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

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

Transcriptomic Module Discovery of Diarrhea-Predominant Irritable Bowel Syndrome: A Causal Network Inference Approach.

Irritable bowel syndrome with diarrhea (IBS-D) is the most prevalent subtype of IBS, characterized by chronic gastrointestinal symptoms in the absence of identifiable pathological findings. This study aims to investigate the molecular mechanisms underlying IBS-D using transcriptomic data. By employing causal network inference methods, we identify key transcriptomic modules associated with IBS-D. Utilizing data from public databases and applying advanced computational techniques, we uncover potential biomarkers and therapeutic targets. Our analysis reveals significant molecular alterations that affect cellular functions, offering new insights into the complex pathophysiology of IBS-D. These findings enhance our understanding of the disease and may foster the development of more effective treatments.

[Drug therapy's new options in the treatment of the severe irritable bowel syndrome].

BACKGROUND: Stress, individual characteristics of each patient, visceral hypersensitivity and intestinal motility have the key importance in the pathogenesis of irritable bowel syndrome (IBS). In recent years, there has been growing interest in the use of selective serotonin and norepinephrine reuptake inhibitors (SNRIs) in the complex therapy of IBS patients with somatoform disorders. AIM: To examine the effectiveness of the SNRIs antidepressant therapy in the treatment of patients with IBS and diarrhea (IBS-D) with extraintestinal manifestations. MATERIALS AND METHODS: 42 patients with severe IBS and diarrhea (IBS-D) were examined, among them 22 female with a median age of 32 years old (22; 38), and 20 male with a median age of 31 years old (25; 35). Treatment with duloxetine 60 mg/day was prescribed. The effectiveness of the therapy was assessed after eight weeks. The IBS clinical symptoms dynamics were assessed by the intensity of pain syndrome and bloating, which were determined using Visual Analogue Pain Scale (VAS), stool frequency and shape based on the Bristol stool scale; Visceral sensitivity threshold was assessed according to the Balloon dilatation test. There was studied the effect of the duloxetine on the extraintestinal manifestations of IBS. The psycho-emotional state was assessed using the Beck scale of anxiety and depression and the Spielberger-Khanin scale by psychiatrist, neurologist-vegetol. RESULTS: All patients showed positive dynamics after eight weeks duloxetine treatment: the decrease of pain syndrome from 9 (9; 10) to 2 (2; 3) points, bloating from 8 (8; 9) points to 2,5 (1; 3) points according to VAS, and defecation frequency from 10 (9; 12) to 2 (1; 2) times a day; the change of stool consistency from 6th (6; 7) to 3rd (3; 4) type. The visceral sensitivity threshold increased: the time of appearance of the first urge to defecate increased from 56 (34; 74) ml to 95 (80; 98) ml. Significantly decreased extraintestinal manifestations of IBS. In reassessing each patient's individual characteristics there were the decrease of the depression level according to the Beck scale from 26 (23; 32) to 11.5 (10; 13) points and personal personal anxiety level according to the Spielberger-Khanin scale from 42.5 (35; 53) to 22 (20; 24) points, as well as the decrease of situational anxiety from 40 (37; 49) to 22 (21; 36) points. CONCLUSION: The severe course of IBS-D is mainly associated with the patients' individual characteristics and anxiety or anxiety-depressive syndromes. The positive impact of duloxetine therapy in severe IBS-D with extraintestinal manifestations is associated with the regulation of serotonergic and noradrenergic activity of the central.

Comparative analysis of the fecal microbiome and metabolomics of healthy versus captive South China tigers with mild diarrhea.

Diarrhea-predominant irritable bowel syndrome (IBS-D) is common among the captive South China tigers in zoos. 16S rRNA gene sequencing was performed to demonstrate the compositions and structures of the gastrointestinal microbiota of this species with IBS-D. Their healthy (F1) and mushy (F2) feces were allocated into two groups. A total of 21 and 31 fecal bacterial communities of major phyla and genera were detected, respectively. The F1 and F2 groups had five common microbiotas at the phylum level (Firmicutes, Proteobacteria, Fusobacteria, Actinobacteria, and Bacteroidetes). Among the five phyla, the abundance of Bacteroidetes in the F2 group was significantly lower than that in the F1 group. The diversity level of fecal microbiota within the mild-diarrhea stool was also significantly lower than that of the healthy counterpart. Thirty-two metabolites were correlated to four genus-level bacteria (Bacteroides, Pseudoclavibacter, Streptococcus, and Ruminococcaceae-UCG-005). Due to its normal role in protein degradation and metabolism, we hypothesized that the lower abundance of Bacteroides within the F2 group could be associated with the IBS-D symptoms. Therefore, this work implied that ameliorating the daily diet with a supplement of probiotics, such as Bacteroides, could improve the gut health of this species.

