The protective effects of electroacupuncture on intestinal barrier lesions in IBS and UC model.

Irritable bowel syndrome (IBS) and ulcerative colitis (UC) are two intestinal diseases with different pathological changes. Electroacupuncture (EA) at Zusanli (ST36) on both IBS and UC is widely used in clinic practice. But it is unclear whether acupuncture at one acupoint can treat two different intestinal diseases at different layers of intestinal barrier. To address this question, we explored three intestinal barrier lesions in IBS and UC mice with the aid of transcriptome data analysis and studied the efficacy of EA at ST36 on them. The transcriptome data analysis showed that both UC and IBS had disrupted intestinal barrier in various layers. And both UC and IBS had epithelial barrier lesions with reduction of ZO-1, Occludin and Claudin-1, while UC rather than IBS had the destruction of the mucus barrier with less MUC2 expression. As to the vascular barrier, UC showed a higher CD31 level and mesenteric blood flow reduction, while IBS showed a lower PV-1 level. EA at ST36 can significantly improve the above lesions of intestinal barrier of IBS and UC. Our results gave more details about the comprehensive protective effect of EA for UC and IBS. We guess the effect of acupuncture may be a kind of homeostasis regulation.

Co-existing polysaccharides affect the systemic exposure of major bioactive ingredients in Chang-Kang-Fang, a multi-herb prescription for treatment of irritable bowel syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Chang-Kang-Fang (CKF) is a traditional Chinese herbal formula used for treatment of irritable bowel syndrome (IBS) in China. Decoction is the administration form of CKF in clinical practice. Previously, CKF has been confirmed with activities of releasing pain and reversing disorders of intestinal propulsion. And alkaloids, monoglycosides, chromones were found as the main bioactive components potentially contributing to the efficacy of CKF. Polysaccharide was also a major constituent in CKF. But if and how polysaccharides influence the systemic exposure of bioactive components in CKF is unknown. AIM OF THE STUDY: In this study, we aimed to demonstrate the contribution of the co-existed polysaccharides on the systemic exposure of the major bioactive components from CKF in normal and IBS model rats. MATERIALS AND METHODS: An UPLC-TQ-MS with multiple reaction monitoring (MRM) scan method was developed and validated for quantifying six major small molecular bioactive ingredients of CKF in the plasma samples, including magnoflorine (MAG), berberine (BBR), albiflorin (ALB), paeoniflorin (PAE), 5-O-methylvisamminol (5-OM) and prim-O-glucosylcimifugin (POG). The rats received CKF decoction (CKF) and CKF small molecule portion (knockout of polysaccharides, CKFSM), respectively. IBS model rats were induced by daily bondage and gavage of Sennae Folium decoction (derived from the leaf of Cassia angustifolia Vahl). The effects of the co-existing polysaccharides on the pharmacokinetic parameters of six small molecular bioactive components in normal and IBS model rats were systematically evaluated. The potential gut microbiota involved mechanisms of the effects was validated by broad-spectrum antibiotic (ABX) treatment. RESULTS: The selectivity, precision, accuracy, recovery and matrix effect of the established quantification method were all within acceptable limits of biological sample. In normal rats, the co-existing polysaccharides significantly reduced the AUC(0-t) of MAG and PAE compared with CKFSM group. The Cmax and AUC(0-t) of other four compound were not influenced by co-existing polysaccharides. However, in IBS model rats, compared with CKFSM group, the Cmax and AUC(0-t) of the six ingredients significantly increased in CKF group. For CKF + ABX group, the Cmax of six ingredients decreased significantly when compared with CKF group, and the AUC(0-t) of MAG, BBR, ALB, PAE also reduced with significant differences. CONCLUSIONS: A reliable and sensitive UPLC-TQ-MS method was successfully developed and validated for evaluating influence of co-existing polysaccharides on pharmacokinetic behavior of six major small molecules components in CKF. The co-existing polysaccharides enhanced the systemic exposure of six bioactive small molecules in CKF under IBS pathological state potentially via gut microbiota involvement.

Identification and molecular study on the interaction of Schisandrin C with human 5-HT3A receptor.

