Irritable Bowel Syndrome With Diarrhea Patients Research Articles

A Mini Literature Review of Probiotics: Transforming Gastrointestinal Health Through Evidence-Based Insights.

As our understanding of the intricate interaction between gut bacteria and human health continues to expand, so too has interest in the ability of probiotics to manage gut microbiota and confer multiple health benefits to the host. The mini literature review focuses on the expanding potential of the use of probiotics in GI health, with a focus on probiotics' potential therapeutic advantages in a variety of gastrointestinal (GI) illnesses. Probiotics play a significant role in managing diarrhea and symptoms of irritable bowel syndrome with diarrhea (IBS-D) by modulating gut microbial communities. Specific probiotic strains have been found to reduce the abundance of harmful bacteria, regulate inflammatory markers like interleukin 6, and improve GI symptoms such as abdominal discomfort and stool consistency. Additionally, probiotic blends have shown potential for preventing GI infections and alleviating GI pain in IBS-D patients. Studies have demonstrated that certain multi-strain probiotics, including Bifidobacterium and Lactobacillus species, can significantly increase the frequency of bowel movements and reduce the proportion of individuals experiencing constipation. It has also been found that probiotic supplementation may reduce the incidence of postoperative complications and mortality, particularly in patients undergoing colorectal adenocarcinoma surgery. Additionally, probiotics have been associated with decreased levels of pro-inflammatory cytokines and improved clinical outcomes in patients with colorectal cancer. Furthermore, probiotics have been associated with enhanced digestive tolerance, reduced GI inflammation, and prolonged clinical remission in certain UC patients. Studies have also shown that probiotics, administered either directly to infants or pregnant women during the perinatal stage, can alleviate symptoms such as inconsolable crying and irritation associated with infant colic, improve bowel movement frequency in cases of functional constipation, and enhance overall conditions in premature infants, including reducing regurgitation and improving feeding tolerance. The review addresses both encouraging results and challenges with probiotic therapy, while also arguing for more studies to elucidate underlying mechanisms and enhance therapeutic techniques. As we traverse the complex field of probiotic therapy in the treatment of GI illnesses, researchers, physicians, and other healthcare professionals can benefit from the informative information provided by this study.

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 administration. Changes in visceral sensitivity after administration of the TRPV1 antagonist were recorded. RESULTS Here, we observed greater expression of the 5-HT2B receptor in the colonic mucosa of patients with IBS-D than in that of controls, which was correlated with abdominal pain scores. Intracolonic instillation of acetic acid and wrap restraint induced obvious chronic visceral hypersensitivity and increased fecal weight and fecal water content. Exogenous 5-HT2B receptor agonist administration increased visceral hypersensitivity, which was alleviated by successive administration of a TRPV1 antagonist. IBS-D rats receiving the 5-HT2B receptor antagonist exhibited inhibited visceral hyperalgesia. Moreover, the percentage of 5-HT2B receptor-immunoreactive (IR) cells surrounded by TRPV1-positive cells (5-HT2B receptor I+) and total 5-HT2B receptor IR cells (5-HT2B receptor IT) in IBS-D rats was significantly reduced by the administration of a 5-HT2B receptor antagonist. CONCLUSION Our finding that increased expression of the 5-HT2B receptor contributes to visceral hyperalgesia by inducing TRPV1 expression in IBS-D patients provides important insights into the potential mechanisms underlying IBS-D-associated visceral hyperalgesia.

Modification of bile acids metabolism with multi-strain probiotic in patients with diarrhea predominant irritable bowel syndrome: a randomized study

one of the irritable bowel syndrome with diarrhea (IBS-D) mechanisms of development isbile acids (BA) malabsorption (BAM). The promising new therapeutic approach for BAM – probiotic
 bacteria producing bile salt hydrolase (BSH). The aim of the study was to compare the effect of multi-strain probiotic and cholestyramine combination with cholestyramine monotherapy on modifying the
 parameters of BA metabolism in IBS-D patients. Materials and methods. The trial was conducted asa randomized, open, parallel study and included 108 patients with IBS-D divided into 2 groups: casegroup (n=57) that received combination of probiotic (L. rhamnosus, L. plantarum, S. thermophilus, L.acidophilus, B. bifidum, B. longum, B. infantis, S. boulardii) with cholestyramine, and control group(n=51) that received cholestyramine monotherapy during 12 weeks. The total relative activity (RA)of gut bacterial BSH, serum BA (sBA) and fecal BA (fBA) were assessed in all patients. Results: total,
 primary and secondary sBA and fBA, proportions of primary and secondary fBA were significantly dif-ferent after 12 weeks within each group comparing to baseline, p<0.05. In case group the proportions of
 primary and secondary sBA, RA of gut bacterial BSH were significantly different after 12 weeks compar-ing to baseline, p<0.05. All the parameters of BA metabolism except absolute levels of secondary sBA
 were significantly different after 12 weeks between the control and case groups, p<0.05. Conclusions:
 combination of cholestyramine and multi-strain probiotic led to more pronounced alterations of BA me-tabolism and increasing of gut bacterial BSH-activity comparing to cholestyramine monotherapy. It may
 explain possible mechanism of action of probiotics in patients with IBS-D and assumed BAM.

