Randomized controlled trial of linaclotide in children aged 6-17 years with functional constipation.

OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for treatment of children 6-17 years old with functional constipation (FC). This study evaluated the safety and efficacy of several linaclotide doses in children 6-17 years old with FC. METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase 2 study, 173 children with FC (based on Rome III criteria) were randomized to once-daily linaclotide (A: 9 or 18 µg, B: 18 or 36 µg, or C: 36 or 72 µg) or placebo in a 1:1:1:1 ratio for 6- to 11-year-olds (dosage determined by weight: 18 to <35 or ≥35 kg) and linaclotide (18, 36, 72, or 145 µg) or placebo in a 1:1:1:1:1 ratio for 12- to 17-year-olds. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency throughout the 4-week treatment period. Adverse events (AE), clinical laboratory values, and electrocardiograms were monitored. RESULTS: Efficacy and safety were assessed in 173 patients (52.0% aged 6-11 years; 48.0% aged 12-17 years); 162 (93.6%) completed the treatment period. A numerical improvement in mean SBM frequency was observed with increasing linaclotide doses (1.90 in 6- to 11-year-olds [36 or 72 µg] and 2.86 in 12- to 17-year-olds [72 µg]). The most reported treatment-emergent AE was diarrhea, with most cases being mild; none were severe. CONCLUSIONS: Linaclotide was well tolerated in this pediatric population, with a trend toward efficacy in the higher doses, warranting further evaluation.

Effects of fermented soymilk with Lacticaseibacillus paracasei YIT 9029 on gut microbiota and defecation habits: a randomised, double-blind, placebo-controlled study.

Previous studies have demonstrated that soymilk and Lacticaseibacillus paracasei YIT 9029 (strain Shirota: LcS) each beneficially affect the gut microbiota and defecation habits. To investigate the effects of daily consumption of fermented soymilk containing LcS (FSM), we conducted a randomised, double-blind, placebo-controlled study of 112 healthy Japanese adults with a low faecal Bifidobacterium count. They consumed 100 ml FSM or placebo (unfermented soymilk base) once daily for 4 weeks. Their gut microbiota was analysed by 16S rRNA gene amplicon sequencing and quantitative reverse transcription-polymerase chain reaction (PCR), and faecal short-chain fatty acids (SCFAs) and urinary putrefactive products were assessed during the pre- and post-consumption periods. Defecation habits were examined weekly using a subjective questionnaire. In the post-consumption period, living LcS were not detected in two subjects in the FSM group (n = 57) but were detected in one subject in the SM group (n = 55). The FSM group had a significantly higher number and relative abundance of faecal lactobacilli compared with the placebo group. The relative abundance of Bifidobacterium, alpha-diversity of microbiota, and concentrations of acetate and total SCFAs in faeces were significantly increased in the FSM group, although no significant differences were detected between the groups. The number of defecations and defecation days per week significantly increased in both groups. Subgroup analysis of 109 subjects, excluding 3 with inconsistent LcS detection (2 and 1 subjects in the FSM and SM groups, respectively), revealed that the FSM group (n = 55) had significantly greater increases in faecal acetate concentration compared with the SM group (n = 54) and significant upregulation of pathways related to energy production or glucose metabolism in the gut microbiota. These findings suggest that daily FSM consumption improves the gut microbiota and intestinal environment in healthy adults and may help to maintain health and prevent diseases. Registered at the University Hospital Medical Information Network (UMIN) clinical trials registry under: UMIN 000035612.

Impacts of genetic polymorphisms and cancer cachexia on naldemedine pharmacokinetics and bowel movements in patients receiving opioid analgesics.

BACKGROUND/OBJECTIVES: Clinical responses to naldemedine vary between individuals with advanced cancer. This is a prospective, single-center, observational study aimed to evaluate the influence of genetic polymorphisms and cachexia status on plasma naldemedine and clinical responses. METHODS: Forty-eight patients being treated with naldemedine for opioid-induced constipation under treatment of cancer pain were enrolled. Plasma naldemedine concentrations were determined on the fourth day or later after administration of naldemedine, and the associations with genotypes, cachexia status, and clinical responses were assessed. RESULTS: Cancer patients exhibited a large variation in the plasma naldemedine concentrations, and it was correlated with serum total protein level. Patients who were homozygous CYP3A5*3 had a higher plasma concentration of naldemedine than those with the *1 allele. ABCB1 genotypes tested in this study were not associated with plasma naldemedine. A negative correlation was observed between the plasma naldemedine concentration and 4ß-hydroxycholesterol level. The plasma naldemedine concentration was lower in patients with refractory cachexia than in those with precachexia and cachexia. While serum levels of interleukin-6 (IL-6) and acute-phase proteins were higher in patients with refractory cachexia, they were not associated with plasma naldemedine. A higher plasma concentration of naldemedine, CYP3A5*3/*3, and an earlier naldemedine administration after starting opioid analgesics were related to improvement of bowel movements. CONCLUSION: Plasma naldemedine increased under deficient activity of CYP3A5 in cancer patients. Cachectic patients with a higher serum IL-6 had a lower plasma naldemedine. Plasma naldemedine, related to CYP3A5 genotype, and the initiation timing of naldemedine were associated with improved bowel movements.

