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We determined the effectiveness of a multi-strain probiotic (Hexbio®) containing microbial cell preparation MCP®BCMC® on constipation symptoms and gut motility in PD patients with constipation. PD patients with constipation (ROME III criteria) were randomized to receive a multi-strain probiotic (Lactobacillus sp and Bifidobacterium sp at 30 X 109 CFU) with fructo-oligosaccaride or placebo (fermented milk) twice daily for 8 weeks. Primary outcomes were changes in the presence of constipation symptoms using 9 items of Garrigues Questionnaire (GQ), which included an item on bowel opening frequency. Secondary outcomes were gut transit time (GTT), quality of life (PDQ39-SI), motor (MDS-UPDRS) and non-motor symptoms (NMSS). Of 55 recruited, 48 patients completed the study: 22 received probiotic and 26 received placebo. At 8 weeks, there was a significantly higher mean weekly BOF in the probiotic group compared to placebo [SD 4.18 (1.44) vs SD 2.81(1.06); (mean difference 1.37, 95% CI 0.68, 2.07, uncorrected p<0.001)]. Patients in the probiotic group reported five times higher odds (odds ratio = 5.48, 95% CI 1.57, 19.12, uncorrected p = 0.008) for having higher BOF (< 3 to 3-5 to >5 times/week) compared to the placebo group. The GTT in the probiotic group [77.32 (SD55.35) hours] reduced significantly compared to placebo [113.54 (SD 61.54) hours]; mean difference -36.22, 95% CI -68.90, -3.54, uncorrected p = 0.030). The mean change in GTT was 58.04 (SD59.04) hour vs 20.73 (SD60.48) hours respectively (mean difference 37.32, 95% CI 4.00, 70.63, uncorrected p = 0.028). No between-groups differences were observed in the NMSS, PDQ39-SI, MDS-UPDRS II and MDS-UPDRS III scores. Four patients in the probiotics group experienced mild reversible side effects. This study showed that consumption of a multi-strain probiotic (Hexbio®) over 8 weeks improved bowel opening frequency and whole gut transit time in PD patients with constipation.

Background: Recent studies in animals have shown that ghrelin stimulates upper gastrointestinal motility through the vagus and enteric nervous system. The aim of the present study therefore was to simultaneously investigate the effect of administration of ghrelin on upper gastrointestinal motility and to elucidate its mode of action by measuring plasma levels of gastrointestinal hormones in humans. Materials and methods: Nine healthy volunteers (four males; aged 22–35 years) underwent combined antroduodenal manometry and proximal stomach barostat study on two separate occasions at least one week apart. Twenty minutes after the occurrence of phase III of the migrating motor complex (MMC), saline or ghrelin 40 μg was administered intravenously over 30 minutes in a double blind, randomised, crossover fashion. Ghrelin, motilin, pancreatic polypeptide, glucagon, and somatostatin were measured by radioimmunoassay in blood samples obtained at 15–30 minute intervals. The influence of ghrelin or saline on MMC phases, hormone levels, and intraballoon volume was compared using paired t test, ANOVA, and χ2 testing. Results: Spontaneous phase III occurred in all subjects, with a gastric origin in four. Administration of ghrelin induced a premature phase III (12 (3) minutes, p<0.001; gastric origin in nine, p<0.05), compared with saline (95 (13) minutes, gastric origin in two). Intraballoon volumes before infusion were similar (135 (13) v 119 (13) ml; NS) but ghrelin induced a longlasting decrease in intraballoon volume (184 (31) v 126 (21) ml in the first 60 minutes; p<0.05). Administration of ghrelin increased plasma levels of pancreatic polypeptide and ghrelin but motilin, somatostatin, and glucagon levels were not altered. Conclusions: In humans, administration of ghrelin induces a premature gastric phase III of the MMC, which is not mediated through release of motilin. This is accompanied by prolonged increased tone of the proximal stomach.

