An Overview of the Effects of Tenapanor on Visceral Hypersensitivity in the Treatment of Irritable Bowel Syndrome with Constipation.

Background: Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults. Aim: This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain. Findings: Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling. Conclusion: By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.

Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation.

BACKGROUND: Bloating is a bothersome symptom in irritable bowel syndrome with constipation (IBS-C). AIM: To evaluate plecanatide efficacy in patients with IBS-C stratified by bloating intensity. METHODS: Pooled phase 3 data (2 randomized, controlled IBS-C trials) from adults treated with plecanatide 3 mg or placebo for 12 weeks were analyzed. Patients were stratified post-hoc by baseline bloating severity (11-point scale: mild [≤ 5] and moderate-to-severe [> 5]). Assessments included change from baseline in bloating, abdominal pain, and complete spontaneous bowel movement (CSBM) frequency. Abdominal pain and bloating composite responders were defined as patients with ≥ 30% improvement from baseline in both bloating and abdominal pain at Week 12. RESULTS: At baseline, 1104/1436 patients with IBS-C (76.9%) reported moderate-to-severe bloating. In the moderate-to-severe bloating subgroup, plecanatide significantly reduced bloating severity versus placebo (least-squares mean change [LSMC]: - 1.7 vs - 1.3; P = 0.002), reduced abdominal pain (- 1.7 vs - 1.3; P = 0.006), and increased CSBM frequency (1.4 vs 0.8; P < 0.0001). In the mild bloating subgroup, significant improvements were observed with plecanatide versus placebo for abdominal pain (LSMC: - 1.3 vs - 1.0; P = 0.046) and CSBM frequency (2.0 vs 1.2; P = 0.003) but not bloating (- 0.9 vs - 0.8; P = 0.28). A significantly greater percentage of patients were abdominal pain and bloating composite responders with plecanatide versus placebo (moderate-to-severe bloating: 33.6% vs 26.8% [P = 0.02]; mild bloating: 38.4% vs 27.2% [P = 0.03]). CONCLUSION: Plecanatide treatment improved IBS-C abdominal and bowel symptoms, including in those who present with moderate-to-severe bloating.

Semaglutide improves metabolic dysfunction-associated steatohepatitis: A 10-year retrospective study.

Background and Aims: Semaglutide has been studied in patients with metabolic dysfunction-associated steatohepatitis (MASH) due to potential benefit from weight loss on liver inflammation. However, preclinical studies suggest that MASH improvement may be independent of weight loss. We aim to assess the impact of semaglutide on MASH in relation to weight loss. Methods: This retrospective study included 420 patients with diabetes on semaglutide for at least 12 months between 2011 and 2022. Exclusion criteria were liver disease other than MASH, decompensated cirrhosis, malignancy, and bariatric surgery. Primary endpoints were clinically significant improvements in AST or ALT (mean difference > 6.3 U/L and > 10.6 U/L respectively). Statistical analysis included Student's t-test/ANOVA, Wilcoxon signed-rank test/Friedman test as appropriate, and binary logistic regression. Results: Median duration of semaglutide was 22.5 months and 80% of patients received 1 mg/week. BMI improved by a mean (SD) of 1.9 points (2.8), weight by 13.3 lbs. (19.1), AST by 4.1 U/L (11.5), and ALT by 5.3 U/L (14.2). In 28% and 22% of patients respectively, AST and ALT had a clinically significant improvement. MASH scores (NFS, FIB4, APRI) improved after semaglutide (p < 0.001). No statistically significant differences in AST or ALT improvement were found when patients were stratified by BMI prior to semaglutide or when stratified by percentage of weight loss. On logistic regression, the duration of semaglutide and pretreatment APRI score increased the odds of clinically significant improvements of AST and ALT. Conclusion: Semaglutide treatment was associated with improvement in transaminases and MASH scores. Higher odds of positive semaglutide effects were observed with longer treatment duration and were independent of weight loss.

A Percutaneous Endoscopic Colostomy Tube to the Rescue.

Percutaneous endoscopic colostomy (PEC) tube placement is a minimally invasive procedure used to treat recurrent colonic pseudo-obstruction, sigmoid volvulus, chronic intractable constipation, and neurogenic bowel. PEC is a viable treatment alternative for patients who have failed conservative therapies and are deemed high risk for surgical management. We present a case of acute colonic pseudo-obstruction after Clostridioides difficile infection that was unresponsive to medical treatment or endoscopic decompression. A PEC tube was placed into the transverse colon with successful resolution of the colonic distension.

Management of Constipation in Hospitalized Patients.