Schisandrin C (Sch C) is one of the main components of Schisandra chinensis (Schisandra). Since the olden times, Schisandra has been used as a traditional herbal medicine in Asia. Recent studies have shown that Schisandra is effective against irritable bowel syndrome (IBS) in an animal model and affects IBS through the 5-HT3A pathway in the IBS rat model. However, there lacks fundamental research on the interaction of specific components of Schisandra with the 5-HT3A receptor for the treatment of IBS. We hypothesized that a component of Schisandra binds to the 5-HT3A receptor and identified Sch C via a screening work using two electrode-voltage clamps (TEVC). Thus, we aimed to elucidate the neuropharmacological actions between Sch C and the 5-HT3A receptor at molecular and cellular levels. Co-treatment of Sch C with 5-HT inhibited I5-HT in a reversible, concentrate-dependent, like-competition, and voltage-independent manner, and IC50 values of Sch C. Besides, the main binding positions of Sch C were identified through 3D modeling and point mutation were V225A and V288Y on 5-HT3A receptor. Thus, we suggest the potential of Sch C in treating IBS in a manner that suppresses excessive neuronal serotonin signaling in the synapse of sensory neurons and enterochromaffin (EC) cells. In conclusion, the results demonstrate the mechanism of interaction between Sch C and 5-HT3A receptor and reveal Sch C as a novel antagonist.

The mechanisms of action of WeiChang'An Pill (WCAP) treat diarrhoea-predominant irritable bowel syndrome (IBS-D) using network pharmacology approach and in vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: WeiChang'An Pill (WCAP) is used in Traditional Chinese Medicine (TCM) to clinically treat diarrhoea-predominant irritable bowel syndrome (IBS-D); however, the underlying pharmacological mechanisms are unclear to date. AIM OF THE STUDY: To explore the mechanism underlying the therapeutic action of WCAP in IBS-D using a network pharmacology approach and in vivo experiments. MATERIALS AND METHODS: The active compounds of WCAP were selected from the TCM Systems Pharmacology Database and TCM Integrated Database, and the potential targets were identified using the Swiss Target Prediction and Similarity Ensemble Approach (SEA) databases. The targets related to IBS-D were mined from the Therapeutic Target Database (TTD), National Center for Biotechnology Information Search database (NCBI), DrugBank database, and DisGeNET database. The intersecting protein-protein interactions (PPIs) of the drug-disease crossover genes were analysed, and the central PPI network was constructed using the String database, version 11.0, and Cytoscape version 3.7.2. Following Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway analyses, the gene-pathway network was constructed for identifying the key target genes and pathways. Based on the results and existing evidence, it was selected the cyclic adenosine monophosphate (cAMP) signalling pathway for further validation using in vivo experiments. RESULTS: A total of 872 targets were identified from the 77 active compounds in WCAP, which shared 78 targets that were predicted to be related to IBS-D. Twenty-one core targets were identified from the PPI network, which was constructed from the common targets. The results of enrichment analysis revealed that HRT2B, ADRA1A, ADRA1D, and CHRM2 could be the key targets of WCAP in IBS-D, and 11 signalling pathways, including the neuroactive ligand-receptor interaction, calcium signalling, and cAMP signalling pathways, were identified as crucial for the therapeutic activity of WCAP in IBS-D. We also identified the possibility of several interactions and crosstalk between the different pathways. Subsequent molecular biology experiments revealed that the expression levels of cAMP, phospho-(Ser/Thr) protein kinase A substrates (p-PKA), 5-hydroxytryptamine, and proteins in the cAMP signalling pathway, including G protein-coupled receptor (GPCR), adenylyl cyclase 5 (AC5), and cAMP-response element binding protein (CREB), were significantly upregulated in rat models of IBS-D following treatment with WCAP (P < 0.05). However, a reverse trend was observed in the expression of nuclear factor kappa-B (NF-κB) (P < 0.05), which could be attributed to the low-grade inflammation that occurs in IBS-D. CONCLUSION: We demonstrated that WCAP may alleviate the symptoms of diarrhoea and visceral sensitivity in IBS-D by regulating the cAMP signalling pathway.

Lipi Guben decoction in treating diarrheal irritable bowel syndrome: A study protocol for a randomized controlled trial.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional bowel disorder. The global incidence of IBS is as high as 9% to 23%, accounting for about 50% of outpatients in gastroenterology, and the new case detection rate is 0.2% every year. IBS has become a global gastrointestinal functional disease. Although IBS is not a life-threatening disease, it seriously affects the quality of life of patients, causing huge economic and mental burden to individuals, society and families. Lipi Guben decoction (LPGBD) is an important auxiliary treatment for IBS, but lack of robust Evidence-based medicine evidence proving its efficacy. Therefore, we designed a randomized controlled trial to evaluate the efficacy and safety of LPGBD in the treatment of IBS. METHODS: In this randomized controlled trial, a total of 100 eligible patients will be allocated to the blank control group or LPGBD group in a ratio of 1:1. The treatment period was 12 weeks. The primary outcome measure will be the total clinical effective rate. The Secondary outcomes will include IBS clinical symptom scores, IBS-Severity Scoring System, IBS-Quality of life, Hamilton Rating Scale for Anxiety, Hamilton Rating Scale for Depression, and Bristol Stool Form Scale. The safety outcome will include Echocardiogram, blood examination (including blood routine test, liver function test, and renal function test), urine routine test and stool routine test. The evaluation indicators and all safety results will be performed at baseline, week 4, week 8 and week 12. RESULTS: This study will be helpful to evaluate the efficacy and safety of LPGBD in the treatment of IBS. CONCLUSION: LPGBD may improve the clinical efficacy of patients with IBS, which has important value in practical application. TRIAL REGISTRATION: Chictr20000039617, registration time: November 3, 2020.

