Abdominal Symptom Improvement During Clinical Trials of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis.

INTRODUCTION: This post hoc analysis evaluated the efficacy of tenapanor on abdominal symptoms in patients with irritable bowel syndrome with constipation. Abdominal symptoms assessed included pain, discomfort, bloating, cramping, and fullness. METHODS: The abdominal symptom data were pooled from 3 randomized controlled trials (NCT01923428, T3MPO-1 [NCT02621892], and T3MPO-2 [NCT02686138]). Weekly scores were calculated for each abdominal symptom, and the Abdominal Score (AS) was derived as the average of weekly scores for abdominal pain, discomfort, and bloating. The overall change from baseline during the 12 weeks was assessed for each symptom weekly score and the AS. The AS 6/12-week and 9/12-week response rates (AS improvement of ≥2 points for ≥6/12- or ≥9/12-week) were also evaluated. The association of weekly AS response status (reduction of ≥30%) with weekly complete spontaneous bowel movement (CSBM) status (=0 and >0) was assessed. RESULTS: Among 1,372 patients (684 tenapanor [50 mg twice a day] and 688 placebo), the least squares mean change from baseline in AS was -2.66 for tenapanor vs -2.09 for placebo ( P < 0.0001). The 6/12-week AS response rate was 44.4% for tenapanor vs 32.4% for placebo ( P < 0.0001), and for 9/12-week AS, 30.6% for tenapanor vs 20.5% for placebo ( P < 0.0001). A significant association between weekly CSBM status and weekly AS response status was observed each week ( P < 0.0001), with a greater proportion achieving an AS reduction in patients with >0 CSBMs in a week. DISCUSSION: Tenapanor significantly reduced abdominal symptoms in patients with irritable bowel syndrome with constipation, particularly pain, discomfort, and bloating measured by AS, compared with placebo.

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. DISCUSSION: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation.

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. DISCUSSION: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation.

Identification of putative transcriptomic biomarkers in irritable bowel syndrome (IBS): Differential gene expression and regulation of TPH1 and SERT by vitamin D.

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders and affects approximately 4% of the global population. The diagnosis of IBS can be made based on symptoms using the validated Rome criteria and ruling out commonly occurring organic diseases. Although biomarkers exist for "IBS mimickers" such as celiac disease and inflammatory bowel disease (IBD), no such test exists for IBS. DNA microarrays of colonic tissue have been used to identify disease-associated variants in other gastrointestinal (GI) disorders. In this study, our objective was to identify biomarkers and unique gene expression patterns that may define the pathological state of IBS. Mucosal tissue samples were collected from the sigmoid colon of 29 participants (11 IBS and 18 healthy controls). DNA microarray analysis was used to assess gene expression profiling. Extraction and purification of RNA were then performed and used to synthesize cDNA. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was employed to identify differentially expressed genes in patients diagnosed with IBS compared to healthy, non-IBS patient-derived cDNA. Additional testing probed vitamin D-mediated regulation of select genes associated with serotonergic metabolism. DNA microarray analyses led to the identification of 858 differentially expressed genes that may characterize the IBS pathological state. After screening a series of genes using a combination of gene ontological analysis and RT-qPCR, this spectrum of potential IBS biomarkers was narrowed to 23 genes, some of which are regulated by vitamin D. Seven putative IBS biomarkers, including genes involved in serotonin metabolism, were identified. This work further supports the hypothesis that IBS pathophysiology is evident within the human transcriptome and that vitamin D modulates differential expression of genes in IBS patients. This suggests that IBS pathophysiology may also involve vitamin D deficiency and/or an irregularity in serotonin metabolism.

Burden of Constipation: Looking Beyond Bowel Movements.

Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) are associated with significant social and economic burdens. To address these burdens, a deeper understanding of their root causes is required. A discrepancy exists between patients' and healthcare providers' (HCPs) perceptions of constipation symptoms and the impact of symptoms associated with CIC and IBS-C. Compared with the HCPs' perceptions of patients' symptoms, a greater percentage of patients report acceptance and feeling in control of their CIC or IBS-C symptoms. Unfortunately, only one-third of individuals with CIC or IBS-C formally consult an HCP about their constipation. Fewer than half take medications, and these are generally over-the-counter therapies rather than prescription therapies. For those who seek help, only one-fifth feel that their constipation symptoms are well managed. Notable sex and cultural differences exist regarding individuals consulting their HCP about constipation. Many individuals with CIC and IBS-C remain inadequately managed and unduly affected, contributing to the high social and economic burden of these conditions.

