Diagnosis and treatment of irritable bowel syndrome with diarrhea: Key clinical considerations

ABSTRACT

Background:

Given their emphasis on holistic, patient-centered care, nurse practitioners (NPs) and physician assistants (PAs) play an increasingly critical role in the care of patients with gastrointestinal conditions, including irritable bowel syndrome (IBS).

Objectives:

To review key clinical considerations for the diagnosis and management of IBS, focusing on IBS with diarrhea (IBS-D), alongside 2 case presentations.

Data Sources:

PubMed and Google Scholar searches of English-language articles published between January 1, 2009, and April 2, 2025, were conducted to identify publications on the burden, diagnosis, and treatment of IBS-D.

Results:

Data indicate that IBS-D impairs quality of life, daily activities, and work productivity and imposes a substantial socioeconomic burden. A positive diagnostic approach involving a detailed medical history and physical examination, with limited laboratory testing in the absence of alarm features, is recommended to facilitate timely and accurate diagnosis. Effective ongoing management relies on a patient–provider relationship that uses shared decision making, patient education and empowerment, and a personalized treatment strategy targeting the IBS subtype and most bothersome symptoms. Treatments considered for IBS-D include dietary management, over-the-counter agents, United States Food and Drug Administration–approved medications, neuromodulators, and gut–brain behavioral therapies.

Conclusions:

Positive diagnosis of IBS-D and an evidence-based, symptom-targeted therapeutic approach are recommended to minimize disease burden.

Implications for Practice:

Both NPs and PAs are well positioned to provide individualized, compassionate, and competent care to patients with IBS-D. Communicating a confident, positive diagnosis and collaborating on a treatment plan that considers symptom presentation and most bothersome symptoms can improve patient outcomes.

Irritable bowel syndrome (IBS) is a chronic disorder of gut–brain interaction (Drossman, 2016) that affects an estimated 4.8%–6.1% of the US population (Almario et al., 2023; Palsson et al., 2020; Sperber et al., 2021) and can markedly reduce quality of life (QOL) (Drossman et al., 2009). This condition is characterized by recurrent abdominal pain occurring at least 1 day per week, on average, during the previous 3 months, with symptom onset at least 6 months before diagnosis. Abdominal pain must be associated with two or more of the following: defecation, change in stool frequency, or change in stool form (Rome [Foundation] IV criteria; Lacy et al., 2016). Additional symptoms of abdominal bloating and distention frequently occur in patients with IBS (Lacy et al., 2016). Irritable bowel syndrome is further subclassified based on the predominant stool appearance (Rome IV criteria; Table 1): IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), IBS mixed type (IBS-M), and IBS unclassified (IBS-U; Lacy et al., 2016; Lewis & Heaton, 1997). Among US adults, IBS-D, IBS-C, and IBS-M each account for approximately 30%–35% of cases of IBS (Almario et al., 2023; Palsson et al., 2020).

Table 1.

Irritable bowel syndrome subtypes (Lacy et al., 2016; Lewis & Heaton, 1997)

Subtypea	Bowel Movements with Constipation or Diarrhea, %
	Constipation (BSFS Types 1 or 2)b	Diarrhea (BSFS Types 6 or 7)c
IBS-C	>25	<25
IBS-D	<25	>25
IBS-M	>25	>25

Note: Table created with data from Lacy, B. E., et al. (2016). Gastroenterology, 150(6), 1393-1407; and Lewis, S. J., & Heaton, K. W. (1997). Scand J Gastroenterol, 32(9), 920-924 (Lacy et al.; Lewis & Heaton, 1997). BSFS = Bristol Stool Form Scale; IBS = irritable bowel syndrome; IBS-C = irritable bowel syndrome with constipation; IBS-D = irritable bowel syndrome with diarrhea; IBS-M = irritable bowel syndrome mixed type.

^aIBS unclassified is a fourth subgroup for individuals who do not meet percentage criteria for IBS-C, IBS-D, or IBS-M (Lacy et al.)

^bSeparate hard lumps, like nuts (type 1), or sausage-shaped but lumpy (type 2; Lewis & Heaton).

^cFluffy pieces with ragged edges, a mushy stool (type 6), or watery, no solid pieces (type 7; Lewis & Heaton).

The pathophysiology of IBS is considered multifactorial and may include alterations in interactions between the brain and the gastrointestinal (GI) tract, gut microbiota dysbiosis, postinfection-related GI changes, increased intestinal epithelial permeability, disrupted GI motility, heightened visceral sensitivity, immune activation, and neural–hormonal system involvement (Burns et al., 2019; Drossman, 2016; Ford et al., 2020; Linsalata et al., 2020; Mayer et al. 2022; Piche et al., 2009; Pisipati et al. 2020; Pittayanon et al., 2019; Simrén et al., 2019; Talley et al., 2020). Of note, postinfectious IBS is a subcategory, with symptoms present after an episode of acute gastroenteritis in an individual who has not previously met, but now currently meets, IBS diagnostic criteria (Barbara et al., 2019; Schwille-Kiuntke et al., 2011; Spiller & Garsed, 2009).