Atractylodes oil alleviates diarrhea-predominant irritable bowel syndrome by regulating intestinal inflammation and intestinal barrier via SCF/c-kit and MLCK/MLC2 pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Atractylodes lancea (Thunb.) DC. is a widely used traditional herb that is well known for treating spleen deficiency and diarrhea. According to traditional Chinese medicine (TCM) theory, diarrhea-predominant irritable bowel syndrome (IBS-D) is caused by cold and dampness, resulting in diarrhea and abdominal pain. Nevertheless, the effect and mechanism of Atractylodes on IBS-D are still unclear. AIM OF THE STUDY: This study was designed to confirm the therapeutic effect of Atractylodes lanceolata oil (AO) in a rat model of IBS-D, and to determine the mechanisms by which AO protects against the disease. MATERIALS AND METHODS: The chemical components in AO were determined using gas chromatography-mass spectrometry (GC-MS). The expression levels of 5-hydroxytryptamine (5-HT), vasoactive intestinal peptide (VIP), and surfactant protein (SP) in serum and colon tissue were measured using enzyme-linked immunosorbent assay (ELISA). Reverse transcription-polymerase chain reaction (RT-PCR), western blotting (WB), immunohistochemistry (IHC), and immunofluorescence (IF) were used to elucidate the mechanism of action of AO toward inflammation and the intestinal barrier in a rat model of IBS-D. RESULTS: The 15 chemical substances of the highest concentration in AO were identified using GC-MS. AO was effective against IBS-D in the rat model, in terms of increased body weight, diarrhea grade score, levels of interleukin-10 (IL-10), aquaporin 3 (AQP3), and aquaporin 8 (AQP8), and reduced fecal moisture content, levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), 5-HT, VIP, and SP, while also reducing intestinal injury, as observed using hematoxylin-eosin (HE) staining. In addition, the results indicated that AO increased the mRNA and protein expression levels of stem cell factor (SCF) and c-kit and enhanced the levels of zonula occludens-1 (ZO-1) and occludin, as well as decreased the levels of myosin light chain kinase (MLCK) and inhibited the phosphorylation of myosin light chain 2 (p-MLC2). CONCLUSIONS: AO was found to be efficacious in the rat model of IBS-D. AO inhibited the SCF/c-kit pathway, thereby reducing inflammation and protecting against intestinal barrier damage via the MLCK/MLC2 pathway.

[A Meta-Analysis on the Effects of Mind-Body Therapy on Patients with Irritable Bowel Syndrome].

PURPOSE: Previous randomized controlled trials (RCT) found that mind-body therapy can improve the health outcomes of patients with irritable bowel syndrome (IBS). The purpose of this meta-analysis was to identify the combined effects of mind-body therapy on patients' IBS symptoms, quality of life, anxiety, and depression. METHODS: A systematic literature search was conducted using various databases such as PubMed, EMBASE, CINAHL CENTRAL, DBpia, RISS, and KISS. The primary outcome variables were IBS symptoms and quality of life; the secondary outcome variables were anxiety and depression. Comprehensive Meta-Analysis version 3.0 was used to analyze the extracted data. The effect size was calculated using standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS: Eleven final RCTs were used for this meta-analysis. Mind-body therapy was found to have a significant effect on the IBS patients' symptoms (SMD, -0.63; 95% CI, -0.77 to -0.48), quality of life (SMD, 1.03; 95% CI, 0.40 to 1.66), anxiety (SMD, -0.28; 95% CI, -0.47 to -0.09), and depression (SMD, -0.31; 95% CI, -0.06 to -0.12). CONCLUSION: This meta-analysis reveals that mind-body therapy significantly improves IBS patients' symptoms, quality of life, anxiety, and depression. The results suggest that, in the future, appropriate mind-body therapy should be applied to Koreans suffering from IBS. Moreover, the therapy's long-term effects should be assessed.