Flupirtine enhances NHE-3-mediated Na+ absorption in rat colon via an ENS-dependent mechanism.

Recent studies in our lab have shown that the KV7 channel activator, flupirtine, inhibits colonic epithelial Cl- secretion through effects on submucosal neurons of the enteric nervous system (ENS). We hypothesized that flupirtine would also stimulate Na+ absorption as a result of reduced secretory ENS input to the epithelium. To test this hypothesis, unidirectional 22Na+ fluxes were measured under voltage-clamped conditions. Pharmacological approaches using an Ussing-style recording chamber combined with immunofluorescence microscopy techniques were used to determine the effect of flupirtine on active Na+ transport in the rat colon. Flupirtine stimulated electroneutral Na+ absorption in partially seromuscular-stripped colonic tissues, while simultaneously inhibiting short-circuit current (ISC; i.e., Cl- secretion). Both of these effects were attenuated by pretreatment with the ENS inhibitor, tetrodotoxin. The Na+/H+ exchanger isoform 3 (NHE-3)-selective inhibitor, S3226, significantly inhibited flupirtine-stimulated Na+ absorption, whereas the NHE-2-selective inhibitor HOE-694 did not. NHE-3 localization near the apical membranes of surface epithelial cells was also more apparent in flupirtine-treated colon versus control. Flupirtine did not alter epithelial Na+ channel (ENaC)-mediated Na+ absorption in distal colonic tissues obtained from hyperaldosteronaemic rats and had no effect in the normal ileum but did stimulate Na+ absorption in the proximal colon. Finally, the parallel effects of flupirtine on ISC (Cl- secretion) and Na+ absorption were significantly correlated with each other. Together, these data indicate that flupirtine stimulates NHE-3-dependent Na+ absorption, likely as a result of reduced stimulatory input to the colonic epithelium by submucosal ENS neurons.NEW & NOTEWORTHY We present a novel mechanism regarding regulation of epithelial ion transport by enteric neurons. Activation of neuronal KV7 K+ channels markedly stimulates Na+ absorption and inhibits Cl- secretion across the colonic epithelium. This may be useful in developing new treatments for diarrheal disorders, such as irritable bowel syndrome with diarrhea (IBS-D).

Patients With Irritable Bowel Syndrome Are Willing to Take Substantial Medication Risks for Symptom Relief.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a common chronic functional bowel disorder for which patients take significant risks to ameliorate symptoms. Unfortunately, there is no cure for IBS. We assessed the willingness of patients with IBS to take medication risks and the costs they would pay to improve symptoms. METHODS: We mailed a survey on medication risk to patients with IBS who met the Rome IV criteria. The survey collected data on patient demographics, symptoms, medication use, prior medication-averse events, and pain catastrophization. A standard gamble evaluated respondents' willingness to take medication risks, and a willingness-to-pay set of questions quantified maximal spending on a hypothetical medication to treat IBS. RESULTS: Among respondents (n = 215; 81.8% female; mean age, 57 y) the average duration of IBS symptoms was 17.7 years. Patients whose predominant symptom was severe diarrhea (diarrhea-predominant IBS) reported accepting a mean 10.2% ± 15.7% risk of sudden death for a 99% chance of cure. Pain catastrophizing scale scores were not associated with an increased likelihood of taking medication risks. Patients with IBS would be willing to pay an average amount of $73 per month (if annual income was <$75,000) and $197 per month (if annual income was >$75,000) for a medication that would resolve their pain. CONCLUSIONS: In a survey of 215 patients with IBS, we found that patients with diarrhea-predominant IBS are willing to take extraordinary risks to improve their symptoms, whereas patients with IBS and pain catastrophization are not. Clinician understanding of patients' willingness to take medication risks might help them guide their patients through complex therapeutic options.

Identification and potential functions of tRNA-derived small RNAs (tsRNAs) in irritable bowel syndrome with diarrhea.

