The alteration of mucosal bile acid profile is associated with nerve growth factor expression in mast cells and bowel symptoms in diarrhea-predominant irritable bowel syndrome.

Mucosal bile acid (BA) profile is still unestablished in diarrhea-predominant irritable bowel syndrome (IBS-D). The aim of this study was to explore colonic mucosal BAs and their associations with mucosal mast cell (MMC)-derived nerve growth factor (NGF) and bowel symptoms in IBS-D. Colonic mucosal biopsies from 36 IBS-D patients and 35 healthy controls (HCs) were obtained for targeted BA profiling. MMC count and the expression of NGF and tight junction proteins (TJPs) were examined. We found that colonic mucosal BA profile was altered in the IBS-D cohort. The proportion of primary BAs was significantly higher and that of secondary BAs was lower in IBS-D patients. According to the 90th percentile of total mucosal BA content of HCs, IBS-D patients were divided into BA-H (n = 7, 19.4%) and BA-L (n = 29, 80.6%) subgroups. BA-H patients showed significantly higher total mucosal BA content compared to BA-L subgroup and HCs. The mucosal content of 11 BA metabolites significantly increased in BA-H subgroup, e.g. cholic acid (CA) and taurocholic acid (TCA). Moreover, BA-H patients displayed significantly elevated MMC count and NGF expression, with decreased expression of TJPs (claudin-1, junctional adhesion molecule-A and zonula occludens-1). Correlation analyses revealed that mucosal TCA content positively correlated with MMC count, MMC-derived NGF levels, and abdominal pain while negatively correlated with TJP expression. In conclusion, IBS-D patients showed an altered BA profile in the colonic mucosa. Approximately 20% of them exhibit elevated mucosal BA content, which may be associated with MMC-derived NGF signaling and bowel symptoms.

Mucosa-Associated Microbiota Dysbiosis in the Terminal Ileum Correlates With Bowel Symptoms in Diarrhea-Predominant Irritable Bowel Syndrome.

INTRODUCTION: The mucosa-associated microbiota (MAM) is not as frequently studied in diarrhea-predominant irritable bowel syndrome (IBS-D) compared with the fecal microbiota. In this study, we examined the MAM in the terminal ileum and its correlation with bowel symptoms in IBS-D. METHODS: Mucosal biopsies of the terminal ileum from 25 patients with IBS-D and 25 healthy controls were collected for 16S ribosomal RNA gene sequencing. Correlation analysis was performed. RESULTS: Compared with healthy controls, the MAM in the terminal ileum showed a decreased alpha diversity in the IBS-D cohort (Chao1 and Shannon indexes, P < 0.05). And the overall MAM profile clustered separately into 2 groups (ADONIS [PERMANOVA, permutational multivariate analysis of variance], P < 0.05). At the phylum level, the relative abundance of Proteobacteria was significantly higher in the ileal MAM of patients with IBS-D while that of Firmicutes was significantly lower. At the genus level, the relative abundance of Pseudomonas was significantly higher in the IBS-D cohort, with lower Bacteroides and Ruminococcus . Moreover, 40.0% of patients with IBS-D had multiple small nodules (nodular lymphoid hyperplasia) on the mucosal surface of the terminal ileum, which indicated a low-grade inflammation. In patients with IBS-D with nodular lymphoid hyperplasia, the changes of Pseudomonas and Bacteroides were more overt. Correlation analysis revealed that the relative abundance of Pseudomonas positively correlated with abdominal pain and the severity of IBS. DISCUSSION: Patients with IBS-D showed a dysbiosis of MAM in the terminal ileum, which may be associated with bowel symptoms. Moreover, 40.0% of them displayed mucosal low-grade inflammation, with a more severe mucosal microbial disturbance.

Stigma and Efficacy of Zhizhu Kuanzhong Capsules Versus Doxepin in the Treatment of Refractory Functional Dyspepsia: A Randomized Controlled Trial.