Larger regional volume of the thalamus in diarrhea-predominant irritable bowel syndrome: a cross-sectional study.

As a relay center between the cerebral cortex and various subcortical brain areas, the thalamus is repeatedly associated with the dysfunction of brain-gut interaction in patients with irritable bowel syndrome (IBS). However, the regional morphological alterations of the thalamus in IBS are not well defined. We acquired structural magnetic resonance data from 34 patients with IBS and 34 demographically similar healthy subjects. Data processing was performed using FMRIB's Integrated Registration and Segmentation Tool (FIRST). Volumetric analysis and surface-based vertex analysis were both carried out to characterize the morphology of the thalamus and other subcortical structures. Our results suggested that the majority (31 cases) of the patients with IBS had diarrhea-predominant symptoms. Volumetric analysis revealed a larger normalized volume of the right thalamus and left caudate nucleus in patients with IBS than in healthy controls. Surface analysis indicated that the difference arose mainly from the laterodorsal nucleus of the right thalamus, and the body of the left caudate nucleus. In addition, patients with IBS had different hemispheric asymmetries of the thalamus (rightward) and caudate nucleus (leftward) from controls (leftward for the thalamus and rightward for the caudate nucleus). In general, our results indicated that patients with diarrhea-predominant IBS had enlarged thalamus and caudate nucleus volumes, as well as altered hemispheric asymmetries of these two structures, compared with healthy controls. The neuroimaging evidence of these structural alterations helps clarify the underlying pathophysiology of diarrhea-predominant IBS.

Tong-Xie-Yao-Fang improves intestinal permeability in diarrhoea-predominant irritable bowel syndrome rats by inhibiting the NF-κB and notch signalling pathways.

BACKGROUND: Tong-Xie-Yao-Fang (TXYF) has been shown to be effective in diarrhoea-predominant irritable bowel syndrome (IBS-D) patients. However, the underlying mechanism remains to be clarified. The aim of this study was to investigate the efficacy and related mechanisms of TXYF in an IBS-D rat model. METHODS: The IBS-D rat model was established with 4% acetic acid and evaluated by haematoxylin-eosin (HE) staining. Then, IBS-D rats were divided into control, TXYF and rifaximin groups and treated intragastrically with normal saline, TXYF and rifaximin, respectively, for 14 days. The following indicators were measured before and after treatment: defecation frequency, faecal water content (FWC) and colorectal distension (CRD). Histopathological changes in the distal colon were observed after treatment. The expression of OCLN and ZO1 in the distal colon of IBS-D rats reflected the intestinal mucosal permeability, as measured by qRT-PCR, western blot, and enzyme-linked immunosorbent assays (ELISAs). The NF-κB and Notch signalling pathways and inflammation-related factors were investigated. RESULTS: After treatment with TXYF, the defecation frequency, FWC and CRD were significantly lower than those in the model group (P < 0.05). HE staining showed that colonic epithelial cells (CECs) in the IBS-D rats displayed significant oedema, impaired intestinal mucosal integrity and an increased influx of inflammatory cells. A significant reduction in granulocyte and CEC oedema was observed after the administration of TXYF and rifaximin compared to that of the model group and blank group (P < 0.05). TXYF significantly upregulated the expression of OCLN and ZO-1 and downregulated inflammation-related factors (IL-6, IL-1ß, and TNF-α and the chemokine KC) in IBS-D rats compared to those in the model group rats (P < 0.05). In terms of the NF-κB and Notch signalling pathways, the expression of NICD, p-ERK, Hes-1 and p-P65 decreased significantly in the TXYF and rifaximin groups, while the expression of ATOH1 increased significantly compared to that in the model group (P < 0.05). CONCLUSION: TXYF can effectively improve intestinal permeability and enhance intestinal mucosal barrier function, which may be related to inhibition of the inflammatory cascade and the NF-κB and Notch signalling pathways.

Antioxidant Capacity and Behavioral Relevance of a Polyphenolic Extract of Chrysanthellum americanum in a Rat Model of Irritable Bowel Syndrome.