IBS-D is a functional bowel disease without clear diagnostic markers and exact pathogenesis. Studies have proved that non-coding RNAs participate in IBS-D. However, tRNA-derived small RNAs (tsRNAs), as a new type of non-coding RNAs that are more suitable as markers, remain to be clarified in IBS-D. Hence, we focused on the identification and potential functions of tsRNAs in IBS-D. Intestinal biopsies were obtained from IBS-D patients and healthy volunteers, and twenty-eight differential tsRNAs were screened by high-throughput sequencing. The changes of tiRNA-His-GTG-001, tRF-Ser-GCT-113, and tRF-Gln-TTG-035 by q-PCR in expanded samples were consistent with the sequencing results. Meanwhile, target gene prediction and bioinformatics showed that the three differential tsRNAs may be involved in some key signal pathways, such as GABAergic synapse, tumor necrosis factor-α (TNF-α), etc. Their regulation on target genes were demonstrated through cell experiments and luciferase reporter assays. In addition, the receiver-operating characteristic (ROC) analysis showed that the three tsRNAs all could be used as candidate markers of IBS-D. The correlation analysis indicated they were related to the degree of abdominal pain, abdominal distension, and stool morphology. So, we believe that the abnormal tiRNA-His-GTG-001, tRF-Ser-GCT-113, and tRF-Gln-TTG-035 are related to the clinical symptoms of IBS-D, and can target regulate the important molecules of the brain-gut axis, even could be expected as potential biomarkers for the diagnosis and treatment of IBS-D.

[Effect of Valeriana jatamansi extract on fecal UPLC-MS/MS metabolomics in rats with diarrheal irritable bowel syndrome].

The purpose of this study was to understand the pharmacodynamic effect of Valeriana jatamansi extract in diarrhea predominant irritable bowel syndrome(IBS-D) rat model induced by maternal separation combined with three kinds of stress, and observe the changes of endogenous metabolites in feces after intervention to find potential biomarkers and related metabolic pathways. The animal model of IBS-D was established by maternal separation combined with restraint, ice swimming and tail clamping. The therapeutic effect of each dose group of V. jatamansi extract was evaluated in terms of abdominal withdrawal reflex pressure threshold, fecal water content and immobility time of forced swimming test. In addition, rat feces were collected for detection of metabolic profiles of small molecular metabolites with UPLC-LTQ-Orbitrap MS platform, so as to find the biomarkers of differential metabolism with multivariate statistical analysis methods such as principal component analysis(PCA) and orthogon partial least squares discrimination analysis(OPLS-DA). The results showed that as compared with the normal group, the threshold of abdominal withdrawal reflex pressure was decreased, the fecal water content was increased, and the immobility time of forced swimming test was prolonged in the model group. The results of fecal metabonomics showed that the levels of 39 metabolites were down-regulated and those of 37 metabolites were up-re-gulated. Further analysis showed that these metabolites were related to bile acid metabolism, unsaturated fatty acid metabolism, amino acid metabolism, ceramide metabolism and other metabolic pathways. This study proved that the extract of V. jatamansi had definite pharmacodynamic effect on IBS-D model rats, and the mechanism was discussed from the perspective of fecal metabonomics.

MiR-144 Increases Intestinal Permeability in IBS-D Rats by Targeting OCLN and ZO1.

BACKGROUND/AIMS: Irritable bowel syndrome with diarrhoea (IBS-D) is a chronic, functional bowel disorder characterized by abdominal pain or diarrhoea and altered bowel habits, which correlate with intestinal hyperpermeability. MicroRNAs (miRNAs) are involved in regulating intestinal permeability in IBS-D. However, the role of miRNAs in regulating intestinal permeability and protecting the epithelial barrier remains unclear. Our goals were to (i) identify differential expression of miRNAs and their targets in the distal colon of IBS-D rats; (ii) verify in vitro whether occludin (OCLN) and zonula occludens 1 (ZO1/TJP1) were direct targets of miR-144 and were down-regulated in IBS-D rats; and (iii) determine whether down-regulation of miR-144 in vitro could reverse the pathological hallmarks of intestinal hyperpermeability via targeting OCLN and ZO1. METHODS: The IBS-D rat model was established using 4% acetic acid and evaluated by haematoxylin-eosin (HE) staining. The distal colon was obtained in order to perform miRNA microarray analysis and to isolate and culture colonic epithelial cells. When differential expression of miRNA was found, the results were verified by qRT-PCR, and the target genes were further explored by bioinformatics analysis. Correlation analyses were carried out to compare the expression of miRNA and target genes. Then, mutants, miRNA mimics and inhibitors of the target genes were constructed and transfected to colonic epithelial cells. qRT-PCR, western blotting, enzyme-linked immunosorbent assays (ELISAs) and dual-luciferase assays were used to investigate the expression of miR-144 and OCLN, ZO1 in IBS-D rats. RESULTS: There were 8 up-regulated and 18 down-regulated miRNAs identified in the IBS-D rat model. Of these, miR-144 was markedly up-regulated and resulted in the down-regulation of OCLN and ZO1 expression. Overexpression of miR-144 by transfection of miR-144 precursor markedly inhibited the expression of OCLN and ZO1. Further studies confirmed that OCLN and ZO1 were direct targets of miR-144. Additionally, intestinal hyperpermeability was enhanced by miR-144 up-regulation and attenuated by miR-144 down-regulation in IBS-D rat colonic epithelial cells. Moreover, rescue experiments showed that overexpression of OCLN and ZO1 significantly eliminated the inhibitory effect of miR-144, which showed a stronger effect on the attenuation of intestinal hyperpermeability. CONCLUSION: Up-regulation of miR-144 could promote intestinal hyperpermeability and impair the protective effect of the epithelial barrier by directly targeting OCLN and ZO1. miR-144 is likely a key regulator of intestinal hyperpermeability and could be a potential therapeutic target for IBS-D.