Evaluation of the Effects of the Tritordeum-Based Diet Compared to the Low-FODMAPs Diet on the Fecal Metabolome of IBS-D Patients: A Preliminary Investigation.

Since irritable bowel syndrome (IBS)-a common gastrointestinal (GI) disorder-still lacks effective therapy, a nutritional approach may represent a practical alternative. Different reports demonstrated that a low-fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) diet (LFD) reduces symptoms in IBS with diarrhea (IBS-D) patients, also inducing beneficial pathophysiological and biochemical modifications. More recently, diets with alternative cereals having a different gluten composition, such as tritordeum, have also been considered (TBD). We investigated the impact of TBD and LFD on the fecal metabolome composition in 38 IBS-D patients randomly allocated to the two diets for 12 weeks. Summarily, at baseline, the profile of fecal volatile organic compounds (VOCs) of IBS-D patients was not significantly different in the two groups. After treatment, significant changes were observed in the two groups regarding the VOCs content since some of them increased in the TBD group (namely, decanoic acid), whereas others (i.e., nonanal and ethanol) increased in the LFD one. Further, at baseline, short-chain fatty acids were positively related to inflammation and showed a significant decreasing trend after both diets compared to baseline values (namely, acetic and propanoic acid). Preliminary results from this pilot study suggest a potential positive intervention of TBD and LFD affecting the fecal metabolome composition in IBS-D patients.

S564 Burden of Disease in U.S. Patients With Irritable Bowel Syndrome With Diarrhea (IBS-D)

Introduction: Symptoms of irritable bowel syndrome with diarrhea (IBS-D) impose a significant burden to patients. Our study examined disease burden and care-seeking behavior of patients with IBS-D. Methods: A cross-sectional, on-line health survey collected data during 8/2020-12/2021 from US adults. IBS-D patients were defined using Rome IV criteria. Health outcomes comparing IBS-D patients to controls included anxiety and depression screeners, health-related quality of life (HRQoL) and productivity measures. Care, treatment and symptom burden were assessed for IBS-D patients. Differences in anxiety, depression, HRQoL, and productivity between IBS-D patients and the general population were assessed with a 1:1 matched sample by sex, age, race, region and Charlson Comorbidity Index score. Categorical data were described by percentage and continuous data by mean and standard deviation. Means were compared with ANOVA and proportions with chi-square tests. Results: Data was collected from 29,359 participants. Matching IBS-D participants resulted in 669 patients and 669 controls. Most patients were female (74.6%), White (84.0%), with a mean age of 41.9 years. IBS-D patients had significantly higher proportions of moderate to severe anxiety and depression (p < .001) and significantly lower HRQoL vs controls (p < .001). Health impact on work productivity and daily activity was significantly higher among IBS-D patients vs controls (Table). Of IBS-D patients, 91.5% sought care for their symptoms, 59.3% within the past year. Of those having an ER visit/hospitalization in the past year (17.3%), abdominal pain was the most reported reason (87.1%). 65.9% of IBS-D patients reported currently taking an Rx and/or an OTC for their symptoms (13.2% Rx alone, 13.9% Rx and OTC, and 38.9% OTC alone). Abdominal pain and abdominal discomfort were the symptoms most experienced (71.0% and 70.9%, respectively). Abdominal pain was reported to be the most bothersome (34.5%) (Figure). IBS-D patients currently taking an Rx with/without an OTC were more satisfied with the control of bowel (39.2% vs 21.5%) and abdominal (40.3% vs 22.7%) symptoms than those currently taking an OTC alone. Conclusion: This large survey study demonstrates that the health impact of IBS-D is high. Nearly 1 in 5 patients sought care at an ER for their symptoms. Abdominal pain and discomfort are common bothersome symptoms with patients reporting better control with Rx medications compared to OTC agents.Figure 1.: Symptom Experience, Frequency and Bothersomeness Table 1. - Characteristics of the Rome IV IBS-D Cohort vs Controls (1) WPAI fielded 12/20-12/21: Rome IV IBS-D cohort n=463; control n=397. (2) GAD-7: Generalized Anxiety Disorder, 7-item; range: 0-21. (3) PHQ-9: Patient Health Questionnaire, 9-item; range: 0-29. (4) Veterans RAND 12-item Health Survey (VR12). (5) Question fielded 12/20-12/21: Rome IV IBS-D cohort n=251; control n=233 Rome IV IBS-D Cohort(N=669) Control(N=669) Sig. Female 74.6% 74.6% 1.000 Age, mean (SD) 41.9 (15.0) 41.9 (15.0) 0.990 Black or African American 7.8% 7.8% 1.000 White 84.0% 84.0% Other 8.2% 8.2% Proportion of Hispanic, Latino or Spanish origin 7.8% 8.5% 0.617 Northeast 17.2% 17.2% 1.000 Midwest 22.6% 22.6% South 42.8% 42.8% West 17.5% 17.5% Charlson Comorbidity Index (CCI) score, mean (SD) 0.6 (1.1) 0.6 (1.1) 1.000 Body Mass Index (BMI) (lbs/in2), mean (SD) 30.2 (9.0) 27.9 (7.4) < 0.001 Proportion employed per Work Productivity and Impairment (WPAI) (1) 54.2% 58.7% 0.187 Median household income (Census derived from zip code), mean (SD) 65,468(28,360) 65,459(26,647) 0.996 Anxiety (GAD-7 [2]) score, mean (SD) 9.9 (6.1) 6.8 (5.8) < 0.001 Depression (PHQ-9 [3]) score, mean (SD) 11.4 (7.3) 7.9 (7.1) < 0.001 Chronic pain 61.4% 38.6% < 0.001 Migraine 64.2% 35.8% < 0.001 Insomnia 67.7% 32.3% < 0.001 GERD 75.9% 24.1% < 0.001 VR-12 Mental Component Summary (MCS [4]), mean (SD) 36.7 (12.5) 43.9 (11.8) < 0.001 VR-12 Physical Component Summary (PCS [4]), mean (SD) 40.3 (11.2) 44.4 (10.6) < 0.001 VR-12 Health utility (VR-6D [4]), mean (SD) 0.60 (0.11) 0.67 (.12) < 0.001 Health problems affected work productivity rating (0-10 scale), mean, SD (5) 3.1 (2.9) 2.1 (2.8) < 0.001 Health problems affected daily activities rating (0-10 scale), mean, SD (1) 4.3 (3.2) 2.6 (3.1) < 0.001

