Feature

Diarrhea-Predominant Irritable Bowel Syndrome: Diagnosis and Therapeutic Options

Volume 58 - Issue 4 - April 2018

Author:
Leonard B. Weinstock, MD

Citation:

Weinstock LB. Diarrhea-predominant irritable bowel syndrome: diagnosis and therapeutic options. Consultant. 2018;58(4):140-147.

 

Irritable bowel syndrome (IBS) is a gastrointestinal (GI) tract disorder characterized by abdominal pain associated with altered bowel habits (ie, frequency, appearance) that occur at least once weekly on average for 3 months or more.1 Based on patient identification of stool form, IBS can be further characterized by subtype (Figure 1)1-3; however, patients may alternate between IBS subtypes during their lifetime.1,4 Diarrhea-predominant IBS (IBS-D), which is the most common IBS subtype, is reported in 40% of patients with IBS, followed by constipation-predominant IBS (IBS-C; 35%) and mixed or alternating IBS (IBS-M; 23%).5 IBS-D is characterized by abnormal bowel movements, which are predominantly diarrhea (> 25% of bowel movements mushy or watery and < 25% hard lumps or sausage-shaped but lumpy).1,6

IBS

Figure 1: 
a Constipation-predominant IBS (IBS-C), in which abnormal bowel movements (BMs) are mostly constipation, or > 25% of BMs with Bristol Stool Scale (BSS) types 1 or 2 and < 25% with BSS types 6 or 7.
b Mixed or alternating IBS (IBS-M), in which abnormal BMs usually alternate between diarrhea and constipation, or > 25% of BMs with BSS types 1 or 2 and > 25% with BSS types 6 or 7.
c Unclassified IBS (IBS-U), in which patients have a diagnosis of IBS, but bowel habits cannot be categorized using the criteria for IBS-D, IBS-C, or IBS-M.
d Diarrhea-predominant IBS (IBS-D), in which abnormal BMs are mostly diarrhea, or > 25% of BMs with BSS types 6 or 7 and < 25% with BSS types 1 or 2.
Figure adapted with permission from Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology. 2016;150(6):1393-1407.e5.1 ©2016 Elsevier, with stool images adapted from the National Institute of Diabetes and Digestive and Kidney Diseases website,2 based on the Bristol Stool Scale created by K W Heaton at the University of Bristol, Bristol, UK.3
Postinfectious IBS (PI-IBS) is a consequence of GI tract exposure to bacterial, viral, or parasitic pathogens.7 The majority of travelers’ diarrhea is caused by bacteria, and the clinical significance of this will be elucidated in this article. One study found that travelers’ diarrhea significantly increased the odds of developing IBS within 6 months after completing travel to a developing country (odds ratio, 3.6; 95% CI, 1.7-7.5).8 Furthermore, in another study, patients were 4 times more likely to develop IBS 90 days or more after a diagnosis of giardiasis compared with individuals without giardiasis.9
While not considered life-threatening, IBS is a chronic condition that negatively affects the daily life, employment, and personal relationships of those affected.10-13 In one longitudinal study of a general population sampling that had baseline and 10-year data, 214 (5.5%) of 3873 individuals had IBS at baseline; of these 214 patients, 67.3% reported IBS symptoms after 10 years.14 In light of the long-term impact of IBS, this article will review the epidemiology, pathophysiology, and diagnosis of IBS and highlight the therapeutic options available for the treatment of patients with IBS-D.