Background/Aims: Stigma related with antidepressants is prevalent in patients with functional dyspepsia. It affects medication compliance and efficacy. Herbal medicine acquired a deep-rooted cultural identity in relieving dyspeptic symptoms in Asians. The research was designed to compare the effectiveness of Zhizhu Kuanzhong capsules (ZZKZ) versus doxepin hydrochloride (doxepin) on alleviating stigma and medication nonadherence among patients with refractory FD (rFD). Methods: Patients with rFD from February 2021 to February 2022 were randomly allocated to receive either doxepin (n = 56) or ZZKZ (n = 57) combined with omeprazole for 4 weeks. Medication possession ratio (MPR), the disease- and medication-associated stigma were analyzed. The scales were utilized to assess dyspeptic symptoms (Leeds Dyspepsia Questionnaire) and psychological conditions (Generalized Anxiety Disorder Questionnaire and Patient Health Questionnaire). Results: The MPR values for ZZKZ were significantly higher than those for doxepin (P < 0.001). The stigma scores decreased in ZZKZ group while increased in doxepin group compared to baseline after treatment. The proportion of patients showing ZZKZ-associated stigma was significantly lower than doxepin-associated stigma (P < 0.001). The MPR values were negatively correlated with post-treatment stigma scores in both groups (P < 0.001). Dyspeptic symptoms and psychological condition were improved in both groups after treatment, with no significant difference on post-treatment Leeds Dyspepsia Questionnaire, Generalized Anxiety Disorder Questionnaire, or Patient Health Questionnaire scores between 2 groups. Conclusion: ZZKZ is superior to doxepin in alleviating stigma and medication non-adherence, with comparable efficacy in improving dyspeptic symptoms and psychological condition of patients with rFD.

The Effect of Clinical Pharmacist Intervention on Renal Function Impairment in Patients with Antimicrobial-Induced Acute Kidney Injury in ICU.

Objective: The purpose of this study was to analyze the improvement effect of clinical pharmacist intervention on renal function impairment in patients with antimicrobial-induced acute kidney injury (AKI). Methods: A total of 145 patients with AKI caused by antibiotics admitted to the ICU department were selected as the research subjects. The patients were divided into the control group (n=57) and the intervention group (n=88) according to whether there were ICU specialist clinical pharmacists involved in clinical treatment. The renal function outcome and infection control were evaluated in the two groups. Results: The proportion of renal function outcome in the intervention group was 88.6%, which was significantly higher than that in the control group. However, there was no statistically significant difference in infection control between the two groups. For the intervention group, the clinical pharmacists adopted three intervention methods: dose adjustment, drug replacement and CRRT treatment, respectively, according to the disease conditions of AKI patients. Among them, dose adjustment and drug replacement were the most frequently used intervention methods. In addition, the proportion of renal function outcome was higher in the group of patients who changed antibiotics and underwent CRRT, which were 93.1% and 100%, respectively. The adjusted-dose group had the highest infection control rate at 82.1%. However, there were no statistically significant differences in renal function outcomes and infection control among the three interventions. Conclusion: Clinical pharmacists participating in the clinical treatment of patients with antimicrobial-induced AKI in ICU can effectively improve the renal function of patients.

Short-course antidepressant therapy reduces discontinuation syndrome while maintaining treatment efficacy in patients with refractory functional dyspepsia: A randomized controlled trial.