MicroRNA-16 inhibits the TLR4/NF-κB pathway and maintains tight junction integrity in irritable bowel syndrome with diarrhea

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic and relapsing inflammatory disorder in which pathogenesis has been shown to be in part the result of miRNA-mediated signaling. Here, we investigated the alleviatory role of miR-16 in IBS-D. First, we established an IBS-D mouse model using colonic instillation of acetic acid and developed an IBS-D cell model using lipopolysaccharide exposure. The experimental data demonstrated that miR-16 was underexpressed in the serum of IBS-D patients, as well as in the colorectal tissues of IBS-D mouse models and lipopolysaccharide-exposed intestinal epithelial cells. Next, miR-16 and TLR4 were overexpressed or inhibited to characterize their roles in the viability and apoptosis of intestinal epithelial cells, inflammation, and epithelial tight junction. We found that miR-16 overexpression increased the viability of intestinal epithelial cells, maintained tight junction integrity, and inhibited cell apoptosis and inflammation. We showed that miR-16 targeted TLR4 and inhibited the TLR4/NF-κB signaling pathway. Additionally, inhibition of NF-κB suppressed the long noncoding RNA XIST, thereby promoting enterocyte viability, inhibiting apoptosis and cytokine production, and maintaining tight junction integrity. Invivo experiments further verified the alleviatory effect of miR-16 on IBS-D symptoms in mice. Taken together, we conclude that miR-16 downregulates XIST through the TLR4/NF-κB pathway, thereby relieving IBS-D. This study suggests that miR-16 may represent a potential target for therapeutic intervention against IBS-D.

Psychological and Gastrointestinal Symptoms of Patients with Irritable Bowel Syndrome Undergoing a Low-FODMAP Diet: The Role of the Intestinal Barrier

A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (LFD) improves both gastrointestinal (GI) symptoms and the psychological profile of patients with irritable bowel syndrome with diarrhea (IBS-D). The effects of 12 weeks of LFD on GI symptom and psychological profiles in relation to inflammation and the involvement of the intestinal barrier were studied in twenty IBS-D patients. The IBS Severity Scoring System, the Symptom Checklist-90-Revised, the Italian version of the 36-Item Short-Form Health Survey, the IBS-Quality of Life (QoL) questionnaire, and the Psychophysiological questionnaire were administered. The GI barrier function was assessed by sugar absorption test, the serum and fecal zonulin levels, and the serum levels of intestinal fatty-acid binding protein and diamine oxidase. Interleukins (ILs) and lipopolysaccharide (LPS) serum levels were evaluated along with dysbiosis. At the end of LFD, GI symptoms, psychological state (mainly anxiety, somatization, psychoticism, and interpersonal sensitivity), and QoL significantly improved in these patients. Simultaneously, an improvement in small intestinal permeability and intestinal mucosal integrity occurred, while IL-6, Il-10, LPS, and fermentative dysbiosis significantly decreased. The LFD can modify the immune-inflammatory features and enhance intestinal permeability and mucosal integrity, thus determining a concurrent improvement in the clinical and psychological conditions.