Nurse practitioners (NPs) and physician assistants (PAs) play an increasingly critical role in the care of patients with GI conditions (Allen et al., 2019; Moses & McKibbin, 2017b). The integration of these health care providers (HCPs) into GI-focused practices expands patient access to care and has been shown to improve treatment outcomes and increase patient satisfaction (Moses & McKibbin, 2017b; Newhouse et al., 2011; Norful et al., 2019; Thurler et al., 2021; van Erp et al., 2021). The emphasis that NPs and PAs place on holistic, patient-centered care provides increased opportunities for education and counseling, and patients with disorders of gut–brain interaction, such as IBS, would benefit from a collaborative treatment approach that validates their experiences and addresses their most bothersome symptoms (Chang, 2021; Dorn, 2010; Thurler et al., 2021). As NP and PA encounters with patients with disorders of gut–brain interaction continue to increase (Moses & McKibbin, 2017a, 2017b), instilling patient confidence in the diagnosis and treatment plan is paramount. This review, focused on IBS-D, provides key clinical considerations for the diagnosis and treatment of IBS, alongside 2 case presentations (Tables 2 and 3).

Table 2.

Case presentation: Patient with irritable bowel syndrome with diarrhea of postinfectious origin

Patient history

A 48-year-old man presented to his primary care provider with recurrent abdominal pain, bloating, cramping, diarrhea, and fecal urgency during the previous year. His symptoms began after a family vacation, during which the patient and several family members developed acute gastrointestinal (GI) symptoms, including nausea, vomiting, and watery diarrhea. Although his family members recovered completely, the patient experienced persistent GI symptoms. He reported no evidence of rectal bleeding or unintentional weight loss and had no known family history of colorectal cancer, inflammatory bowel disease (IBD), or other GI conditions. A screening colonoscopy conducted 2 years prior was negative for colorectal cancer. The patient was taking loperamide routinely (almost daily), which improved frequency of bowel movements but did not improve the abdominal pain and bloating

Patient evaluation and diagnosis
A complete physical examination was normal. Blood work (including serologic testing for celiac disease, Giardia infection, and IBD) and fecal calprotectin results were within normal limits, and no alarm features were evident. The patient was diagnosed with irritable bowel syndrome with diarrhea (IBS-D), with a suspected etiology of postinfection GI-related changes

Treatment plan and outcomes
• Rifaximin 550 mg 3 times daily was prescribed for 14 days and improved the patient's IBS-D symptoms
• Loperamide was discontinued and limited to use on an as-needed basis
• 6 months posttreatment, the patient returned to the clinic, reporting that several symptoms of mild to moderate intensity had returned
• A second course of rifaximin 550 mg 3 times daily for 14 days was prescribed and, after receiving counseling on dietary management strategies, he decided to alter his diet to avoid dairy products
• He reported almost complete improvement in IBS-D symptoms and health-related quality of life with the second course of rifaximin treatment and adjunct dietary modification compared with the first course
• The patient was counseled that an additional course of rifaximin would be appropriate if symptoms worsened or recurred

Table 3.

Case presentation: Patient with irritable bowel syndrome with diarrhea and comorbid anxiety

Patient history

A 20-year-old woman premedical student presented to her primary care provider with recurrent abdominal pain, diarrhea, and fecal urgency. She reported having GI-related symptoms, to a varying degree, during most of her adolescent and adult life. These symptoms had progressively worsened during the previous 18 months. Over time, she started avoiding travel, eating in public places, going out with friends, and attending in-person classes due to unpredictability and fecal urgency fears. The patient also noted increased symptoms in the setting of high levels of stress and anxiety related to her studies. Prompted by her own research, she had pursued several dietary management strategies, including adding soluble fiber to her diet and avoiding dairy, gluten, and/or fermentable oligosaccharides, disaccharides, monosaccharides, and polyols when possible. However, there was a lack of symptom improvement, and she could not identify any food triggers that worsened symptoms. Loperamide helped to reduce stool frequency but not the abdominal pain, and it typically led to constipation. Peppermint oil capsules 3 times daily did not improve symptoms

Patient evaluation and diagnosis
Results were normal for complete blood count, thyroid-stimulating hormone level, stool culture, serologic testing for celiac disease, and fecal calprotectin level for inflammatory bowel disease, and there were no findings on physical examination. The patient did not present with any alarm features and was diagnosed with irritable bowel syndrome with diarrhea

