Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome

BACKGROUND Serotonin receptor 2B(5-HT2B receptor)plays a critical role in many chronic pain conditions.The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea(IBS-D)was investigated in the present study.AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D.METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls.The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores.The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint.Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1(TRPV1)expression were examined following 5-HT2B receptor antagonist adminis-tration.Changes in visceral sensitivity after administration of the TRPV1 antago-INTRODUCTION Irritable bowel syndrome(IBS)is a chronic functional bowel disorder characterized by recurrent abdominal pain with altered bowel habits that affects approximately 15%of the population worldwide[1].IBS significantly impacts the quality of life of patients.Although the pathogenesis of IBS is not completely understood,the role of abnormal visceral sensitivity in IBS has recently emerged[2,3].5-Hydroxytryptamine(5-HT)is known to play a key role in the physiological states of the gastrointestinal tract.Plasma 5-HT levels in IBS with diarrhea(IBS-D)patients were greater than those in healthy controls[4],suggesting a possible role of 5-HT in the pathogenesis of IBS-D.The serotonin receptor 2(5-HT2 receptor)family comprises three subtypes:5-HT2A,5-HT2B,and 5-HT2c.All 5-HT2 receptors exhibit 46%-50%overall sequence identity,and all of these receptors preferentially bind to Gq/11 to increase inositol phosphates and intracellular calcium mobilization[5].5-HT2B receptors are widely expressed throughout the gut,and experimental evidence suggests that the primary function of 5-HT2B receptors is to mediate contractile responses to 5-HT through its action on smooth muscle[6].The 5-HT2B receptor is localized to both neurons of the myenteric nerve plexus and smooth muscle in the human colon.The 5-HT2B receptor mediates 5-HT-evoked contraction of longitudinal smooth muscle[6].These findings suggest that the 5-HT2B receptor could play an important role in modulating colonic motility,which could affect sensory signaling in the gut.Other laboratories have shown that the 5-HT2B receptor participates in the development of mechanical and formalin-induced hyperalgesia[7,8].A 5-HT2B receptor antagonist reduced 2,4,6-trinitrobenzene sulfonic acid(TNBS)and stress-induced visceral hyperalgesia in rats[9,10].However,the role of the 5-HT2B receptor in IBS-D patients and in acetic acid-and wrap restraint-induced IBS-D rat models was not investigated.

Clinical Effect of Modified Shengyang Yiwei Decoction in the Treatment of Diarrhea-Predominant Irritable Bowel Syndrome due to Spleen and Stomach Weakness

Objective:To explore the therapeutic effect of Shengyang Yiwei Decoction in patients with diarrhea-predominant irritable bowel syndrome(IBS)due to spleen and stomach weakness.Methods:40 patients with diarrhea-predominant IBS who were treated from April 2018 to April 2020 were taken as samples.TCM(traditional Chinese medicine)syndrome differentiation found that they were all due to spleen and stomach weakness.They were randomly divided into two groups.Group A was treated with modified prescriptions of Shengyang Yiwei Decoction,while Group B was treated with Western medicine.The therapeutic effects in the two groups were compared.Results:The treatment efficacy in Group A was higher than that in Group B(P<0.05);the symptom scores of Group A such as loose stools,chills,physical weakness,poor appetite,and abdominal distension after meals were all lower than those in Group B(P<0.05);the SF-36(36-Item Short Form Health Survey)scores of patients with diarrhea-predominant IBS in Group A were higher than those in Group B(P<0.05);the treatment satisfaction of Group A was higher than that of Group B(P<0.05).Conclusion:Treatment of diarrhea-predominant IBS patients with spleen and stomach weakness by Shengyang Yiwei Decoction can promote the disappearance of gastrointestinal discomfort symptoms,improve the quality of life,and enhance treatment efficacy.Hence,it is an efficient and feasible treatment for diarrhea-predominant IBS due to spleen and stomach weakness.

Comparison of 5-hydroxytryptophan signaling pathway characteristics in diarrhea-predominant irritable bowel syndrome and ulcerative colitis

