Neurogastroenterology and Motility最新文献

Background: Increasing age increases the incidence of chronic constipation and fecal impaction. The contribution of the natural aging process to this phenotype is unclear. This study explored the effects of age on key motility patterns in the murine colon and determined the contribution that altered neurokinin 2 (NK₂) -mediated signaling made to the aging phenotype.

Methods: Mucosal reflexes, colonic migrating motor complexes (CMMCs) and colonic motility assays were explored in isolated ex vivo colons from 3, 12-14, 18- and 24-months old mice and the NK₂-mediated response determined. Electrical field stimulation (EFS) or exogenous drug application were used to explore the role of the mucosa in colonic segments.

Key results: Aging reduced the force of contraction of the distal colon mucosal reflex, the frequency and force of contraction of CMMCs and the NK₂-mediated component of both motility patterns. Ondansetron, a 5-HT₃ receptor antagonist, blocked a component of both motility patterns in full thickness but not in mucosa-free segments of the distal colon. 5, hydroxytryptamine (5-HT) and EFS-evoked NK₂-dependent contractions were reduced with increasing age. Smooth muscle sensitivity to 5-HT or neurokinin A (NKA) was not altered with age. In isolated colon motility assays application of NKA decreased transit time in 24-months colon and the NK₂ antagonist GR159897 increased transit times in both 3- and 24-months old colons.

Conclusions and inferences: Aging impairs key motility patterns in the murine colon. These changes involve a decrease in mucosally-evoked NK₂-mediated signaling. Targeting NK₂-mediated signaling may provide a novel approach to treating age-related motility disorders in the lower bowel.

Background: Rikkunshito (RKT), a traditional Japanese medicine, can relieve epigastric discomfort and anorexia in patients with functional dyspepsia. RKT enhances the orexigenic hormone, ghrelin. Ghrelin regulates food motivation by stimulating the appetite control center in the hypothalamus and the brain mesolimbic dopaminergic pathway (MDPW). However, the effect of RKT on MDPW remains unclear. Here, we aimed to investigate the central neural mechanisms underlying the orexigenic effects of RKT, focusing on the MDPW.

Methods: We examined the effects of RKT on food intake and neuronal c-Fos expression in restraint stress- and cholecystokinin octapeptide-induced anorexia in male rats.

Key results: RKT treatment significantly restored stress- and cholecystokinin octapeptide-induced decreased food intake. RKT increased c-Fos expression in the ventral tegmental area (VTA), especially in tyrosine hydroxylase-immunoreactive neurons, and nucleus accumbens (NAc). The effects of RKT were suppressed by the ghrelin receptor antagonist [D-Lys³]-GHRP-6. RKT increased the number of c-Fos/orexin-double-positive neurons in the lateral hypothalamus (LH), which project to the VTA. The orexin receptor antagonist, SB334867, suppressed RKT-induced increase in food intake and c-Fos expression in the LH, VTA, and NAc. RKT increased c-Fos expression in the arcuate nucleus and nucleus of the solitary tract of the medulla, which was inhibited by [D-Lys³]-GHRP-6.

Conclusions & inferences: RKT may restore appetite in subjects with anorexia through ghrelin- and orexin-dependent activation of neurons regulating the brain appetite control network, including the hypothalamus and MDPW.

Background: Gastric fluid plays a key role in food digestion and drug dissolution, therefore, the amount of gastric fluid present in a fasted state may influence subsequent digestion and drug delivery. We aimed to describe intra- and interindividual variation in fasted gastric content volume (FGCV) and to determine the association with age, sex, and body size characteristics.

Methods: Data from 24 MRI studies measuring FGCV in healthy, mostly young individuals after an overnight fast were pooled. The analysis included 366 participants who had up to 6 repeated measurements, with a total of 870 measurements. Linear mixed model analysis was performed to calculate intra- and interindividual variability and to assess the effects of age, sex, weight, height, weight*height as a proxy for body size, and body mass index (BMI).

Results: FGCV ranged from 0 to 156 mL, with a mean (± SD) value of 33 ± 25 mL. The overall coefficient of variation within the study population was 75.6%, interindividual SD was 15 mL, and the intraindividual SD was 19 mL. Age, weight, height, weight*height, and BMI had no effect on FGCV. Women had lower volumes compared to men (MD: -6 mL), when corrected for the aforementioned factors.

Conclusion: FGCV is highly variable, with higher intraindividual compared to interindividual variability, indicating that FGCV is subject to day-to-day and within-day variation and is not a stable personal characteristic. This highlights the importance of considering FGCV when studying digestion and drug dissolution. Exact implications remain to be studied.

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: Postoperative ileus (POI) is a condition marked by a temporary suppression of gastrointestinal motility following abdominal surgery. The mechanism of POI encompasses various factors and is characterized by two phases: the early neurogenic phase involving both adrenergic and non-adrenergic neural pathways; the later immune-mediated phase is characterized by a sterile inflammatory response that lasts several days. Activation of muscularis macrophages triggers a sterile inflammatory process that results in dysfunction of the enteric nervous system (ENS) and a reversible inhibition of gastrointestinal motility.

Purpose: In this minireview, recent insights in the pathophysiological mechanisms underlying POI and potential new therapeutic strategies are described.

Background: Accumulating evidence has suggested that neuropeptides such as orexin, ghrelin, or oxytocin act centrally in the brain to regulate intestinal barrier function through the vagus nerve. It has been reported that the vagal cholinergic anti-inflammatory pathway was blocked by splenectomy. In the present study, we therefore examined the effect of splenectomy on neuropeptides-induced improvement of increased intestinal permeability.

Methods: Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 min spectrophotometrically in rats.