Real-World Treatment Strategies to Improve Outcomes in Patients With Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

Chronic idiopathic constipation and irritable bowel syndrome with constipation are complex, overlapping conditions. Although multiple guidelines have informed healthcare providers on appropriate treatment options for patients with chronic idiopathic constipation and irritable bowel syndrome with constipation, little direction is offered on treatment selection. First-line treatment options usually include fiber and over-the-counter osmotic laxatives; however, these are insufficient for many individuals. When these options fail, prescription secretagogues (plecanatide, linaclotide, lubiprostone, and tenapanor [pending commercial availability]), or serotonergic agents (prucalopride and tegaserod) are generally preferred. Individuals experiencing concurrent abdominal pain and/or bloating may experience greater overall improvements from prescription therapies because these agents have been proven to reduce concurrent abdominal and bowel symptoms. Should initial prescription treatments fail, retrying past treatment options (if not adequately trialed initially), combining agents from alternative classes, or use of adjunctive therapies may be considered. Given the broad spectrum of available agents, therapy should be tailored by mutual decision-making between the patient and practitioner. Overall, patients need to be actively monitored and managed to maximize clinical outcomes.

A Pain in the Butt: Hemorrhoids, Fissures, Fistulas, and Other Anorectal Syndromes.

Painful and bothersome anorectal syndromes can be a diagnostic and therapeutic challenge for clinicians because structural and functional abnormalities may often coexist and require a multidisciplinary approach to management. Although it is often difficult to attribute all of a patient's anorectal symptoms to a singular disorder with definitive intervention and cure, improving quality of life, treating coexistent conditions such as functional constipation and/or defecation disorders, addressing psychological comorbidities if present, and confirming there is no evidence of inflammatory or malignant conditions are top priorities.

An Open-label, Multicenter Study to Assess the Efficacy and Safety of a Novel Probiotic Blend in Patients With Functional Gastrointestinal Symptoms.

GOAL: A novel 5-strain (Bl-04, Bi-07, HN019, NCFM, and Lpc-37) probiotic blend was developed and its safety and efficacy were evaluated in patients with functional gastrointestinal (GI) symptoms. BACKGROUND: These strains administered together have not previously been investigated. STUDY: Patients aged 18 to 75 years with functional GI symptoms were eligible for inclusion in a single-arm, open-label, multicenter study (NCT04155801). An oral capsule containing the novel probiotic blend was administered once daily for 30 days. The primary efficacy endpoint was patient-reported improvement in overall GI well-being at day 30. Secondary efficacy endpoints included changes in GI symptoms assessed using the GI Health Symptom Questionnaire. Incidence of treatment-emergent adverse events was recorded at all visits. RESULTS: Of 188 enrolled patients, 72.3% were female and mean (SD) age was 44.1 (13.4) years. At day 30, 85.1% of patients achieved the primary endpoint, a positive response signifying improvement in overall GI well-being. Improvements from baseline were reported at day 30 in diarrhea frequency (baseline frequency≥3 to 4 d/wk) and severity (baseline severity≥5/10) for 75.8% and 87.3% of patients, respectively. Over the same time period, constipation frequency (baseline frequency≥3 to 4 d/wk) and severity (baseline severity≥5/10) improved in 73.6% and 80.4% of patients, respectively. Most patients reported improvements at day 30 in frequency and severity of straining, urgency, abdominal pain/discomfort, bloating, and distention. Improvements reported at day 30 were generally observable at day 14. No safety signals were identified. CONCLUSION: A novel 5-strain probiotic blend improved functional GI symptoms and was safe.

Survey Finds Gender Disparities Impact Both Women Mentors and Mentees in Gastroenterology.

INTRODUCTION: Gastroenterologists at all levels of practice benefit from formal mentoring. Much of the current literature on mentoring in gastroenterology is based on expert opinion rather than data. In this study, we aimed to identify gender-related barriers to successful mentoring relationships from the mentor and mentee perspectives. METHODS: A voluntary, web-based survey was distributed to physicians at 20 academic institutions across the United States. Overall, 796 gastroenterology fellows and faculty received the survey link, with 334 physicians responding to the survey (42% response rate), of whom 299 (90%; 129 women and 170 men) completed mentorship questions and were included in analysis. RESULTS: Responses of women and men were compared. Compared with men, more women preferred a mentor of the same gender (38.6% women vs 4.2% men, P < 0.0001) but less often had one (45.5% vs 70.2%, P < 0.0001). Women also reported having more difficulty finding a mentor (44.4% vs 16.0%, P < 0.0001) and more often cited inability to identify a mentor of the same gender as a contributing factor (12.8% vs 0.9%, P = 0.0004). More women mentors felt comfortable advising women mentees about work-life balance (88.3% vs 63.8%, P = 0.0005). Nonetheless, fewer women considered themselves effective mentors (33.3% vs 52.6%, P = 0.03). More women reported feeling pressured to mentor because of their gender (39.5% vs 0.9% of men, P < 0.0001). Despite no gender differences, one-third of respondents reported negative impact of the COVID-19 pandemic on their ability to mentor and be mentored. DISCUSSION: Inequities exist in the experiences of women mentees and mentors in gastroenterology, which may affect career advancement and job satisfaction.