 

THE BURDEN OF IBS

The overall global prevalence of IBS in adults is reportedly 11.2%,5 suggesting that approximately 36 million individuals in the United States may be affected. Overall, IBS is more prevalent in women than in men (64% vs 36%, respectively), and although the reasons are currently unclear, at least 1 factor may be a greater willingness to seek medical care among women; although IBS can occur at any age, those affected are typically less than age 50.5,15,16

In the United States, the economic burden of IBS is substantial. The total direct and indirect costs of IBS have been estimated to total $30 billion annually17 and are estimated to be greater than those of other common chronic illnesses, including congestive heart failure, asthma, and migraine.18 Direct costs attributed to IBS have been reported to range from $2269 to $12,007 (2012 US dollars) per patient each year.19 Factors that contribute to the economic burden of IBS include outpatient care (eg, primary care visits, medication costs) and the negative impact on patient employment status.10,19 In one study, at least half of 1966 patients surveyed reported limiting employment and academic and social activities because of IBS11; in one retrospective analysis that included 18 studies, days of work missed related to IBS ranged between 8.5 and 21.6 annually.10

Because of IBS symptoms, patients with IBS may alter their lifestyle by limiting social activity (62%) and by remaining homebound (54%).11 Also, in a study of patients with IBS (N = 175), most (91%) reported either comorbid physical (eg, allergy, gastroesophageal reflux) or psychological disorders (eg, anxiety, depression),20 which were associated with decreased health-related quality of life and increased GI symptom severity.20,21 Compared with patients with IBS-C, patients with IBS-D have reported significantly lower quality of life (P = .01).22 In addition, patients with IBS may perceive themselves as stigmatized because of their condition by family, friends, and health care providers.23,24 In 1 study, patients with IBS expressed beliefs that others considered IBS to be more of a mental condition than a physical condition, that others did not understand when plans had to be changed, and that others did not take them seriously, which negatively affected their perception(s) of how others responded to them and IBS.24 Thus, it is apparent that IBS is associated with a substantial socioeconomic burden and negatively impacts patient quality of life.

 

NEXT: Pathophysiology and Diagnosis of IBS

PATHOPHYSIOLOGY AND DIAGNOSIS OF IBS

The pathophysiology of IBS remains an area of investigation, is considered multifactorial, and may include visceral hypersensitivity, fecal microbiota dysbiosis, increased GI tract permeability, altered immune responses, altered GI tract motility, small intestinal bacterial overgrowth (SIBO), altered gut-brain axis interactions, and food sensitivity.25-29 During the past 2 decades, the potential role of SIBO in IBS has been a subject of ongoing research.30 Negative consequences are associated with higher concentrations of bacteria in areas of the intestine that normally harbor few bacteria. These include the effects of fermentation of food by bacteria, with subsequent gas, diarrhea, and inflammation, resulting in increased permeability of the epithelium and activation of mucosal immune response.30-32 Furthermore, compared with healthy individuals, persons with IBS exhibit differences in the quantity and composition of gut microbiota in the large intestine.33,34

IBS is underdiagnosed—one general-population survey-based study (N = 1924) reported that 43.1% of adults who met the diagnostic criteria had not received a formal diagnosis of IBS.13 Diagnosis is based on symptoms and an absence of alarm features (Figure 2).1,18,25,35,36 Abdominal symptoms (eg, pain, discomfort, bloating) rather than a change in bowel habits (eg, frequency, consistency) tend to lead patients to seek health care.37 Importantly, abdominal pain is a key symptom required for a diagnosis of IBS.1 While most patients may experience bloating, abdominal distension, or both, neither of these symptoms is required to establish a diagnosis of IBS.1

IBS

Figure 2: Abbreviations: BMs, bowel movements; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; OTC, over-the-counter; Rx, prescription; TCAs, tricyclic antidepressants.

 

A biomarker test has become available that has the potential to aid in the diagnosis of IBS. Some patients with IBS-D have been shown to have increased concentrations of antibodies against bacterial cytolethal distending toxin B (CdtB) and human vinculin compared with healthy individuals (CdtB: 43.3% vs 9.3%, respectively; P < .001; vinculin: 32.4% vs 6.9%; P = .002).38,39 While the use of these antibodies as diagnostic biomarkers of IBS may have some utility, additional studies are needed to validate these findings.39 Data from PI-IBS models have suggested that autoimmune antibodies play a role in IBS and, particularly, in SIBO. In a Campylobacter jejuni infection rat model in which animals develop an IBS-like phenotype, bacterial CdtB toxins are produced, CdtB antibody development occurs, and molecular mimicry leads to vinculin antibody formation in the host.40 Anti-vinculin antibodies reduce vinculin availability and negatively impact the number of interstitial cells of Cajal, which are considered intestinal pacemakers and modulate intestinal motility.41 Negatively impacting the cleansing motility wave of the small intestine results in insufficient bacterial clearance and increased potential for SIBO.41

