecting rectal ultrasound gel the study was performed in resting, squeezing and defecation sequences. At least four defecation sequences were obtained to assess for complete evacuation of rectal vault. The images were then carefully reviewed to identify for descent of urinary bladder (cystocele), uterus, enterocele and rectum. The degree of prolapse was then measured and graded according to the set guidelines in radiology literature. Anismus was identified if the patient was unable to evacuate the rectal gel in four separate sequences of defecation. A total of 66 patients underwent MRI Defecography. Majority of the patients referred for MRI had clinical history of constipation and to assess for compartment prolapse.The most common finding was excessive compartmental descent in 77% of patients and anismus in 38% (Table). Two patients had normal study and two patients had tumours identified as the cause for their symptoms. Most patients were referred by gastroenterologists and very few (5%) had anorectal manometry. Dynamic MR defecography is a novel tool for identification of both anatomic and functional pelvic floor abnormalities. The information it provides may allow for effective management (eg physiotherapy and/or biofeedback for anismus, and surgical correction for significant prolapse). Complete evaluation of the pelvis can also yield additional information such as tumors or other miscellaneous findings. However, while sensitivity appears excellent, further study is required to ascertain specificity of MR diagnosis of anismus due to patients who may have difficulty defecating due to the non-physiologic aspect of supine defecation. Given that MR scanners are much more common than anorectal manometry labs, wider adoption of MR defecography may improve diagnostic capability for pelvic floor dysfunction, which is commonly under-diagnosed. RESULTS RESULTS None
Supplementary Table 1 from Efficacy of Levo-1-Methyl Tryptophan and Dextro-1-Methyl Tryptophan in Reversing Indoleamine-2,3-Dioxygenase–Mediated Arrest of T-Cell Proliferation in Human Epithelial Ovarian Cancer
<div>Abstract<p>It has been reported that levo-1-methyl tryptophan (L-1MT) can block indoleamine-2,3-dioxygenase (IDO) expressed by human dendritic cells (DC), whereas dextro-1-methyl tryptophan (D-1MT) is inefficient. However, whether L-1MT or D-1MT can efficiently reverse IDO-induced arrest of human T-cell proliferation has not been clarified. Here, we show a marked immunosuppressive effect of IDO derived from <i>INDO</i>-transfected 293 cell, IDO<sup>+</sup> ovarian cancer cells, and monocyte-derived DCs on CD4<sup>+</sup> Th1 cells, CD8<sup>+</sup> T cells, and natural killer cells derived from peripheral blood, ascites, and tumors of ovarian cancer patients. We found that, whereas L-1MT and D/L-1MT can restore proliferation of tumor-derived and peripheral blood T-cell subsets, D-1MT does not effectively restore IDO-induced arrest of T-cell proliferation. Although D-1MT inhibited kynurenine production at high concentrations, L-1MT was more effective in abrogating kynurenine generation and tryptophan depletion, whereas tryptophan was completely depleted by IDO even in the presence of high amounts of D-1MT. Together, the results indicate that, whereas the generation of tryptophan metabolites (kynurenines) by IDO is important in mediating suppression of T-cell proliferation, the degree to which tryptophan depletion is restored by 1MT is also critical in overcoming IDO-induced arrest of T-cell proliferation. [Cancer Res 2009;69(13):5498–504]</p></div>
Supplementary Figure 3 from Efficacy of Levo-1-Methyl Tryptophan and Dextro-1-Methyl Tryptophan in Reversing Indoleamine-2,3-Dioxygenase–Mediated Arrest of T-Cell Proliferation in Human Epithelial Ovarian Cancer
LINKED CONTENT This article is linked to Andrews et al papers. To view these articles, visit https://doi.org/10.1111/apt.17265 and https://doi.org/10.1111/apt.17300
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