Chrysanthellum americanum L. (Vatke) is a medicinal plant from the Compositae family used in west-African traditional medicine, known for its flavonoid and saponin richness and for its strong antioxidant potential. In the present study, we assessed the effects of Chrysanthellum americanum polyphenolic extract in the psychological stress-induced rat model of irritable bowel syndrome (IBS), a chronic functional digestive tract disorder marked by immune and inflammatory-related disturbances of central nervous and peripheral intestinal systems, which is often associated with mood disorders including depression and anxiety. Consequently, memory impairment, anxiety and depression behavioral indicators, and cerebral oxidative stress biomarker dynamics were evaluated in a multifactorial heterotypic stress-exposed IBS rats after 6-day gavage with polyphenolic C. americanum extract (100 mg/kg body weight). Y-maze, elevated plus maze, and forced swimming tests were used for assessing behavioral responses. Administration of the extract exhibited significant anxiolytic and antidepressant-like effects coupled with significantly increased temporal lobe antioxidant enzyme specific activity (superoxide dismutase and glutathione peroxidase) and decreased malondialdehyde levels, a well-known lipid peroxidation marker. Furthermore, linear regression statistical analyses showed significant correlations between the oxidative stress parameters and behavioral tests. In conclusion, our results suggest that the administration of Chrysanthellum americanum polyphenolic extract could ameliorate mood and cognitive disturbances related to stress-induced in an IBS rat model. This could be also related to cerebral oxidative stress status attenuation.

Mechanisms of Probiotic VSL#3 in a Rat Model of Visceral Hypersensitivity Involves the Mast Cell-PAR2-TRPV1 Pathway.

BACKGROUND: Mast cells (MCs), PAR2 and TRPV1, play a key role in the regulation of visceral pain. Several studies have found that probiotics regulate visceral sensitivity. AIMS: The purpose of the current study was to explore the role of MC-PAR2-TRPV1 in VH and the mechanism of VSL#3 in a rat model of VH. METHODS: A total of 64 rats were randomly divided into eight groups: Control VH, VH + ketotifen, VH + FSLLRY-NH2, VH + SB366791, VH + VSL#3, VH + VSL#3 + capsaicin, and VH + VSL#3 + SLIGRL-NH2. The rat model of VH was induced by acetic acid enema and the partial limb restraint method. VH was assessed by the abdominal withdrawal reflex score. MCs in colonic tissue were detected by the toluidine blue staining assay. The expression of PAR2 and TRPV1 in DRGs (L6-S1) was measured by immunohistochemistry and Western blotting. RESULTS: The established VH was abolished by treatment with ketotifen, a mast cell stabilizer FSLLRY-NH2, a PAR2 antagonist SB366791 a TRPV1 antagonist, and probiotic VSL#3 in rats. The administration of ketotifen or probiotic VSL#3 caused a decrease in mast cell number in the colon and decreased PAR2 and TRPV1 expression in DRGs. Intrathecal injection of FSLLRY-NH2 or SB366791 caused decreased expression of PAR2 and/or TRPV1 in DRGs in VH rats. SLIGRL-NH2, a PAR2 agonist, and capsaicin, a TRPV1 agonist, blocked the effects of probiotic VSL#3. CONCLUSIONS: The probiotic VSL#3 decreases VH in rat model of VH. The mechanism may be related with the mast cell-PAR2-TRPV1 signaling pathway.

NaV1.1 inhibition can reduce visceral hypersensitivity.

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Preclinical Animal Studies of Intravesical Recombinant Human Proteoglycan 4 as a Novel Potential Therapy for Diseases Resulting From Increased Bladder Permeability.

OBJECTIVE: To test in an animal model the hypothesis that recombinant human proteoglycan 4 (rhPRG4; lubricin), a highly O-glycosylated mucin-like glycoprotein, may be a novel surface-active therapeutic for treating bladder permeability with comorbid bowel permeability. Previously we showed that inducing bladder permeability in rats with dilute protamine sulfate (PS) produced colonic permeability and visceral hypersensitivity, suggesting increased bladder permeability could represent an etiologic factor in both interstitial cystitis-bladder pain syndrome and irritable bowel syndrome. METHODS: We used an animal model of catheterized ovariectomized female rats instilled intravesically with 1 mg/mL PS for 10 minutes that after 24 hours were treated with 1.2 mg/mL lubricin or with vehicle alone. After 24 hours the bladder and colon were removed and permeability assessed electrophysiologically with the Ussing chamber to measure the transepithelial electrical resistance. A second set of rats was treated identically, except permeability was assessed on day 3 and on day 5 using contrast-enhanced magnetic resonance imaging with gadolinium diethylenetriamine penta-acetic acid instilled into the bladder. RESULTS: Intravesical lubricin reversed bladder permeability induced by PS and prevented the concomitant increase in permeability induced in the bowel (organ crosstalk). The protective effect was confirmed with magnetic resonance imaging, and because individual rats could be followed over time, the impermeability of the bladder restored by rhPRG4 remained for 5 days. CONCLUSION: These data indicate that instillation of rhPRG4 into a permeable bladder can restore its normally impermeable state, and that the effect lasts for 5 days and also prevents bowel symptoms often comorbid with interstitial cystitis-bladder pain syndrome.