Other symptoms, while not considered in the diagnosis of IBS, also are common in patients with IBS. Extraintestinal symptoms are reported more frequently by patients with IBS than by patients with GI symptoms unrelated to IBS and include fatigue (69.3% vs 41.3%, respectively; P < .001), sleep disruption (47.5% vs 30.8%; P < .001), and back pain (37.3% vs 21.9%; P < .001).42 Nausea, fibromyalgia, chronic pelvic pain syndromes, and restless legs syndrome are also found as comorbid conditions in patients with IBS; some of these conditions also are associated with SIBO.43-46 In addition, patients with IBS indicated that pain, bowel problems, bloating, and dietary limitations contributed most to their disease severity, with most patients (90.4%) experiencing 2 or more of these factors.11

Also, the severity of IBS symptoms has been associated with misclassification as other diseases (eg, colorectal cancer, inflammatory bowel disease, celiac disease, thyroid dysfunction); the risk of misclassification, although low, has been found to be significantly greater in patients with moderate to severe IBS compared with mild IBS (hazard ratio, 2.6; 95% CI, 1.1-6.5; P = .03).47 A consultation with a gastroenterologist should be considered if the accuracy of a diagnosis of IBS is in question, particularly if the condition is refractory to treatment; however, after establishing a formal diagnosis of IBS, further management can often be provided in the primary care setting.35

 

NEXT: IBS-D treatments

IBS-D TREATMENTS

One goal of IBS-D treatment is to provide adequate symptom relief, which can start with dietary and lifestyle modifications and over-the-counter therapies such as loperamide and probiotics.25,36 If symptoms worsen during probiotic administration, then comorbid SIBO should be considered. Most often, prescription therapies are necessary and may be administered continually, intermittently, or as needed (Table).4,25,36,48-66 To date, only 3 pharmacologic agents have received regulatory approval for the treatment of patients with IBS-D in the United States: alosetron, eluxadoline, and rifaximin. Overall, pharmacologic therapies used concurrently with diet and lifestyle modification and psychologic interventions (eg, cognitive-therapy, relaxation training or therapy, hypnotherapy) may benefit patients with IBS-D.25 When considering a treatment plan for patients with IBS-D, it is important to evaluate potential benefit vs risk, and data on the number needed to harm can provide guidance to health care providers (Table).50

IBS

IBS

 

Continuous treatment. Treatments administered continuously (eg, daily) in patients with IBS-D include eluxadoline, serotonergic agents (eg, alosetron), antidepressants, and psychologic interventions.4,36,48-54 Eluxadoline, an orally administered μ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist indicated for the treatment of adults with IBS-D, is believed to slow GI tract motility and improve abdominal pain.48,67,68 In 2 double-blind studies, a significantly greater percentage of patients with IBS-D randomly assigned to receive eluxadoline 75 mg or 100 mg twice daily achieved a 30% or greater decrease from mean baseline score for their worst abdominal pain concurrent with a stool consistency score less than 5 (ie, on a 7-point scale; primary efficacy endpoint) for 50% or more of days assessed vs placebo during weeks 1 to 12 (26.2% and 27.0% vs 16.7%, respectively; P < .001 for both vs placebo) and during weeks 1 to 26 (26.7% and 31.0% vs 19.5%; P < .001 for both vs placebo).67 The most common adverse events (AEs) reported with eluxadoline (≤ 26 weeks in 1 study, ≤ 52 weeks in 1 study) included constipation (8.0%), nausea (7.7%), abdominal pain (6.5%), upper respiratory tract infection (4.4%), and vomiting (4.1%).67 Postmarketing safety data showed that eluxadoline was associated with an increased risk of pancreatitis, with some occurrences associated with severe outcomes in some patients who had cholecystectomy.61 Thus, this surgical history, along with a history of sphincter of Oddi dysfunction, pancreatitis, and alcohol use (> 3 beverages per day) are contraindications for eluxadoline use.61