Low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols diet compared with traditional dietary advice for diarrhea-predominant irritable bowel syndrome: a parallel-group, randomized controlled trial with analysis of clinical and microbiological factors associated with patient outcomes

The efficacy and factors associated with patient outcomes for a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (LFD) compared with traditional dietary advice (TDA) based on modified National Institute for Clinical Excellence guidelines for irritable bowel syndrome with diarrhea (IBS-D) in regions consuming a non-Western diet are unclear. We aimed to determine the efficacy of an LFD compared with TDA for the treatment of IBS-D in Chinese patients and to investigate the factors associated with favorable outcomes. One hundred and eight Chinese IBS-D patients (Rome III criteria) were randomly assigned to an LFD or TDA. The primary endpoint was a ≥50-point reduction in the IBS Severity Scoring System at 3 wk. Fecal samples collected before and after the dietary intervention were assessed for changes in SCFAs and microbiota profiles. A logistic regression model was used to identify predictors of outcomes. Among the 100 patients who completed the study, the primary endpoint was met in a similar number of LFD (30 of 51, 59%) and TDA (26 of 49, 53%) patients (∆6%; 95% CI: -13%, 24%). Patients in the LFD group achieved earlier symptomatic improvement in stool frequency and excessive wind than those following TDA. LFD reduced carbohydrate-fermenting bacteria such as Bifidobacterium and Bacteroides, and decreased saccharolytic fermentation activity. This was associated with symptomatic improvement in the responders. High saccharolytic fermentation activity at baseline was associated with a higher symptom burden (P=0.01) and a favorable therapeutic response to the LFD (log OR: 4.9; 95% CI: -0.1, 9.9; P=0.05). An LFD and TDA each reduced symptoms in Chinese IBS-D patients; however, the LFD achieved earlier symptomatic improvements in stool frequency and excessive wind. The therapeutic effect of the LFD was associated with changes in the fecal microbiota and the fecal fermentation index. At baseline, the presence of severe symptoms and microbial metabolic dysbiosis characterized by high saccharolytic capability predicted favorable outcomes to LFD intervention.This trial was registered at clinicaltrials.gov as NCT03304041.

Intrinsic brain abnormalities of irritable bowel syndrome with diarrhea: a preliminary resting-state functional magnetic resonance imaging study

BackgroundThe aim of the present study was to explore the brain active characteristics of patients with irritable bowel syndrome with diarrhea (IBS-D) using resting-state functional magnetic resonance imaging technology.MethodsThirteen IBS-D patients and fourteen healthy controls (HC) were enrolled. All subjects underwent head MRI examination during resting state. A voxel-based analysis of fractional amplitude of low frequency fluctuation (fALFF) maps between IBS-D and HC was performed using a two-sample t-test. The relationship between the fALFF values in abnormal brain regions and the scores of Symptom Severity Scale (IBS-SSS) were analyzed using Pearson correlation analysis.ResultsCompared with HC, IBS-D patients had lower fALFF values in the left medial superior frontal gyrus and higher fALFF values in the left hippocampus and right precuneus. There was a positive correlation between the duration scores of IBS-SSS and fALFF values in the right precuneus.ConclusionThe altered fALFF values in the medial superior frontal gyri, left hippocampus and right precuneus revealed changes of intrinsic neuronal activity, further revealing the abnormality of gut-brain axis of IBS-D.

Lactobacillus plantarum CCFM8610 Alleviates Irritable Bowel Syndrome and Prevents Gut Microbiota Dysbiosis: A Randomized, Double-Blind, Placebo-Controlled, Pilot Clinical Trial

Abstract Irritable bowel syndrome with diarrhea (IBS-D) is chronic intestinal dysfunction with diarrhea and other complicated clinical symptoms, and it has a great impact on the daily life and mental state of patients. Some studies have reported that ingestion of probiotics can significantly alleviate a variety of intestinal diseases. The purpose of this study was to investigate the IBS-D-alleviating effects of a probiotic strain, Lactobacillus plantarum (L. plantarum) CCFM8610, with multiple health-promoting effects. The study was a 12-week, randomized, double-blind, placebo-controlled, pilot clinical trial. Seventy-five patients were randomly assigned to receive the placebo, oligosaccharides, or L. plantarum CCFM8610 (1 × 1010 colony-forming units (CFU) per day), with a 2-week run-in period, an 8-week intervention period, and a 2-week follow-up observation period. The patients’ clinical symptoms and quality of life were examined by the IBS symptom severity scale (IBS-SSS) and the IBS quality of life scale (IBS-QOL). Changes in gut microbiota composition and diversity were measured at the end of the intervention period. The oral administration of L. plantarum CCFM8610 significantly decreased the IBS-SSS and IBS-QOL scores, reduced IBS-D symptom severity, recovered gut microbiota diversity, decreased the relative abundance of bloating-related genus Methanobrevibacter, and increased the relative abundance of butyric acid-producing genera, including Anaerostipes, Anaerotruncus, Bifidobacterium, Butyricimonas, and Odoribacter. These findings suggest that ingestion of L. plantarum CCFM8610 can significantly alleviate clinical symptoms and gut microbiota dysbiosis in IBS-D patients. The IBS-D-alleviating effect of L. plantarum CCFM8610 may be related to the increase in the relative abundance of butyric acid-producing genera in the intestine.