Constipation is frequently encountered in hospital settings and can have potentially serious consequences yet is often underrecognized and undertreated. Opioid-induced constipation is a common cause of constipation in hospitalized patients. Opioids induce constipation through agonistic effects on enteric µ-opioid receptors. This review aims to provide insight on the identification and management of constipation in inpatient settings, with a particular focus on opioid-induced constipation. Constipation assessment should be routinely initiated at hospital admission and can be facilitated by thorough symptom assessments; relevant patient history, including recent medication use; physical examination; and patient assessment tools developed to evaluate the impact of constipation. Management of opioid-induced constipation should begin with ensuring adequate hydration and electrolyte balance and encouraging patient mobilization. Other treatments may include laxatives, enemas, intestinal secretagogues, peripherally acting µ-opioid receptor antagonists, and manual disimpaction. Surgical intervention may be required for some patients as a salvage therapy in severe, refractory cases.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.

Rifaximin Treatment for Individual and Multiple Symptoms of Irritable Bowel Syndrome With Diarrhea: An Analysis Using New End Points.

PURPOSE: Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. The current aim was to evaluate rifaximin efficacy on individual and composite IBS-D symptoms using definitions not previously examined. METHODS: Phase III post hoc analyses of two randomized, double-blind, placebo-controlled trials and the open-label phase of a randomized, double-blind, placebo-controlled trial were conducted. Adults with IBS-D received a 2-week course of rifaximin 550 mg TID. Individual and composite responses for abdominal pain (mean weekly improvements from baseline of ≥30%, ≥40%, or ≥50%), bloating (mean weekly improvements from baseline of ≥1 or ≥2 points; or ≥30%, ≥40%, or ≥50%), stool consistency (mean weekly average stool consistency score <3 or <4), and urgency (improvement from baseline of ≥30% or ≥40% in percentage of days with urgency) for ≥2 of the first 4 weeks after treatment, and weekly for 12 weeks, were assessed. FINDINGS: Overall, 1258 patients from the double-blind trials (rifaximin [n = 624]; placebo [n = 634]) and 2438 from an open-label trial were analyzed. The percentage of bloating or urgency responders was significantly greater with double-blind rifaximin versus placebo (P ≤ 0.03). A significantly greater percentage of the double-blind group were composite abdominal pain and bloating responders versus placebo for all thresholds analyzed (P < 0.05). A significantly greater percentage of the double-blind group were tri-symptom composite end point responders (abdominal pain, bloating, and fecal urgency) versus placebo (P = 0.001). A significantly greater percentage of patients achieved response (≥30% composite tri-symptom threshold) with double-blind rifaximin versus placebo as early as 1 week posttreatment, with significance maintained through ≥5 weeks after treatment. Open-label results were consistent with those of the double-blind study. IMPLICATIONS: Rifaximin significantly improved multiple, concurrent IBS-D symptoms, using clinically relevant definitions of treatment response. Using a novel tri-symptom composite end point (ie, abdominal pain, bloating, fecal urgency), adults with IBS-D treated with a 2-week course of rifaximin were significantly more likely to be composite end point responders than those receiving placebo (≥30% or ≥40% threshold) for the three symptoms. Thus, rifaximin not only met current standard thresholds used for adjudication of responders in clinical trials but also achieved higher thresholds for many of these symptoms, suggesting potential for even more robust clinical improvements. CLINICALTRIALS: gov identifiers: NCT00731679, NCT00724126, and NCT01543178.

Nutrient Drink Test to Assess Gastric Accommodation in Cyclic Vomiting Syndrome: Single-blinded Parallel Grouped Prospective Study.

Background/Aims: Cyclic vomiting syndrome (CVS) is characterized by episodes of nausea and vomiting, separated by symptom-free intervals. The pathogenesis of CVS is poorly understood. Limited data exist on evaluating impaired gastric accommodation as a mechanistic means for symptoms. We aim to determine if CVS patients demonstrate impaired gastric accommodation applying a nutrient drink test (NDT) protocol. Methods: Through this single-blinded pilot clinical trial, patients with CVS per Rome IV critera and healthy controls were assessed for presence of impaired gastric accommodation by administering an established NDT protocol. Statistical analysis was performed, with data presented as medians and interquartile range. Results: Eleven CVS patients and 15 healthy controls participated in the study between January 2018 and October 2018. Median age was 42.0 years and 37.0 years; majority of subjects were female, 72.7% and 73.3%, respectively. Demographics were similar between CVS and healthy controls. Almost all healthy controls (93.3%) ingested the complete 500 mL protocol, whereas a smaller proportion (72.7%) were able to complete all 4 doses in the CVS group (P = 0.188). Post-prandial visual analogue scale scores of nausea and abdominal pain were found to be significantly higher in CVS patients compared to healthy controls. Conclusions: To our knowledge, this is the first NDT protocol in CVS evaluating the role of impaired gastric accommodation and hypersensitivity as a possible pathophysiologic mechanism. Findings from this study suggest the presence of gastric hypersensitivity in a subset of CVS patients. These results provide the foundational data necessary for future larger testing of NDT and diagnostic accuracy in CVS.