Do synbiotics really enhance beneficial synbiotics effect on defecation symptoms in healthy adults?: Randomized, double-blind, placebo-controlled trial.

GOALS: We examined whether synbiotics enhance improvement by probiotics. BACKGROUND: Probiotics, which are beneficial microbacteria, are a nutritional intervention for treatment of functional constipation or its tendency. Prebiotics, meanwhile, can promote the proliferation of probiotics in the gastrointestinal tract and enhance their beneficial effects. Synbiotics, a combination of probiotics and prebiotics, may be superior to probiotics in the treatment of defecation-related symptoms, but this requires elucidation. STUDY: This randomized, double-blind, placebo-controlled study enrolled 69 healthy adults with constipation tendency. Participants were allocated to either control, probiotics, or synbiotics groups and they recorded details of their defecations and their condition. The first 2 weeks were the observation period and the latter 2 weeks were the intervention period, in which participants took test foods. Probiotic foods included Bifidobacterium longum NT strain (1010 CFU/day), synbiotic foods included the NT strain (1010 CFU/day) and galactooligosaccharide (1 g/day). Placebo foods contained the vehicle only. Participants answered questionnaires (Patient Assessment on Constipation Symptoms [PAC-SYM], and one on dietary history) on the last day of each period. RESULTS: Nine participants withdrew consent, and 2 of the remaining 60 had missing data. Age, body mass index, and sex were not significantly different between the 3 groups. Frequency of bowel movements in the fourth week, the primary endpoint, was not increased in the probiotics or synbiotics groups compared with the control group, and the frequency of bowel movements and days with defecation were not changed by probiotics or synbiotics during the intervention period. Probiotics and synbiotics did not improve stool conditions, although incomplete defecation was improved by probiotics but not by synbiotics compared with placebo. PAC-SYM indicated that stool condition and total scores were improved by probiotics but not by synbiotics during the intervention compared with placebo. CONCLUSION: The probiotic strain Bifidobacterium longum NT can improve constipation symptoms, especially stool condition, but it does not increase bowel movement frequency in healthy adults with constipation tendency. Synbiotics treatment seemed to diminish this improvement of constipation induced by probiotics. This study indicates the possibility of attenuation of beneficial effects from probiotics by the use of synbiotics, contrary to synbiotics theory.

Prebiotic Galacto-Oligosaccharides Impact Stool Frequency and Fecal Microbiota in Self-Reported Constipated Adults: A Randomized Clinical Trial.

Constipation is a major issue for 10-20% of the global population. In a double-blind randomized placebo-controlled clinical trial, we aimed to determine a dose-response effect of galacto-oligosaccharides (GOS) on stool characteristics and fecal microbiota in 132 adults with self-reported constipation according to Rome IV criteria (including less than three bowel movements per week). Subjects (94% females, aged: 18-59 years) received either 11 g or 5.5 g of BiotisTM GOS, or a control product, once daily for three weeks. Validated questionnaires were conducted weekly to study primarily stool frequency and secondary stool consistency. At base- and endline, stool samples were taken to study fecal microbiota. A trend towards an increased stool frequency was observed after the intervention with 11 g of GOS compared to control. While during screening everybody was considered constipated, not all subjects (n = 78) had less than three bowel movements per week at baseline. In total, 11 g of GOS increased stool frequency compared to control in subjects with a low stool frequency at baseline (≤3 bowel movements per week) and in self-reported constipated adults 35 years of age or older. A clear dose-response of GOS was seen on fecal Bifidobacterium, and 11 g of GOS significantly increased Anaerostipes hadrus. In conclusion, GOS seems to be a solution to benefit adults with a low stool frequency and middle-aged adults with self-reported constipation.

Evaluation of the antidiarrheal activity of 80% methanol extract and solvent fractions of the leaf of Bersama abyssinica fresen (Melianthaceae) in mice.