Background and objective: Long-course (LC) antidepressants for the treatment of disorders of gut-brain interaction, such as refractory functional dyspepsia (rFD), pose patients at risk of antidepressant discontinuation syndrome (ADS). Short-course (SC) therapy of rapid-acting antidepressant may reduce discontinuation syndromes while maintaining efficacy for dyspeptic symptoms. However, the evidence-based research is lacking. This study aims to determine whether SC therapy with antidepressants could decrease the risk of ADS with comparable treatment efficacy to LC therapy in rFD. Methods: This randomized clinical trial with rFD patients was conducted at a tertiary hospital in China. Participants (N = 240) were randomly allocated to receive flupentixol-melitracen (FM) plus omeprazole therapy for 2 (SC group) or 4 (LC group) weeks, respectively. Scores for Leeds Dyspepsia Questionnaire (LDQ), Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 for Depression (PHQ-9) were assessed at baseline and every 2 weeks, ending at 4 weeks after treatment. ADS was assessed after drug cessation. Medication possession ratio (MPR) for FM was calculated. Results: The severity and incidence of ADS of patients in SC group were significantly lower than those in LC group (0.60 ± 0.62 vs. 1.71 ± 1.58 and 3.64 vs. 39.45%; both P < 0.0001). The MPR values for FM were significantly higher in patients of SC group than in LC group (P < 0.0001). Scores for LDQ, GAD-7 and PHQ-9 decreased in patients of both groups, and the symptom improvement in SC group was comparable to that in LC group after treatment. Conclusions: Compared to 4-week FM therapy, the 2-week FM therapy reduces the risk of ADS with non-inferior treatment efficacy in patients with rFD. Clinical trial registration: Clinical trials.gov, identifier NCT05099913.

Improving Clinician-Patient Communication Alleviates Stigma in Patients With Functional Dyspepsia Receiving Antidepressant Treatment.

BACKGROUND/AIMS: Antidepressants are effective in patients with functional dyspepsia (FD). However, stigma associated with FD and antidepressants may affect treatment adherence. This study aims to explore possible communication strategies to alleviate stigma and improve adherence in patients with FD. METHODS: In this randomized, single-center, and single-blind trial, 160 patients with FD initiating antidepressant treatment were recruited. Different communication strategies were performed when prescribing antidepressants. Participants in Group 1 were told that brain is the "headquarters" of gut, and that antidepressants could act as neuromodulators to relieve symptoms of FD through regulating the functions of gut and brain. Participants in Group 2 were told that antidepressants were empirically effective for FD. Stigma scores, medication-related stigma, treatment compliance, and efficacy were analyzed. RESULTS: After 8-week antidepressant treatment, the proportion of patients with FD with decreased stigma scores in Group 1 was significantly higher than in Group 2 (internalized stigma: 64.10% vs 12.00%; perceived stigma: 55.13% vs 13.33%; P < 0.01). Medication-related stigma was lower in Group 1 than in Group 2 (P < 0.05 for 3 of 4 questions). Concurrently, patients in Group 1 had better treatment compliance (0.71 ± 0.25 vs 0.60 ± 0.25, P < 0.01) and efficacy. In Group 1, participants with decreased post-treatment stigma scores showed better treatment compliance and efficacy than those with non-decreased scores. Decrease in stigma scores positively correlated with treatment compliance. CONCLUSION: Improving knowledge of patients with FD of the disease and antidepressants via proper communication may be an effective way to alleviate stigma and promote adherence.

Chronic Jet Lag Exacerbates Jejunal and Colonic Microenvironment in Mice.

Background: Evidence suggests that circadian rhythm disorder is associated with a variety of gastrointestinal diseases, and the circadian rhythm plays a key role in maintaining the homeostasis of intestinal flora. The underlying mechanisms are still not completely identified. This study was aimed to explore whether jet lag-caused circadian disruption influences gut microbiome and its metabolites. Methods: Mice were synchronized with 12-h light/dark cycles (control group) or subjected to daily 8-h advance of the light/dark cycle for every 3 days (jet-lagged group). Four months later, fecal samples and jejunal contents were collected and analyzed by 16S rRNA gene sequencing. In addition, fecal samples were subjected to metabolome analysis with ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Results: The results of 16s rRNA sequencing showed that chronic jet lag led to decreased microbial abundance, richness, and diversity in both feces and jejunal contents. ANOSIM analysis revealed significant difference between control and jet-lagged groups. As the colonic microbiome, the abundance of Bacteroidetes phylum was significantly decreased and that of Actinobacteria phylum was increased in jet-lagged mice. Jet lag increased the ratio of Firmicutes to Bacteroidetes, an indicator for the imbalance of gut microbiota. Metabolome analysis of fecal samples showed that the levels of tryptophan and its derivatives were decreased in jet-lagged mice. In addition, fecal levels of secondary bile acids changed under jet lag conditions. Correlation analysis identified associations between tryptophan (and its derivatives) levels and colonic microbiota. Conclusions: This study presents a comprehensive landscape of gut microbiota and its metabolites in mice subjected to chronic jet lag. The results suggest that circadian disruption may lead to changes in fecal and jejunal microbiota and fecal metabolites. Moreover, our results demonstrate a novel interplay between the gut microbiome and metabolome.

