Neurogastroenterology and Motility最新文献

Background: Functional defecation disorders (FDD) are a common etiology of refractory chronic constipation (CC). FDD diagnosis (dyssynergic defecation [DD] and inadequate defecatory propulsion [IDP]), requires diagnostic tests including anorectal manometry (ARM) and balloon expulsion test (BET). Biofeedback (BF) is the treatment of choice for DD. The aims of our study were to evaluate: the outcome of BF in a group of constipated patients with defecatory disorders of any etiology; the efficacy of two simple diagnostic tools in predicting BF outcome in the short-term.

Methods: One hundred and thirty-one refractory CC patients failing the BET underwent BF therapy. Before BF, all patients underwent the following: ARM. Straining questionnaire. The answers were: "belly muscles"; "anal muscles"; "both"; "Don't know/No answer." Digital rectal examination augmented by abdominal palpation on straining (augmented-DRE). The BF therapist was blinded to ARM, straining questionnaire, and augmented-DRE results.

Key results: Eighty-one patients responded to BF. Gender, age, and IBS-C showed no significant impact on BF response. Both DD and IDP responded equally to BF, while the rate of response in patients with isolated structural pelvic floor abnormalities was lower (p < 0.001). The answer "anal muscles" to straining questionnaire showed a strong association with BF response (p < 0.001). A lack in abdominal contraction and in anal relaxation on augmented-DRE were strongly associated with BF response (p < 0.01). Absence of manual maneuvers to facilitate defecation was associated with BF response (p < 0.001).

Conclusions & inferences: BF is the therapy of choice for refractory constipation due to FDD of any etiology, inducing both clinical and anorectal physiology improvement in the short term. Comorbid IBS-C did not affect outcome while symptomatic isolated pelvic floor abnormalities appeared refractory to behavior treatment. The straining questionnaire and augmented-DRE outcomes showed a strong correlation with BF response and can be implemented in clinical practice to improve the management of constipated patients by prompting early referral to BF.

Background: Impaired gastric accommodation is one of the most frequent symptoms of functional dyspepsia. The safety and efficacy of conventional treatments remain to be proven and alternative herbal therapies have been proposed to alleviate gastrointestinal symptoms. This preclinical study examined the role of herbal Amara extract (containing Artemisia absinthium, Centaurium erythraea, Cichorium intybus, Gentiana lutea, Juniperus communis, Achillea millefolium, Peucedanum ostruthium, Salvia officinalis, and Taraxacum extracts) on gastric (fundus) accommodation and the possible implication of muscarinic receptors in its regulation.

Methods: The effect of Amara extract on fundus motility was investigated in organ baths of smooth muscle strips isolated from the fundus of guinea pigs, and the role of the muscarinic receptor pathway was evaluated using functional and radioligand binding assays in cell lines expressing the M2 or M3 muscarinic receptor.

Key results: Amara extract inhibited carbachol-induced contraction of guinea pig smooth muscle strips in a dose-dependent manner. This relaxant effect was not affected by the M3 antagonist J-104129. Amara extract also inhibited M2, but not M3, receptor activity in CHO-K1 cells (IC₅₀ 219 μg mL^-1), and specifically bound the M2 receptor (IC₅₀ 294 μg mL^-1). Of the nine herbal components of Amara extract, Juniperus communis, P. ostruthium, and Salvia officinalis inhibited M2 receptor activity (IC₅₀ 32.0, 20.8, and 20.1 μg mL^-1, respectively), and P. ostruthium was sufficient to reverse carbachol-induced ex vivo contraction of guinea pig fundic smooth muscles.

Conclusion and inferences: Amara extract relaxes gastric smooth muscles by inhibiting the M2 muscarinic receptor. This study suggests the potential benefit of Amara extract for patients with impaired gastric accommodation.

Background: Inhibitory neuromuscular transmission in the gastrointestinal tract is mediated by intrinsic nitrergic and purinergic neurons. Purines activate G protein-coupled receptor P2Y₁ receptors, increasing intracellular Ca²⁺ that activates small conductance calcium-activated potassium (SK_Ca) channels. Little is known about the effect of adrenergic receptor activation on intestinal smooth muscle. In vascular tissue, stimulation of α-adrenoceptors causes smooth muscle contraction, while their effect on intestinal tissue is poorly understood. This study aimed to pharmacologically characterize the effect of α-adrenoceptor activation in the rat colon, which shares similar inhibitory pathways to the human colon.

Methods: Muscle bath experiments were performed with the rat proximal, mid, and distal colon oriented both circularly and longitudinally.