INTRODUCTION: The use of traditional medicinal plants in the management of diarrhea has long been practiced in Ethiopia. B. abyssinica fresen is one of the plants traditionally used to treat diarrhea whereas an in vivo study had not yet been conducted. Thus, this study aimed to evaluate the antidiarrheal activity of crude extract and solvent fractions of the leaf of B. abyssinica in mice. METHODS: Cold maceration within 80% methanol was used to extract the leaf powder and extract of the leaf was fractionated using n-hexane, chloroform, and distilled water. The in vivo antidiarrheal activity of crude extracts and solvent fractions were tested in experimental models of castor oil-induced diarrhea, enteropooling, and antimotility test. Five groups each with 6 mice were used under the three antidiarrheal models. Positive controls were treated with loperamide 3 mg/kg and atropine 5 mg/kg and 2% tween 80 was used in the treatment of negative controls. The extract and solvent fractions were administered at doses of 100, 200, and 400 mg/kg. Time of onset of diarrhea, number and weight of total and wet feces, the percent reduction in the number of wet feces, weight and volume of intestinal contents, and percent inhibition of intestinal motility were recorded. Data were analyzed using SPSS version 20. RESULT: Defecation of castor oil-induced diarrheal or loose stools was inhibited (p < 0.01 to p < 0.001) at 200 mg/kg and 400 mg/kg of crude extract and aqueous fraction. The crude extract and the aqueous fraction at three doses (p < 0.01 to p < 0.001), the chloroform fraction at 200 mg/kg and 400 mg/kg (p < 0.01 to p < 0.001), and the n-hexane fraction at 400 mg/kg (p < 0.05) reduced intraluminal fluid accumulation compared with the negative control. Castor oil-induced intestinal motility was significantly suppressed with the three-doses of aqueous fraction (p < 0.05 to p < 0.001), 200 mg/kg and 400 mg/kg of crude extract (p < 0.05 to p < 0.01), 400 mg/kg of chloroform and n-hexane (p < 0.01 to p < 0.001) compared with negative control. CONCLUSION: The crude extract, aqueous, and chloroform fractions of B. abyyssinica leaves have promising anti-diarrheal effects, supporting the plant's traditional use to treat diarrhea.

Combination of Enhanced Instructions Improve Quality of Bowel Preparation: A Prospective, Colonoscopist-Blinded, Randomized, Controlled Study.

BACKGROUND: Appropriate bowel preparation is highly important for the efficacy of colonoscopy; however, up to one-third of patients do not accomplish adequate bowel preparation. OBJECTIVE: We investigated the impact of the combination of enhanced instruction on the quality of bowel preparation and its impact on clinically relevant outcomes. DESIGN: This was a colonoscopist-blinded, prospective, randomized trial. SETTINGS: All patients received regular instructions for bowel preparation. Patients were randomly assigned to the control, telephone reeducation, and combined enhanced instruction groups. PATIENTS: Outpatients aged 19 to 75 years scheduled to undergo colonoscopy were included. MAIN OUTCOME MEASURES: The main outcome was adequate bowel preparation rate. RESULTS: A total of 311 patients were randomly assigned to the combined enhanced instruction (n = 104), telephone reeducation (n = 101), and control groups (n = 106). An intention-to-treat analysis showed that the adequate bowel preparation rate was higher in the combined enhanced instruction group than in the telephone reeducation and control groups (92.3% vs 82.2% vs 76.4%, p = 0.007). The rate of compliance with the instructions was significantly higher in the combined enhanced instruction group than in the telephone reeducation and control groups. Method of education was associated with proper bowel preparation (adjusted OR 17.46; p < 0.001 for combined enhanced instruction relative to control). LIMITATIONS: This was a single-center study conducted in Korea. CONCLUSIONS: Combined enhanced instruction as an adjunct to regular instructions much improved the quality of bowel preparation and patients' adherence to the preparation instructions. The combined enhanced instruction method could be the best option for bowel preparation instruction. See Video Abstract at http://links.lww.com/DCR/B673. LA COMBINACIN DE INSTRUCCIONES MEJORADAS, INCREMENTA LA CALIDAD DE LA PREPARACIN INTESTINAL ESTUDIO PROSPECTIVO, CONTROLADO, ALEATORIO Y CIEGO PARA EL COLONOSCOPISTA: ANTECEDENTES:La preparación adecuada del intestino es muy importante para la eficacia de la colonoscopia; sin embargo, hasta un tercio de los pacientes no logran buenos resutlados.OBJETIVO:Investigar el impacto de la combinación de instrucciónes claras en la calidad de la preparación intestinal y su impacto en los resultados clínicos.DISEÑO:Trabajo aleatorio, prospectivo y ciego para el colonoscopista.AJUSTES:Los pacientes recibieron instrucciones periódicas para la preparación intestinal. Fueron asignados aleatoriamente al grupo control, educación telefónica y de instrucción mejoradas.PACIENTES:Se incluyeron pacientes ambulatorios de 19 a 75 años programados para ser sometidos a colonoscopia.PRINCIPALES MEDIDAS DE RESULTADO:El principal resultado fue una adecuada preparación intestinal.RESULTADOS:Un total de 311 pacientes fueron asignados al azar a la instrucción mejorada combinada (n = 104), reeducación telefónica (n = 101) y grupo de control (n = 106). El análisis estadístico mostró que la tasa de preparación intestinal adecuada fue mayor en el grupo combinado de instrucción mejorada que en los grupos de reeducación telefónica y control (92,3% vs 82,2% vs 76,4%, p = 0,007). La tasa de cumplimiento de las instrucciones fue significativamente mayor en el grupo de instrucción mejorada combinada que en los otros. El método de educación se asoció con una preparación intestinal adecuada (razón de posibilidades ajustada de 17,46; p <0,001 para la instrucción mejorada combinada en relación con el control.LIMITACIONES:Estudio en un solo centro realizado en Corea.CONCLUSIONES:La instrucción mejorada combinada como complemento de las instrucciones regulares mejoró mucho la calidad de la preparación intestinal y la adherencia de los pacientes a las instrucciones de preparación. El método de instrucción mejorado combinado podría ser la mejor opción para la instrucción de preparación intestinal. Consulte Video Resumen en http://links.lww.com/DCR/B673.