AIM: To study differences in the visceral sensitivity of the colonic mucosa between patients with diarrheapredominant irritable bowel syndrome(IBS-D) and those with ulcerative colitis(UC) in remission and to relate these differences with changes in the 5-hydroxytryptophan(5-HT) signaling pathway. METHODS: Gastrointestinal symptoms were used to determine the clinical symptom scores and rectal visceral sensitivity of patients with IBS-D and patients with UC in remission. Blood levels of 5-HT and5-hydroxyindoleacetic acid(5-HIAA) were measured using an HPLC-electrochemical detection system. The levels of 5-HT 3 receptor(3R), 4R, and 7R m RNAs in colonic biopsy samples were detected using reverse transcription-polymerase chain reaction. The protein expression of TPH1 was analyzed by Western blot and immunohistochemistry.RESULTS: Abdominal pain or discomfort, stool frequency, and the scores of these symptoms in combination with gastrointestinal symptoms were higher in the IBS-D and UC groups than in the control groups. However, no significant differences were observed between the IBS-D and UC remission groups. With respect to rectal visceral sensitivity, the UC remission and IBS-D groups showed a decrease in the initial perception threshold, defecating threshold and pain threshold. However, these groups exhibited significantly increased anorectal relaxation pressure. Tests examining the main indicators of the 5-HT signaling pathway showed that the plasma 5-HT levels, 5-HIAA concentrations, TPH1 expression in the colonic mucosa, and 5-HT3 R and 5-HT5 R expression were increased in both the IBS-D and the UC remission groups; no increases were observed with respect to 5-HT7 R expression.CONCLUSION: The IBS-D and UC groups showed similar clinical symptom scores, visceral sensitivity, and levels of serotonin signaling pathway indicators in the plasma and colonic mucosa. However, the pain threshold and 5-HT7 R expression in the colonic mucosa were significantly different between these groups. The results reveal that(1) IBS-D and UC are related to visceral sensitivity pathogenesis and the clinical manifestations of these conditions and(2) the observed differences in visceral hypersensitivity are possibly due to differences in levels of the 5-HT7 receptor, a component of the 5-HT signaling pathway.

Factorial study of moxibustion in treatment of diarrhea-predominant irritable bowel syndrome

AIM: To identify an appropriate therapeutic regimen for using aconite cake-separated moxibustion to treat diarrhea-predominant irritable bowel syndrome (D-IBS).

Efficacy and dose response of Lactiplantibacillus plantarum in diarrhea-predominant irritable bowel syndrome

BACKGROUND Probiotics have shown promise in alleviating symptoms of diarrhea-predominant irritable bowel syndrome(IBS-D);however,the certainty of evidence is low.Wellpowered randomized controlled dose-ranging trials are warranted on promising single-strain candidates.AIM To investigate the clinical efficacy of Lactiplantibacillus plantarum(L.plantarum)Lpla33(DSM34428)in adults with IBS-D.METHODS This is a randomized,double-blind,placebo-controlled,multi-center,and doseranging study.Three hundred and seven adults,18-70 years of age,with IBS-D,according to Rome IV criteria,were allocated(1:1:1)to receive placebo or L.plantarum Lpla33 at 1×10^(9)(1B)or 1×10^(10)(10B)colony-forming units/d over an 8-wk intervention period.The primary outcome was the change in IBS severity scoring system(IBS-SSS)total score after 8 wk,while secondary and exploratory outcomes included abdominal pain severity,IBS related quality of life,stool and microbial profile,and perceived stress.RESULTS IBS-SSS was significantly reduced,after 8 wk,in participants receiving L.plantarum 1B(-128.45±83.30;P<0.001)and L.plantarum 10B(-156.77±99.06;P<0.001),compared to placebo(-58.82±74.75).Further,a dose-ranging effect was observed,with a greater absolute reduction in the L.plantarum 10B group(P<0.05).A reduction in sub-scores related to abdominal pain,abdominal distension,bowel habits,and quality of life was observed in both L.plantarum groups compared to placebo(P<0.001).Further,62.5%and 88.4%of participants administered L.plantarum 1B and 10B,respectively,were classified as stool consistency responders based on a reduction in diarrheal stool form,as compared to 26.3%in the placebo group(P<0.001).In contrast,no significant shifts were observed in microbial diversity.CONCLUSION L.plantarum Lpla33(DSM34428)is well tolerated and improves IBS symptom severity with a dose-ranging effect and a corresponding normalization of bowel habits in adults with IBS-D.

Study on the effect of Xi-Feng-Hua-Shi granules on intestinal flora in patients with diarrhea-predominant irritable bowel syndrome based on 16S rDNA sequencing

Background:Diarrhea-predominant irritable bowel syndrome(IBS-D)is a common functional gastrointestinal disease,that significantly impacts the quality of life and social interactions of patients,and also consumes a significant amount of medical resources.Xi-Feng-Hua-Shi(XFHS)granule is an empirical formula developed by Professor Yao-Zhou Tian,a famous TCM doctor in Jiangsu Province.Clinical experience has shown that XFHS granules are effective at relieving the symptoms of IBS-D patients.Therefore,this study used 16S rDNA sequencing to determine the species and richness of microflora in order to explore the overall efficacy and changes in the intestinal microflora of IBS-D patients after treatment with XFHS granules,and to further understand the mechanism of drug action as a potential new therapeutic method for the clinical treatment of IBS-D.Methods:A total of 66 IBS-D patients who were treated at Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine from June 2021 to January 2022 were recruited and randomly divided into a reatment group and a control group.The treatment group was given XFHS granules and the control group was given placebo granules for 4 weeks.Traditional Chinese medicine(TCM)syndrome scores of patients before and after treatment were recorded,and fresh fecal samples of some patients before and after treatment were collected to analyze the changes of intestinal flora by 16S rDNA sequencing method.Results:The effective rate in the treatment group was 92.86%,which was significantly higher than the control group(P<0.05).The bacterial diversity of IBS-D patients did not change significantly after treatment with XFHS granules,but the species composition analysis showed that the abundance of Firmicutes,Proteobacteria and Cyanobacteria decreased,while the abundance of Bacteroidetes,Actinobacteria and Bifidobacteria increased.Conclusion:XFHS granules can effectively improve the clinical symptoms of IBS-D patients,and its therapeutic effect may be related to regulating the structure and abundance of intestinal flora.