Results: The α₁-adrenoceptor agonist phenylephrine (PE) (10^-8-10^-5 M) evoked concentration-dependent relaxations of the intestinal smooth muscle from all regions and orientations. However, in the mid-circular colon at low PE concentrations, a contraction sensitive to 10^-5 M phentolamine (non-selective α-adrenoceptor blocker), the neural blocker tetrodotoxin (TTX; 10^-6 M), and atropine (10^-6 M) was recorded. PE-induced relaxations were insensitive to TTX (10^-6 M) and the nonselective β-adrenoceptor blocker propranolol (10^-6 M). In contrast, PE-induced relaxations were blocked by phentolamine (10^-5 M), prazosin (10^-6 M) (α₁-adrenoceptor blocker), and RS17053 (10^-6 M) (α_1A-blocker), but not by yohimbine (10^-6 M) (α₂-adrenoceptor blocker). Apamin (10^-6 M), a SK_Ca channel blocker, abolished PE-induced relaxations.

Conclusions: Contractile responses in the circular muscle of the mid colon could be attributed to α-adrenoceptors located on enteric cholinergic neurons. Stimulation of α_1A-adrenoreceptors activates SK_Ca channels to cause smooth muscle relaxation, which constitutes a signaling pathway that shares similarities with P2Y₁ receptors.

Background: Chronic constipation is a gastrointestinal functional disorder which affects patient quality of life. Therefore, many studies were oriented to search herbal laxative agents. In this study, we investigated the phytochemical composition of beetroot juice (BJ) and its laxative potential in an experimental model of constipation and colonic dysmotility induced by loperamide (LOP) in Wistar rats.

Methods: Animals were concurrently pretreated with LOP (3 mg/kg, b.w., i.p.) and BJ (5 and 10 mL/kg, b.w., p.o.), or yohimbine (2 mg/kg, b.w., i.p.), during 1 week. The laxative activity was determined based on the weight, frequency, and water content of the feces matter. The gastric-emptying test and intestinal transit were determined. Colon histology was examined, and oxidative status was evaluated using biochemical-colorimetric methods.

Key results: The in vivo study revealed that LOP induced a significant inhibition of gastrointestinal motility, negative consequences on defecation parameters, oxidative stress, and colonic mucosa lesions. Conversely, administration of BJ reestablished these parameters and restored colonic oxidative balance. Importantly, BJ treatment protected against LOP-induced inflammatory markers (pro-inflammatory cytokines and WBC) and the increase in intracellular mediators such as hydrogen peroxide, free iron, and calcium levels.

Conclusions & inferences: This study demonstrated that the bioactive compounds in BJ provided an anti-constipation effect by modulating intestinal motility and regulating oxidative stress and inflammation induced by LOP intoxication.

Background: A high prevalence of disorders of gut-brain interaction (DGBI) exist in patients with hypermobile Ehlers-Danlos Syndrome (hEDS) and hypermobility spectrum disorders (HSD). However, it is unknown if clusters of hEDS/HSD patients exist which overlap with different DGBIs and whether this overlap influences presence of comorbidities and quality of life. We aimed to study these knowledge gaps.

Methods: A prospectively collected hEDS/HSD cohort of 1044 individuals were studied. We undertook Uniform Manifold Approximation and Projection-enabled (UMAP) dimension reduction to create a representation of nonlinear interactions between hEDS/HSD and DGBIs, from which individuals were stratified into clusters. Somatization, Postural Tachycardia Syndrome (PoTS), autonomic symptoms, psychological factors and quality of life were statistically compared between clusters.

Key results: The mean age of patients was 40 ± 13.2 years; 87.8% were female. Patients segregated into three clusters: Cluster 0 (n = 466): hEDS/HSD+ functional foregut disorders (FFD) + irritable bowel syndrome (IBS); Cluster 1 (n = 180): hEDS/HSD+ IBS and Cluster 2 (n = 337): hEDS/HSD alone. In cluster 0, we demonstrated increased somatization (p <0.0001), anxiety (p <0.0001), depression (p <0.0001), PoTS prevalence (p = 0.003), autonomic symptoms (p <0.0001) and reduced quality of life (p <0.0001) compared to cluster 2. Cluster 0 had greater comorbidity burden than cluster 1.

Conclusions: Within hEDS/HSD, subgroups exist with a high prevalence of FFD and IBS. These subgroups have a higher prevalence of psychological disorders, dysautonomia and poorer quality of life compared with hEDS/HSD alone. Further research should focus on healthcare utilization, management and prognosis in hEDS/HSD and DGBI overlap.