Antiemetics improve the tolerance of polyethylene glycol for colonoscopy preparation: A randomized clinical trial.

BACKGROUND: Bowel preparation is essential to the success of colonoscopy. However, many patients cannot finish the preparation due to nausea and vomiting when taking polyethylene glycol (PEG). Dopamine-2 receptor antagonists, such as domperidone and sulpiride, are classical antiemetic drugs. This study aimed to explore the effect of domperidone and sulpiride on reducing the discomforts associated with PEG. METHODS: Patients scheduled for colonoscopy were enrolled and randomly allocated into 3 groups. Patients in the domperidone group (Dom group) or sulpiride group (Sul group) took 2 doses of domperidone or sulpiride before PEG. Patients in the control group (Con group) followed the regular routine of PEG. Discomforts during bowel preparation and the quality of bowel preparation were assessed. RESULTS: A total of 306 patients were enrolled. The participants in the Dom group and Sul group completed PEG better and had fewer abdominal discomforts than those in the Con group. The severity of nausea and abdominal fullness was lower in the Dom group and Sul group. The quality of bowel preparation was better in the Dom group and Sul group than Con group. CONCLUSIONS: Domperidone and sulpiride could reduce the PEG-related discomfort and improve the quality of bowel preparation. This method may be a promising way to improve the satisfaction of bowel preparation for both patients and endoscopists.

The impact of stigma on medication adherence in patients with functional dyspepsia.

BACKGROUND: Psychological factors contribute to the pathogenesis of functional dyspepsia (FD). Antidepressant agents are beneficial in treatment of refractory FD. However, their efficacy is greatly hindered by the poor treatment adherence. Stigma is present in patients with chronic diseases or mental disorders and could affect adherence. The present study was aimed to evaluate stigma prevalence in FD patients and to explore the impact of stigma on treatment adherence to antidepressants. METHODS: Functional dyspepsia patients unsatisfied with the regular first-line treatment and received newly initiated antidepressant medicine were recruited and subjected to antidepressant treatment for 8 weeks. Stigma scales and symptom scores of dyspepsia, depression, and anxiety were analyzed before and after treatment. Associations between stigma and medication adherence were evaluated. KEY RESULTS: One hundred and ten of the enrolled 138 participants reported minimal disease-related internalized stigma, and 28 reported mild stigma before antidepressant therapy. Male gender, lower education, and higher scores of dyspepsia, depression, and anxiety were predictors of stigma before treatment. The mean stigma scores increased after 8-week antidepressant treatment. A proportion (36.4%-89.9%) of patients showed stigma attached to antidepressant therapy in the 4-question survey. Post-treatment stigma scores negatively correlated with treatment adherence and efficacy. Patients with decreased post-treatment stigma scores displayed better medication adherence and symptom improvement compared to those with elevated or unaltered post-treatment stigma scores. CONCLUSIONS: Patients with refractory FD report stigma attached to the disease and antidepressants. It is an obstacle to treatment adherence and efficacy of antidepressant medication in FD therapy.

"Smoking paradox" is not true in patients with ischemic stroke: a systematic review and meta-analysis.