Inhibitory effects of patchouli alcohol on stress-induced diarrhea-predominant irritable bowel syndrome.

AIM: To elucidate the mechanism of patchouli alcohol (PA) in treatment of rat models of diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS: We studied the effects of PA on colonic spontaneous motility using its cumulative log concentration (3 × 10-7 mol/L to 1 × 10-4 mol/L). We then determined the responses of the proximal and distal colon segments of rats to the following stimuli: (1) carbachol (1 × 10-9 mol/L to 1 × 10-5 mol/L); (2) neurotransmitter antagonists including Nω-nitro-L-arginine methyl ester hydrochloride (10 µmol/L) and (1R*, 2S*)-4-[2-Iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester tetraammonium salt (1 µmol/L); (3) agonist α,ß-methyleneadenosine 5'-triphosphate trisodium salt (100 µmol/L); and (4) single KCl doses (120 mmol/L). The effects of blockers against antagonist responses were also assessed by pretreatment with PA (100 µmol/L) for 1 min. Electrical-field stimulation (40 V, 2-30 Hz, 0.5 ms pulse duration, and 10 s) was performed to observe nonadrenergic, noncholinergic neurotransmitter release in IBS-D rat colon. The ATP level of Kreb's solution was also determined. RESULTS: PA exerted a concentration-dependent inhibitory effect on the spontaneous contraction of the colonic longitudinal smooth muscle, and the half maximal effective concentration (EC50) was 41.9 µmol/L. In comparison with the KCl-treated IBS-D group, the contractile response (mg contractions) in the PA + KCl-treated IBS-D group (11.87 ± 3.34) was significantly decreased in the peak tension (P < 0.01). Compared with CCh-treated IBS-D rat colon, the cholinergic contractile response of IBS-D rat colonic smooth muscle (EC50 = 0.94 µmol/L) was significantly decreased by PA (EC50 = 37.43 µmol/L) (P < 0.05). Lack of nitrergic neurotransmitter release in stress-induced IBS-D rats showed contraction effects on colonic smooth muscle. Pretreatment with PA resulted in inhibitory effect on L-NAME-induced (10 µmol/L) contraction (P < 0.05). ATP might not be the main neurotransmitter involved in inhibitory effects of PA in the colonic relaxation of stress-induced IBS-D rats. CONCLUSION: PA application may serve as a new therapeutic approach for IBS-D.

Fructans Exacerbate Symptoms in a Subset of Children With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Dietary fructans exacerbate symptoms in some, but not all, adults with irritable bowel syndrome (IBS). We sought to determine whether fructans worsen symptoms in children with IBS and whether clinical and psychosocial factors, and/or gas production, can identify those who are fructan sensitive. METHODS: We performed a double-blind placebo-controlled (maltodextrin) cross-over trial of 23 children with IBS, based on pediatric Rome III criteria, from September 2014 through December 2016. At baseline, participants completed 1-week pain and stool diaries and a 3-day food record and psychosocial factors (depression, anxiety, and somatization) were measured. Subjects were randomly assigned to groups that were provided meals for 72 hours containing either fructans or maltodextrin (0.5 g/kg; maximum, 19 g). Following a washout period of 10 days or more, the subjects received the meal they were not given during the first study period (crossed over). Gastrointestinal symptoms and breath hydrogen and methane production were captured during each meal period. Fructan sensitivity was defined as an increase of 30% or more in abdominal pain frequency following fructan ingestion. RESULTS: Subjects had more mean episodes of abdominal pain/day during the fructan-containing diet (3.4 ± 2.6) vs the maltodextrin-containing diet (2.4 ± 1.7) (P < .01), along with more severe bloating (P < .05) and flatulence (P = .01). Hydrogen (but not methane) production was greater while subjects were on the fructan-containing diet (617 ± 305 ppm∗h) than the maltodextrin-containing diet (136 ± 78 ppm*h) (P < .001). Eighteen subjects (78.2%) had more frequent abdominal pain while on the fructan-containing diet and 12 (52.2%) qualified as fructan sensitive. We found no difference between fructan-sensitive and fructan-insensitive subjects in baseline abdominal pain or bowel movement characteristics, dietary intake, psychosocial parameters, IBS subtype, or gas production. CONCLUSIONS: In a randomized controlled trial of children with IBS, we found fructans to exacerbate several symptoms. However, fructan sensitivity cannot be identified based on baseline gastrointestinal symptoms, dietary intake, psychosocial factors, or gas production. Clinicaltrials.gov no: NCT02842281.