Prevalence of Colonic Polyps in Patients Undergoing Kidney Transplant Evaluation: A Meta-Analysis and Systematic Review.

OBJECTIVES: Colorectal canceris the third most common cancer worldwide, and kidney transplant patients have up to a 2.5-fold increased risk of colorectal cancer compared with the general population. Presently, colorectal cancer screening recommendations in kidney transplant candidates are the same as for the general population. We explored the literature on the prevalence of colonic polyps in patients with renal failure undergoing screening colonoscopy as part of kidney transplant evaluation. MATERIALS AND METHODS: We conducted a systematic review in PubMed, Embase, and Cochrane databases from inception through June 2023 to identify studies that explored the prevalence of colonic polyps in patients with chronic kidney disease undergoing a screening colonoscopy as part of their pretransplant evaluation. RESULTS: Of 937 patients, 371 had ≥1 polyp on their screening colonoscopy (39.6%; 95% CI, 29.3%-50.3%), 243 patients had ≥1 adenoma (25.9%; 95% CI, 14.3%- 39.6%), and 75 had ≥1 high-risk adenoma (8.7%; 95% CI, 6.9%-10.7%). Pooled analysis of the 2 studies comparing patients with end-stage renal disease versus matched control groups indicated higher pooled prevalence of adenomas in the end-stage renal disease group (33.4%) versus the control group (23.9%). CONCLUSIONS: Our results suggest an average or increased prevalence of polyps and adenomatous polyps in patients with chronic kidney disease undergoing colonoscopy during evaluation for kidney transplant. The pooled analysis of the studies comparing the end-stage renal disease population versus a matched control group indicates higher prevalence of adenomatous polyps in patients with end-stage renal disease. Multiple studies have shown that screening colonoscopy in this patient group is safe and does not delay kidney transplant evaluation or waitlistrates; hence, screening colonoscopy should be routinely considered.

Gallbladder Dyskinesia.

Gallbladder dyskinesia is a functional disorder of the gastrointestinal tract, which can result in debilitating episodes of abdominal pain and associated symptoms. Key diagnostic criteria include a diminished gallbladder ejection fraction on scintigraphy and absence of other causes for the symptoms. Pathologic findings and follow-up suggest a distinct mechanistic basis for this condition. Unfortunately, the complexities of diagnosis and treatment combined with patient and provider preferences will likely continue to preclude randomized controlled studies to provide a clearer evidence-based management for this disorder. Patients meeting the clinical and diagnostic criteria for gallbladder dyskinesia should be referred for cholecystectomy, and most of these patients will have relief of their symptoms. A comprehensive preoperative discussion on expected outcomes needs to take place.

The serotonin receptor 3E variant is a risk factor for female IBS-D.

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.

Episodic Memories Among Irritable Bowel Syndrome (IBS) Patients: An Important Aspect of the IBS Symptom Experience.

Objective: Some IBS patients possess detailed memories of the events surrounding their bowel symptom onset ("episodic memories"). In this exploratory study we sought to: (1) examine memory relationship with gastrointestinal (GI) symptom severity, extraintestinal symptoms, and mood; (2) qualitatively explore memory valence and content in IBS patients with or without episodic memories. Methods: Referral IBS patients n = 29; age 47.0± 2.2 years, 79.3% female) enrolled in this cross-sectional, mixed methods research study. Participants completed validated specific memory instruments [Autobiographical Memory Test (AMT), Sentence Completion for Events from the Past Test (SCEPT)] and relevant questionnaires [IBS symptoms 10-cm visual analog scale); SF-36 Health-related quality of life (HRQOL); Perley-Guze and PHQ-15/12: somatization; Beck Depression/Anxiety Inventories). Qualitative analysis examined the content and valence of general memories. Results: 14/29 (48.3%) of IBS subjects endorsed episodic memories of IBS symptom onset, often GI infections/enteritis (35.7%). Recall of the exact year (69%) and month (60%) of symptom onset were common. Episodic memories were associated with greater IBS symptom severity/bother, higher anxiety/depression, and poorer HRQOL. Though AMT and SCEPT memory specificity were not different based on episodic memories, overgeneralization to negatively-valenced cues in the AMT was associated with more severe IBS in those without episodic memory. Qualitative analysis revealed no observable differences in topic focus of IBS patients with and without episodic memories. Conclusions: IBS patients often endorse episodic memories associated with symptom onset, and this recall seems to associate with more severe symptoms. Overgeneralization responses to negative stimuli may lead to worse bowel symptoms in those without episodic memories. IBS memory specificity may associate with qualitative differences in processing psychosocial experiences and might be important to IBS pathophysiology.

Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS). AIM: To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS. METHODS: In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays. RESULTS: Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model (F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score (F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT3AC variant receptors. CONCLUSION: We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.

A Narrative Review of Irritable Bowel Syndrome with Diarrhea: A Primer for Primary Care Providers.

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic disorder of gut-brain interaction, characterized by recurrent abdominal pain in association with more frequent, loose stools. The pathophysiology of irritable bowel syndrome (IBS) includes disordered gut motility, alterations in gut microbiota, neural-hormonal system abnormalities, immune reactivity, and visceral hypersensitivity. Timely diagnosis of IBS-D can be achieved easily using clinical criteria. Formal IBS diagnosis is important for optimizing treatment and patient outcomes and facilitating patient access to appropriate educational resources. Yet, given the symptom overlap with other gastrointestinal conditions, diagnosis of IBS-D often is perceived to be challenging. Treatment of IBS includes both nonpharmacologic and pharmacologic options. Rifaximin, alosetron, and eluxadoline are effective treatments indicated for IBS-D, but have limited availability internationally. Dietary approaches may also be indicated for certain patients with IBS-D. Psychological interventions may be effective in treating abdominal pain alone and global symptoms in IBS. We describe use of these diverse therapies and provide an overview to facilitate the primary care provider's approach to distinguishing IBS-D from other conditions with symptom overlap.

Segmental Colitis Associated With Diverticulosis Masquerading as Polyploid-Appearing Mucosa in the Rectosigmoid Area on Endoscopy and as Focal Thickening on Imaging.

Segmental colitis associated with diverticulosis (SCAD) is an inflammatory disease affecting segments of the large bowel with diverticular disease. SCAD presents several challenges in diagnoses and treatment because it often mimics a range of disorders including inflammatory bowel disease and malignancy. Here, we present the case of a 72-year-old man with lower abdominal pain and bloody stools whose initial abdominal workup showed nonspecific large bowel thickening and concerns for malignancy. Ultimately, the patient was diagnosed with mild SCAD and treated conservatively with a resolution of symptoms. He had no symptoms at the three-month and 1-year follow-ups. This case highlights the importance of including SCAD in the initial differential diagnosis to allow accurate identification and treatment.

Emerging therapies in the management of Irritable Bowel Syndrome (IBS).

INTRODUCTION: Irritable bowel syndrome (IBS) is a symptom-based disorder of chronic abdominal pain and altered bowel habits. The pathogenesis of IBS is multifactorial, leading to the potential for the development of diverse treatment strategies. This mechanistic heterogeneity suggests that available therapies will only prove effective in a subset of IBS sufferers. Current US Food and Drug Administration (FDA) approved therapies for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C) are reviewed. Limited symptom responses and side effect experiences lead to considerable patient dissatisfaction with currently available IBS treatments. Only a small percentage of IBS patients are on prescription therapies underscoring the potential market and need for additional therapeutic options. AREAS COVERED: Expanding on currently available therapies, the serotonergic and endogenous opioid receptor systems continue to be a focus of future IBS treatment development. Additional novel emerging therapies include the endogenous cannabinoid system, bile acid secretion and sequestration, and exploit our enhanced understanding of visceral sensory signaling and intestinal secretomotor function. EXPERT OPINION: While challenges remain for the future development of IBS therapies, the diverse etiologies underlying the disorder present an opportunity for novel therapies. Hence, great potential is anticipated for future IBS treatment options.

Mechanisms of Action of Current Pharmacologic Options for the Treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

Multiple therapeutic agents are currently available for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. A better understanding of the mechanism of action of each treatment provides important insights into expected responses and is key to optimizing treatment outcomes. Some constipation treatments, such as stimulant laxatives, may increase bowel movement frequency but are ineffective at relieving, and may even exacerbate, abdominal symptoms. On the contrary, prescription treatments, such as the guanylyl cyclase-C agonists, for example, may improve bowel symptoms and reduce visceral hypersensitivity. This review summarizes the mechanisms of action of commonly used over-the-counter and prescription therapies for chronic idiopathic constipation and irritable bowel syndrome with constipation, outlining how these mechanisms contribute to the efficacy and safety of each treatment option.