BACKGROUND: Ischemic stroke (IS) is a common cause of death from vascular diseases. Studies have found that smoking increases the risk of ischemic stroke, but the association of smoking with the outcome of IS remains unclear. This meta-analysis aims to investigate the effect of smoking on the prognosis of IS. METHODS: We searched four electronic databases including PubMed, EMBASE, Cochrane library and Web of science for papers, published before January 2019. In this meta-analysis, Review Manager 5.3 software was used to calculate for the pooled estimate effect, as well as the inverse-variance method for pooled mean difference (MD) and odds ratio (OR) of incidence in two groups of population. RESULTS: A total of 14,789 citations were identified during the literature search, 21 studies were included in the meta-analyses after screening. The full-adjusted OR of poor prognostic outcome in smoking and nonsmoking patients with stroke was pooled as 0.96 (95% CI 0.77-1.21), suggested that smoking or not has no impact on prognosis of IS. The pooled MD of onset age between smoking and nonsmoking IS patients was - 10.05 (- 12.91, - 7.19), indicated that smoking causes first onset of IS to occur 10 years earlier. CONCLUSIONS: This meta-analysis showed that smoking was not a protective factor for poor prognosis of IS. Smoking patients with IS are 10 years younger than nonsmoking patients at time of the first onset of stroke.

Acute stress induces visceral hypersensitivity via glucocorticoid receptor-mediated membrane insertion of TRPM8: Involvement of a non-receptor tyrosine kinase Pyk2.

BACKGROUND: Psychological stress is an important factor for the development and recurrence of irritable bowel syndrome (IBS). The mechanisms underlying stress-induced visceral hypersensitivity (VH), a key pathophysiological component in IBS, are still incompletely understood. We aimed to test whether transient receptor potential melastatin 8 (TRPM8) participates in acute stress-induced VH. METHODS: Rats were subjected to 1-hour water avoidance stress (WAS). Visceral sensitivity was measured with visceromotor response to colorectal distension. Western blot and immunofluorescence were applied to evaluate the expression of GR and TRPM8 and activation of PKA, Akt, and PKC pathways. RESULTS: WAS-caused VH depended on glucocorticoid receptors (GRs) and TRPM8 channels. In a dorsal root ganglion (DRG)-derived cell line, corticosterone rapidly (within 30 minutes) induced membrane expression of TRPM8. This effect was inhibited by GR antagonism and was mimicked by membrane-impermeable corticosterone. PKA, PI3K/Akt, and PKC pathways, which lied downstream of GR and acted in parallel to promote membrane expression of TRPM8, contributed to WAS-induced VH. The non-receptor tyrosine kinase Pyk2, which may serve as a convergence point for PKA, PI3K/Akt, and PKC pathways, facilitated membrane insertion of TRPM8 via tyrosine-phosphorylating TRPM8 in L6-S2 DRGs and participated in WAS-induced VH. CONCLUSIONS: Collectively, acute stress-induced VH could involve membrane-bound GR-dependent enhancement of TRPM8 function in nociceptive DRG neurons. Mechanistically, Pyk2 could act as a key mediator that coordinates multiple protein kinase signaling and triggers phosphorylation and membrane insertion of TRPM8.

Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis.

Increased colonic bile acid (BA) exposure, frequent in diarrhea-predominant irritable bowel syndrome (IBS-D), can affect gut function. Nerve growth factor (NGF) is implicated in the development of visceral hypersensitivity (VH). In this study, we tested the hypothesis that BAs cause VH via mucosal mast cell (MMC)-to-nociceptor signaling, which involves the farnesoid X receptor (FXR)/NGF/transient receptor potential vanilloid (TRPV)1 axis. BAs were intracolonically administered to rats for 15 d. Visceral sensitivity to colorectal distention and colonic NGF expression were examined. BAs caused VH, an effect that involved MMC-derived NGF and was accompanied by enhanced TRPV1 expression in the dorsal root ganglia. Anti-NGF treatment and TRPV1 antagonism inhibited BA-induced VH. BAs induced NGF mRNA and protein expression and release in cultured mast cells. Colonic supernatants from patients with IBS-D with elevated colonic BA content transcriptionally induced NGF expression. In FXR-/- mice, visceral sensitivity and colonic NGF expression were unaltered after BA treatment. Pharmacological antagonism and FXR silencing suppressed BA-induced NGF expression and release in mast cells. Mitogen-activated protein kinase kinase (MKK) 3/6/p38 MAPK/NF-κB signaling was mechanistically responsible for FXR-mediated NGF expression and secretion. The findings show an MMC-dependent and FXR-mediated pronociceptive effect of BAs and identify the BA/FXR/NGF/TRPV1 axis as a key player in MMC-to-neuron communication during pain processing in IBS.-Li, W.-T., Luo, Q.-Q., Wang, B., Chen, X., Yan, X.-J., Qiu, H.-Y., Chen, S.-L. Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis.