Background: The aims of this study were to confirm the non-inferiority of tegoprazan to lansoprazole up to week 4 in patients with erosive esophagitis (EE) and to evaluate its effectiveness in rapid mucosal healing and symptom relief at week 2.

Methods: In this multi-center, randomized, double-blind, active-comparator non-inferiority trial, 218 patients with endoscopically confirmed EE (Los Angeles Classification Grades A-D) were randomly allocated to either the tegoprazan (50 mg) or lansoprazole (30 mg) group. The primary endpoint was the cumulative proportion of patients with healed EE up to week 4, as confirmed through endoscopy. The proportion of patients with healed EE at week 2 was also evaluated. Furthermore, CYP2C19 genotypes, symptoms, safety, and tolerability were assessed.

Key results: In the full-analysis set, 103 and 109 participants in the tegoprazan and lansoprazole groups, respectively, were analyzed. The cumulative healing rates up to week 4 were 95.2% (98/103) and 86.2% (94/109) (difference [95% confidence interval], 8.91 [1.22-16.59]; p < 0.0001 for non-inferiority and 0.0266 for superiority), while those at week 2 were 88.4% (91/103) and 82.6% (90/109) (5.78 [-3.66-15.22], p = 0.0005 for non-inferiority) for tegoprazan and lansoprazole, respectively. Tegoprazan showed consistent healing rates regardless of CYP2C19 genotypes.

Conclusions and inferences: Tegoprazan was superior to lansoprazole in the treatment of EE up to 4 weeks. Further studies are necessary to confirm these findings and clarify the superiority of tegoprazan, especially in the treatment of severe EE.

Trial registration: ClinicalTrials.gov identifier: NCT05267743.

Background: Oropharyngeal dysphagia is prevalent among neurological patients, often necessitating enteral tube feeding with a nasogastric tube (NGT) or percutaneous endoscopic gastrostomy (PEG). These patients are at significant risk of developing aspiration pneumonia. This study aimed to assess the impact of oropharyngeal dysphagia on pneumonia risk requiring hospitalization in neurological patients on long-term enteral tube feeding.

Methods: This retrospective observational study was conducted between 2015 and 2022. It included neurological patients who underwent upper gastrointestinal endoscopy combined with a Modified Flexible Endoscopic Evaluation of Swallowing (mFEES) for suspect dysphagia, characterized by difficulty or discomfort in swallowing. Participants were either orally fed or had been on long-term enteral tube feeding via NGT or PEG. A 2-year follow-up was conducted to monitor pneumonia cases requiring hospitalization. Multivariate analyses were conducted to identify risk factors for pneumonia requiring hospitalization.

Key results: A total of 226 orally fed and 152 enteral tube-fed patients were enrolled. Multivariate analyses showed a significantly increased risk of pneumonia in patients with a history of pneumonia and those receiving enteral tube feeding. Subgroup analysis indicated a significantly lower risk of pneumonia among enteral tube-fed patients with oropharyngeal dysphagia who PEG-fed patients compared to NGT-fed patients (adjusted HR: 0.21, 95% CI: 0.10-0.44, p < 0.001). The cumulative incidence of pneumonia requiring hospitalization was significantly lower in the PEG group than in the NGT group (p < 0.001).

Conclusion: mFEES could be a screening tool for oropharyngeal dysphagia. PEG is preferred over NGT for long-term enteral feeding, as it significantly reduces the risk of pneumonia requiring hospitalization, especially in patients with oropharyngeal dysphagia.

Background: Gastro-esophageal reflux disease (GERD) is the most common cause for noncardiac chest pain (NCCP), with an estimated prevalence rate ranging between 30% and 60%. Heartburn and NCCP may share common mechanisms.

Aims/methods: To assess whether particular patterns of impedance-pH variables characterize patients with dominant heartburn, regurgitation, or NCCP and their ability to predict proton pump inhibitor (PPI) response for each symptom, GERD patients, evaluated with high-resolution manometry (HRM) and impedance-pH, were included.