Health-related quality of life, work productivity, and indirect costs among patients with irritable bowel syndrome with diarrhea.

BACKGROUND: Irritable bowel syndrome (IBS) affects 10-15% of adults in the US, and is associated with significant impairment in health-related quality of life (HRQoL); however, information specific to the diarrhea subtype (IBS-D) is lacking. We assessed the impact of IBS-D on HRQoL, work productivity, and daily activities, and the associated indirect costs, among a sample of the US population. METHODS: Respondents (≥18 years) from the 2012 US National Health and Wellness Survey who reported an IBS-D diagnosis by a physician or symptoms consistent with Rome II criteria for IBS-D were identified as having IBS-D. Controls included respondents without IBS-D or inflammatory bowel disease. HRQoL was assessed via the Short Form 36 Health Survey version 2 questionnaire and summarized into Mental and Physical Component Summary (MCS; PCS) scores and a Short Form-6 dimension (SF-6D) utility score. Work and activity impairment were assessed via the Work Productivity and Activity Impairment Questionnaire: General Health version (WPAI:GH), which measures absenteeism, presenteeism, overall work productivity loss, and daily activity impairment. Indirect costs were calculated using unit cost data from the Bureau of Labor Statistics and variables from the WPAI:GH. Generalized linear models were used to examine differences in health outcomes between respondents with IBS-D and controls, controlling for demographic and health characteristics. RESULTS: In total, 66,491 respondents (1102 IBS-D; 65,389 controls) were analyzed. Mean age was 48.7 years; 50% were female. Compared with controls, the IBS-D cohort reported significantly lower HRQoL (mean MCS: 45.16 vs. 49.48; p < 0.001; mean PCS: 47.29 vs. 50.67; p < 0.001; mean SF-6D: 0.677 vs. 0.741; p < 0.001) and greater absenteeism (5.1% vs. 2.9%; p = 0.004), presenteeism (17.9% vs. 11.3%; p < 0.001), overall work productivity loss (20.7% vs. 13.2%; p < 0.001), and activity impairment (29.6% vs. 18.9%; p < 0.001). Respondents with IBS-D also incurred an estimated $2486 more in indirect costs ($7008 vs. $4522; p < 0.001). CONCLUSIONS: Compared with controls, IBS-D is associated with significantly lower HRQoL, greater impairments in work and daily activities, and higher indirect costs, imposing a substantial burden on patients and employers. These findings suggest a significant unmet need exists for effective IBS-D treatments.

Psychometric assessment of the IBS-D Daily Symptom Diary and Symptom Event Log.

PURPOSE: Diarrhea-predominant irritable bowel syndrome (IBS-D) can considerably impact patients' lives. Patient-reported symptoms are crucial in understanding the diagnosis and progression of IBS-D. This study psychometrically evaluates the newly developed IBS-D Daily Symptom Diary and Symptom Event Log (hereafter, "Event Log") according to US regulatory recommendations. METHODS: A US-based observational field study was conducted to understand cross-sectional psychometric properties of the IBS-D Daily Symptom Diary and Event Log. Analyses included item descriptive statistics, item-to-item correlations, reliability, and construct validity. RESULTS: The IBS-D Daily Symptom Diary and Event Log had no items with excessive missing data. With the exception of two items ("frequency of gas" and "accidents"), moderate to high inter-item correlations were observed among all items of the IBS-D Daily Symptom Diary and Event Log (day 1 range 0.67-0.90). Item scores demonstrated reliability, with the exception of the "frequency of gas" and "accidents" items of the Diary and "incomplete evacuation" item of the Event Log. The pattern of correlations of the IBS-D Daily Symptom Diary and Event Log item scores with generic and disease-specific measures was as expected, moderate for similar constructs and low for dissimilar constructs, supporting construct validity. Known-groups methods showed statistically significant differences and monotonic trends in each of the IBS-D Daily Symptom Diary item scores among groups defined by patients' IBS-D severity ratings ("none"/"mild," "moderate," or "severe"/"very severe"), supporting construct validity. CONCLUSIONS: Initial psychometric results support the reliability and validity of the items of the IBS-D Daily Symptom Diary and Event Log.