Xi-Feng-Hua-Shi granules for diarrhea-predominant irritable bowel syndrome:protocol for a randomized,double-blind,placebo-controlled multi-center clinical trial

Background:Irritable bowel syndrome(IBS)is a common functional bowel disorder that can severely affect the quality of life of patients.Limited drugs have been reported for modern medical IBS treatment.The advantages of traditional Chinese medicine(TCM)treatment are gradually becoming prominent.Xi-Feng-Hua-Shi granules have been clinically used for diarrhea-predominant IBS(IBS-D)treatment for many years in TCM practice.Thus,this study aimed to further verify the effectiveness and safety of Xi-Feng-Hua-Shi(XFHS)granules in IBS-D treatment through a randomized,double-blind,placebo-controlled multi-center clinical trial and provide high-quality evidence for its effectiveness and safety in treatment,as well as provide a basis for clinical rational drug use and explore new clinical IBS-D treatment plans.Methods:A randomized,double-blind,placebo-controlled multi-center clinical trial will be performed in 23 hospitals.A total of 300 participants will be randomly divided into the experimental group(prescribed with XFHS granules)and the control group(prescribed with the placebo granules),with 150 participants in each group.The appearance,shape,color,and taste of the placebo granules are the same as those of XFHS granules.All participants will receive a 4-week treatment and a 6-month follow-up.The primary outcome is the overall clinical efficacy;the secondary outcomes are the IBS-Symptom Severity Score(IBS-SSS),TCM Syndrome Evaluation,and the IBS-Quality of Life(IBS-QoL)score,mental state assessment,and recurrence rate.Outcome measures(including primary and secondary outcome measures)are collected at baseline,as well as 2,4,16,and 28 weeks post-intervention.Discussion:This randomized,placebo-controlled,multi-center trial may provide high-quality evidence for the clinical XFHS granule efficacy in IBS-D treatment.Additionally,this study will conduct safety evaluations to provide a basis for clinical rational drug use.

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 folowing stimuli:(1) carbachol(1 × 10^(-9) mol/L to 1 × 10^(-5) mol/L);(2) neurotransmitter antagonists including N~ω-nitro-l-arginine methyl ester hydrochloride(10μmol/L) and(1 R~*, 2 S~*)-4-[2-Iodo-6-(methylamino)-9 Hpurin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0]hexane-1-methanol dihydrogen phosphate ester tetraammonium salt(1 μmol/L);(3) agonist α,β-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(EC_(50)) 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(EC_(50) = 0.94 μmol/L) was significantly decreased by PA(EC_(50) = 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 stressinduced IBS-D rats.CONCLUSION PA application may serve as a new therapeutic approach for IBS-D.

Increased intestinal mucosal leptin levels in patients with diarrhea-predominant irritable bowel syndrome

AIM To measure the leptin levels in patients with diarrheapredominant irritable bowel syndrome(IBS-D) and analyze the relationship of leptin with clinical features, visceral sensitivity, mast cells, and nerve fibers. METHODS Forty-two patients with IBS-D fulfilling the Rome Ⅲ criteria and 20 age-and sex-matched healthy controls underwent clinical and psychological evaluations using validated questionnaires(including IBS Symptom Severity Scale, IBS-specific Quality of Life, Hamilton Anxiety Scale, and Hamilton Depression Scale), along with colonoscopy, colonic mucosal biopsy, and visceral sensitivity testing. Serum leptin levels were assayed using enzyme-linked immunosorbent assay. Mucosal leptin expression and localization were evaluated using immunohistochemistry and immunofluorescence.Mucosal leptin m RNA levels were quantified using quantitative real-time reverse transcription polymerase chain reaction. Mast cell counts and activation rates were investigated by toluidine blue staining. Correlation analyses between these parameters were performed.RESULTS There were no statistically significant differences in age, gender, or body mass index between the IBS-D group and the control group. The median IBS Symptom Severity Scale score in the IBS-D group was 225.0(range, 100-475). IBS-D patients had significantly increased anxiety [IBS-D: median, 6.5; interquartile range(IQR), 3.3; control: median, 2.0; IQR, 2.0; P < 0.001] and depression(IBS-D: median, 7.0; IQR, 3.0; control: median, 3.0; IQR, 2.0; P < 0.001) scores. IBS-D patients had significantly lower first sensation threshold(IBS-D: median, 50.6; IQR, 25.9; control: median, 80.5; IQR, 18.6; P < 0.001), defecation sensation threshold(IBS-D: median, 91.5; IQR, 29.3; control: median, 155.0; IQR, 21.1; P < 0.001) and maximum tolerable threshold(IBS-D: median, 163.2; IQR, 71.2; control: median, 226.2; IQR, 39.3; P < 0.001). Mucosal leptin expression, as reflected by integrated optical density(IBS-D: median, 4424.71; IQR, 4533.63; control: median, 933.65; IQR, 888.10; P < 0.001), leptin mR NA expression(IBS-D: median, 1.1226; IQR, 1.6351; control: median, 0.8947; IQR, 0.4595; P = 0.009), and mast cell activation rate(IBS-D: median, 71.2%; IQR, 12.9%; control group: median, 59.4%; IQR, 18.88%; P < 0.001) were significantly increased in IBS-D patients. The colocalization of leptin and leptin receptors was observed on mast cells and PGP9.5-positive nerve fibers in the intestinal mucosa. Also, leptin expression was positively correlated with anxiety, depression, and the mast cell activation rate, but negatively correlated with the defecation sensation threshold and the maximum tolerance threshold during visceral sensitivity testing(adjusted P < 0.0038).CONCLUSION Increased levels of mucosal leptin may interact with mast cells and the nervous system to contribute to the pathogenesis of IBS-D.