Treatment plan and outcomes
• The patient was counseled on treatment options and expressed initial hesitation regarding gut–brain behavioral therapy and tricyclic antidepressants (TCAs); her concerns were related to fear of being perceived negatively by her peers Note: Stigma remains around the use of TCAs and gut–brain behavior therapy; however, these are evidenced-based therapies for IBS. Referring to TCAs as neuromodulators may help patients understand their clinical purpose/role
• Her medical history did not include pancreatitis or cholecystectomy, and she stated that she did not routinely consume alcohol
• Eluxadoline 100 mg twice daily was prescribed, which improved diarrhea and fecal urgency but did not adequately control the intensity of her abdominal pain
• At the follow-up appointment, she expressed more openness to gut–brain behavioral therapies and neuromodulators
• Nortriptyline 10 mg every night at bedtime was prescribed as add-on therapy, with good tolerability and mild improvement in abdominal pain, diarrhea, and urgency; the dose was increased to 25 mg every night at bedtime at a 3-month follow-up visit
• She reported better symptom control compared with eluxadoline alone; however, she was still experiencing mild to moderate anxiety about her symptoms and was referred to a psychologist for gut–brain behavioral therapy
• Routine follow-up was scheduled every 3–6 months with her primary care provider; based on the response to behavior therapy and nortriptyline, eluxadoline was discontinued

Methods

PubMed and Google Scholar searches of English-language articles published between January 1, 2009, and April 30, 2025, were conducted to identify publications on the burden, diagnosis, and treatment of IBS-D. Search terms included “irritable bowel syndrome,” “irritable bowel syndrome with diarrhea,” “gastroenterology,” “nurse practitioner,” “physician assistant,” “advanced practice provider,” “patient education,” “burden,” “diagnosis,” “novel,” “innovative,” and “treatment.”

Burden of IBS with diarrhea

The severity of IBS is multidimensional and is influenced by abdominal and bowel symptoms (e.g., abdominal pain), psychological comorbidities, health care utilization, and health-related QOL, daily activity, and work productivity impairments (Buono, Carson, & Flores, 2017; Drossman et al., 2011; Knowles et al., 2023; Lacy et al., 2024). An online survey conducted on behalf of the American Gastroenterological Association (AGA) indicated that patients with IBS-D were significantly more likely than those with IBS-C to report that they avoided leaving the house, avoided places without bathrooms, experienced difficulty making plans, and restricted their travel (Ballou et al., 2019). Approximately one-third of patients with IBS-D reported that their symptoms interfered with participation in personal activities at least 10 days per month. A survey of 2,470 adults with IBS indicated that among patients with IBS-D (n = 917), approximately half reported often or always having dietary limitations related to their condition, 40% often or always had social activity limitations, and one-quarter reported that they often or always experienced trouble sleeping (Bhinder et al., 2023). Another survey reported that adults with IBS would be willing to give up a mean of 15.1 years (∼25% of their remaining lifespan) to achieve perfect health (Drossman et al., 2009).

In addition to the impact on health-related QOL, IBS-D is associated with a substantial socioeconomic burden. A retrospective administrative claims database analysis of a commercially insured US population found that patients with IBS-D had significantly higher health care utilization (all-cause hospitalizations, emergency department visits, physician office visits, and monthly prescription refills) compared with matched controls without IBS-D (Buono, Mathur, et al., 2017). Based on data from the 2012 US National Health and Wellness survey, indirect costs associated with absenteeism and presenteeism were $2,486 higher annually for employees with IBS-D compared with controls (Buono, Carson, & Flores, 2017).

Diagnosis of IBS with diarrhea

The 2021 American College of Gastroenterology (ACG) guideline for IBS management strongly recommends a positive IBS diagnostic strategy (i.e., not a diagnosis of exclusion), which involves a detailed medical history, physical examination, and limited diagnostic testing (Lacy et al., 2021; Figure 1). However, a survey of 250 US primary care providers published in 2025 identified that 81% considered IBS a diagnosis of exclusion, and 78% considered IBS difficult to diagnose with confidence (Heidelbaugh et al., 2025). Additionally, survey data found that only 25% of individuals with IBS-D are diagnosed within 1 year of initial symptom onset. These studies support that education for both HCPs and patients is important and should be ongoing (The American Gastroenterological Association, 2015).

Figure 1.

Diagnostic algorithm for IBS with diarrhea (Lacy et al., 2021). ^aAlarm features include iron-deficiency anemia; unintentional weight loss; new symptom onset age ≥45 years; rectal bleeding; and/or first-degree family history of colon cancer, inflammatory bowel disease, or other significant gastrointestinal disease. Note: BSFS = Bristol Stool Form Scale; CRP = C-reactive protein; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome; IBS-D = IBS with diarrhea.

As noted in the introduction, Rome IV criteria, lack of alarm symptoms, and limited diagnostic testing should be used to formalize a confident diagnosis of IBS and treatment approach (Lacy et al., 2016). Alarm features to be considered include iron-deficiency anemia of unknown etiology; unintentional weight loss; new symptom onset after 45 years of age; rectal bleeding; and a first-degree family history of colon cancer, inflammatory bowel disease (IBD), or other significant GI disease (Lacy et al., 2016, 2021). The Bristol Stool Form Scale (BSFS) can be helpful for classifying the IBS subtype, as well as monitoring changes in stool consistency and treatment effectiveness (Lacy et al., 2016, 2021). According to the BSFS, IBS-D is classified as having more than 25% of bowel movements consisting of mushy or watery stool (type 6 or 7 on BSFS) and fewer than 25% of bowel movements having hard or lumpy stool (type 1 or 2; Lacy et al., 2016).