A diet low in FODMAPs reduces symptoms of irritable bowel syndrome.

BACKGROUND & AIMS: A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) often is used to manage functional gastrointestinal symptoms in patients with irritable bowel syndrome (IBS), yet there is limited evidence of its efficacy, compared with a normal Western diet. We investigated the effects of a diet low in FODMAPs compared with an Australian diet, in a randomized, controlled, single-blind, cross-over trial of patients with IBS. METHODS: In a study of 30 patients with IBS and 8 healthy individuals (controls, matched for demographics and diet), we collected dietary data from subjects for 1 habitual week. Participants then randomly were assigned to groups that received 21 days of either a diet low in FODMAPs or a typical Australian diet, followed by a washout period of at least 21 days, before crossing over to the alternate diet. Daily symptoms were rated using a 0- to 100-mm visual analogue scale. Almost all food was provided during the interventional diet periods, with a goal of less than 0.5 g intake of FODMAPs per meal for the low-FODMAP diet. All stools were collected from days 17-21 and assessed for frequency, weight, water content, and King's Stool Chart rating. RESULTS: Subjects with IBS had lower overall gastrointestinal symptom scores (22.8; 95% confidence interval, 16.7-28.8 mm) while on a diet low in FODMAPs, compared with the Australian diet (44.9; 95% confidence interval, 36.6-53.1 mm; P < .001) and the subjects' habitual diet. Bloating, pain, and passage of wind also were reduced while IBS patients were on the low-FODMAP diet. Symptoms were minimal and unaltered by either diet among controls. Patients of all IBS subtypes had greater satisfaction with stool consistency while on the low-FODMAP diet, but diarrhea-predominant IBS was the only subtype with altered fecal frequency and King's Stool Chart scores. CONCLUSIONS: In a controlled, cross-over study of patients with IBS, a diet low in FODMAPs effectively reduced functional gastrointestinal symptoms. This high-quality evidence supports its use as a first-line therapy. CLINICAL TRIAL NUMBER: ACTRN12612001185853.

Rome III functional constipation and irritable bowel syndrome with constipation are similar disorders within a spectrum of sensitization, regulated by serotonin.

BACKGROUND & AIMS: Patients with irritable bowel syndrome with constipation (IBS-C) and patients with functional constipation (FC) have similar symptoms, and these disorders overlap in their diagnostic features. Little is known about their overlap in physiology or the involvement of serotonin signaling. We investigated relationships between platelet-depleted plasma concentrations of serotonin, gastrointestinal symptoms, and motor-sensory function in patients with FC or IBS-C compared with healthy volunteers (controls). METHODS: We measured platelet-depleted plasma concentrations of serotonin in fasting and fed individuals with IBS-C (n = 23; 19-50 years old), FC (n = 11; 25-46 years old), and controls (n = 23; 20-49 years old) recruited in Manchester, UK. We also quantified abdominal and bowel-related symptoms, rectal sensitivity, oro-cecal transit, and colonic (whole intestine) transit. RESULTS: Patients with IBS-C or FC had similar baseline symptoms, bowel habits, oro-cecal and colonic transit, and fasting concentrations of serotonin and response to meal ingestion. Only patients with IBS-C had increased symptoms after ingestion of a meal (P < .001)-these patients tended to have lower sensory thresholds than patients with FC. Defecation frequency in the combined group of patients with IBS-C or FC correlated inversely with serotonin concentration (r = -0.4; P = .03). Serotonin concentration also correlated with pain threshold (r = 0.4; P = .02) and stool threshold (r = 0.5; P = .06), which correlated inversely with defecation frequency (r = -0.3; P = .10). CONCLUSIONS: FC and IBS-C, based on Rome III criteria, are not distinct disorders, symptomatically or physiologically. Instead, they appear to lie in a spectrum of visceral sensitivity modulated by serotonin signaling. Symptom response to meal ingestion should be considered in patient classification.

Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study.