Altered profiles of fecal metabolites correlate with visceral hypersensitivity and may contribute to symptom severity of diarrhea-predominant irritable bowel syndrome

BACKGROUND Fecal metabolites are associated with gut visceral sensitivity,mucosal immune function and intestinal barrier function,all of which have critical roles in the pathogenesis of irritable bowel syndrome(IBS).However,the metabolic profile and pathophysiology of IBS are still unclear.We hypothesized that altered profiles of fecal metabolites might be involved in the pathogenesis of IBS with predominant diarrhea(IBS-D).AIM To investigate the fecal metabolite composition and the role of metabolites in IBSD pathophysiology.METHODS Thirty IBS-D patients and 15 age-and sex-matched healthy controls(HCs)underwent clinical and psychological assessments,including the IBS Symptom Severity System(IBS-SSS),an Italian modified version of the Bowel Disease Questionnaire,the Bristol Stool Form Scale(BSFS),the Hospital Anxiety and Depression Scale,and the Visceral Sensitivity Index.Visceral sensitivity to rectal distension was tested using high-resolution manometry system by the same investigator.Fecal metabolites,including amino acids and organic acids,were measured by targeted metabolomics approaches.Correlation analyses between these parameters were performed.RESULTS The patients presented with increased stool water content,more psychological symptoms and increased visceral hypersensitivity compared with the controls.In fecal metabolites,His[IBS-D:0.0642(0.0388,0.1484),HC:0.2636(0.0780,0.3966),P=0.012],Ala[IBS-D:0.5095(0.2826,0.9183),HC:1.0118(0.6135,1.4335),P=0.041],Tyr[IBS-D:0.1024(0.0173,0.4527),HC:0.5665(0.2436,1.3447),P=0.018],Phe[IBS-D:0.1511(0.0775,0.3248),HC:0.3967(0.1388,0.7550),P=0.028],and Trp[IBS-D:0.0323(0.0001,0.0826),HC:0.0834(0.0170,0.1759),P=0.046]were decreased in IBS-D patients,but isohexanoate[IBS-D:0.0127(0.0060,0.0246),HC:0.0070(0.0023,0.0106),P=0.028]was significantly increased.Only Tyr was mildly correlated with BSFS scores in all subjects(r=-0.347,P=0.019).A possible potential biomarker panel was identified to correlate with IBS-SSS score(R2 Adjusted=0.693,P<0.001).In this regression model,the levels of Tyr,Val,hexanoate,fumarate,and pyruvate were significantly associated with the symptom severity of IBS-D.Furthermore,visceral sensation,including abdominal pain and visceral hypersensitivity,was correlated with isovalerate,valerate and isohexanoate.CONCLUSION Altered profiles of fecal metabolites may be one of the origins or exacerbating factors of symptoms in IBS-D via increasing visceral sensitivity.

Effect of cognitive behavior therapy combined with exercise intervention on the cognitive bias and coping styles of diarrhea-predominant irritable bowel syndrome patients