Chemical profiles and pharmacological activities of Chang-Kang-Fang, a multi-herb Chinese medicinal formula, for treating irritable bowel syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Chang-Kang-Fang formula (CKF), a multi-herb traditional Chinese medicinal formula, has been clinically used for treatment of irritable bowel syndrome (IBS). The mechanisms of CKF for treating IBS and the components that are responsible for the activities were still unknown. AIM OF THE STUDY: To investigate the chemical profiles and effects of CKF on IBS model. MATERIALS AND METHODS: The chemical profiles of CKF were investigated by ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS/MS). On colon irritation induced rat neonates IBS model, the influence of CKF on neuropeptides, including substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and 5-hydroxytryptamine (5-HT), were measured by ELISA, and the effect on intestinal sensitivity was assessed based on the abdominal withdrawal reflex (AWR) scores. In addition, the activities of CKF against acetic acid-induced nociceptive responses and prostigmin methylsulfate triggered intestinal propulsion in mice were also evaluated. RESULTS: 80 components were identified or tentatively assigned from CKF, including 11 alkaloids, 20 flavanoids, 4 monoterpenoids, 9 iridoid glycoside, 9 phenylethanoid glycosides, 10 chromones, 7 organic acid, 3 coumarins, 2 triterpene and 5 other compounds. On IBS rat model, CKF was observed to reduce AWR scores and levels of SP, CGRP, VIP and 5-HT. Moreover, CKF reduced the acetic acid-induced writhing scores at all dosages and reduced the intestinal propulsion ration at dosage of 7.5 and 15.0g/kg/d. CONCLUSIONS: CKF could alleviate the symptoms of IBS by modulating the brain-gut axis through increasing the production of neuropeptides such as CGRP, VIP, 5-HT and SP, releasing pain and reversing disorders of intestinal propulsion. Berberine, paeoniflorin, acteoside, flavonoids and chromones may be responsible for the multi-bioactivities of CKF.

Effect of Yoga in the Therapy of Irritable Bowel Syndrome: A Systematic Review.

BACKGROUND & AIMS: This review aims to systematically survey the effects of yoga on symptoms of irritable bowel syndrome (IBS), pain, quality of life, mood, stress, and safety in patients with IBS. METHODS: MEDLINE/Pubmed, Scopus, the Cochrane Library, CAM-QUEST, CAMbase, and IndMED were screened through November 2015. Randomized controlled trials comparing yoga with usual care, nonpharmacologic, or pharmacologic interventions were analyzed for patients with IBS. Primary outcomes included gastrointestinal symptoms, quality of life, and pain. Anxiety, mood, and safety were defined as secondary outcomes. Risk of bias was assessed according to the Cochrane Collaboration recommendations. RESULTS: Six randomized controlled trials with a total of 273 patients were included in the qualitative analysis. There was evidence for a beneficial effect of a yogic intervention over conventional treatment in IBS, with significantly decreased bowel symptoms, IBS severity, and anxiety. Furthermore, there were significant improvements in quality of life, global improvement, and physical functioning after yoga compared with no treatment. Two randomized controlled trials reported safety data stating that no adverse events occurred. Overall, risk of bias of the included studies was unclear. CONCLUSIONS: The findings of this systematic review suggest that yoga might be a feasible and safe adjunctive treatment for people with IBS. Nevertheless, no recommendation can be made regarding yoga as a routine intervention for patients with IBS because of major flaws in study methods. More research is needed with respect to a high-quality study design and consensus in clinical outcome measurements in IBS. ClinicalTrials.gov number, NCT02721836.

A Comprehensive Self-Management Irritable Bowel Syndrome Program Produces Sustainable Changes in Behavior After 1 Year.

BACKGROUND & AIMS: We developed a comprehensive self-management (CSM) program that combines cognitive behavioral therapy with relaxation and dietary strategies; 9 sessions (1 hour each) over 13 weeks were shown to reduce gastrointestinal symptoms and increase quality of life in a randomized trial of patients with irritable bowel syndrome (IBS), compared with usual care. The aims of this study were to describe strategies patients with IBS selected and continued to use, 12 months after the CSM program began. METHODS: We performed a cohort study to continue to follow 81 adults with IBS (87% female; mean age, 45 ± 15 years old) who received the CSM program in the previous clinical trial. During the last CSM session, participants selected strategies they intended to continue using to manage their IBS. CSM strategies were categorized into subthemes of diet (composition, trigger foods, meal size or timing, and eating behaviors), relaxation (specific relaxation strategies and lifestyle behaviors), and alternative thoughts (identifying thought distortions, challenging underlying beliefs, and other strategies). Twelve months later, participants were asked how often they used each strategy (not at all or rarely, occasionally, often, very often, or almost always). RESULTS: At the last CSM session, 95% of the patients selected the subthemes of specific relaxation strategies, 90% selected diet composition, and 90% identified thought distortions for continued use. At 12 months, 94% of the participants (76 of 81) were still using at least 6 strategies, and adherence was greater than 79% for all subthemes. CONCLUSIONS: We developed a CSM program to reduce symptoms and increase quality of life in patients with IBS that produced sustainable behavioral changes in almost all patients (94%) after 1 year of follow-up.