For patients who meet Rome IV criteria for IBS-D and have no alarm features, a diagnosis based on symptoms alone is potentially accurate in up to 98% of patients (Tables 2 and 3; Cash et al., 2002; Vanner et al., 1999). Access to educational materials during patient visits is often helpful when a diagnosis is being formed. Serum C-reactive protein and stool fecal calprotectin or lactoferrin levels can be checked, and if normal, are considered sufficient evidence to exclude IBD (Lacy et al., 2021). Serological antibody testing for celiac disease is also recommended. Additional testing for food sensitivities and allergies is not recommended, unless the patient presents with symptoms suggestive of a food allergy that have rapid onset and are reproducible and absent during avoidance (Lacy et al., 2021).

A diagnostic colonoscopy is not recommended to diagnose IBS in patients who are not due for a screening/surveillance colonoscopy and do not have alarm features (Table 2; Lacy et al., 2021). There is limited evidence to support a colonoscopy to rule out microscopic colitis (Asghar et al., 2022); colonoscopy with random colonic biopsies should be considered in patients older than 45 years with secretory diarrhea unresponsive to antidiarrheals (Lacy et al., 2016). Note that use of nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, proton pump inhibitors, or statins, for example, are risk factors for microscopic colitis (Tarar et al., 2022). Stool testing for pathogens is not advised unless the patient is at the risk for giardiasis (Lacy et al., 2021). It is often helpful to provide educational materials during patient visits to support the diagnoses being formed.

Treatment of IBS with diarrhea

Effective management of IBS relies on a patient–provider relationship that uses shared decision making, confident positive diagnosis, patient education and empowerment, and personalized treatment that targets the patient's IBS subtype and most bothersome symptoms (Chang, 2021; Lacy et al., 2021). Both NPs and PAs are particularly qualified to provide this level of care and establish and maintain positive patient–provider relationships (Patel et al., 2021). A wide range of treatments have been considered for IBS-D, including dietary management (e.g., the low-fermentable oligosaccharides, disaccharides, monosaccharides, and polyols [FODMAP] diet), over-the-counter antidiarrheal agents (e.g., loperamide), dietary supplements (e.g., peppermint oil; soluble fiber supplements), US Food and Drug Administration–approved medications (e.g., eluxadoline, rifaximin), neuromodulators (e.g., tricyclic antidepressants [TCAs]), and gut–brain behavioral therapies (Lacy et al., 2021; Lembo et al., 2022). Other explorative therapeutical approaches with limited evidence are available, such as artificial intelligence (AI)–assisted personalized diet, acupuncture, and app-based or virtual reality (VR)–based cognitive–behavioral therapy (CBT; Fu et al., 2025; Hunt et al., 2021; Spiegel et al., 2022; Suchak et al., 2024; Tunali et al., 2024; Wang, Zhao, et al., 2024). Several therapies are recommended by the ACG and/or AGA and are listed in Tables 4 and 5 (Lacy et al., 2021; Lembo et al., 2022).

Table 4.

ACG- and AGA-recommended over-the-counter treatments and dietary modification for irritable bowel syndrome and/or irritable bowel syndrome with diarrhea (Lacy et al., 2021; Lembo et al., 2022)

Treatment	Recommended Use	Key Considerations
Over-the-counter agents or dietary modification
Low FODMAP diet	• Limited trial recommended by the ACG to improve global IBS symptoms	• Consider referral to a dietitian • Restrictive diets are not appropriate for all patients (e.g., those with history of eating disorders, including ARFID, OCD, or poor health insight)
Soluble fiber	• Recommended by ACG to treat global IBS symptoms	• Dietary supplement (e.g., psyllium)
Peppermint oil	• Recommended by ACG and AGAa for patients with IBS • Dosing example: Two 90-mg capsules (180 mg) 3 times daily, 30–90 minutes before a meal, for 4 weeksb	• Dietary supplement • Few peppermint oil products have been rigorously tested for efficacy and safety • Should not be administered in patients with GERD or active gastric ulcers
Loperamide	• Recommended by AGA for patients with IBS-D	• Nonprescription medication • Not recommended by ACG as a first-line therapy for IBS-D because it may improve diarrhea but not global IBS symptoms

Note: ACG = American College of Gastroenterology; AGA = American Gastroenterological Association; ARFID = avoidant/restrictive food intake disorder; FODMAP = fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; GERD = gastroesophageal reflux disease; GI = gastrointestinal; IBS = irritable bowel syndrome; IBS-D = IBS with diarrhea; OCD = obsessive–compulsive disorder.

^aAGA broadly recommends antispasmodics, which include peppermint oil, for patients with IBS.