The effect of sodium carboxymethyl starch with high degree of substitution on defecation.

Sodium carboxymethyl starch (CMS-Na), a kind of food additive with high degree of substitution, is also known as a prebiotic. The aim of this study was to determine the effect of CMS-Na on defecation. Constipated mouse model was prepared by loperamide. Normal rats were also used in the study. Short-chain fatty acids in rat feces were detected by gas chromatography. The bacterial communities in rat feces were identified by 16S rDNA gene sequencing. 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (Tph1) were measured by ELISA. The results showed that CMS-Na increased the fecal granule counts and intestinal propulsion rate in constipated mice. The contents of water, acetic acid, propionic acid and n-butyrate in feces, Tph1 in colon and 5-HT in serum of rats were increased. In addition, CMS-Na shortened the colonic transport time in rats. The 16S rDNA gene sequencing results indicated that CMS-Na increased the relative abundance of Alloprevotella and decreased the proportion of Lactobacillus. However, the biodiversity of the normal intestinal flora was not altered. In conclusion, CMS-Na can promote defecation in constipated mice. The mechanism may be related to the regulation of Alloprevotella and Lactobacillus in colon, the increase of short-chain fatty acids, and the promotion of the synthesis of Tph1 and 5-HT.

Impact of Glucosamine Supplementation on Gut Health.

Glucosamine (GLU) is a natural compound found in cartilage, and supplementation with glucosamine has been shown to improve joint heath and has been linked to reduced mortality rates. GLU is poorly absorbed and may exhibit functional properties in the gut. The purpose of this study was to examine the impact of glucosamine on gastrointestinal function as well as changes in fecal microbiota and metabolome. Healthy males (n = 6) and females (n = 5) (33.4 ± 7.7 years, 174.1 ± 12.0 cm, 76.5 ± 12.9 kg, 25.2 ± 3.1 kg/m2, n = 11) completed two supplementation protocols that each spanned three weeks separated by a washout period that lasted two weeks. In a randomized, double-blind, placebo-controlled, crossover fashion, participants ingested a daily dose of GLU hydrochloride (3000 mg GlucosaGreen®, TSI Group Ltd., Missoula, MT, USA) or maltodextrin placebo. Study participants completed bowel habit and gastrointestinal symptoms questionnaires in addition to providing a stool sample that was analyzed for fecal microbiota and metabolome at baseline and after the completion of each supplementation period. GLU significantly reduced stomach bloating and showed a trend towards reducing constipation and hard stools. Phylogenetic diversity (Faith's PD) and proportions of Pseudomonadaceae, Peptococcaceae, and Bacillaceae were significantly reduced following GLU consumption. GLU supplementation significantly reduced individual, total branched-chain, and total amino acid excretion, with no glucosamine being detected in any of the fecal samples. GLU had no effect on fecal short-chain fatty acids levels. GLU supplementation provided functional gut health benefits and induced fecal microbiota and metabolome changes.