Serotonin type 3 (5-HT3) receptors expressed in the GI tract are targeted by the selective 5-HT3 receptor antagonists alosetron and ondansetron.49,51,69 Alosetron is indicated for the treatment of women with severe IBS-D with symptoms lasting 6 months or longer that have not responded to conventional therapy.49 However, alosetron is associated with the risk of developing ischemic colitis and serious complications of constipation. In addition, health care providers must complete special training to prescribe alosetron.49

As noted, comorbid neuropsychiatric conditions such as depressive and anxiety disorders are frequently observed in patients with IBS.70 A meta-analysis indicated that treatment with antidepressants (ie, tricyclic antidepressants [TCAs] and selective serotonin-reuptake inhibitors) resulted in a higher percentage of patients (56.1% of 592 patients) experiencing symptom improvement vs placebo (35.0% of 508 patients), including abdominal pain (52.2% of 182 patients vs 27.2% of 169 patients, respectively).53 However, a greater percentage of AEs occurred with antidepressants vs placebo (31.3% vs 16.5%, respectively; relative risk of any AE, 1.6; 95% CI, 1.2-2.2), with drowsiness and dry mouth more common with TCAs than with placebo.53 In some patients with IBS, psychologic interventions (eg, cognitive-behavioral therapy, relaxation training or therapy, hypnotherapy), which are typically administered in multiple sessions over variable time periods, improved GI symptoms (eg, pain, diarrhea), with demonstrated short-term and long-term efficacy (ie, from 1 month after treatment up to 1 year after treatment).53,71

 

NEXT: Short-course treatment 

Short-course treatment. Rifaximin 550 mg is an oral nonsystemic antibiotic indicated for the treatment of adults with IBS-D and is administered 3 times daily for 2 weeks.55 US prescribing information indicates that patients who experience symptom recurrence may receive up to 2 additional 2-week courses to help manage symptoms.55 However, retrospective studies have shown that at least 7 courses of rifaximin have been successful in managing IBS symptoms.72,73 Although the mechanism of action is unclear, rifaximin is believed to improve symptoms of IBS through its modulation of the gut microbiota and host interactions, including treating SIBO via antimicrobial activity, inhibiting bacterial translocation, and altering inflammatory responses.74,75

The efficacy of rifaximin in patients with IBS-D was demonstrated in 2 identically designed, randomized, double-blind, placebo-controlled studies of rifaximin 550 mg administered 3 times daily or placebo for 2 weeks (pooled, N = 1260).76 A significantly greater percentage of patients who received rifaximin achieved adequate relief of global IBS symptoms for at least 2 of the first 4 weeks after treatment vs placebo (40.7% vs 31.7%, respectively; P < .001).76 The efficacy and safety of repeat treatment with 2-week courses of rifaximin were confirmed in a phase 3 study (up to 2 repeat treatment courses)58 and 2 retrospective studies (up to 7 repeat treatment courses).72,73 A pooled analysis of the data from the safety populations of 1 phase 2b and 2 phase 3 clinical studies of rifaximin (N = 1932) confirmed that the overall safety profile of rifaximin was generally comparable with that of placebo.60 For patients who received rifaximin, the most commonly reported AEs included headache, upper respiratory tract infection, and nausea. Furthermore, for rifaximin vs placebo, the incidence of serious AEs (1.5% vs 2.2%, respectively) and AEs that led to study discontinuation (2.0% vs 1.7%, respectively) were comparable.60

