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.

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.

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.

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.

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).

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.

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.

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.

Clinical characteristic and fecal microbiota responses to probiotic or antidepressant in patients with diarrhea-predominant irritable bowel syndrome with depression comorbidity: a pilot study

To the Editor: Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder that presents as abdominal pain with altered bowel habits. The pathophysiologic mechanism of IBS is not well understood, although many hypotheses have been proposed, including visceral hypersensitivity, gastrointestinal dysmotility, lowgrade inflammation of the intestinal mucosa, and dysfunction of the brain-gut interaction. Dysfunction of the braingut interaction is thought to be involved in IBS because a considerable proportion of patients with IBS have some form of psychologic comorbidity, such as depression or anxiety. In addition, mental and psychologic problems increase the risk for IBS and the symptom severity of IBS. Recently, changes in the gut microbiota have also been suggested to contribute to both IBS and depression. Our previous study demonstrated significant altered gut microbiota profiles in patients with diarrhea-predominant IBS (IBS-D) and depression.

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.

Effectiveness of an amino acid beverage formulation in diarrheapredominant irritable bowel syndrome:A pragmatic real-world study

BACKGROUND Amino-acid based medical foods have shown promise in alleviating symptoms of drug induced gastrointestinal side effects;particularly,diarrhea-predominant symptoms.Irritable bowel syndrome(IBS)is a gastrointestinal disorder that affects up to 9% of people globally,with diarrhea predominant IBS(IBS-D)being the most prevalent subtype.Further trials are needed to explore potential added benefits when integrated into standard care for IBS-D.AIM To assess the effectiveness of an amino acid-based medical food as an adjunct to standard of care for adults with IBS-D.METHODS This is a pragmatic,real world,open label,single arm study comparing a 2-week baseline assessment to a 2-week intervention period.One hundred adults,aged 18 to 65 years,with IBS-D,according to Rome IV criteria,were enrolled after completing a 2-week baseline assessment period and received a 2-week supply of an amino acid based medical food which was consumed at home twice daily on top of their standard of care.The primary outcome was an assessment of tolerability after 2-weeks of consumption,while secondary outcomes included changes in stool consistency(Bristol Stool Form Scale),severity of abdominal pain&discomfort,symptoms of urgency,Global Improvement Survey(GIS),and the IBS severity scoring system(IBS-SSS).RESULTS The test product was well-tolerated as each participant successfully completed the full 14-day trial,and there were no instances of dropouts or discontinuation of the study product reported.Forty percent of participants achieved a 50% or more reduction in the number of days with type 6-7 bowel movements(IBS-D stool consistency responders).Fifty-three percent of participants achieved a clinically meaningful reduction of 30% in mean weekly pain scores,and 55%experienced the same for mean weekly discomfort scores(IBS-D pain and discomfort responders).Participants experienced a mean-109.4(95% confidence interval:-130.1,-88.8)point reduction on the IBS-SSS and 52% experienced a minimally clinically important difference of>95 points.An IBS-SSS category shift from severe to moderate or mild occurred in 69% of participants.For functional symptoms,76% of participants reported symptom relief on the GIS.CONCLUSION The amino acid-based medical food was well-tolerated,when added to the standard of care,and demonstrated improvements in both overall IBS symptom severity and IBS-D symptoms within just 2 wk.

Regulating effect of Tong Xie-Yao Fang on colonic epithelial secretion via Cl- and HCO3- channel