BACKGROUND & AIMS: Simultaneous agonism of the µ-opioid receptor and antagonism of the δ-opioid receptor can reduce abdominal pain and diarrhea in patients with irritable bowel syndrome with diarrhea (IBS-D) without constipating side effects. We evaluated the efficacy and safety of a minimally absorbed, µ-opioid receptor agonist and δ-opioid receptor antagonist (eluxadoline) in a phase 2 study in patients with IBS-D. METHODS: We randomly assigned 807 patients to groups that received oral placebo twice daily or 5, 25, 100, or 200 mg oral eluxadoline for 12 weeks. The primary end point was clinical response at week 4, defined by a mean reduction in daily pain score from baseline of ≥ 30%, and of at least 2 points on 0-10 scale, as well as a stool consistency score of 3 or 4 on the Bristol Stool Scale (1-7) for at least 66% of daily diary entries during that week. RESULTS: Significantly more patients receiving 25 mg (12.0%) or 200 mg (13.8%) eluxadoline met the primary end point of clinical response than patients given placebo (5.7%; P < .05). Patients receiving eluxadoline at 100 mg and 200 mg also had greater improvements in bowel movement frequency and urgency, global symptoms, quality of life, and adequate relief assessments (P < .05). Additionally, patients receiving 100 mg (28.0%) or 200 mg (28.5%) eluxadoline were significantly more likely than those receiving placebo (13.8%; P < .005) to meet the US Food and Drug Administration response end point during the full 12 weeks of the study. Eluxadoline was well tolerated with a low incidence of constipation. CONCLUSIONS: In a phase 2 study of the mixed µ-opioid receptor agonist/δ-opioid receptor antagonist eluxadoline vs placebo in patients with IBS-D, patients given eluxadoline were significantly more likely to be clinical responders, based on a composite of improvement in abdominal pain and stool consistency. Further study of eluxadoline is warranted to assess its potential as a treatment for IBS-D.

Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier.

OBJECTIVE: Recently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoea-predominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations. DESIGN: A clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117(+) cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy. RESULTS: Compared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms. CONCLUSION: The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.

A randomized double-blind, placebo-controlled trial to evaluate the safety and efficacy of live Bifidobacterium longum CECT 7347 (ES1) and heat-treated Bifidobacterium longum CECT 7347 (HT-ES1) in participants with diarrhea-predominant irritable bowel syndrome.

To determine the efficacy of the probiotic Bifidobacterium longum CECT 7347 (ES1) and postbiotic heat-treated Bifidobacterium longum CECT 7347 (HT-ES1) in improving symptom severity in adults with diarrhea-predominant irritable bowel syndrome (IBS-D), a randomised, double-blind, placebo-controlled trial with 200 participants split into three groups was carried out. Two capsules of either ES1, HT-ES1 or placebo were administered orally, once daily, for 84 days (12 weeks). The primary outcome was change in total IBS-Symptom Severity Scale (IBS-SSS) score from baseline, compared to placebo. Secondary outcome measures were stool consistency, quality of life, abdominal pain severity and anxiety scores. Safety parameters and adverse events were also monitored. The change in IBS-SSS scores from baseline compared to placebo, reached significance in the ES1 and HT-ES1 group, on Days 28, 56 and 84. The decrease in mean IBS-SSS score from baseline to Day 84 was: ES1 (-173.70 [±75.60]) vs placebo (-60.44 [±65.5]) (p < .0001) and HT-ES1 (-177.60 [±79.32]) vs placebo (-60.44 [±65.5]) (p < .0001). Secondary outcomes included changes in IBS-QoL, APS-NRS, stool consistency and STAI-S and STAI-T scores, with changes from baseline to Day 84 being significant in ES1 and HT-ES1 groups, compared to the placebo group. Both ES1 and HT-ES1 were effective in reducing IBS-D symptom severity, as evaluated by measures such as IBS-SSS, IBS-QoL, APS-NRS, stool consistency, and STAI, in comparison to the placebo. These results are both statistically significant and clinically meaningful, representing, to the best of the authors' knowledge, the first positive results observed for either a probiotic or postbiotic from the same strain, in this particular population.

What is already known on this topicIBS is a chronic functional gastrointestinal disorder characterized by abdominal pain, bloating and abnormalities in stool frequency or form. The gut microbiota of people living with IBS differs markedly to the microbiota of healthy individuals. Gut microbiota may play a key role in IBS aetiology and IBS symptoms may be alleviated by modulating the gut microbiota. Several proposed ways to modulate gut health include normalizing the gut microbiota, preventing the overgrowth of pathogenic bacteria, modulating visceral afferent pathways, and enhancing intestinal barrier function. However, significant heterogeneity between studies, study quality and population, study design and concerns about sample size have limited national and supranational bodies from recommending probiotics for IBS. Further well-powered, randomized, repeatable and controlled trials are warranted.What this study addsThe results of this study substantially contribute to the IBS research field, firstly by providing clinically meaningful and statistically significant results from a rigorous, well designed randomized, placebo-controlled trial and secondly, by exploring the use of postbiotics in IBS, an area of research still in its infancy. Probiotic (ES1) and postbiotic (HT-ES1) supplementation significantly reduced IBS symptom severity scores compared to placebo. This study met primary and secondary outcomes and strongly suggest that ES1 and HT-ES1 could be beneficial in the management of IBS.How this study might affect research, practice, or policyThis study adds to the current evidence base, supporting the use of probiotic/postbiotics for IBS. This research could be used to inform health professionals about using probiotics in IBS and help improve the quality of life and wellbeing for people living with the condition.