^bDosing noted for “when in flare” situations. “Daily and proactive gut-health support” dosing is two 90-mg capsules once daily, taken 30–90 minutes before a meal.

Table 5.

American College of Gastroenterology- and American Gastroenterological Association-recommended US Food and Drug Administration-approved and other prescribed therapies for irritable bowel syndrome and/or IBS with diarrhea (Lacy et al., 2021; Lembo et al., 2022)

Treatment	Recommended Use	Key Considerations
FDA-approved therapies for IBS-D (recommended by ACG and AGA)
Rifaximin	• 550 mg 3 times daily for 14 days • Indicated in adults with IBS-D	• Gut targeted medication • Short-course therapy; up to 2 retreatment courses are indicated if symptoms recur
Eluxadoline	• 100 mg twice daily with food • Reduced dosage of 75 mg twice daily with food in certain situationsa • Indicated in adults with IBS-D	• Contraindications: History of cholecystectomy, biliary duct obstruction, sphincter of Oddi dysfunction; alcohol >3 drinks/day; pancreatitis, severe hepatic impairment, or constipation complications
Alosetron	• 0.5–1 mg twice daily • Indicated in women with severe IBS-Db	• Population is narrowly defined • Rare cases of ischemic colitis and serious constipation complications
Non–FDA-approved prescribed therapies (varied recommendations)
Antispasmodics	• Recommended by AGA for IBS • Examples include dicyclomine and hyoscyamine	• Not recommended by ACG due to low-quality efficacy evidence for global IBS symptoms
Tricyclic antidepressants	• Recommended by ACG and AGA for patients with IBS • Amitriptyline or nortriptyline (10 mg once daily for 2 weeks, then 25–75 mg once daily, as tolerated)	• Off-label use; best studied neuromodulator • Moderate certainty of evidence for global IBS symptoms; low certainty for abdominal pain • Consider taking at bedtime to minimize potential anticholinergic sedative effects • Start with low dose, with gradual up-titration • Consider SNRI duloxetine for abdominal pain for those who cannot tolerate TCAs
Gut–brain behavioral therapy	• Recommended by ACG for global IBS symptoms	• Consider referral to local qualified provider or approved app

Note: ACG = American College of Gastroenterology; AGA = American Gastroenterological Association; FDA = US Food and Drug Administration; IBS = irritable bowel syndrome; IBS-D = IBS with diarrhea; SNRI = serotonin and norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant.

^a75 mg twice daily is advised for those who are unable to tolerate 100-mg dose, are receiving a concomitant OATP1B1 inhibitor, have mild/moderate hepatic or moderate/severe renal impairment, or have end-stage renal disease without concurrent dialysis.

^bIBS symptoms ≥6 months and lack of adequate response to conventional treatment.

Dietary management strategies

Food intolerance is increasingly being recognized as a trigger for IBS symptoms. The ACG guideline recommends a limited (e.g., 6-week) trial of an elimination/reintroduction low FODMAP diet to identify trigger foods and thus improve global IBS symptoms (Lacy et al., 2021). FODMAPs comprise a class of poorly digested and/or absorbed carbohydrates contained in a broad range of foods (e.g., fruits, vegetables, dairy products; Gibson & Shepherd, 2005). Consumption of FODMAPs increases water secretion into the GI tract and enhances bacterial fermentation in the large intestine, resulting in production of short-chain fatty acids and gases (Lacy et al., 2021). This combination can cause the intestines to stretch and expand, triggering digestive symptoms after meals in patients with IBS. The ACG recommendation regarding the low FODMAP diet is conditional and based on a very low quality of evidence. A 2025 meta-analysis concluded that the low FODMAP diet had positive (although not statistically significant) effects on global IBS symptom improvement and significantly improved bloating, abdominal pain, stool consistency, and stool frequency. Restrictive diets may not be appropriate for some patients (e.g., those with current or history of eating disorders, including avoidant/restrictive food intake disorder [Chey, 2019]; obsessive–compulsive disorder; or poor health insight).

The ACG guideline recommends use of soluble (e.g., beans, barley, oat bran, psyllium/ispaghula husk) rather than insoluble (e.g., whole grains, wheat bran) fiber as a first-line therapy for global IBS symptoms (Lacy et al., 2021). In particular, supplementation with psyllium/ispaghula husk is considered a reasonable first step in treatment, related, in part, to low bacterial fermentation, tolerability, and low cost (Currò, 2022). The role of the GI microbiota in the pathophysiology of IBS—and, therefore, the potential utility of probiotics and other gut microbiome modulators as treatment—has been suggested by studies showing differences in the gut microbiome between patients with IBS compared with healthy controls (Jalanka-Tuovinen et al., 2014; Sundin et al., 2015) and the potential role of prior antibiotic use in the development of IBS (Krogsgaard et al., 2018). However, the ACG guideline recommends against the use of probiotics to treat global IBS symptoms due to component heterogeneity, variability in strains and concentrations evaluated, lack of evaluation of FDA-recommended efficacy endpoints, and inconsistent results across studies (Lacy et al., 2021). Data suggest that low daily doses of prebiotics (fructooligosaccharides and beta-galactooligosaccharides) might help improve IBS symptoms, but the clinical data on prebiotics are inconclusive, and further studies are needed before recommendations can be made with respect to prebiotic use (Currò, 2022).