Dietary Supplementation with Fermented Brassica rapa L. Stimulates Defecation Accompanying Change in Colonic Bacterial Community Structure.

Our previous studies have elucidated that oral administration of Brassica rapa L. extract, known as Nozawana in Japan, alters immune responses and gut microbiota composition, increasing the numbers of butyrate-producing bacteria. Therefore, further investigation would help elucidate the mechanism attributable for the changes and health-promoting effects observed after B rapa L. extract ingestion. To reveal the modulation effects of fermented B. rapa L. on immune function and intestinal bacterial community structure, we conducted an intervention study with healthy volunteers followed by a mouse feeding study. The pilot intervention study was conducted for healthy volunteers aged 40-64 years under the hypothesis that the number of subjects exhibiting any change in gut microbiota in response to fermented B. rapa L. consumption may be limited. In total, 20 volunteers consumed 30 g of fermented B. rapa L. per day for 4 weeks. The fecal bacterial community composition of the volunteers was characterized using terminal-restriction fragment length polymorphism patterning followed by clustering analysis. To evaluate the detailed changes in the immune responses and the gut bacterial composition, assessed by high-throughput sequencing, we fed healthy mice with freeze-dried, fermented B. rapa L. for 2 weeks. The fecal bacterial community composition of the volunteers before the intervention was divided into three clades. Regardless of the clade, the defecation frequency significantly increased during the intervention weeks compared with that before the intervention. However, this clustering detected a specific increase of Prevotella in one cluster (low to zero Prevotella and high occupation of Clostridium at clusters IV and XIVa) post-ingestion. The cytokine production of spleen cells significantly increased due to feeding fermented B. rapa L. to the mice. This supplementary in vivo trial provided comparable results to the volunteer study regarding the effects of ingestion of the material given the compositional change complying with that of dietary fiber, particularly in the increase of genera Prevotella, Lachnospira, and genera in the Ruminococcaceae family, and the increase in daily defecation amount during 2 weeks of administration. We conclude that feeding fermented B. rapa L. may be responsible for the observed modulation in gut microbiota to increase fiber-degrading bacteria and butyrate-producing bacteria which may be relevant to the improvement in bowel function such as defecation frequency.

Using Electronic Medical Records of Nursing Care to Characterize Constipation in Patients with Intracerebral Hemorrhage.

INTRODUCTION: Constipation is one of the common poststroke complications that directly affect the patients' quality of life in patients with intracerebral hemorrhage (ICH), which has not been paid enough attention. OBJECTIVE: This study investigates constipation's clinical characteristics and its risk factors in ICH patients driven by the electronic medical records of nursing care. METHODS: This retrospective chart review investigated patients with acute spontaneous ICH admitted at a tertiary care center from October 2010 to December 2018. Poststroke constipation was defined as a first stool passage occurring after 3 days postadmission and the use of enemas or laxatives after ICH. The associations between constipation present and potential factors were evaluated. RESULTS: Of 1,748 patients, 408 (70.3% men, mean age 58 ± 14 years) patients with poststroke constipation were identified. After adjusting for potential confounding variables, the risk factors independently associated with poststroke constipation are admission Glasgow Coma Scale score (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.44-0.88; p = 0.007), use of mechanical ventilation (OR 3.74, 95% CI 2.37-5.89, p < 0.001), enteral nutrition (OR 2.82, 95% CI 1.85-4.30, p < 0.001), hematoma evacuation (OR 2.10, 95% CI 1.40-3.16; p < 0.001), opioid analgesics (OR 1.86, 95% CI 1.32-2.62; p < 0.001), sedation (OR 1.83, 95% CI 1.20-2.77; p = 0.005), and vasopressors (OR 1.81, 95% CI 1.26-2.61; p = 0.001) in order. Similar associations were observed in the prespecified length of the stay subgroup. Patients with constipation were associated with a longer hospital stay length (2.24 days, 95% CI 1.43-3.05, p < 0.001) but not with in-hospital mortality (OR 1.05, 95% CI 0.58-1.90, p = 0.871). CONCLUSIONS: Our findings suggested that risk factors influence the absence of constipation after ICH with the synergy of different weights. The occurrence of constipation likely affects a longer length of stay, but not in-hospital mortality. Future prospective investigations are warranted to validate our findings and identify the optimal management of constipation that may improve the quality of life in patients with ICH.