The enteric nervous system (ENS) is crucial for essential gastrointestinal physiologic functions such as motility, fluid secretion, and blood flow. The gut is colonized by trillions of bacteria that regulate host production of several signaling molecules including serotonin (5-HT) and other hormones and neurotransmitters. Approximately 90% of 5-HT originates from the intestine, and activation of the 5-HT₄ receptor in the ENS has been linked to adult neurogenesis and neuroprotection. Here, we tested the hypothesis that the gut microbiota could induce maturation of the adult ENS through release of 5-HT and activation of 5-HT₄ receptors. Colonization of germ-free mice with a microbiota from conventionally raised mice modified the neuroanatomy of the ENS and increased intestinal transit rates, which was associated with neuronal and mucosal 5-HT production and the proliferation of enteric neuronal progenitors in the adult intestine. Pharmacological modulation of the 5-HT₄ receptor, as well as depletion of endogenous 5-HT, identified a mechanistic link between the gut microbiota and maturation of the adult ENS through the release of 5-HT and activation of the 5-HT₄ receptor. Taken together, these findings show that the microbiota modulates the anatomy of the adult ENS in a 5-HT–dependent fashion with concomitant changes in intestinal transit.

Microbial conversion of dietary or drug substrates into small bioactive molecules represents a regulatory mechanism by which the gut microbiota alters intestinal physiology. Here, we show that a wide variety of gut bacteria can metabolize the dietary supplement and antidepressant 5-hydroxytryptophan (5-HTP) to 5-hydroxyindole (5-HI) via the tryptophanase (TnaA) enzyme. Oral administration of 5-HTP results in detection of 5-HI in fecal samples of healthy volunteers with interindividual variation. The production of 5-HI is inhibited upon pH reduction in in vitro studies. When administered orally in rats, 5-HI significantly accelerates the total gut transit time (TGTT). Deciphering the underlying mechanisms of action reveals that 5-HI accelerates gut contractility via activation of L-type calcium channels located on the colonic smooth muscle cells. Moreover, 5-HI stimulation of a cell line model of intestinal enterochromaffin cells results in significant increase in serotonin production. Together, our findings support a role for bacterial metabolism in altering gut motility and lay the foundation for microbiota-targeted interventions.

BackgroundColonic motility in constipation can be assessed non-invasively using MRI.ObjectiveTo compare MRI with high-resolution colonic manometry (HRCM) for predicting treatment response.DesignPart 1: 44 healthy volunteers (HVs), 43 patients with irritable bowel syndrome with constipation (IBS-C) and 37 with functional constipation (FC) completed stool diaries and questionnaires and underwent oral macrogol (500–1000 mL) challenge. Whole gut transit time (WGTT), segmental colonic volumes (CV), MRI-derived Motility Index and chyme movement by ‘tagging’ were assessed using MRI and time to defecation after macrogol recorded. Left colonic HRCM was recorded before and after a 700 kcal meal. Patients then proceeded to Part 2: a randomised cross-over study of 10-days bisacodyl 10 mg daily versus hyoscine 20 mg three times per day, assessing daily pain and constipation.ResultsPart 1: Total CVs median (range) were significantly greater in IBS-C (776 (595–1033)) and FC (802 (633–951)) vs HV (645 (467–780)), p<0.001. Patients also had longer WGTT and delayed evacuation after macrogol. IBS-C patients showed significantly reduced tagging index and less propagated pressure wave (PPW) activity during HRCM versus HV. Compared with FC, IBS-C patients were more anxious and reported more pain. Abnormally large colons predicted significantly delayed evacuation after macrogol challenge (p<0.02), impaired manometric meal response and reduced pain with bisacodyl (p<0.05).Part 2: Bisacodyl compared with hyoscine increased bowel movements but caused more pain in both groups (p<0.03).ConclusionAn abnormally large colon is an important feature in constipation which predicts impaired manometric response to feeding and treatment responses. HRCM shows that IBS-C patients have reduced PPW activity.Trial registration numberThe study was preregistered on ClinicalTrials.gov, Reference: NCT03226145.