BACKGROUND Irritable bowel syndrome(IBS)is a common digestive system disease with a high incidence rate and is common in women.The cause of IBS remains unclear.Some studies have shown that mental and psychological diseases are independent risk factors for IBS.At present,the treatment of IBS is mainly symptomatic treatment.Clinically,doctors also use cognitive behavioral therapy to improve patients'cognitive ability to diseases and clinical symptoms.In recent years,exercise therapy has attracted more and more attention from scholars.Improving the symptoms of IBS patients through psychosomatic treatment strategy may be a good treatment method.AIM To explore the effects of an intervention of cognitive behavioral therapy combined with exercise(CBT+E)on the cognitive bias and coping styles of patients with diarrhea-predominant irritable bowel syndrome(IBS-D);and to provide a theoretical reference for the management of IBS.METHODS Sixty IBS-D patients and thirty healthy subjects were selected.The 60 IBS-D patients were randomly divided into experimental and control groups.The experimental group was treated with the CBT+E intervention,while the control group was treated with conventional drugs without any additional intervention.The cognitive bias and coping styles of the participants were evaluated at baseline and after 6 wk,12 wk and 24 wk using the Automatic Thoughts Questionnaire(ATQ),Dysfunctional Attitudes Scale(DAS)and Pain Coping Style Questionnaire(CSQ)instruments,and the intervention effect was analyzed using SPSS 17.0 statistical software.RESULTS At baseline,the scores on the various scales showed that all subjects had cognitive bias and adverse coping styles.The IBS Symptom Severity Scale(IBSSSS)scores,ATQ total scores,DAS scores and CSQ scores of the two groups were not significantly different(P>0.05).Compared with baseline,after 6 wk of the CBT+E intervention,there were significant differences in the ATQ scores,the dependence and total scores on the DAS,and the catastrophization,distraction and prayer scores on the CSQ(P<0.05).After 12 wk,there were significant differences in the scores for perfectionism on the DAS and in the scores for reinterpretation,neglect and pain behavior on the CSQ in the experimental group(P<0.05).After 24 wk,there were significant differences in the vulnerability,dependence,perfectionism,and total scores on the DAS and in the catastrophization,distraction and prayer scores on the CSQ in the experimental group(P<0.01).The IBS-SSS scores were negatively correlated with the ATQ and DAS total scores(P<0.05)but were positively correlated with the CSQ total score(P<0.05).CONCLUSION Intervention consisting of CBT+E can correct the cognitive bias of IBS-D patients and eliminate their adverse coping conditions.CBT+E should be promoted for IBS and psychosomatic diseases.

Electroacupuncture at Tianshu (ST 25) for diarrhea-predominant irritable bowel syndrome using positron emission tomography Changes in visceral sensation center

Previous studies have demonstrated that electroacupuncture therapy is effective in the treatment of irritable bowel syndrome. However, the precise mechanism of this therapy is unknown. The present study served to investigate the effects of electroacupuncture therapy on treatment of patients with diarrhea-predominant irritable bowel syndrome （IBS）. We compared brain activation maps based on the changes of cerebral glucose metabolism obtained by 18-fluorodeoxyglucose positron emission tomography scanning under three conditions： resting, rectal balloon distension and rectal balloon distension plus electroacupuncture. Under the resting condition, compared with healthy controls, IBS patients displayed an increasing regional cerebral metabolic rate of glucose over a wide range： bilateral superior temporal gyrus, right middle occipital gyrus, superior frontal gyrus and bilateral middle frontal gyrus. However, there was no significant activity in the visceral pain center. Compared with the resting condition, under the rectal balloon distension condition, patients with IBS had a greater regional cerebral metabolic rate of glucose in the prefrontal cortex, left anterior cingulate cortex, postcentral gyrus, precentral gyrus and temporal gyrus. Under the rectal balloon distension plus electroacupuncture condition, stimulation by electroacupuncture at Tianshu （ST 25） manifested a decreased regional cerebral metabolic rate of glucose in the left cingulate gyrus, right insula, right caudate nucleus, fusiform gyrus and hippocampal gyrus. Electroacupuncture therapy relieved abdominal pain, distension or discomfort by decreasing glucose metabolism in the brain.

Serotonin transporter and cholecystokinin in diarrhea-predominant irritable bowel syndrome: Associations with abdominal pain, visceral hypersensitivity and psychological performance

BACKGROUND Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome(IBS).Previous studies have found that cholecystokinin(CCK)can enhance colon movement and that serotonin transporter(SERT)is a transmembrane transport protein with high affinity for 5-hydroxytryptamine,which can rapidly reuptake 5-hydroxytryptamine and then regulate its action time and intensity.We speculate that SERT and CCK might play a role in the pathogenesis of diarrheapredominant IBS(IBS-D)by affecting visceral sensitivity and the brain-gut axis.AIM To determine SERT and CCK levels in IBS-D patients diagnosed using Rome IV criteria and to analyze their associations with abdominal pain,visceral hypersensitivity and psychological performance.METHODS This study collected data from 40 patients with IBS-D at the China-Japan Friendship Hospital from September 2017 to April 2018 and 18 healthy controls.The severity of abdominal pain,visceral sensitivity and psychological performance were evaluated in IBS-D patients and healthy controls,the levels of SERT and CCK in plasma and colonic mucosa were evaluated,and the correlations between them were analyzed.RESULTS There were significant differences in the initial sensation threshold(31.00±8.41 mL vs 52.22±8.09 mL,P<0.001),defecating sensation threshold(51.75±13.57 mL vs 89.44±8.73 mL,P<0.001)and maximum tolerable threshold(97.25±23.64 mL vs 171.11±20.83 mL,P<0.001)between the two groups.IBS-D patients had more severe anxiety(7.78±2.62 vs 2.89±1.02,P<0.001)and depressive(6.38±2.43 vs 2.06±0.73,P<0.001)symptoms than healthy controls.Significant differences were also found in mucosal CCK(2.29±0.30 vs 1.66±0.17,P<0.001)and SERT(1.90±0.51 vs 3.03±0.23,P<0.001)between the two groups.There was a significant positive correlation between pain scores and mucosal CCK(r=0.96,0.93,0.94,P<0.001).Significant negative correlations between anxiety(r=-0.98;P<0.001),depression(r=-0.99;P<0.001),pain evaluation(r=-0.96,-0.93,-0.95,P<0.001)and mucosal SERT were observed.CONCLUSION IBS-D patients had psychosomatic disorders and visceral hypersensitivity.SERT and CCK might be involved in the pathogenesis of IBS-D by regulating the braingut axis and affecting visceral sensitivity.This provides a new potential method for identifying a more specific and effective therapeutic target.