Imaging findings of pelvic venous insufficiency in patients with postural orthostatic tachycardia syndrome.

OBJECTIVES: Some patients with postural orthostatic tachycardia syndrome (POTS) demonstrate improved dysautonomic symptoms following treatment for pelvic venous insufficiency (PVI). This study assessed the prevalence of significant left common iliac vein (LCIV) compression in POTS patients. METHODS: Radiologists retrospectively reviewed CT images of pelvic veins for 216 women (191 with POTS and 25 age-comparable controls).Quantitative vascular analysis identified percent-diameter compression of the LCIV by the right common iliac artery. Significant LCIV compression was defined as >50%. RESULTS: Significant LCIV compression was found in 69% (131/191) of females with POTS versus 40% (10/25) in controls. The hypothesis that venous compression and presence of POTS are independent was rejected (p = .005). CONCLUSIONS: Significant LCIV compression was noted in a majority of female POTS patients, suggesting that incidence of iliac venous obstruction may be higher than the general population. Patients with POTS and symptoms of PVI may benefit from assessment for venous outflow obstruction.

Evaluation and Treatment of Constipation in the Geriatric Population.

Chronic constipation affects one-third of the US population and occurs disproportionately in the elderly and female individuals, increasing in older individuals who are institutionalized. This condition has a significant impact on health care costs and quality of life. Clinicians need to consider primary as well as secondary causes of constipation in elderly individuals because the cause is often multifactorial. Diagnostic algorithms should eliminate red-flag symptoms that may indicate a malignancy but also consider pelvic floor dysfunction, which is more common in this age group. An appropriate treatment plan is tailored to the severity of the patient's symptoms.

Impact of patient and disease characteristics on the efficacy and safety of eluxadoline for IBS-D: a subgroup analysis of phase III trials.

BACKGROUND: Irritable bowel syndrome with diarrhea (IBS-D) is a prevalent gastrointestinal (GI) disorder with a varied presentation, often overlapping with other GI and non-GI disorders. Eluxadoline is a locally active mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved for the treatment of IBS-D in adults. As IBS-D is a heterogeneous disease, factors such as patient demographics, symptom severity, and symptom pattern history can potentially inform treatment selection. METHODS: Here, we report additional prospectively planned analyses of two large double-blind, placebo-controlled studies (IBS-3001 and IBS-3002) enrolling patients meeting Rome III criteria for IBS-D. Patients were randomized 1:1:1 to receive placebo or eluxadoline 75 mg or 100 mg twice daily. Efficacy (abdominal pain, stool consistency, and composite, simultaneous improvement in both) and safety were assessed for prospectively defined patient subgroups stratified by age, sex, race, presence of comorbidities, and baseline disease characteristics. RESULTS: Across all age, sex, race, comorbidity, and disease characteristic subgroups, a greater proportion of patients were composite responders with both eluxadoline doses as compared with placebo, including patients with a history of depression or a history of gastroesophageal reflux disease. Among patients aged ⩾65 years, a greater proportion of patients receiving eluxadoline 75 mg were composite, abdominal pain, and stool consistency responders compared with those receiving 100 mg. The proportion of patients with at least one adverse event was slightly higher in patients aged ⩾65 years and also in female patients. CONCLUSIONS: This analysis suggests that eluxadoline is effective in treating IBS-D across a range of commonly encountered patient types. In contrast to the overall population, patients aged ⩾65 years demonstrated a greater proportion of responders at the lower approved 75 mg eluxadoline dose.

Factors Associated With Use of Nonoral Nutrition and Hydration Support in Adult Patients With Postural Tachycardia Syndrome.

BACKGROUND: Patients with postural tachycardia syndrome (POTS) often have gastrointestinal (GI) symptoms. Occasionally, these symptoms can be so severe that nonoral nutrition/hydration support (NONHS), including intravenous fluids (IVFs), enteral nutrition (EN), and parenteral nutrition (PN), becomes necessary. METHODS: This is a retrospective cohort study of adult patients diagnosed with POTS at the Mayo Clinic Arizona from January 2010 to January 2017 with a minimum of 6 months of follow up. Demographic information, symptomatology, medications, GI testing, autonomic and autoantibody testing, and healthcare utilization data were abstracted from the electronic medical record. RESULTS: Three-hundred thirty-two patients with POTS were included, of which 32 required NONHS. Patients receiving NONHS were more likely to be female; have lower body mass index; have GI symptoms including nausea, vomiting, diarrhea, and constipation; have abdominal pain; use opiates; have delayed gastric emptying; see more specialists; and be seen in an emergency room or be hospitalized for symptoms. Of these patients, 21 (66%) required IVF, 19 (59%) required EN, and 9 (28%) required PN. Six (19%) patients required all 3 NONHS modalities at some point during their follow-up period. CONCLUSIONS: NONHS may be required in a subset of patients with POTS. Those receiving NONHS have more severe symptoms and abnormal GI motility and autonomic testing and exhibit greater healthcare utilization. Management of these patients is complex and challenging and requires a multidisciplinary approach. Further prospective studies are needed to identify optimal management strategies.