Kamikihito, a traditional Japanese Kampo medicine, increases the secretion of oxytocin in rats with acute stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Kamikihito (KKT) is a Kampo medicine that is prescribed in Japan for the treatment of anemia, insomnia and mental anxiety in Japan. However, its precise mechanism of action remains unclear. AIM OF THE STUDY: This study aimed to evaluate the possible antistress effect of KKT in rats with acute stress and the contribution of oxytocin to the process. MATERIALS AND METHODS: Acute immobilization stress (AIS; for 90 min) was used to assess the effect of KKT on acute stress. Male Wistar rats were orally treated with KKT. Parameters of stress were evaluated, and concentrations of oxytocin in plasma and cerebrospinal fluid (CSF) were measured. RESULTS: AIS-induced defecation and fecal weight were significantly decreased because of treatment with KKT. The plasma levels of stress-related hormones following AIS were investigated. The pre-administration of KKT significantly increased adrenocorticotrophic hormone (ACTH) and corticosterone (CORT) levels following AIS. Conversely, there was no significant change in the plasma oxytocin level. Microdialysis and hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) were used to monitor the oxytocin secretion in CSF. Oxytocin level increased during AIS following the treatment of KKT. At 30 min after AIS, the level remained higher than before AIS. Furthermore, using an open field test, the locomotion (exploratory behavior) immediately after AIS was examined. The total traveled distance decreased after AIS; however, the decrease was significantly inhibited by the treatment of KKT. However, the effect of KKT was obstructed by the pre-administration of the oxytocin receptor antagonist. CONCLUSIONS: These results suggest that KKT has antistress activity and increased oxytocin secretion may be a mechanism underlying this phenomenon.

The effect of microbial composition and proteomic on improvement of functional constipation by Chrysanthemum morifolium polysaccharide.

In this paper, SD rat constipation model was established with loperamide hydrochloride to study the effect of Chrysanthemum morifolium polysaccharide on the improvement of functional constipation, and the mechanism of improving constipation was investigated with the proteomics and intestinal flora. The results showed that the HD group of C. morifolium polysaccharide could significantly increase the levels of water content of stool pellets, small intestine propulsion rate, gastrin (MTL), gastrin (GAS) and substance P (SP), decrease the level of growth inhibitor (SS) and improved gastrointestinal motility in rats. Gut microbial studies showed that C. morifolium polysaccharide could significantly increase species abundance and flora diversity and improve flora structure. The relative abundance of Lactobacillus and Romboutsia increased, while the relative abundance of Lachnospiraceae_NK4A136_group and Roseburia decreased compared with the MC group. Proteomics studies suggested that C. morifolium polysaccharides could reduce intestinal lesions, enhance intestinal homeostasis, increase amino acid uptake, promote intestinal motility and relieve constipation by regulating the expression of RAS, FABP1 and SLC1A5 proteins.

Efficacy and Safety of Over-the-Counter Therapies for Chronic Constipation: An Updated Systematic Review.

INTRODUCTION: Constipation is commonly treated with over-the-counter (OTC) products whose efficacy and safety remain unclear. We performed a systematic review of OTC therapies for chronic constipation and provide evidence-based recommendations. METHODS: We searched PubMed and Embase for randomized controlled trials of ≥4-week duration that evaluated OTC preparations between 2004 and 2020. Studies were scored using the US Preventive Services Task Force criteria (0-5 scale) including randomization, blinding, and withdrawals. The strengths of evidence were adjudicated within each therapeutic category, and recommendations were graded (A, B, C, D, and I) based on the level of evidence (level I, good; II, fair; or III, poor). RESULTS: Of 1,297 studies identified, 41 met the inclusion criteria. There was good evidence (grade A recommendation) for the use of the osmotic laxative polyethylene glycol (PEG) and the stimulant senna; moderate evidence (grade B) for psyllium, SupraFiber, magnesium salts, stimulants (bisacodyl and sodium picosulfate), fruit-based laxatives (kiwi, mango, prunes, and ficus), and yogurt with galacto-oligosaccharide/prunes/linseed oil; and insufficient evidence (grade I) for polydextrose, inulin, and fructo-oligosaccharide. Diarrhea, nausea, bloating, and abdominal pain were common adverse events, but no serious adverse events were reported. DISCUSSION: The spectrum of OTC products has increased and quality of evidence has improved, but methodological issues including variability in study design, primary outcome measures, trial duration, and small sample sizes remain. We found good evidence to recommend polyethylene glycol or senna as first-line laxatives and moderate evidence supporting fiber supplements, fruits, stimulant laxatives, and magnesium-based products. For others, further validation with more rigorously designed studies is warranted.