Altered metabolism of bile acids correlates with clinical parameters and the gut microbiota in patients with diarrhea-predominant irritable bowel syndrome

BACKGROUND Bile acids(BAs)have attracted attention in the research of irritable bowel syndrome with predominant diarrhea(IBS-D)due to their ability to modulate bowel function and their tight connection with the gut microbiota.The composition of the fecal BA pool in IBS-D patients is reportedly different from that in healthy populations.We hypothesized that BAs may participate in the pathogenesis of IBS-D and the altered BA profile may be correlated with the gut microbiome.AIM To investigate the role of BAs in the pathogenesis of IBS-D and the correlation between fecal BAs and gut microbiota.METHODS Fifty-five IBS-D patients diagnosed according to the Rome Ⅳ criteria and twentyeight age-,sex-,and body mass index-matched healthy controls(HCs)were enrolled in this study at the gastroenterology department of China-Japan Friendship Hospital.First,clinical manifestations were assessed with standardized questionnaires,and visceral sensitivity was evaluated via the rectal distension test using a high-resolution manometry system.Fecal primary BAs including cholic acid(CA)and chenodeoxycholic acid(CDCA),secondary BAs including deoxycholic acid(DCA),lithocholic acid(LCA),and ursodeoxycholic acid(UDCA)as well as the corresponding tauro-and glyco-BAs were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry.The gut microbiota was analyzed using 16S rRNA gene sequencing.Correlations between fecal BAs with clinical features and gut microbiota were explored.RESULTS Fecal CA(IBS-D:3037.66[282.82,6917.47]nmol/g,HC:20.19[5.03,1304.28]nmol/g;P<0.001)and CDCA(IBS-D:1721.86[352.80,2613.83]nmol/g,HC:57.16[13.76,1639.92]nmol/g;P<0.001)were significantly increased,while LCA(IBSD:1621.65[58.99,2396.49]nmol/g,HC:2339.24[1737.09,2782.40];P=0.002)and UDCA(IBS-D:8.92[2.33,23.93]nmol/g,HC:17.21[8.76,33.48]nmol/g;P=0.025)were significantly decreased in IBS-D patients compared to HCs.Defecation frequency was positively associated with CA(r=0.294,P=0.030)and CDCA(r=0.290,P=0.032)and negatively associated with DCA(r=−0.332,P=0.013)and LCA(r=−0.326,P=0.015)in IBS-D patients.In total,23 of 55 IBS-D patients and 15 of 28 HCs participated in the visceral sensitivity test.The first sensation threshold was negatively correlated with CDCA(r=−0.459,P=0.028)in IBS-D patients.Furthermore,the relative abundance of the family Ruminococcaceae was significantly decreased in IBS-D patients(P<0.001),and 12 genera were significantly lower in IBS-D patients than in HCs(P<0.05),with 6 belonging to Ruminococcaceae.Eleven of these genera were negatively correlated with primary BAs and positively correlated with secondary BAs in all subjects.CONCLUSION The altered metabolism of BAs in the gut of IBS-D patients was associated with diarrhea and visceral hypersensitivity and might be ascribed to dysbiosis,especially the reduction of genera in Ruminococcaceae.