Antispasmodics and bile acid sequestrants

Antispasmodics are hypothesized to improve IBS symptoms by relaxing smooth muscle, reducing GI motility, and possibly reducing visceral hypersensitivity (Camilleri & Boeckxstaens, 2017; Khalif et al., 2009). Commercially available antispasmodics in the United States include hyoscine/hyoscyamine, dicyclomine, and peppermint oil (Lacy et al., 2021; Lembo et al., 2022). Although the AGA guideline supports antispasmodic use for the treatment of IBS (Lembo et al., 2022), the ACG guideline recommends against antispasmodics (overall class) due to limited, low-quality trial efficacy data (Lacy et al., 2021). However, because it specifically relates to peppermint oil, both the ACG guideline and the AGA guideline suggest its use to treat global IBS symptoms (low quality/certainty of evidence). Peppermint oil is an over-the-counter dietary supplement that blocks calcium channels in smooth muscles, resulting in an antispasmodic effect (Alammar et al., 2019; Hawthorn et al., 1988); additionally, peppermint oil has antimicrobial properties (Chumpitazi et al.). A 2022 meta-analysis concluded that peppermint oil was more efficacious than placebo for global IBS symptoms (7 studies; relative risk [RR] for symptom persistence is 0.6; 95% confidence interval [CI], 0.4–1.0; p = .04; Ingrosso et al., 2022).

Bile acid sequestrants have been considered for patients with IBS-D and bile acid malabsorption (Camilleri et al., 2015; Fernández-Bañares et al., 2015; Vijayvargiya et al., 2020). However, the ACG guideline does not recommend their use due to the lack of randomized controlled trials in IBS-D (Lacy et al., 2021). Although they may help with diarrheal symptoms (e.g., stool form/frequency) in some patients, controlled trial data are lacking to support bile acid sequestrants for global IBS-D symptoms (e.g., pain, distention, bloating; Lacy et al., 2021).

Loperamide

Loperamide is an over-the-counter antidiarrheal agent that acts by reducing peristalsis, inhibiting secretion of water and electrolytes into the intestines, and prolonging intestinal transit time (Hughes et al., 1984; Lembo et al., 2022). Although the ACG guideline recommends against its use as a first-line treatment for IBS (Lacy et al., 2021), the AGA guideline recommends loperamide for the treatment of IBS-D based on older studies that showed improvement in diarrheal symptoms (Hovdenak, 1987; Lavö et al., 1987; Lembo et al., 2022). According to the AGA guideline, the optimal dose of loperamide and the frequency of administration (e.g., daily or as needed) has not been established and may vary among patients (Lembo et al., 2022). Although loperamide may improve diarrhea, it does not target global IBS-D symptoms, including abdominal pain (Lacy et al., 2021).

FDA-approved pharmacotherapies for IBS with diarrhea

Rifaximin is a nonsystemic antibiotic indicated for the treatment of adults with IBS-D. Negligible intestinal absorption (ie, gut targeted) allows rifaximin to reach high intraluminal concentrations in the GI tract while minimizing systemic exposure, thereby modulating gut microbiome dysbiosis, a potential factor in the pathophysiology of IBS-D (Lacy et al., 2021). Rifaximin is prescribed as a short course of therapy (550 mg 3 times daily for 14 days), with up to two additional 14-day courses indicated, as needed, for symptom recurrence (Table 2).

In two, phase 3, randomized trials in patients with IBS-D, after a 2-week course of therapy, a significantly greater percentage of patients achieved adequate global IBS symptom relief with rifaximin versus placebo (40.7% vs. 31.7% [pooled data]; p < .001) for at least two of the first 4 weeks posttreatment (Pimentel et al., 2011). Improvements were superior to placebo through 10 weeks after treatment completion (p = .001). The most frequently reported AEs (≥5.0% of patients) with rifaximin versus placebo were headache (6.1% vs. 6.6%), upper respiratory tract infection (5.6% vs. 6.2%), and abdominal pain (4.6% vs. 5.5%). There were no cases of Clostridioides difficile–associated diarrhea or ischemic colitis (Pimentel et al., 2011).