Xiaoyao-san, a traditional Chinese herbal formula, for the treatment of irritable bowel syndrome: A protocol for a systematic review and meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is a disorder which has considerable effect to patient's quality of life and social functioning. Its main symptoms include recurrent abdominal pain and/or bloating associated with abnormal stool form or frequency. The recommendable treatment of IBS is a medication including loperamide, cimetropium, tricyclic antidepressants, and selective serotonin receptor inhibitors, but it has limited effects and several side effects dissatisfy IBS patients. As an alternative therapy, Xiaoyao-san (XYS) is gaining interest for IBS patients. XYS, a traditional Chinese medicine (TCM), has wide scope of indications and it can be prescribed for various gastrointestinal disorders in TCM syndromes but there has been no systematic review on IBS. Therefore, this review aims on systematically validating the curative effect of XYS on IBS. METHODS: Electronic databases, manual search, and contact to author e-mail will be used for searching randomized controlled trials about the use of XYS for IBS. We will select studies by the predefined criteria and collect the data on study participants, interventions, control groups, outcome measurement, adverse events, and risk of bias. Primary outcome will be the efficacy rate, and secondary outcomes will be the IBS-centered indices (abdominal pain score, abdominal distension score, diarrhea or constipation score, bowel symptom severity scale), index about quality of life, and adverse events. Review Manager software and Cochrane Collaboration "risk of bias" tools will be used for meta-analysis and assessment of risk of bias. RESULTS: This review will identify the clinical evidence of XYS's effectiveness and safety for IBS according to formal evaluation aspects. CONCLUSION: This review will further support the evidence-based usage of XYS for IBS treatment. ETHICS AND DISSEMINATION: No ethical approval is required since there is no personal information collection and patient recruitment. TRIAL REGISTRATION NUMBER: Research Registry; reviewregistry986.

Inhibitory Effects of Dexmedetomidine and Propofol on Gastrointestinal Tract Motility Involving Impaired Enteric Glia Ca2+ Response in Mice.

Propofol and dexmedetomidine are popular used for sedation in ICU, however, inadequate attention has been paid to their effect on gastrointestinal tract (GIT) motility. Present study aimed to compare the effect of propofol and dexmedetomidine on GIT motility at parallel level of sedation and explore the possible mechanism. Male C57BL/6 mice (8-10 weeks) were randomly divided into control, propofol and dexmedetomidine group. After intraperitoneal injection of propofol or dexmedetomidine, comparable sedative level was confirmed by sedative score, physiological parameters and electroencephalogram (EEG). Different segments of GIT motility in vivo (gastric emptying, small intestine transit, distal colon bead expulsion, stool weight and number of fecal pellets, gastrointestinal transit and whole gut transit time) and colonic migrating motor complexes (CMMCs) pattern in vitro were evaluated. The Ca2+ response of primary enteric glia was examined under the treatment of propofol or dexmedetomidine. There is little difference in physiological parameters and composite permutation entropy index (CPEI) between administration of 50 mg/kg propofol and 40 µg/kg dexmedetomidine, indicated that parallel level of sedation was reached. Data showed that propofol and dexmedetomidine had significantly inhibitory effect on GIT motility while dexmedetomidine was stronger. Also, the amplitude (ΔF/F0) of Ca2+ response in primary enteric glia was attenuated after treated with the sedatives while the effect of dexmedetomidine was greater than propofol. These findings demonstrated that dexmedetomidine caused stronger inhibitory effects on GIT motility in sedative mice, which may involve impaired Ca2+ response in enteric glia. Hence, dexmedetomidine should be carefully applied especially for potential GIT dysmotility patient.

Effect of Pancrelipase Therapy on Exocrine Pancreatic Insufficiency Symptoms and Coefficient of Fat Absorption Associated With Chronic Pancreatitis.