Mucosal-Associated Microbiota Other Than Luminal Microbiota Has a Close Relationship With Diarrhea-Predominant Irritable Bowel Syndrome

Studies have linked dysbiosis of gut microbiota to irritable bowel syndrome (IBS). However, dysbiosis only referring to structural changes without functional alteration or focusing on luminal microbiota are incomplete. To fully investigate the relationship between gut microbiota and clinical symptoms of Irritable Bowel Syndrome with Diarrhea (IBS-D), fecal samples, and rectal mucosal biopsies were collected from 69 IBS-D patients and 20 healthy controls (HCs) before and during endoscopy without bowel preparation. 16S rRNA genes were amplified and sequenced, and QIIME pipeline was used to process the composition of microbial communities. PICRUSt was used to predict and categorize microbial function. The composition of mucosa-associated microbiota (MAM) was significantly different in IBS-D patients compared to HCs; while no difference in luminal microbiota (LM). MAM, but not LM, was significantly positively correlated with abdominal pain and bloating. A greater number of MAM functional genes changed in IBS-D patients than that of LM compared with HCs. Metabolic alteration in MAM not in LM was related to abdominal pain and bloating. There was a close relationship between the composition and function of MAM and clinical symptoms in IBS-D patients which suggests the important role of MAM in pathogenesis and therapies in IBS-D and it should be highlighted in the future.

Noninvasive Biomarkers of Gut Barrier Function in Patients Suffering from Diarrhea Predominant-IBS: An Update.

The intestinal barrier plays a crucial role in the absorption of nutrients and in preventing the entry of pathogenic microorganisms and toxic molecules. Several studies have shown a compromised intestinal barrier associated with low-grade inflammation in the small intestinal mucosa in celiac disease, inflammatory bowel disease, and irritable bowel syndrome (IBS), particularly in IBS with diarrhea (IBS-D). In light of these new data, IBS is no longer considered a functional disease but rather a heterogeneous syndrome that has yet to be carefully studied. Therefore, investigating the integrity and function of the intestinal barrier is now essential to improving knowledge of the pathophysiology of IBS-D and to improving the management of IBS-D patients. However, the study of the intestinal barrier must clarify some still unsolved methodological aspects and propose standardised assays before becoming a useful diagnostic tool. In this framework, this review will discuss data about the tests that noninvasively evaluate the integrity and functionality of the human intestinal barrier, paying particular attention to patients with IBS-D, in both clinical and research situations.

Circulating neurotransmitter levels in irritable bowel syndrome: correlation of laboratory tests and clinical findings

Objective: to estimate blood levels of serotonin and melatonin neurotransmitters in patients with irritable bowel syndrome and to evaluate the role of neurohumoral imbalance in the development and clinical manifestations of irritable bowel syndrome phenotypes.Materials and methods: the study included 60 patients (range, 18 – 45 years) diagnosed with irritable bowel syndrome according to the Roman IV criteria for irritable bowel syndrome (2016). 20 patients with a confirmed diagnosis of ulcerative colitis (UC) were assigned to a comparison group. The control group was composed of 45 apparently healthy subjects. All subjects were assigned to subgroups based on the prominent clinical presentation: irritable bowel syndrome with constipation (IBS-C), irritable bowel syndrome with diarrhea (IBS-D) and mixed irritable bowel syndrome (IBS-M). In addition to all the necessary procedures (clinical, laboratory and instrumental), blood concentrations of endogenous serotonin and melatonin were measured using enzyme-linked immunosorbent assay (ELISA).Results: the concentrations of endogenous serotonin and melatonin were significantly lower in patients with irritable bowel syndrome as compared with those having ulcerative colitis or healthy individuals. The detection rates of lowering serotonin levels were 53.3 % and 65 % — for melatonin. Low levels of melatonin were detected both in IBS-D and IBS-C patients. 69.57 % of IBS-D patients had elevated levels of serotonin as compared with the reference values for healthy subjects. We found a strong correlation between the severity of bloating and abdominal pain on the one hand, and low levels of endogenous serotonin and melatonin, on the other hand.Conclusion: our findings suggest that serotonin and melatonin neurotransmitters play a significant role in the pathophysiology and clinical manifestations of estimate blood levels of serotonin and melatonin neurotransmitters in patients with irritable bowel syndrome.

Clinical efficacy and safety of ketotifen in treating irritable bowel syndrome with diarrhea.