Electroacupuncture protects the intestinal mucosal barrier in diarrhea-predominant Irritable Bowel Syndrome rats by regulating the MCs/Tryptase/PAR-2/MLCK pathway.

OBJECTIVE: The pathogenesis of diarrhea-predominant irritable bowel syndrome (IBS-D) is related to damage to the intestinal mucosal barrier function. Based on the Mast cell (MC)/Tryptase/Protease-activated receptor-2 (PAR-2)/Myosin light chain kinase (MLCK) pathway, this study explored the effect of electroacupuncture (EA) on IBS-D rats and its possible mechanism of protecting the intestinal mucosal barrier. METHODS: The IBS-D rat model was established by mother-offspring separation, acetic acid enema, and chronic restraint stress. The efficacy of EA on IBS-D rats was evaluated by observing the rate of loose stool (LSP) and the minimum volume threshold of abdominal withdrawal reflex (AWR) in rats. Mast cells and the ultrastructure of intestinal mucosa were observed by H&E staining, toluidine blue staining, and transmission electron microscopy. The expression levels of Tryptase, PAR-2, MLCK, zonula occludens-1 (ZO-1), and Occludin in rats were detected by ELISA, qRT-PCR, and western blot. RESULTS: After 7 days of intervention, compared to the IBS-D group, the loose stool rates of rats in IBS-D + EA group and IBS-D + ketotifen group were decreased (P < 0.01), the minimum volume thresholds of AWR were improved (P < 0.01), the inflammation of colon tissue decreased, the number of MCs were decreased (P < 0.01), the expression of Tryptase, PAR-2, and MLCK were lowered (P < 0.01, P < 0.05), and the expression of ZO-1 and Occludin were enhanced (P < 0.01, P < 0.05). Compared to the EA group, there was no significant difference in each index between the ketotifen groups (P > 0.05). CONCLUSION: EA has a good therapeutic effect on IBS-D rats. Regulating the MCs/Tryptase/PAR-2/MLCK pathway may be a mechanism to protect the intestinal mucosal barrier.

A diet low in fermentable oligo-, di-, monosaccharides and polyols improves abdominal and overall symptoms in persons with all subtypes of irritable bowel syndrome.

BACKGROUND: A diet low in fermentable oligo-, di-, monosaccharides and polyols (LFD) improves symptoms in patients with irritable bowel syndrome (IBS). Previous studies have focused on patients with IBS and diarrhea (IBS-D). It is unclear whether LFD is effective for IBS with constipation (IBS-C) or IBS with mixed bowel habits (IBS-M). This open-label, real-world study evaluates the relative effectiveness of the LFD among IBS subtypes. METHODS: This study analyzes data from a service that provides low-FODMAP meals to individuals with IBS. Participants met with a registered dietitian and completed the IBS symptom severity survey (IBS-SSS) before and after undergoing a 2-4-week period of FODMAP restriction. The primary endpoint was the proportion of participants with ≥50-point decrease in IBS-SSS between the three IBS subtypes. KEY RESULTS: After FODMAP restriction, 90% of participants with IBS-D, 75% with IBS-C, and 84% with IBS-M met the primary endpoint (p = 0.045). Similar improvement was seen for a 100-point decrease, but the difference between IBS subtypes was not significant (p = 0.46). After FODMAP restriction, all groups had statistically significant improvement in total IBS-SSS as well as individual symptom categories. Improvement in IBS-SSS subcategories was similar among the groups except for the categories of bloating severity (IBS-M had greatest improvement) and bowel movement satisfaction (IBS-C had less improvement). CONCLUSION & INFERENCES: Though the proportion of responders was highest for IBS-D and lowest for IBS-C, the LFD led to robust improvement in overall symptoms in all IBS subtypes. Key individual symptoms also showed significant improvements in all IBS subtypes.

Impaired Epithelial CD200L Tolerance Signaling in Irritable Bowel Syndrome Cases With Diarrhea May Be Associated With Recurrent Miscarriages.