OBJECTIVE: The aim of this study was to evaluate whether improvement in coefficient of fat absorption (CFA) with pancreatic enzyme replacement therapy correlates with clinical symptoms in patients with chronic pancreatitis with moderate to severe exocrine pancreatic insufficiency. METHODS: Data were pooled from 2 randomized double-blind trials of the effects of 1 week of pancrelipase (n = 59) versus placebo (n = 57) on CFA and stool frequency, stool consistency, abdominal pain, and flatulence; 1 trial included a 51-week open-label pancrelipase treatment period (n = 34). RESULTS: Compared with placebo, significantly more patients receiving pancrelipase reported decreased stool frequency at week 1 (72% vs 38%; P < 0.001). Although 30% of patients receiving pancrelipase and 20% receiving placebo reported improved stool consistency, changes in stool consistency, abdominal pain, and flatulence were not different between groups. Mean CFA absolute change from baseline was significantly greater with pancrelipase versus placebo (24.7% vs 6.4%; P < 0.001). Improvements in stool consistency and frequency correlated with CFA improvement. Symptom improvements persisted or further improved through 52 weeks of treatment. CONCLUSIONS: Pancrelipase significantly improved exocrine pancreatic insufficiency maldigestive symptoms. Improvements in objective stool symptoms with pancreatic enzyme replacement therapy correlated with CFA improvement at 1 week.

7,8-Dihydroxyflavone Enhanced Colonic Cholinergic Contraction and Relieved Loperamide-Induced Constipation in Rats.

BACKGROUND: Whether 7,8-dihydroxyflavone (7,8-DHF), a tyrosine kinase receptor B (TrkB) agonist, modulates colonic smooth muscle motility and/or alleviates constipation has not yet been studied. AIMS: Here, we aimed to determine how 7,8-DHF influences carbachol (CCh)-stimulated contraction of colonic strips and the in vivo effect of 7,8-DHF on constipation. METHODS: Muscle strips were isolated from rat colons for recording contractile tension and performing western blotting. Constipation was induced in rats with loperamide. RESULTS: Although it specifically activated TrkB, 7,8-DHF applied alone neither activated PLCγ1 in the colonic strips nor induced colonic strip contraction. However, 7,8-DHF enhanced CCh-stimulated PLCγ1 activation and strip contraction. The PLCγ1 antagonist U73122 suppressed both CCh-stimulated and 7,8-DHF-enhanced/CCh-stimulated contraction. While clarifying the underlying mechanism, we revealed that 7,8-DHF augmented muscarinic M3 receptor expression in the colonic strips. The M3-selective antagonist tarafenacin specifically inhibited the 7,8-DHF-enhanced/CCh-stimulated contraction of the colonic strips. Since 7,8-DHF increased Akt phosphorylation, and LY294002 (an antagonist of PI3K upstream of Akt) dramatically inhibited both 7,8-DHF-augmented M3 expression and 7,8-DHF-enhanced/CCh-stimulated contractions, we assumed that 7,8-DHF/TrkB/Akt was associated with the modulation of M3 expression in the colonic strips. ANA-12, a specific TrkB antagonist, not only inhibited TrkB activation by 7,8-DHF but also suppressed 7,8-DHF-enhanced cholinergic contraction, 7,8-DHF/CCh-mediated activation of PLCγ1/Akt, and M3 overexpression in colonic strips. In vivo 7,8-DHF, also by promoting intestinal motility and M3 expression, significantly alleviated loperamide-induced functional constipation in rats. CONCLUSIONS: Our results suggest that 7,8-DHF regulates colonic motility possibly via a TrkB/Akt/M3 pathway and may be applicable for alleviating constipation.

Puerarin from Pueraria lobata alleviates the symptoms of irritable bowel syndrome-diarrhea.

As a functional bowel disorder, irritable bowel syndrome (IBS), especially IBS-diarrhea (IBS-D), affects approximately 9-20% of the population worldwide. Classical treatments for IBS usually result in some side effects and intestinal microbial disorders, which inhibit the clinical effects. Natural edible medicines with beneficial effects and few side effects have received more attention in recent years. Puerarin is the main active ingredient in pueraria and has been used in China to treat splenasthenic diarrhea and as a natural food in folk medicine for hundreds of years. However, there have been no reports of using puerarin in the treatment of IBS-D, and the underlying mechanism is also still unclear. In this study, a comprehensive model that could reflect the symptoms of IBS-D was established by combining neonatal maternal separation (NMS) and adult colonic acetic acid stimulation (ACAAS) in rats. The results showed that puerarin could reverse the abdominal pain and diarrhea in IBS-D rats. The therapeutic effect was realized by regulating the richness of the gut microbiota to maintain the stabilization of the intestinal micro-ecology. Furthermore, the possible mechanism might be related to the activity of the hypothalamic-pituitary-adrenal (HPA) axis by the suppressed expression of corticotropin-releasing hormone receptor (CRF) 1. At the same time, intestinal function was improved by enhancing the proliferation of colonic epithelial cells by upregulating the expression of p-ERK/ERK and by repairing the colonic mucus barrier by upregulating occludin expression. All these results suggest that puerarin could exert excellent therapeutic effects on IBS-D.