The aim of the study was to investigate the clinical efficacy and safety of ketotifen for the treatment of irritable bowel syndrome with diarrhea (IBS-D). A total of 108 enrolled IBS-D patients were randomly divided into a ketotifen group (n = 55) and a control (placebo) group (n = 53). The patients in the ketotifen group received ketotifen tablets (1 mg, oral) two times daily; patients in the control group received oral placebo for 8 weeks. Before and after 8 weeks of treatment, gastrointestinal symptoms, anorectal sensory function and the number and activity status of mast cells were assessed for both groups. (1) The overall effective rate of gastrointestinal symptom improvement in the ketotifen group was significantly higher than that in the control group (76.4 vs. 37.7%, P < 0.001). (2) First sensation, defecation urgency and discomfort/pain threshold in the ketotifen group improved significantly after treatment (P < 0.05); no significant changes were observed in the control group (P > 0.05). (3) In the ketotifen group, the number of mast cells in the terminal ileum decreased, and the percentages of degranulated mast cells in the sigmoid colon, ascending colon and terminal ileum decreased significantly after treatment compared with before treatment; these differences were statistically significant (P < 0.01). In the control group, the number of mast cells and the percentages of degranulated mast cells in various sites did not change significantly before and after treatment (P > 0.05). (4) Six patients (10.9%) in the ketotifen group experienced drowsiness and fatigue, but the symptoms disappeared after 1 week of treatment. Ketotifen significantly alleviated gastrointestinal symptoms and improved visceral hypersensitivity in patients with IBS-D. The therapeutic effect of ketotifen is related to a reduced number and decreased activity of mast cells in the intestinal mucosa, especially in the terminal ileum.

Bile Acid Diarrhea and NAFLD: Shared Pathways for Distinct Phenotypes.

Irritable bowel syndrome with diarrhea (IBS‐D) and NAFLD are both common conditions that may be influenced by shared pathways of altered bile acid (BA) signaling and homeostatic regulation. Pathophysiological links between IBS‐D and altered BA metabolism include altered signaling through the ileal enterokine and fibroblast growth factor 19 (FGF19) as well as increased circulating levels of 7α‐hydroxy‐4‐cholesten‐3‐one, a metabolic intermediate that denotes increased hepatic BA production from cholesterol. Defective production or release of FGF19 is associated with increased BA production and BA diarrhea in some IBS‐D patients. FGF19 functions as a negative regulator of hepatic cholesterol 7α‐hydroxylase; therefore, reduced serum FGF19 effectively de‐represses hepatic BA production in a subset of IBS‐D patients, causing BA diarrhea. In addition, FGF19 modulates hepatic metabolic homeostatic response signaling by means of the fibroblast growth factor receptor 4/klotho beta receptor to activate cascades involved in hepatic lipogenesis, fatty acid oxidation, and insulin sensitivity. Emerging evidence of low circulating FGF19 levels in subsets of patients with pediatric and adult NAFLD demonstrates altered enterohepatic BA homeostasis in NAFLD. Conclusion: Here we outline how understanding of shared pathways of aberrant BA homeostatic signaling may guide targeted therapies in some patients with IBS‐D and subsets of patients with NAFLD.

Acupuncture plus Chinese Herbal Medicine for Irritable Bowel Syndrome with Diarrhea: A Systematic Review and Meta-Analysis.

Purpose To comprehensively evaluate the efficacy and safety of acupuncture combined with Chinese herbal medicine (CHM) in treating irritable bowel syndrome with diarrhea (IBS-D). Methods Relevant randomized controlled trials (RCTs) were systemically retrieved from electronic databases from inception to March 2018, including the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese Biological Medical Database (CBM, SinoMed), China Science and Technology Journal Database (VIP), and Wan Fang Data. Meanwhile, pooled estimates, including the 95% confidence interval (CI), were calculated for primary and secondary outcomes of IBS-D patients. Besides, quality of relevant articles was evaluated using the Cochrane Collaboration's risk of bias tool, and the Review Manager 5.3 and Stata12.0 softwares were employed for analyses. Results A total of 21 RCTs related to IBS-D were included into this meta-analysis. Specifically, the pooled results indicated that (1) acupuncture combined with CHM might result in more favorable improvements compared with the control group (relative risk [RR] 1.29; 95% CI 1.24–1.35; P =0.03); (2) the combined method could markedly enhance the clinical efficacy in the meantime of remarkably reducing the scores of abdominal pain (standardized mean difference [SMD] –0.45; 95% CI –0.72, –0.17; P = 0.002), abdominal distention/discomfort (SMD –0.36; 95% CI –0.71, –0.01; P = 0.04), diarrhea (SMD –0.97; 95% CI –1.18, –0.75; P < 0.00001), diet condition (SMD –0.73; 95% CI –0.93, –0.52; P<0.00001), physical strength (SMD –1.25; 95% CI –2.32, –0.19; P = 0.02), and sleep quality (SMD –1.02; 95% CI –1.26, –0.77; P < 0.00001) compared with those in the matched groups treated with western medicine, or western medicine combined with CHM. Additionally, a metaregression analysis was constructed according to the name of prescription, acupuncture type, treatment course and publication year, and subgroup analyses stratified based on the names of prescriptions and acupoints location were also carried out, so as to explore the potential heterogeneities; and (3) IBS-D patients treated with the combined method only developed inconspicuous adverse events; more importantly, the combined treatment had displayed promising long-term efficacy. Conclusions Findings in this study indicate that acupuncture combined with CHM is suggestive of an effective and safe treatment approach for IBS-D patients, which may serve as a promising method to treat IBS-D in practical application. However, more large-scale, multicenter, long-term, and high-quality RCTs are required in the future, given the small size, low quality, and high risk of the studies identified in this meta-analysis.