A third phase 3 trial evaluated rifaximin repeat treatment in adults with IBS-D and included a rifaximin open-label phase followed by a randomized, double-blind, placebo-controlled phase for open-label responders (≥30% reduction from baseline in abdominal pain and ≥50% decrease in loose stool frequency for ≥2 of the first 4 weeks posttreatment) who experienced symptom recurrence (Lembo, Pimentel et al., 2016). Overall, 1,074 of 2,438 patients (44.1%) responded to open-label rifaximin (Lembo, Pimentel et al., 2016). During the randomized, double-blind phase, a significantly larger percentage of patients were responders to repeat rifaximin treatment compared with placebo (38.1% vs. 31.5%; p = .03; Lembo, Pimentel et al., 2016). One patient in the rifaximin repeat-treatment group developed a C. difficile colitis infection 37 days after treatment, which emerged immediately following completion of a 10-day course of cefdinir for a urinary tract infection (Lembo, Pimentel et al., 2016). Both the ACG and AGA recommend rifaximin for patients with IBS-D (Lacy et al., 2021; Lembo et al., 2022).

Eluxadoline is a peripherally acting mu- and kappa-opioid receptor agonist and delta-opioid receptor antagonist indicated in adults for the treatment of IBS-D. The daily recommended dose is 100 mg twice daily, taken with food (Table 3). A reduced dosage of 75 mg twice daily is advised for those who are unable to tolerate the higher dose, are receiving a concomitant OATP1B1 inhibitor, have mild/moderate hepatic or moderate/severe renal impairment, or have end-stage renal disease without concurrent dialysis. Eluxadoline is contraindicated in patients with biliary duct obstruction; sphincter of Oddi dysfunction; alcohol use greater than three drinks per day; severe hepatic impairment; or a history of pancreatitis, cholecystectomy, chronic or severe constipation, or active GI obstruction. There is also a risk for eluxadoline-associated pancreatitis, most frequently in those without a gallbladder (Coté, 2018).

In two, phase 3, randomized trials in patients with IBS-D, after 26 weeks of treatment, a significantly greater percentage of patients achieved a greater than 30% reduction from baseline in abdominal pain and BSFS score less than 5 on the same day for greater than or equal to 50% of days with eluxadoline 75 mg twice daily (n = 806 [pooled]; 26.7% vs. 19.5%; p < .001) and 100 mg twice daily (n = 809 [pooled]; 31.0% vs. 19.5%; p < .001) compared with placebo (n = 808; Lembo, Lacy et al., 2016). The most frequently reported adverse events (AEs; ≥5.0% of patients) with eluxadoline (dose groups combined) versus placebo were constipation (8.0% vs. 2.5%), nausea (7.7% vs. 5.1%), and abdominal pain (6.5% vs. 4.1%; Lembo, Lacy et al., 2016). Both ACG and AGA guidelines recommend eluxadoline use in patients with IBS-D (Lacy et al., 2021; Lembo et al., 2022).

Alosetron is a selective serotonin 5-HT₃ receptor antagonist indicated for women with severe IBS-D with chronic (≥6 months) IBS symptoms and an inadequate response to conventional therapy. Treatment should be discontinued in patients with inadequate control of IBS symptoms after 4 weeks of 1 mg twice daily dosing. An analysis of 11 randomized controlled trials of alosetron showed superior efficacy compared with placebo for improving global IBS symptoms (RR, 1.6; 95% CI, 1.4–1.8) and abdominal pain/discomfort (RR, 1.2; 95% CI, 1.2–1.3]) (Zheng et al., 2017). Both ACG and AGA guidelines recommend the use of alosetron in women with severe IBS-D who have shown inadequate response to traditional therapy (Lacy et al., 2021; Lembo et al., 2022). Note that alosetron has a boxed warning for infrequent but serious GI adverse reactions, including ischemic colitis and serious constipation-related complications.

Gut–brain neuromodulators

Tricyclic antidepressants are hypothesized to target visceral pain through action at norepinephrine and dopamine receptors and impact diarrheal symptoms by slowing GI transit through anticholinergic effects (Drossman et al., 2018). Selection of a specific TCA is typically based on the symptoms presented by patients; for example, nortriptyline and amitriptyline have been recommended for IBS-D (Chang, 2021; Drossman et al., 2018). Initiating TCAs at a low dose at bedtime is advised because of potential adverse effects (e.g., dry mouth, orthostatic hypotension, sedation), with gradual dose escalation based on tolerability (Chang, 2021; Drossman et al., 2018; Lacy et al., 2021; Lembo et al., 2022). The impact of TCAs on IBS symptoms appears to be independent of their antidepressant action and might require several weeks to become apparent (Lembo et al., 2022). Both ACG and AGA guidelines recommend the use of TCAs in patients with IBS (Table 3) (Lacy et al., 2021; Lembo et al., 2022).

Duloxetine, a serotonin and norepinephrine reuptake inhibitor, may be considered for abdominal pain modulation for those who cannot tolerate TCAs; however, the certainty of evidence for this class of medication is low (Khasawneh et al., 2025), and its use is based on evidence from other chronic pain conditions (e.g., fibromyalgia and migraines). Similarly, the noradrenergic and specific serotonergic antidepressant mirtazapine may be considered in difficult-to-treat patients with IBS-D who have abdominal pain, anxiety, and/or depression or sleep difficulties (Chang, 2021) based on results of a single 8-week randomized, double-blind, placebo-controlled trial in 67 patients with IBS-D (Khalilian et al., 2021).