Results: In total, 109 NCCP, 68 heartburn, and 64 regurgitation patients were included. Pathological reflux episodes were observed in 28%, 19%, and 56% (p < 0.001). Pathological mean nocturnal baseline impedance (MNBI) values were observed in 55%, 53%, and 34% (p < 0.05). Hypomotility was more frequent in NCCP compared to heartburn patients (p < 0.05). When comparing NCCP with heartburn, hypomotility was associated with NCCP perception (OR: 2.34, 95% CI: 1.23-4.43; p < 0.01). When comparing NCCP with regurgitation, >80 refluxes and type 2/3 esophagogastric junction (EGJ) were associated with regurgitation perception (OR: 0.31, 95% CI: 0.16-0.59; p < 0.001, and OR: 0.5, 95% CI: 0.27-0.93; p < 0.05), while pathological MNBI was associated with NCCP perception (OR: 2.34, 95% CI: 1.23-4.43; p < 0.01). 45.5% NCCP patients, 45.6% with heartburn, and 36% with regurgitation responded to PPIs (p < 0.05). At multivariate analysis, pathological MNBI or PSPW index were associated with PPI responsiveness in patients with NCCP or heartburn, while in patients with regurgitation, pathological MNBI was associated with PPI responsiveness and a reflux number >80 to PPI refractoriness.

Conclusions: We highlight the usefulness of an accurate clinical and functional evaluation of GERD patients, allowing to discriminate particular characteristics in patients with dominant heartburn, NCCP, or regurgitation, which may benefit of distinct therapeutic strategies.

Background: There is a bidirectional relationship between sleep and pain disturbances. Sleep disturbances increase the risk for chronic pain, while chronic pain can interfere with sleep. Hence, we assessed the subjective sleep characteristics of youth with functional abdominal pain disorders (FAPDs) compared to healthy youth and examined associations with gastrointestinal symptoms.

Methods: We included youth ages 10-18 years without a sleep or organic GI disorder diagnosis from a large private school. Participants completed demographics, sleep history, and validated questionnaires: sleep quality (ASWS-SF), insomnia (PISI), daytime sleepiness (ESS), sleep disturbance (PROMIS SD), sleep-related impairment (PROMIS SRI), and Rome 4 diagnostic questionnaire. Cases (FAPDs) completed abdominal pain index (API), nausea severity (NSS), anxiety, depression (PROMIS), and functional disability (FDI). Parents filled sleep hygiene metrics (SHIP). Cases were matched 1:1 with controls based on age and gender.

Results: Of 120 youth (60 cases and 60 controls), the mean age was 13.5 ± 1.9 years and 50% were females. Youth with FAPDs had higher insomnia, sleep disturbance, sleep-related impairment, daytime sleepiness, sleep hygiene, gasping, and nightmares than healthy youth (p < 0.05). Higher insomnia severity was associated with worse abdominal pain (r = 0.41, p < 0.01), higher daytime sleepiness with a family history of disorders of gut-brain interaction (DGBIs, OR = 14.7, p = 0.002), and higher sleep-related impairment (OR = 5.6, p = 0.02) and depression (OR = 6.1, p = 0.01) with black race.

Conclusion: Youth with FAPDs have worse sleep than healthy youth and multiple sleep parameters are associated with abdominal pain. Future studies could focus on determining mechanisms by which sleep disturbances affect abdominal pain and vice versa.

Background: Evaluate the impact of Spondias mombin L. juice (SM), alone and in combination with Lactobacillus acidophilus, in an experimental model of intestinal mucositis.

Methods: Swiss mice were orally administered with saline, SM, or SM combined with L. acidophilus NRRL B-4495 at 1 × 10⁹ colony-forming unit (CFU/mL) for 15 days before the induction of intestinal mucositis by a single intraperitoneal injection of 5-fluorouracil (5-FU) at 450 mg/kg. On the 18th day, following euthanasia, tissue samples were collected for histopathological examination. Jejunum tissues were analyzed for MUC-2 immunoexpression, concentrations of interleukin-1-beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor (TNF)-α, and invertase activity.

Key results: 5-FU induced intestinal damage in all intestinal segments, and this damage involved villus blunting, flattened and vacuolated cells, crypt necrosis, inflammatory cell infiltration, and mucosa and submucosal edema compared to the control group. In contrast, SM or SM with L. acidophilus prevented these morphological alterations in all intestinal segments (p < 0.05). Both treatments reduced the intestinal concentration of IL-1 beta (p < 0.05), IL-6 (p < 0.05), and TNF-alpha (p < 0.05). Notably, the combination of SM and L. acidophilus, but not SM alone, prevented the 5-FU-induced decrease in invertase activity and mucin expression (p < 0.05). Furthermore, SM combined with L. acidophilus resulted in an increased population of lactic acid bacteria in feces on the 7th and 18th days. Combining SM with L. acidophilus also decreased fecal excretion of γ-Ergostenol and γ-sitosterol.

Conclusions and inferences: SM, alone and combined with Lactobacillus acidophilus demonstrated significant protective effects against 5-FU-induced intestinal mucositis, reducing inflammatory markers.