Effect of Antidepressants and Psychological Therapies in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-Analysis.

OBJECTIVES: Irritable bowel syndrome (IBS) is a chronic functional bowel disorder that is thought to be due to a disorder of brain-gut function. Drugs acting centrally, such as antidepressants, and psychological therapies may, therefore, be effective. METHODS: We updated a previous systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, PsychINFO, and the Cochrane Controlled Trials Register were searched (up to July 2017). Trials recruiting adults with IBS, which compared antidepressants versus placebo, or psychological therapies versus control therapy or "usual management" were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). RESULTS: The search strategy identified 5316 citations. Fifty-three RCTs, reported in 51 separate articles, were eligible for inclusion: 17 compared antidepressants with placebo, 35 compared psychological therapies with control therapy or "usual management", and one compared both psychological therapy and antidepressants with placebo. Four of the trials of psychological therapies, and one of the RCTs of antidepressants, were identified since our previous meta-analysis. The RR of IBS symptoms not improving with antidepressants versus placebo was 0.66 (95% CI 0.57-0.76), with similar treatment effects for both tricyclic antidepressants and SSRIs, although with heterogeneity between RCTs of the latter (I(2) = 49%, P = 0.07). The RR of symptoms not improving with psychological therapies was 0.69 (95% CI 0.62-0.76). Cognitive behavioral therapy, relaxation therapy, multi-component psychological therapy, hypnotherapy, and dynamic psychotherapy were all beneficial when data from two or more RCTs were pooled. There was significant heterogeneity between studies (I(2) = 69%, P < 0.001) and significant funnel plot asymmetry. There were also issues regarding trial design, including lack of blinding. CONCLUSIONS: Antidepressants are efficacious in reducing symptoms in IBS patients. Psychological therapies also appear to be effective treatments for IBS, although there are limitations in the quality of the evidence, and treatment effects may be overestimated as a result.

Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic functional bowel disorder. Disturbances in the gastrointestinal microbiome may be involved in its aetiology. AIM: To perform a systematic review and meta-analysis to examine the efficacy of prebiotics, probiotics, synbiotics and antibiotics in IBS. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to July 2017). Randomised controlled trials (RCTs) recruiting adults with IBS, comparing prebiotics, probiotics, synbiotics or antibiotics with placebo or no therapy were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). Continuous data were pooled using a standardised mean difference with a 95% CI. RESULTS: The search identified 4017 citations. Data for prebiotics and synbiotics were sparse. Fifty-three RCTs of probiotics, involving 5545 patients, were eligible. Particular combinations of probiotics, or specific species and strains, appeared to have beneficial effects on global IBS symptoms and abdominal pain, but it was not possible to draw definitive conclusions about their efficacy. There were five trials of similar design that used rifaximin in non-constipated IBS patients, which was more effective than placebo (RR of symptoms persisting = 0.84; 95% CI 0.79-0.90). Adverse events were no more common with probiotics or antibiotics. CONCLUSIONS: Which particular combination, species or strains of probiotics are effective for IBS remains, for the most part, unclear. Rifaximin has modest efficacy in improving symptoms in non-constipated IBS.

Postural Tachycardia Syndrome (POTS) and the GI Tract: A Primer for the Gastroenterologist.

Postural tachycardia syndrome (POTS) is one of the most common causes of orthostatic intolerance and is being increasingly recognized in clinical practice. Gastrointestinal (GI) symptoms are reported commonly in patients with POTS and pose a considerable management challenge, making it imperative that gastroenterologists be aware of this condition and its GI comorbidities. Although the evidence presented herein does not prove causation, it does support an association between GI symptoms, GI dysmotility, and POTS. At present, the evaluation and treatment of GI symptoms in patients with POTS remains largely empirical. General measures to treat POTS may lead to improvement in both GI and non-GI symptoms. GI symptoms refractory to these measures should prompt further diagnostic evaluation of gastrointestinal dysmotility and appropriate dietary and pharmacologic management. This review focuses its attention on the involvement of the GI tract in POTS including a discussion of GI symptoms and conditions associated with POTS, followed by an analysis of abnormalities in gut physiology described in POTS, and concluding with an overview of management and suggestions for research directions.