Close association between abnormal expressed enzymes of energy metabolism and diarrhea-predominant irritable bowel syndrome.

Background:Irritable bowel syndrome (IBS) is one of the most common functional intestinal diseases, but its pathogenesis is still unknown. The present study aimed to screen the differentially expressed proteins in the mucosa of colon between IBS with diarrhea (IBS-D) patients and the healthy controls.Methods:Forty-two IBS-D patients meeting the Rome III diagnostic criteria and 40 control subjects from July 2007 to June 2009 in Chinese PLA General Hospital were enrolled in the present study. We examined the protein expression profiles in mucosa of colon corresponding to IBS-D patients (n = 5) and controls (n = 5) using 2-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS). Secondly, Western blot and immunohistochemical analysis were carried out to validate the screened proteins in 27 IBS-D patients and 27 controls. Thirdly, high-performance liquid chromatography (HPLC) was further carried out to determine ATP concentration in the mucosa of colon between 10 IBS-D patients and 8 controls. Comparisons between 2 groups were performed by Student's t-test or Mann-Whitney U-test.Results:Twelve differentially expressed proteins were screened out. The α-enolase (ENOA) in the sigmoid colon (0.917 ± 0.007 vs. 1.310 ± 0.100, t = 2.643, P = 0.017) and caecum (0.765 ± 0.060 vs. 1.212 ± 0.122, t = 2.225, P = 0.023), Isobutyryl-CoA dehydrogenase (ACAD8) in the sigmoid colon (1.127 ± 0.201 vs. 1.497 ± 0.392, t = 7.093, P = 0.008) of the IBS-D group were significantly lower while acetyl-CoA acetyltransferase (CT) in the caecum (2.453 ± 0.422 vs. 0.931 ± 0.652, t = 8.363, P = 0.015) and ATP synthase subunit d (ATP5H) in the sigmoid (0.843 ± 0.042 vs. 0.631 ± 0.042, t = 8.613,P = 0.007) of the IBS-D group was significantly higher, compared with the controls. The ATP concentration in the mucosa of the sigmoid colon in IBS-D group was significantly lower than that of control group (0.470 [0.180, 1.360] vs. 5.350 [2.230, 7.900], U = 55, P < 0.001).Conclusions:Many proteins related to energy metabolism presented differential expression patterns in the mucosa of colon of the IBS-D patients. The abnormalities in energy metabolism may be involved in the pathogenesis of IBS which deserves more studies to elucidate.

Eluxadoline-induced Recurrent Pancreatitis in a Young Female without a Gallbladder: A Case Report and Literature Review

Eluxadoline is a mixed opioid receptor agonist and antagonist approved for the treatment of diarrhea-predominant irritable bowel syndrome (IBS). It is believed to decrease visceral hypersensitivity without completely inhibiting intestinal motility. Pooled safety data from two phase three randomized trials have reported few cases of pancreatitis especially in patients with sphincter of Oddi (SO) dysfunction and cholecystectomy patients. We present a rare case of eluxadoline-induced recurrent pancreatitis in a 31-year-old female without a gallbladder. Her medical history was significant for irritable bowel syndrome with diarrhea (IBS-D), cholecystectomy, and depression. She was started on 75 mg of eluxadoline (the recommended dose for IBS-D patients without a gallbladder) three weeks prior to the first episode of pancreatitis. She had a recurrent episode of pancreatitis after few weeks and her symptoms and lipase levels improved significantly two days after stopping eluxadoline. The exact mechanism of eluxadoline to cause pancreatitis is unknown but it is believed to increase SO contractions. The absence of gallbladder prevents cholecystokinin mediated relaxation of the SO thus contributing more to spasms with eluxadoline. Few cases of severe pancreatitis and death have been reported even with the reduced dose of eluxadoline recommended for cholecystectomy patients. This case highlights the importance of considering drug-induced pancreatitis and avoidance of eluxadoline even in reduced doses in patients without a gallbladder.