PROBLEM: There is a higher incidence of irritable bowel syndrome with miscarriages, and recurrent miscarriages of otherwise normal embryos have been linked to subnormal expression of the immune checkpoint inhibitor CD200L. We sought to determine if alterations in the expression of the CD200 immune checkpoint inhibitor occur in colonic tissue in IBS-D patients. METHOD OF STUDY: Quantitative immunohistochemical staining of biopsies from proximal and distal colon or rectum for the inhibitory CD200L and CD200S molecules was done. CD56 cells were also enumerated as they play a role in recurrent miscarriages and may express CD200S. RESULTS: CD200L was decreased and CD200S was unchanged in epithelium but not stroma of 3 IBS-D cases. One case had an increase in both CD200L and CD200S. CD56 cells were also stained for CD200S. Degranulation was assessed by the percentage of extracellular CD200S that was increased as epithelial CD200L decreased. CONCLUSIONS: This pilot study was promising and warrants a larger sample to determine if a correlation between uterine implantation site CD200L and CD200S expression in normal and failing implantation sites is needed. Colonic epithelial CD200L may then provide useful information about the pathogenesis of the spontaneous miscarriage in individual cases.

Chang-Kang-Fang alleviates diarrhea predominant irritable bowel syndrome (IBS-D) through inhibiting TLR4/NF-κB/NLRP3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Chang-Kang-Fang (CKF), originated from traditional Chinese medicine (TCM) formulas, has been utilized to treat diarrhea predominant irritable bowel syndrome (IBS-D) based on clinical experience. However, the underlying mechanism of CKF for treating IBS-D remains unclear and need further clarification. AIM OF THE STUDY: The objective of this present investigation was to validate the efficacy of CKF on IBS-D model rats and to uncover its potential mechanism for the treatment of IBS-D. MATERIALS AND METHODS: We first established the IBS-D rat model through neonatal maternal separation (NMS) in combination with restraint stress (RS) and the administration of senna decoction via gavage. To confirm the therapeutic effect of CKF on treating IBS-D, abdominal withdrawal reflex (AWR) scores, the quantity of fecal pellets, and the fecal water content (FWC) were measured to evaluate the influence of CKF on visceral hypersensitivity and the severity of diarrhea symptom after the intragastric administration of CKF for 14 days. Subsequently, enzyme linked immunosorbent assay (ELISA) was applied to assess the effect of CKF on neuropeptides substance P (SP) and 5-hydroxytryptamine (5-HT), as well as inflammatory cytokines in serum and in intestinal tissues. Further, colonic pathological changes, the amount of colonic mast cells, and the expression level of occludin in rat colon tissues, were investigated by hematoxylin-eosin (HE) staining, toluidine blue staining, and immunohistochemistry, respectively. To explore the underlying mechanisms, alterations in colonic RNA transcriptomics for the normal, model, and CKF treatment groups were assessed using RNA sequencing (RNA-Seq). Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot (WB), and immunofluorescence (IF) assays were applied to validate the effect of CKF on predicted pathways in vivo and in vitro. In addition, to elucidate the potential active compounds in CKF, 11 representative components found in CKF were selected, and their anti-inflammation potentials were evaluated using LPS-treated RAW264.7 cell models. RESULTS: CKF treatment significantly reduced the number of fecal pellets, attenuated visceral hypersensitivity, and decreased 5-HT and SP concentrations in serum and colon tissues, along with a reduction in colonic mast cell counts, correlating with improved symptoms in IBS-D rats. Meanwhile, CKF treatment reduced the colonic inflammatory cell infiltration, lowered the levels of IL-6, TNF-α, and IL-1ß in serum and colon tissues, and increased the occludin protein expression in colon tissues to improve inflammatory response and colonic barrier function. RNA-Seq, in conjugation with our previous network pharmacology analysis, indicated that CKF might mitigate the symptoms of IBS-D rats by inhibiting the Toll like receptor 4/Nuclear factor kappa-B/NLR family pyrin domain-containing protein 3 (TLR4/NF-κB/NLRP3) pathway, which was confirmed by WB, IF, and qRT-PCR experiments in vivo and in vitro. Furthermore, coptisine, berberine, hyperoside, epicatechin, and gallic acid present in CKF emerged as potential active components for treating IBS-D, as they demonstrated in vitro anti-inflammatory effects. CONCLUSION: Our findings demonstrate that CKF effectively improves the symptoms of IBS-D rats, potentially through the inhibition of the TLR4/NF-κB/NLRP3 pathway. Moreover, this study unveils the potential bioactive components in CKF that could be applied in the treatment of IBS-D.