Administration of antibiotics is considered a risk factor for the development of Clostridium difficile infection.77 However, several clinical studies have demonstrated that the development of C difficile infection after the administration of nonsystemic rifaximin is rare, and the 1 reported case in clinical trials was associated with systemic antibiotic use.58,60 After only 10 days of treatment with systemic antibiotics, the gut microbiota can be altered for up to 1 year78,79; however, both the single and the repeat 2-week courses of nonsystemic rifaximin had minimal effects on the gut microbiota of patients with IBS-D.59 Repeat treatment with rifaximin (ie, 2 repeat treatments) did not have a clinically meaningful impact on the long-term resistance of stool or skin bacteria to either rifampin or non-rifamycin antibiotics in patients with IBS-D.80,81

In addition, antispasmodic agents, which are believed to improve abdominal pain in patients with IBS by relaxing the smooth muscle of the GI tract,25 have received a weak recommendation by the American College of Gastroenterology (ACG) for short-term symptomatic relief.4 In clinical studies, a significantly greater percentage of patients with IBS reported AEs with antispasmodic agents compared with placebo (16.3% vs 10.4%, respectively; relative risk, 1.6; 95% CI, 1.1-2.4).4 The most common AEs reported with antispasmodics included dry mouth, dizziness, and blurred vision.4 The antispasmodic peppermint oil is available as an over-the-counter medical food or by prescription only, depending on the formulation.4,25 A pooled analysis of 5 randomized, controlled trials of 482 patients with IBS reported that peppermint oil had greater efficacy than placebo, and its safety profile was generally comparable with that of placebo.4 Furthermore, a formulation of peppermint oil encased in triple-coated microsphere capsules was shown to be efficacious and generally well tolerated for patients with IBS-D or IBS-M.62

Finally, loperamide is an over-the-counter, on-demand therapy that is often considered first by patients to help manage IBS-D symptoms.36 However, because of insufficient evidence, loperamide is not recommended by the ACG for relief of global IBS symptoms.4

Medical and functional foods. Beyond simple nutrition, medical foods and functional foods may provide patients with IBS-D health benefits.82 Serum-derived bovine immunoglobulin (SBI) is a prescription medical food indicated for the dietary management of chronic loose or frequent stools, including for patients with IBS-D.63 The mechanism of action by which SBI is believed to improve intestinal permeability and inflammation is by binding microbial components or endotoxins with the potential to beneficially alter the composition or activity of the gut microbiota, decrease the permeability of the GI tract, and restore GI barrier function.57,83 Results of a randomized, double-blind, placebo-controlled study of patients with IBS-D (N = 51) who received SBI 5 g/day, SBI 10 g/day, or placebo for 6 weeks, indicated that SBI treatment improved symptom severity scores for loose stools, hard stools, flatulence, nausea, urgency, straining, and incomplete evacuation from week 2 through week 6; however, differences in symptom severity scores did not differ between SBI and placebo.57 SBI had a safety profile generally comparable with that of placebo.57

Probiotics and synbiotics are functional foods that improve symptoms in patients with IBS.4,84 A systematic review and meta-analysis that included 35 randomized, controlled IBS studies (N = 3452) reported that probiotics (single or multiple strains) were more efficacious than placebo for improving global IBS symptoms, abdominal pain, bloating, and flatulence; however, AEs were more likely to occur with probiotics vs placebo.56 The ACG has provided a weak recommendation for the administration of probiotics for IBS, citing inconsistencies across studies in formulation and dosing, and in the bacterial species and strains used.4 A systematic review and meta-analysis that examined the efficacy and safety of synbiotics reported no significant effect on the improvement of IBS symptoms; however, the 2 studies (N = 198) included in the analysis showed positive efficacy and safety findings.56 Furthermore, synbiotics and probiotics have not been studied in a head-to-head randomized, controlled study.85 The ACG lacked sufficient evidence to recommend synbiotics for patients with IBS.4 A systematic review and meta-analysis found no studies that examined the efficacy and safety of prebiotics in patients with IBS56; thus, the ACG lacked evidence for a recommendation of prebiotics for patients with IBS.4

 