Herbal prescription Chang'an II repairs intestinal mucosal barrier in rats with post-inflammation irritable bowel syndrome.

AIM: The herbal prescription Chang'an II is derived from a classical TCM formula Tong-Xie-Yao-Fang for the treatment of liver-qi stagnation and spleen deficiency syndrome of irritable bowel syndrome (IBS). In this study we investigated the effects of Chang'an II on the intestinal mucosal immune barrier in a rat post-inflammation IBS (PI-IBS) model. METHODS: A rat model of PI-IBS was established using a multi-stimulation paradigm including early postnatal sibling deprivation, bondage and intrarectal administration of TNBS. Four weeks after TNBS administration, the rats were treated with Chang'an II (2.85, 5.71 and 11.42 g · kg(-1) · d(-1), ig) for 14 d. Intestinal sensitivity was assessed based on the abdominal withdrawal reflex (AWR) scores and fecal water content. Open field test and two-bottle sucrose intake test were used to evaluate the behavioral changes. CD4(+) and CD8(+) cells were counted and IL-1ß and IL-4 levels were measured in intestinal mucosa. Transmission electron microscopy was used to evaluate ultrastructural changes of the intestinal mucosal barrier. RESULTS: PI-IBS model rats showed significantly increased AWR reactivity and fecal water content, and decreased locomotor activity and sucrose intake. Chang'an II treatment not only reduced AWR reactivity and fecal water content, but also suppressed the anxiety and depressive behaviors. Ultrastructural study revealed that the gut mucosal barrier function was severely damaged in PI-IBS model rats, whereas Chang'an II treatment relieved intestinal mucosal inflammation and repaired the gut mucosal barrier. Furthermore, PI-IBS model rats showed a significantly reduced CD4(+)/CD8(+) cell ratio in lamina propria and submucosa, and increased IL-1ß and reduced IL-4 expression in intestinal mucosa, whereas Chang'an II treatment reversed PI-IBS-induced changes in CD4(+)/CD8(+) cell ratio and expression of IL-1ß and IL-4. CONCLUSION: Chang'an II treatment protects the intestinal mucosa against PI-IBS through anti-inflammatory, immunomodulatory and anti-anxiety effects.

The efficacy of Shugan Jianpi Zhixie therapy for diarrhea-predominant irritable bowel syndrome: a meta-analysis of randomized, double-blind, placebo-controlled trials.

BACKGROUND: Shugan Jianpi Zhixie therapy (SJZT) has been widely used to treat diarrhea-predominant irritable bowel syndrome (IBS-D), but the results are still controversial. A meta-analysis of randomized, double-blind, placebo-controlled trials was performed to assess the efficacy and tolerability of SJZT for IBS-D. METHODS: The MEDLINE, EMBASE, Cochrane Library, the China National Knowledge Infrastructure database, the Chinese Biomedical Literature database and the Wanfang database were searched up to June 2014 with no language restrictions. Summary estimates, including 95% confidence intervals (CI), were calculated for global symptom improvement, abdominal pain improvement, and Symptom Severity Scale (BSS) score. RESULTS: Seven trials (N=954) were included. The overall risk of bias assessment was low. SJZT showed significant improvement for global symptom compared to placebo (RR 1.61; 95% CI 1.24, 2.10; P =0.0004; therapeutic gain = 33.0%; number needed to treat (NNT) = 3.0). SJZT was significantly more likely to reduce overall BSS score (SMD -0.67; 95% CI -0.94, -0.40; P < 0.00001) and improve abdominal pain (RR 4.34; 95% CI 2.64, 7.14; P < 0.00001) than placebo. The adverse events of SJZT were no different from those of placebo. CONCLUSIONS: This meta-analysis suggests that SJZT is an effective and safe therapy option for patients with IBS-D. However, due to the high clinical heterogeneity and small sample size of the included trials, further standardized preparation, large-scale and rigorously designed trials are needed.