Efficacy and Safety of Eluxadoline in IBS-D Patients Who Report Inadequate Symptom Control With Prior Loperamide Use: A Phase 4, Multicenter, Multinational, Randomized, Placebo-controlled, Double-blinded Study (RELIEF): Presidential Poster Award

Introduction: Irritable bowel syndrome with diarrhea (IBS-D) is a functional gastrointestinal disorder with limited treatment options. We evaluated the efficacy and safety of eluxadoline, an FDA-approved mixed μ-opioid receptor (OR) and ?-OR agonist and d-OR antagonist compared to placebo in IBS-D patients who reported inadequate symptom control with prior use of loperamide, an over-the-counter μ-OR agonist. Methods: Adults with IBS-D (Rome III criteria) who reported inadequate symptom control subsequent to loperamide use within the preceding 12 months were randomized 1:1 to placebo or eluxadoline 100 mg twice daily taken with food for 12 weeks. Patients recorded daily IBS-D symptoms, including worst abdominal pain (WAP) on a 0 to 10-point scale and stool consistency (evaluated by Bristol Stool Score [BSS]). The primary efficacy endpoint was the proportion of composite responders, defined as patients who met daily composite response criteria (WAP improvement by ≥40% AND BSS score <5 or absence of bowel movement accompanied by ≥40% WAP improvement compared to baseline) for at least 50% of treatment days, and had ≥60 days of diary entries over the 12-week treatment period. Results: 346 patients were enrolled. The majority (70%) were female, and mean age was 44 years. A significantly greater proportion of patients receiving eluxadoline achieved the primary composite responder endpoint compared to placebo (22.7% [39/172] vs. 10.3% [18/174]; p=0.0022). Additionally, a higher proportion of patients achieved the secondary endpoints of improvements in stool consistency (27.9% [48/172] vs. 16.7% [29/174]; p=0.0119) and WAP (43.6% [75/172] vs. 31.0% [54/174]; p=0.0174) with eluxadoline than placebo, respectively. Throughout the 12-week study, a greater proportion of eluxadoline patients met the monthly composite responder endpoint compared with placebo (Weeks 1-4:14.0% vs. 6.9%, p=0.0330; Weeks 5-8: 26.7% vs. 14.9%, p=0.0063; Weeks 9-12: 30.8% vs. 16.7%, p=0.0018). A comparable number of patients reported treatment-emergent adverse events (TEAEs) with eluxadoline (124 events; 37.4% [64/171]) and placebo (112 events, 35.3% [61/173]). More patients discontinued treatment due to TEAEs with eluxadoline compared with placebo (10 vs. 3). No treatment-related serious AE was reported. Conclusion: Eluxadoline appears safe, effective, and well tolerated for treating IBS-D symptoms in patients who report inadequate symptom control with prior loperamide use.

Impact of comorbid psychological disorders on intestinal symptoms in patients with irritable bowel syndrome with diarrhea

Objective To investigate the clinical symptoms and mental state of patients with irritable bowel syndrome with diarrhea (IBS-D), and to analyze the characteristics of psychological disorders in patients with IBS-D and their impacts on intestinal symptoms. Methods From July 2009 to June 2012, patients met Rome Ⅲ criteria of IBS-D were consecutively enrolled at Peking Union Medical College Hospital. The symptoms of IBS were investigated by IBS symptoms questionnaire and mental state were evaluated by Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD). The differences in intestinal symptoms between patients with comorbid psychological disorders and without psychological disorders were compared. And the correlation between the scores of HAMA, HAMD and intestinal symptoms were analyzed. Two independent sample t-tests, chi square test and Fisher exact probability were performed for statistical analysis. Spearman rank correlation was used for correlation analysis. Results A total of 231 patients with IBS-D were enrolled. There were 133 males and 98 females with an age of (42.8±11.1) years old and a disease course of (4.5 years (8.0 years)). The HAMA and HAMD scores were 17.00±7.12 and 14.05±6.00, respectively, and 72.29% (167/231) patients had comorbid psychological disorders, 32.90% (76/231) patients had moderate to severe anxiety and/or depression, mainly had anxiety. The proportion of patients with ordinary abdominal pain or discomfort and the proportion of moderate to severe abdominal pain or discomfort in patients with psychological disorders were higher than those of patients without psychological disorders (53.29%, 89/167 vs. 34.37%, 22/64; 49.44%, 44/89 vs. 18.18%, 4/22), and the differences were statistically significant (χ2=6.634 and 7.002, P=0.010 and 0.009). In patients with comorbid psychological disorders, more patients had frequent onset of abdominal pain or discomfort, less achieved completely improvement after defecation, and often accompanied with defecation related symptoms. The HAMD score was positively correlated with the onset frequency of IBS (r=0.172, P=0.009), and the HAMA score was positively correlated with the degree of abdominal pain or discomfort before defecation (r=0.134, P=0.042). The HAMA and HAMD scores were negatively correlated with the improvement degree of abdominal pain or discomfort after defecation (r=-0.215, P=0.001; r=-0.251, P<0.01), and were positively correlated with waiting time for symptoms improvement (r=0.175, P=0.008; r=0.219, P= 0.001). Conclusion Most IBS-D patients have comorbid psychological disorders, anxiety and/or depression greatly impact the intestinal symptoms of patients with IBS. Key words: Irritable bowel syndrome; Depression; Anxiety; Psychological disorders; Intestinal symptoms