Common traditional Chinese medicine therapies for diarrhea-predominant irritable bowel syndrome: An overview of systematic reviews

Objective: To critically evaluate and summarize the methodological quality of systematic reviews(SRs)and present objective and important outcomes on the effectiveness of traditional Chinese medicine(TCM) therapies, including Chinese herbal medicine(CHM), acupuncture, and moxibustion, for diarrheapredominant irritable bowel syndrome(IBS-D).Methods: We conducted a comprehensive literature search for SRs in 7 databases until April 16, 2022.Two reviewers independently extracted data and assessed the methodological quality of the reviews according to the Assessing the Methodological Quality of Systematic Reviews 2(AMSTAR-2), the Risk of Bias in Systematic reviews(ROBIS) tool, and the Preferred Reporting Item for Systematic Review and Meta-analysis(PRISMA) statement. The Grading of Recommendations, Assessment, Development, and Evaluation(GRADE) was used to rate the quality of evidence.Results: IBS-D patients included in 12 reviews were diagnosed in accordance with the Rome criteria, 9 reviews focused on CHM, 2 articles observed moxibustion and heat-sensitive moxibustion, 1 article studied acupuncture and CHM. The outcomes of the SRs were the effectiveness rate, the total effectiveness rate,global symptom improvement, and adverse effects. Based on AMSTAR-2, which measures the quality of methodology, all of the included studies were of low or critically low quality. According to the ROBIS tool, 10 SRs(83.33%) had a high risk of bias. With the PRISMA checklist, only 3 SRs reached over 90% compliance.Based on GRADE, most evidence was of low quality, and there was a moderate quality of evidence that the effectiveness rate of modified-Tongxie Yaofang was superior to Western medicine in the treatment of IBS-D.Conclusion: Given the suboptimal reporting and methodological quality of existing SRs, more studies are needed to clarify whether TCM therapies are more effective or safe than pharmacological medicine.Future studies should combine evidence-based medicine with TCM research according to the characteristics of TCM.

Nerve growth factor and diarrhea-predominant irritable bowel syndrome(IBS-D):a potential therapeutic target?

Irritable bowel syndrome （IBS） is a common functional gastrointestinal disorder characterized by recurrent abdominal pain or discomfort associated with abnormal bowel habits. Diarrhea-predominant IBS （IBS-D） is a major subtype of IBS, the predominant manifestations of which are abdominal pain and diarrhea. The pathogenesis of IBS-D remained unknown until recently. The effects of psychosocial stress, central hypervigilance, neuroendocrine abnor- mality, disturbed gastrointestinal motility, mucosal immune activation, intestinal barrier dysfunction, visceral hyper- sensitivity （VH）, altered gut flora, and genetic susceptibility may be involved in its development. Recently, increased attention has been placed on the neural-immune-endocrine network mechanism in IBS-D, especially the role of var- ious neuroendocrine mediators. As a member of the neurotrophin family, nerve growth factor （NGF） has diverse bio- logical effects, and participates in the pathogenesis of many diseases. Basic studies have demonstrated that NGF is associated with inflammatory- and stress-related VH, as well as stress-related intestinal barrier dysfunction. The aim of this study is to summarize recent literature and discuss the role of NGF in the pathophysiology of IBS-D, especially in VH and intestinal barrier dysfunction, as well as its potential as a therapeutic target in IBS-D.

Acupuncture for diarrhea-predominant irritable bowel syndrome:A randomized control study

Objective:To verify the effectiveness of acupuncture for diarrhea-predominant irritable bowel syndrome(IBS-D).Methods:Sixty-five patients with IBS-D were randomized into an acupuncture group(33 cases)and a sham-acupuncture group(32 cases).In the acupuncture group,Tiānshū(天枢ST25),Zhōngwǎn(中脘CV12),Zúsānlǐ(足三里ST36),Shàngjùxū(上巨虚ST37),Gōngsūn(公孙SP4),Fēnglóng(丰隆ST40),Zhāngmén(章门LR13)and Yīnlíngquán(阴陵泉SP9)were selected and stimulated with routine acupuncture technique,once every two days,3 times weekly,for 8 weeks consecutively,24 times in total.In the shamacupuncture group,the sham-acupoints were selected,0.5 cun or 1 cun superior,inferior,lateral or medial to the corresponding points separately.The blunt-tip needles were used to stimulate only the skin surface of each point.The treatment frequency and courses were the same as the acupuncture group.Before treatment,in 4 weeks of treatment,after treatment and in follow-up,the changes in the score of IBS symptom severity scale(IBS-SSS),Bristol stool form scale and defecation satisfaction were observed in the patients of two groups.After treatment,the effectiveness was assessed in the two groups.Results:In 4 weeks of treatment,after treatment and in follow-up,IBS-SSS score,Bristol stool form scale and defecation satisfaction were all lower than those before treatment in either group(all P<0.01).Bristol stool form scale in the acupuncture group was lower than that in the sham-acupuncture group in4 weeks of treatment,after treatment and in follow-up,while,IBS-SSS score and defecation satisfaction were lower than the sham-acupuncture group in follow-up(all P<0.05).Conclusion:Acupuncture can effectively relieve diarrhea and improves defecation satisfaction in the patients with IBS-D.