Prognostic Factors, Survival, and Treatment for Intracranial World Health Organization Grade II Chordoid Meningiomas and Clear-Cell Meningiomas.

OBJECTIVE: Chordoid meningioma (CM) and clear-cell meningioma (CCM) are rare World Health Organization grade II meningioma subtypes. This study aimed to evaluate favorable factors and appropriate therapeutic strategies for these lesions. METHODS: We retrospectively reviewed clinical data from 111 cases of grade II meningiomas, including 55 cases of CM and 56 cases of CCM, between January 2011 and December 2015. RESULTS: The mean follow-up time of the rare World Health Organization grade II meningiomas (n = 111) was 45.3 months. In the CM group, 8 patients (14.5%) experienced recurrence, and 2 patients (3.6%) died. In the CCM group, 22 patients (39.3%) experienced recurrence, and 9 patients (16.1%) died. Significant differences were observed between the CM and CCM groups in tumor size (P = 0.019), history of surgery (P = 0.038), and peritumoral edema (P = 0.004). In the CM group, gross total resection was associated with favorable progression-free survival (hazard ratio, 0.144; 95% confidence interval, 0.029-0.714; P = 0.018). In the CCM group, univariate analyses showed that preoperative Karnofsky Performance Status <80 (P < 0.001), tumor size ≥5 cm (P = 0.015), tumor size (per-centimeter increase) (P = 0.022), bone invasion (P = 0.004), a history of surgery (P < 0.001), and subtotal resection (P = 0.009) were associated with worse progression-free survival. Male gender (P = 0.039), tumor size (per-centimeter increase) (P = 0.043), bone invasion (P = 0.030), and a history of surgery (P = 0.007) were associated with poor overall survival. CONCLUSIONS: This study showed that gross total resection should be achieved in grade II meningiomas. Patients with larger tumors and/or surgical histories had worse outcomes.

Effect of clinician-patient communication on compliance with flupentixol-melitracen in functional dyspepsia patients.

AIM: To explore whether clinician-patient communication affects adherence to psychoactive drugs in functional dyspepsia (FD) patients with psychological symptoms. METHODS: A total of 262 FD patients with psychological symptoms were randomly assigned to four groups. The patients in Groups 1-3 were given flupentixol-melitracen (FM) plus omeprazole treatment. Those in Group 1 received explanations of both the psychological and gastrointestinal (GI) mechanisms of the generation of FD symptoms and the effects of FM. In Group 2, only the psychological mechanisms were emphasized. The patients in Group 3 were not given an explanation for the prescription of FM. Those in Group 4 were given omeprazole alone. The primary endpoints of this study were compliance rate and compliance index to FM in Groups 1-3. Survival analyses were also conducted. The secondary end points were dyspepsia and psychological symptom improvement in Groups 1-4. The correlations between the compliance indices and the reductions in dyspepsia and psychological symptom scores were also evaluated in Groups 1-3. RESULTS: After 8 wk of treatment, the compliance rates were 67.7% in Group 1, 42.4% in Group 2 and 47.7% in Group 3 (Group 1 vs Group 2, P = 0.006; Group 1 vs Group 3, P = 0.033). The compliance index (Group 1 vs Group 2, P = 0.002; Group 1 vs Group 3, P = 0.024) with the FM regimen was significantly higher in Group 1 than in Groups 2 and 3. The survival analysis revealed that the patients in Group 1 exhibited a significantly higher compliance rate than Groups 2 and 3 (Group 1 vs Group 2, P = 0.002; Group 1 vs Group 3, P = 0.018). The improvement in dyspepsia (Group 1 vs Group 2, P < 0.05; Group 1 vs Group 3, P < 0.05; Group 1 vs Group 4, P < 0.01) and psychological symptom scores (anxiety: Group 1 vs Group 2, P < 0.01; Group 1 vs Group 3, P < 0.05; Group 1 vs Group 4, P < 0.01; depression: Group 1 vs Group 2, P < 0.01; Group 1 vs Group 3, P < 0.01; Group 1 vs Group 4, P < 0.01) in Group 1 were greater than those in Groups 2-4. The compliance indices were positively correlated with the reduction in symptom scores in Groups 1-3. CONCLUSION: Appropriate clinician-patient communication regarding the reasons for prescribing psychoactive drugs that emphasizes both the psychological and GI mechanisms might improve adherence to FM in patients with FD.

Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats.

Serotonin (5-HT) plays pivotal roles in the pathogenesis of postinfectious irritable bowel syndrome (PI-IBS), and luminal 5-HT time-dependently modulates visceral nociception. We found that duodenal biopsies from PI-IBS patients exhibited increased 5-HT and decreased anandamide levels and that decreased anandamide was associated with abdominal pain severity, indicating a link between 5-HT and endocannabinoid signaling pathways in PI-IBS. To understand this, we investigated the role of endocannabinoids in 5-HT modulation of visceral nociception in a rat model. Acute intraduodenally applied 5-HT attenuated the visceromotor response (VMR) to colorectal distention, and this was reversed by the cannabinoid receptor 1 (CB1) antagonist AM251. Duodenal anandamide (but not 2-arachidonoylglycerol) content was greatly increased after luminal 5-HT treatment. This effect was abrogated by the 5-HT 3 receptor (5-HT3R) antagonist granisetron, which was luminally delivered to preferentially target vagal terminals. Chemical denervation of vagal afferents blocked 5-HT-evoked antinociception and anandamide release. Chronic luminal 5-HT exposure for 5 days increased baseline VMR and VMR post-5-HT (days 4 and 5). Duodenal levels of anandamide and N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD, the anandamide-synthesizing enzyme) protein gradually declined from day 1 to 5. The time-dependent effects of 5-HT were abolished by daily granisetron pretreatment. Daily pretreatment with CB1 agonists or anandamide from day 3 attenuated 5-HT-induced hyperalgesia. These data suggest that vagal 5-HT3R-mediated duodenal anandamide release contributes to acute luminal 5-HT-induced antinociception via CB1 signaling, whereas decreased anandamide is associated with hyperalgesia upon chronic 5-HT treatment. Further understanding of peripheral vagal anandamide signaling may provide insights into the mechanisms underlying 5-HT-related IBS.

Vagal afferents mediate antinociception of estrogen in a rat model of visceral pain: the involvement of intestinal mucosal mast cells and 5-hydroxytryptamine 3 signaling.

UNLABELLED: Estrogen reportedly facilitates visceral nociception at the spinal or supraspinal level. The present study was aimed to investigate whether estrogen modulates visceral pain through the vagal pathway. Ovariectomized rats received estradiol, which was administered subcutaneously (to act through both the vagal and spinal pathways) or intraduodenally (to preferentially act through the vagal pathway). Luminally applied estradiol induced a rapid and significant decrease in the visceromotor response to colorectal distension, with increased c-Fos expression in nodose ganglion neurons. Systemically injected estradiol increased visceromotor response and c-Fos expression in both nodose and dorsal root ganglion (T6-12) neurons. The antinociceptive effect of estrogen was abolished by surgical vagotomy or chemical denervation of vagal afferents. Both luminally and systemically administered estradiol elicited selective 5-hydroxytryptamine secretion from the duodenum. Granisetron, a 5-hydroxytryptamine 3 receptor antagonist, reversed the antinociceptive effect of estrogen. Intestinal mucosal mast cell stabilizers prevented estradiol-induced antinociception and 5-hydroxytryptamine secretion. Ultrastructural analysis revealed that estradiol caused piecemeal degranulation of intestinal mucosal mast cells. The actions of estradiol were inhibited by an estrogen receptor ß antagonist and mimicked by an estrogen receptor ß agonist. These results suggest that estrogen can trigger vagus-mediated antinociception, which is masked by its spinally mediated pronociception. PERSPECTIVE: This study is the first to show a vagus-mediated estrogenic antinociception, in which the nongenomic estrogen receptor ß-mediated, intestinal mucosal mast cell-derived 5-hydroxytryptamine/5-hydroxytryptamine 3 receptor pathway is involved. This work may provide new insights into the sex hormone modulation of visceral sensitivity related to irritable bowel syndrome and indicate potential therapeutic targets to manage this disease.