AIM To investigate the pharmacological effect of Tong XieYao Fang(TXYF) formula, a Chinese herbal formula, on Diarrhea-predominant irritable bowel syndrome(D-IBS) rats.METHODS In a neonatal maternal separation plus restraint stress(NMS + RS) model of D-IBS, male Sprague Dawley rats were randomly divided into two groups(NMS + RS group and TXYF-formula group) with no handlings were used as controls(NH group). Starting from postnatalday 60, rats in TXYF-formula group were administered TXYF-formula(4.92 g/100 g bodyweight) orally twice a day for 14 consecutive days while NH group and NMS + RS group were given distilled water. Using short-circuit current technology, we observed 5-HT-induced changes of current across ion channels, such as cystic fibrosis transmembrane conductance regulator(CFTR) Clchannel, epithelial Na+ channel(ENaC), Ca2+-dependent Cl- channel(CACC), Na+-K+-2Cl- co-transporter(NKCC), and Na+-HCO-3 co-transporter(NBC), in the colonic epithelium of three groups after exposure to drugs and specific blockers with a Power Lab System(AD Instruments International).RESULTS Under basal conditions, the changes of short-circuit current(?Isc, μA/cm2) induced by 5-HT were similar in NH group and TXYF-formula group, and both higher than NMS + RS group(70.86 μA/cm2 ± 12.32 μA/cm2, 67.67 μA/cm2 ± 11.68 μA/cm2 vs 38.8 μA/cm2 ± 7.25 μA/cm2, P < 0.01, respectively). When CACC was blocked by 4,4′-diisothiocyanato-stilbene-2,2′-disulfonic acid, 5-HT-induced ?Isc was smaller in NMS + RS group than in NH group and TXYF-formula group, respectively(48.41 μA/cm2 ± 13.15 μA/cm2 vs 74.62 μA/cm2 ± 10.73 μA/cm2, 69.22 μA/cm2 ± 11.7 μA/cm2, P < 0.05, respectively). The similar result could be obtained when ENaC was blocked by Amiloride(44.69 μA/cm2 ± 12.58 μA/cm2 vs 62.05 μA/cm2 ± 11.26 μA/cm2, 62.11 μA/cm2 ± 12.01 μA/cm2, P < 0.05, respectively). However, when CFTR Cl- channel was blocked by 1,1-dimethyl piperidinium chloride(DPC), 5-HT-induced ?Isc did not significantly differ in three groups(42.28 μA/cm2 ± 10.61 μA/cm2 vs 51.48 μA/cm2 ± 6.56 μA/cm2 vs 47.75 μA/cm2 ± 7.99 μA/cm2, P > 0.05, respectively). The similar results could also be obtained in three groups when NBC and NKCC were respectively blocked by their blockers.CONCLUSION TXYF-formula can regulate the Cl- and HCO-3 secretion of colonic mucosa via CFTR Cl- channel, Cl-/HCO-3 exchanger, NBC and NKCC co-transporters.

Microscopic colitis: Common cause of unexplained nonbloody diarrhea

Microscopic colitis(MC) is characterized by chronic, watery, secretory diarrhea, with a normal or near normal gross appearance of the colonic mucosa. Biopsy is diagnostic and usually reveals either lymphocytic colitis or collagenous colitis. The symptoms of collagenous colitis appear most commonly in the sixth decade. Patients report watery, nonbloody diarrhea of a chronic, intermittent or chronic recurrent course. With collagenous colitis, the major microscopic characteristic is a thickened collagen layer beneath the colonic mucosa, and with lymphocytic colitis, an increased number of intraepithelial lymphocytes. Histological workup can confirm a diagnosis of MC and distinguish the two distinct histological forms, namely, collagenous and lymphocytic colitis. Presently, both forms are diagnosed and treated in the same way; thus, the description of the two forms is not of clinical value although this may change in the future. Since microscopic colitis was first described in 1976 and only recently recognized as a common cause of diarrhea, many practicing physicians may not be aware of this entity. In this review, we outline the epidemiology, risk factors associated with MC, its etiopathogenesis, the approach to diagnosis and the management of these individuals.

The role of 5-HT_7 Receptor in the pathogenesis of IBS

Objective：To investigate the role of 5-HT7 receptor in the pathogenesis of irritable bowel syndrome（IBS）. Methods：Rat model of D-IBS was established by intracolonic instillation of acetic acid and restraint stress; Rat model of C-IBS was established by stomach irrigated with 0-4℃ cool water daily for 14 d. The content and distribution of 5-HT7 receptor at the brain and bowel was examined by immunohistochemistry and the expression of 5-HT7 receptor mRNA was detected by fluorescence quantitative RT-PCR（Real-time PCR）. Results：Immunocytochemistry result showed the 5-HT7 rceptor positive staining at hippocampus and hypothalamus of both C-IBS and D-IBS group was stronger than that of control group（P 〈 0.01）. The 5-HT7R expression at ileum, proximate colon, distal colon of C-IBS group was significantly stronger than that of control group（P 〈 0.05）. Realtime-PCR analysis results showed the expression level of 5-HT7 receptor at hippocampus and hypothalamus of both C-IBS and D-IBS group was increased than that of control group（P〈 0.05）. At proximal and distal colon of C-IBS group, the 5-HT7 receptor mRNA expression was increased compared with control group（P〈 0.05）. Conclusion：The up-regulated expression of 5-HT7 receptor at brain and colon may play an important role in the pathogenesis of C-IBS.

Effect of Tongxie Yaofang(痛泻要方) Granule in Treating Diarrhea-Predominate Irritable Bowel Syndrome

Objective:To study the clinical effect of Tongxie Yaofang(痛泻要方,TXYF) Granule in treating diarrhea-predominate irritable bowel syndrome(D-IBS) and its possible mechanism.Methods:A total of 120 patients were assigned to two groups using stratified block randomization,80 in the intervention group and 40 in the control group.To the intervention group the TXYF granule was given at one package each time,twice a day; the control group was treated with Miyarisan three times a day,two tablets each time.The course of...