Background Restoration of intestinal function after open surgery remains a significant challenge in gynecological practice. Bacillus coagulans TBC169 probiotics may enhance intestinal motility and recovery. Aim This randomized controlled trial aimed to evaluate the efficacy and safety of Bacillus coagulans TBC169 in promoting intestinal function recovery after gynecological open abdominal surgery. Method Patients undergoing open surgery were randomly assigned to high-dose (HDG), conventional-dose (CDG), or placebo-controlled (PCG) groups. The primary outcome was the time to first flatus (TFF). Secondary outcomes included time to first defecation (TFD), time to first bowel sounds (TFBS), duration of hospital stay (DHS), and postoperative complication rate (PCR). Results A total of 114 patients were included, with 38 patients allocated to each group. TFF was significantly shorter in the CDG (25.8 h vs. 38.1 h, P  < 0.001) and the HDG (23.1 h vs. 38.1 h, P  < 0.001) than the PCG. TFBS was significantly reduced in the CDG (16.1 h vs. 19.3 h, P  < 0.05) and the HDG (14.3 h vs. 19.3 h, P  < 0.001). Patients in the HDG had a significantly shorter TFD than the PCG (61.2 h vs. 66.4 h, P  < 0.05). However, DHS did not differ significantly among the groups. PCR was markedly lower in the CDG (34.2% vs. 68.4%, P  < 0.01) and HDG (21.1% vs. 68.4%, P  < 0.001) compared to the PCG. No adverse events were reported across the groups. Conclusion Bacillus coagulans TBC169 accelerates intestinal function recovery and reduces postoperative complications following gynecologic open surgery. Trial Registration The study protocol was registered with the China Clinical Trials Registry (ChiCTR2200059518).

Background:Functional gastrointestinal disturbance occurs after abdominal surgeries and could last for an extended period of time in some cases. This study was designed (1) to evaluate the effects of needleless transcutaneous electrical acustimulation (TEA) on postoperative recovery, and (2) to investigate the mechanisms involving autonomic function in postoperative patients after removal of gastrointestinal cancers.Methods:Forty-two patients (33 male, age: 69.5 ± 1.5 years) scheduled for abdominal surgical removal of gastrointestinal cancers were randomized to TEA (n = 21) and sham-TEA (n = 21). TEA was performed via acupoints ST36 and PC6 1 h twice daily from the postoperative day (POD) 1 to day 3. Sham-TEA was performed at non-acupoints.Results:(1) TEA improved major postoperative symptoms by about 30%, including a reduction in time to defecation by 31.7% (P < 0.01 vs. sham-TEA), time to first flatus by 35.9% (P < 0.001), time to ambulation by 42.8% (P < 0.01), time to resuming diet by 26.5% (P < 0.01) and hospital stay by 30% (P < 0.05) as well as pain score by 50% (P < 0.01). (2) TEA significantly increased vagal activity (P < 0.001) and decreased sympathetic activity on POD 4 (P < 0.001) compared with POD 1 as well as the serum level of NE (P < 0.05). (3) The vagal activity, high frequency assessed from the spectral analysis of heart rate variability, was negatively correlated with time to resuming diet, whereas the sympathetic measurement, serum norepinephrine was positively correlated with time to resuming diet and time to flatus. (4) TEA but not sham-TEA decreased TNF-α by 17.4% from POD 1 to POD 4. (5) TEA was an independent predictor of a shorter hospital stay.Conclusions:Needleless TEA improves major postoperative symptoms by enhancing vagal and suppressing sympathetic activities.