Autonomic functioning in irritable bowel syndrome measured by heart rate variability: a meta-analysis.

OBJECTIVE: To analyze autonomic functioning which presented as the high frequency (HF) component of heart rate variability, a measurement of vagal tone, and the ratio of low frequency (LF) to HF (LF : HF), an indicator of sympathovagal balance in irritable bowel syndrome (IBS) patients. METHODS: We identified relevant studies by performing a literature search of MEDLINE, EMBASE and the ISI Web of Knowledge to 31 March 2013. Pooled effect sizes with 95% confidence interval (CI) were calculated using a random effects model. Between-study heterogeneity was assessed using the Q test and I(2) statistic. RESULTS: In all, 11 articles including 392 IBS patients and 263 controls met the inclusion criteria of the analysis. IBS patients had lower HF band power (Hedges's g = -0.38, 95% CI -0.68 to -0.09) than the controls (I(2) = 63.6%, P = 0.003). Moreover, IBS patients showed a higher LF : HF (Hedges's g = 0.43, 95% CI 0.13-0.74), with no significant heterogeneity. A subgroup analysis of the HF index according to the recording time yielded different results for the IBS patients and controls. Additionally, constipation-predominant IBS (IBS-C) patients had decreased HF band power, whereas no significant difference was found in LF : HF. CONCLUSIONS: Impaired parasympathetic functioning and abnormal sympathovagal balance may be involved in the pathogenesis of IBS. Vagal dysfunction is more obvious in the IBS-C subgroup.

Efficacy of mosapride plus proton pump inhibitors for treatment of gastroesophageal reflux disease: a systematic review.

AIM: To assess the potential benefits of mosapride plus proton pump inhibitors (PPIs) in the treatment of gastroesophageal reflux disease. METHODS: A literature search was performed through MEDLINE, EMBASE, and the ISI Web of Knowledge. The clinical trials that compared the benefit of mosapride plus PPI treatment with that of PPI monotherapy were analyzed. The rate of responders was evaluated by the pooled relative risk (PRR) and improvement in symptom scores was assessed by single effect size of a standardized mean, while Hedges'g was used as the effect size. Pooled effect sizes with 95%CIs were calculated using a fixed-effects model. Between-study heterogeneity was assessed using Q test and I (2) analyses. In addition, studies that assessed the additional efficacy of mosapride in PPI-resistant patients were also reviewed. RESULTS: This systematic review included information on a total of 587 patients based on 7 trials. Four trials compared the efficacy of combination therapy of mosapride plus a PPI with that of PPI monotherapy. The statistical analysis for the effect of additional mosapride showed equivocal results (PRR = 1.132; 95%CI: 0.934-1.372; P = 0.205; Hedges'g = 0.24; 95%CI: 0.03-0.46; P = 0.023). No heterogeneity and publication bias were found among the studies. Three open-labeled trials assessed the additional efficacy of mosapride in PPI-resistant patients. However, since these trials did not set the control group, the results may be considerably biased. CONCLUSION: Mosapride combined therapy is not more effective than PPI alone as first-line therapy. Whether it is effective in PPI-resistant patients needs to be determined.