Clinical Evaluation of Soothing Gan(肝) and Invigorating Pi(脾)Acupuncture Treatment on Diarrhea-predominant Irritable Bowel Syndrome

Objective： To explore the effect of Soothing Gan （肝） and invigorating Pi （脾） （SGIP） acupuncture treatment on the clinical symptoms and quality of life （QOL） in patients with diarrhea-predominant irritable bowel syndrome （IBS-D）. Methods： With a single-blinded randomized control study adopted, 63 patients who met the inclusion criteria were assigned by a random number table to two groups, 31 in the treatment group and 32 in the drug control group. The treatment group received SGIP acupuncture therapy; while the control group was treated orally with pinaverium bromide. The treatment duration of both groups was 28 days. The clinical efficacy was evaluated and compared by scoring patient＇s symptom and QOL. Results： A significant difference was found by variance analysis in efficacies between the two groups （P〈0.01）, shown as the quicker initiation of effect （P〈0.05） and the more evident clinical improvement in symptoms along the increase in treatment duration, as well as the more significant elevation of QOL in the acupuncture treatment group （P〈0.01）. SGIP displayed its superiority especially in improving dysphoria, conflict behavior, dietary restrictions, and social responses. Conclusion： SGIP acupuncture treatment could effectively alleviate the degree and frequency of symptoms＇ attack in IBS-D patients, such as abdominal pain, diarrhea, abdominal distension, etc., markedly relieve the tenesmic sensation, with the efficacy better than that of pinaverium bromide, showing a preponderance in improving patient＇s QOL.

New paradigm of oral rehydration in patients affected by irritable bowel syndrome with chronic diarrhea

Irritable bowel syndrome with diarrhea is a very frequent clinical condition characterized by disabling intestinal symptoms.This disease presents with daily abdominal pain for at least 3 months related to defecation and associated with a change in the frequency of bowel movements and the shape of the stool.International surveys about this disease report a global prevalence of about 1.5%.A new amino acid based electrolyte solution has recently been commercialized for oral rehydration in diarrhea.It is composed of water,electrolytes,and five selected amino acids that function as sodium co-transporters without containing glucose.In recent years,some studies explored the effectiveness of the amino acid based electrolyte beverage in oncologic patients with gastrointestinal mucositis,reporting good results.Recently,a prospective study to evaluate the clinical impact of the amino acid based medical beverage was conducted in patients with diarrhea predominant irritable bowel syndrome.The research was based on a real-life methodology minimizing the disruption of the routine care.One hundred patients suffering from irritable bowel syndrome with diarrhea drank a solution based on selected amino acids twice a day for 2 wk.Each enrolled patient completed the study and showed a significant response rate with regard to stool consistency and pain reduction.Based on this data,we can hypothesize that the amino acid based oral rehydration solution could be a valid tool in the treatment of patients affected by irritable bowel syndrome with diarrhea.It is certainly necessary to plan highquality clinical trials comparing glucose based oral solutions and amino acid based solutions in patients with persisting diarrhea.Probably in the near future all oral rehydration solutions will contain amino acids.

Comparison of Electroacupuncture and Moxibustion on BrainGut Function in Patients with Diarrhea-Predominant Irritable Bowel Syndrome:A Randomized Controlled Trial

Objective： To compare the effects of electroacupuncture （EA） and moxibustion therapies on patients with diarrhea-predominant irritable bowel syndrome （D-IBS）. Methods： A total of 60 D-IBS patients were randomly allocated to the EA group （30 cases） and moxibustion group （30 cases）. Before and after treatment, the gastrointestinal symptoms and psychological symptoms were scored by Visual Analogue Scale, Bristol Stool Form Scale, Hamilton Anxiety Rating Scale （HAMA）, and Hamilton Depression Rating Scale （HAMD）; the expressions of 5-hydroxytryptamine （5-HT）, 5-HT3 receptor （5-HT3R）, and 5-HT4 receptor （5-HT4R） in the sigmoid mucosal tissue were measured by immunohistochemical staining. Additionally, the effects on the functional brain areas of the anterior cingulate cortex （ACC）, insular cortex （IC） and prefrontal cortex （PFC） were observed by functional magnetic resonance imaging. Results： Compared with before treatment, both EA and moxibustion groups reported significant improvements in abdominal pain and abdominal bloating after treatment （P〈0.01 or P〈0.05）. The moxibustion group reported greater improvements in defecation emergency, defecation frequency, and stool feature than the EA group （P〈0.01）. Both HAMA and HAMD scores were significantly decreased in the moxibustion group than in the EA group （P〈0.01）. Both groups demonstrated significantly reduced expressions of 5-HT, 5-HT3R and 5-HT4R in the colonic mucosa after treatment （P〈0.01）, with a greater reduction of 5-HT in the moxibustion group （P〈0.05）. Finally, decreased activated voxel values were observed in the left IC, right IC and PFC brain regions of patients in the moxibustion group under stimulation with 150 mL colorectal distension after treatment （P〈0.05 or P〈0.01）, while in the EA group only PFC area demonstrated a reduction （P〈0.05）. Conclusion： Moxibustion can significantly improve the symptoms of D-IBS, suggesting that moxibustion may be a more effective therapy than EA for D-IBS patients.