Nonpharmacologic neuromodulation

Noninvasive neuromodulation techniques, including acupuncture, are emerging as a nonpharmacological approach for managing visceral pain in GI disorders such as IBS (Alam & Chen, 2023). Meta-analyses of randomized controlled trials support the effectiveness of acupuncture for improving symptoms and QOL in patients with IBS, although studies were mostly conducted in China, varied considerably in methodology, and outcome measures were ill-defined (Fang et al., 2025; Wang, Zhao, et al., 2024). Additionally, a meta-analysis of 16 randomized controlled trials (N = 1,309) in patients with IBS-D and comorbid anxiety and/or depression found that, compared with oral medication (consisting of Chinese herbal medicine, antidiarrheal medication, or antispasmodic medication), acupuncture/acupuncture plus Chinese herbal medicine improved IBS overall symptom severity (mean difference, 37.5; 95% CI, 12.2–62.8], p = .004) and reduced anxiety and depression symptoms (Wang, Hou, et al., 2024). A randomized, sham-controlled trial in China is ongoing and will evaluate acupuncture in patients with IBS-D using FDA-recommended clinical efficacy endpoints (Fu et al., 2025).

Gut–brain behavioral therapies

Gut–brain behavioral therapies target environmental and psychological factors that may contribute to IBS symptoms, such as mood and anxiety disorders and cognitive–affective processes (Table 3; Van Oudenhove et al., 2016). Cognitive–behavioral therapy and GI-directed hypnotherapy are the most commonly studied modalities and have demonstrated improvements in global IBS symptoms and/or abdominal pain in randomized controlled trials (Black et al., 2020; Everitt et al., 2019; Lackner et al., 2018; Peters et al., 2016; Van Oudenhove et al., 2016). Cognitive-behavioral therapy for IBS involves self-monitoring triggers, somatic sensations, and emotions that typically accompany symptom flares, as well as cognitive strategies to modify maladaptive thought patterns that bias information processing and relaxation techniques (Van Oudenhove et al., 2016). With GI-directed hypnotherapy for IBS, patients receive suggestions for control and normalization of gut function while in a state of deep relaxation (Häuser, 2024; Van Oudenhove et al., 2016).

The ACG guideline recommends incorporation of gut–brain behavioral modalities in conjunction with other evidence-based IBS therapies for the treatment of global IBS symptoms in patients who show cognitive–affective drivers of symptoms (Lacy et al., 2021). The Rome Foundation offers a searchable directory of HCPs providing GI-focused psychotherapy services (https://romegipsych.org/). Because potential barriers (e.g., provider availability and insurance coverage) may limit patient access to gut–brain behavioral therapy, app- and VR-based GI-directed therapies represent a new approach aimed at increasing availability. Zemedy is a mobile app that includes two modules of psychoeducation on IBS etiology and CBT effectiveness, and eight modules focused on CBT strategies for adults with IBS (Hunt et al., 2021). Nerva is a 6-week, app-based, GI-directed hypnotherapy program (subscription required; Simicich et al., 2024). In addition, VR-based CBT is being evaluated for IBS (Spiegel et al., 2022; Suchak et al., 2024).

Conclusions

Effective management of IBS-D requires communicating a confident, positive diagnosis and providing patient education and a personalized treatment plan within a supportive patient–provider relationship. Several evidence-based treatments for IBS-D are available. Treatment selection should consider symptom presentation, including those symptoms considered most bothersome by the patient. Certain treatments (e.g., low FODMAP diet, gut–brain behavioral therapies) warrant a referral to a qualified specialty provider. Other therapeutic approaches may potentially complement existing strategies (e.g., AI-assisted personalized diet, acupuncture) or facilitate access to gut–brain behavioral therapies (e.g., app-based CBT). Both NPs and PAs are well positioned to provide holistic, compassionate, and competent care to patients with IBS-D, related to their advanced training, accessibility (e.g., longer appointment times), and strong emphasis on communication, evidence-based care, continuity of care, and shared decision making.

Authors' Contributions

A.M. Ladewski, K.D. Orleck, and K.F. Skarbinski were involved with developing the manuscript concept, had access to all data presented, and were involved with drafting, critically revising the manuscript, and preparing and approving the manuscript for final submission. A.M. Ladewski, K.D. Orleck, and K.F. Skarbinski contributed equally.

Funding

Development of this manuscript was supported by Salix Pharmaceuticals. The authors did not receive any financial compensation for manuscript development.

Competing Interests

A.M. Ladewski reports being a presenter and advisor for Ardelyx, and an advisor for Salix Pharmaceuticals and Phathom. K.D. Orleck reports being on speakers' bureaus and being an advisory board participant for AbbVie, Ardelyx, and Salix Pharmaceuticals. K.F. Skarbinski reports being a presenter for Ironwood and an advisory board participant for Ardelyx and Salix Pharmaceuticals.