ObjectivesVagus nerve stimulation (VNS), most likely via enteric neurons, prevents postoperative ileus (POI) by reducing activation of alpha7 nicotinic receptor (α7nAChR) positive muscularis macrophages (mMφ) and dampening surgery-induced intestinal inflammation. Here, we evaluated if 5-HT4 receptor (5-HT4R) agonist prucalopride can mimic this effect in mice and human.DesignUsing Ca2+ imaging, the effect of electrical field stimulation (EFS) and prucalopride was evaluated in situ on mMφ activation evoked by ATP in jejunal muscularis tissue. Next, preoperative and postoperative administration of prucalopride (1–5 mg/kg) was compared with that of preoperative VNS in a model of POI in wild-type and α7nAChR knockout mice. Finally, in a pilot study, patients undergoing a Whipple procedure were preoperatively treated with prucalopride (n=10), abdominal VNS (n=10) or sham/placebo (n=10) to evaluate the effect on intestinal inflammation and clinical recovery of POI.ResultsEFS reduced the ATP-induced Ca2+ response of mMφ, an effect that was dampened by neurotoxins tetrodotoxin and ω-conotoxin and mimicked by prucalopride. In vivo, prucalopride administered before, but not after abdominal surgery reduced intestinal inflammation and prevented POI in wild-type, but not in α7nAChR knockout mice. In humans, preoperative administration of prucalopride, but not of VNS, decreased Il6 and Il8 expression in the muscularis externa and improved clinical recovery.ConclusionEnteric neurons dampen mMφ activation, an effect mimicked by prucalopride. Preoperative, but not postoperative treatment with prucalopride prevents intestinal inflammation and shortens POI in both mice and human, indicating that preoperative administration of 5-HT4R agonists should be further evaluated as a treatment of POI.Trial registration number NCT02425774.

Millions of patients worldwide suffer from gastrointestinal (GI) motility disorders such as gastroparesis. These disorders typically include debilitating symptoms, such as chronic nausea and vomiting. As no cures are currently available, clinical care is limited to symptom management, while the underlying causes of impaired GI motility remain unaddressed. The efficient movement of contents through the GI tract is facilitated by peristalsis. These rhythmic slow waves of GI muscle contraction are mediated by several cell types, including smooth muscle cells, enteric neurons, telocytes, and specialised gut pacemaker cells called interstitial cells of Cajal (ICC). As ICC dysfunction or loss has been implicated in several GI motility disorders, ICC represent a potentially valuable therapeutic target. Due to their availability, murine ICC have been extensively studied at the molecular level using both normal and diseased GI tissue. In contrast, relatively little is known about the biology of human ICC or their involvement in GI disease pathogenesis. Here, we demonstrate human gastric tissue as a source of primary human cells with ICC phenotype. Further characterisation of these cells will provide new insights into human GI biology, with the potential for developing novel therapies to address the fundamental causes of GI dysmotility.

Purpose To evaluate prospectively duration and effectiveness of aperistalsis achieved by glucagon(GLU) or hyoscine N-butylbromide(HBB) following various administration routes. Materials and methods Six volunteers underwent Magnetic Resonance Imaging (MRI) after standardized oral preparation in random order five separate MR examinations with both spasmolytic agents (HBB intravenous(i.v.) or intramuscular(i.m.), GLU i.v. or i.m., and a combined scheme). The MR protocol included a sagittal 2D cross-section of the small bowel with a temporal resolution of 0.55 s acquired over 60 to 90 min. To quantify bowel motility, small bowel cross-sectional areas were summated over time. Results The anti-peristaltic i.v. effects of HBB and glucagon started on average after 85 s/65 s and ended after 21 min/23.3 min, respectively. By comparison, the anti-peristaltic effects of i.m. HBB and glucagon started significantly later 5.1/11.6 min ( P  = 0.001; Wilcoxon signed ranks test) and lasted for 17.7/28.2 min with greater inter-individual differences ( P  = 0.012; Brown-Forsythe test). The combined scheme resulted in a rapid onset after 65 s with effect duration of 31 min. Conclusion Anti-peristaltic effects on the small bowel are drug dependant, i.e., their onset is faster and more reliable when administering i.v. than i.m.. Combining i.v. GLU with i.m. HBB provides an early onset of effect, sustained spasmolysis and the highest degree of motility impairment. Key Points • Anti-persitaltic agents are widely used before various diagnostic procedures of the abdomen . • The combination of iv-glucagon with im-hyoscine provides reliable spasmolysis with early onset . • Intravenous spasmolysis is more reliable compared to intramuscular administration . • Intravenous glucagon has a prolonged spasmolytic effect compared to intravenous hyoscine .