Results: Splenectomy increased colonic permeability. The increased permeability by splenectomy was significantly blocked by vagal activation induced by carbachol or 2-deoxy-d-glucose which was prevented by atropine, suggesting vagal activation could prevent colonic hyperpermeability in splenectomized rats. In the splenectomized rats, intracisternal injection of orexin, ghrelin, oxytocin, or butyrate failed to inhibit increased colonic permeability while intracisternal glucagon-like peptide-1 (GLP-1) analogue, liraglutide, potently blocked the increased colonic permeability in a dose-dependent manner. The liraglutide-induced improvement of increased colonic permeability was blocked by atropine in splenectomized rats. Intracisternal injection of GLP-1 receptor antagonist attenuated 2-deoxy-d-glucose-induced improvement of colonic hyperpermeability in splenectomized rats.

Conclusion: The present results suggested that the spleen is important in the improvement of intestinal barrier function by brain orexin, ghrelin or oxytocin, and butyrate. On the other hand, GLP-1 acts centrally in the brain to improve colonic hyperpermeability in a spleen-independent manner. All these results suggest that dual mechanisms (spleen dependent or independent) may exist for the brain-gut regulation in intestinal barrier function.

Background and aims: The group of disorders known as Disorders of Gut Brain Interaction (DGBI) were originally labeled functional GI disorders and were thought to be disorders of the gastrointestinal tract that had several psychological conditions as comorbidities. Despite mounting evidence that psychological morbidity plays an innate role in the etiology and maintenance of DGBI, none of the Rome IV criteria include any measure of psychological symptoms. This study tested the hypothesis that individuals would cluster differently if GI symptoms alone were considered versus GI symptoms combined with measures of psychological symptoms.

Methods: Data were obtained from the Rome Foundation Global Epidemiology Study measuring Rome IV GI symptoms, psychological measures and demographic characteristics. Latent profile models were used to cluster individuals based on (i) GI symptoms only (GI only) and then (ii) GI and psychological measures (GI + Psych).

Key results: Individuals clustering into the same group of individuals whether formed via GI only or GI + Psych, ranged from 96% for a 2-class solution (the most simplistic) to 76% with 6 classes (the parsimonious system) and 59% with twenty-two classes (mimicking Rome IV). The generalisability of this finding between six geographic regions was confirmed with agreement varying between 95%-97% for 2 clusters and 71-79% for 6 classes and 51%-63% for 22 classes. These findings were also consistent between DGBI (range 94% with 2 classes to 50% with 22 classes) and non-DGBI (range 97% with 2 clusters to 65% with 22 classes) groups.

Conclusions & inferences: Our data suggest that considering psychological as well as gastrointestinal symptoms would lead to a different clustering of individuals in more complex, and accurate, classification systems. For this reason, future work on DGBI classification should consider inclusion of psychological traits.

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: Disorders of primary peristalsis are associated with a higher percent time pH <4 in the esophagus suggesting poor acid clearance. However, there are no studies of secondary peristalsis and its relationship to microscopic or erosive esophagitis. The goal of this study was to determine the relationship between secondary peristalsis using functional luminal imaging probes (EndoFLIP) and the presence or absence of esophagitis.

Methods: We reviewed the endoscopic and EndoFLIP 2.0 tracings for 103 consecutive patients including those with a history of upper gastrointestinal surgery undergoing upper endoscopy. Esophagogastric junction (EGJ) distensibility and diameter, repetitive antegrade contraction (RACs) presence and frequency, and occlusive diameters were measured. Measurements were then compared between patients with and without microscopic and/or erosive esophagitis. Means were compared using t-tests. Proportions were compared using Chi-Squared analyses.

Key results: One hundred and three patients were included (mean age: 14.4 + 6.4 years). Ten patients had erosive esophagitis and 28 patients had microscopic esophagitis. Erosive and microscopic esophagitis were associated with abnormal or absent of RACs (p < 0.001). Occlusive diameters were higher in patients with esophagitis compared to those without (p < 0.001). There was no relationship between EGJ distensibility and the presence of erosive or microscopic esophagitis (p = 0.4). The absence of RACs was the only independent predictor of esophagitis (erosive and microscopic), after controlling for age, proton pump inhibitors (PPI) use and EGJ distensibility (p < 0.001).

Conclusions & inferences: Abnormal secondary peristalsis is associated with microscopic and gross esophagitis, suggesting that EndoFLIP should be part of the diagnostic algorithm for esophagitis.

Enteric glia are a heterogeneous population of peripheral glia within the enteric nervous system and play pivotal roles in gut homeostasis, tissue integrity, coordination of motility, and intestinal immune responses. Under physiological conditions, they communicate with enteric neurons to control intestinal motility. In contrast, enteric glia undergo reactive changes in response to inflammatory signals during enteric neuroinflammation and participate in immune control. In this state, these glia are called reactive enteric glia, which promote cytokine and chemokine secretion and perpetuate immune cell recruitment, thereby affecting disease progression. Interestingly, reactive glia exhibit a huge plasticity and adapt to or shape the immune environment towards a resolving phenotype during inflammation and neuropathies. Recent studies revealed a bidirectional communication between enteric glia and resident and infiltrating immune cells under healthy conditions and in the context of inflammation-based intestinal disorders and neuropathies. While recent reviews give a superb general overview of enteric glial reactivity, we herein discuss the latest evidence on enteric glial reactivity in two prominent inflammatory conditions: acute postoperative inflammation, resulting in postoperative ileus, and chronic inflammation in inflammatory bowel diseases. We define their plasticity during inflammation and the interplay between reactive enteric glia and intestinal macrophages. Finally, we sketch important questions that should be addressed to clarify further the impact of enteric glial reactivity on intestinal inflammation.