NEXT: Conclusions and References

CONCLUSIONS

IBS-D is a common, chronic condition that is underdiagnosed, and its pathophysiology is not always well defined. IBS is a substantial burden on patients and negatively impacts activities of daily living and quality of life. The diagnosis of IBS is symptom based and includes the key symptom of abdominal pain. Management of IBS-D includes diet and lifestyle modifications in combination with pharmacologic agents that may need to be administered continuously (eg, eluxadoline, antidepressants), intermittently (eg, rifaximin), or on demand (eg, antispasmodics). The benefit to risk profile associated with some treatment modalities (eg, eluxadoline, alosetron) should be carefully considered when evaluating therapeutic options for patients with IBS-D. Repeat treatment with the nonsystemic antibiotic rifaximin has been shown to be safe and efficacious in patients with IBS-D, as has treatment with medical and functional foods (eg, SBI, probiotics). Thus, health care providers have a number of options when considering the treatment of patients with IBS-D. Of key importance, health care providers who can effectively communicate and project empathy to patients with IBS have the potential to more positively affect outcomes.86

 

Leonard B. Weinstock, MD, is an associate professor of clinical medicine at Washington University School of Medicine and president at Specialists in Gastroenterology in St Louis, Missouri.

 

DISCLOSURES:

Dr Weinstock reports being on the speakers bureaus for Actavis, Romark Laboratories LC, and Salix Pharmaceuticals. Technical editorial and medical writing assistance for this article was provided under the direction of Dr Weinstock by Mary Beth Moncrief, PhD, and Sophie Bolick, PhD, at Synchrony Medical Communications in West Chester, Pennsylvania. Funding for this support was provided by Salix Pharmaceuticals, Bridgewater, New Jersey.

 

REFERENCES:

  1. Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology. 2016;​150(6):1393-1407.e5.
  2. NIDDK Image Library. National Institute of Diabetes and Digestive and Kidney Diseases website. https://catalog.niddk.nih.gov/Catalog/imagelibrary/detail.cfm?id=1427. Accessed March 28, 2018.
  3. Heaton KW, Ghosh S, Braddon FE. How bad are the symptoms and bowel dysfunction of patients with the irritable bowel syndrome? A prospective, controlled study with emphasis on stool form. Gut. 1991;32(1):73-79.
  4. Ford AC, Moayyedi P, Lacy BE, et al; Task Force on the Management of Functional Bowel Disorders. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(suppl 1):S2-S26.
  5. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012;10(7):712-721.
  6. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32(9):920-924.
  7. Grover M, Camilleri M, Smith K, Linden DR, Farrugia G. On the fiftieth anniversary. Postinfectious irritable bowel syndrome: mechanisms related to pathogens. Neurogastroenterol Motil. 2014;26(2):156-167.
  8. Pitzurra R, Fried M, Rogler G, et al. Irritable bowel syndrome among a cohort of European travelers to resource-limited destinations. J Travel Med. 2011;18(4):250-256.
  9. Nakao JH, Collier SA, Gargano JW. Giardiasis and subsequent irritable bowel syndrome: a longitudinal cohort study using health insurance data. J Infect Dis. 2017;215(5):798-805.
  10. Maxion-Bergemann S, Thielecke F, Abel F, Bergemann R. Costs of irritable bowel syndrome in the UK and US. Pharmacoeconomics. 2006;24(1):21-37.
  11. Drossman DA, Morris CB, Schneck S, et al. International survey of patients with IBS: symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit. J Clin Gastroenterol. 2009;43(6):541-550.
  12. Buono JL, Carson RT, Flores NM. Health-related quality of life, work productivity, and indirect costs among patients with irritable bowel syndrome with diarrhea. Health Qual Life Outcomes. 2017;15(1):35.
  13. Sayuk GS, Wolf R, Chang L. Comparison of symptoms, healthcare utilization, and treatment in diagnosed and undiagnosed individuals with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol. 2017;112(6):892-899.
  14. Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P. Irritable bowel syndrome: a 10-yr natural history of symptoms and factors that influence consultation behavior. Am J Gastroenterol. 2008;103(5):1229-1239.
  15. Hungin APS, Chang L, Locke GR, Dennis EH, Barghout V. Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact. Aliment Pharmacol Ther. 2005;21(11):1365-1375.
  16. Saito YA, Schoenfeld P, Locke GR III. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002;​97(8):1910-1915.
  17. Martin BC, Ganguly R, Pannicker S, Frech F, Barghout V. Utilization patterns and net direct medical cost to Medicaid of irritable bowel syndrome. Curr Med Res Opin. 2003;19(8):771-780.
  18. Cash B, Sullivan S, Barghout V. Total costs of IBS: employer and managed care perspective. Am J Manag Care. 2005;11(1 suppl):S7-S16.
  19. Nellesen D, Yee K, Chawla A, Lewis BE, Carson RT. A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation. J Manag Care Pharm. 2013;19(9):755-764.
  20. Lackner JM, Ma CX, Keefer L, et al. Type, rather than number, of mental and physical comorbidities increases the severity of symptoms in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2013;11(9):1147-1157.
  21. Vu J, Kushnir V, Cassell B, Gyawali CP, Sayuk GS. The impact of psychiatric and extraintestinal comorbidity on quality of life and bowel symptom burden in functional GI disorders. Neurogastroenterol Motil. 2014;26(9):1323-1332.
  22. Singh P, Staller K, Barshop K, et al. Patients with irritable bowel syndrome-diarrhea have lower disease-specific quality of life than irritable bowel syndrome-constipation. World J Gastroenterol. 2015;21(26):8103-8109.
  23. Taft TH, Bedell A, Naftaly J, Keefer L. Stigmatization toward irritable bowel syndrome and inflammatory bowel disease in an online cohort. Neurogastroenterol Motil. 2017;29(2). doi:10.1111/nmo.12921
  24. Taft TH, Riehl ME, Dowjotas KL, Keefer L. Moving beyond perceptions: internalized stigma in the irritable bowel syndrome. Neurogastroenterol Motil. 2014;26(7):1026-1035.
  25. Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: a clinical review. JAMA. 2015;313(9):949-958.
  26. Löwe B, Lohse A, Andresen V, Vettorazzi E, Rose M, Broicher W. The development of irritable bowel syndrome: a prospective community-based cohort study. Am J Gastroenterol. 2016;111(9):1320-1329.
  27. Pimentel M, Soffer EE, Chow EJ, Kong Y, Lin HC. Lower frequency of MMC is found in IBS subjects with abnormal lactulose breath test, suggesting bacterial overgrowth. Dig Dis Sci. 2002;47(12):2639-2643.
  28. Park SH, Videlock EJ, Shih W, Presson AP, Mayer EA, Chang L. Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity. Neurogastroenterol Motil. 2016;28(8):1252-1260.
  29. Böhn L, Störsrud S, Törnblom H, Bengtsson U, Simrén M. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am J Gastroenterol. 2013;108(5):634-641.
  30. Ghoshal UC, Srivastava D. Irritable bowel syndrome and small intestinal bacterial overgrowth: meaningful association or unnecessary hype. World J Gastroenterol. 2014;20(10):2482-2491.
  31. Dunlop SP, Hebden J, Campbell E, et al. Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes. Am J Gastroenterol. 2006;101(6):1288-1294.
  32. Martínez C, Lobo B, Pigrau M, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut. 2013;62(8):1160-1168.
  33. Carroll IM, Ringel-Kulka T, Siddle JP, Ringel Y. Alterations in composition and diversity of the intestinal microbiota in patients with diarrhea-predominant irritable bowel syndrome. Neurogastroenterol Motil. 2012;24(6):521-530.
  34. Rajilić-Stojanović M, Biagi E, Heilig HGHJ, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology. 2011;141(5):1792-1801.
  35. Enck P, Aziz Q, Barbara G, et al. Irritable bowel syndrome. Nat Rev Dis Primers. 2016;2:16014.
  36. Kuritzky L. Individualizing pharmacologic management of irritable bowel syndrome. J Fam Pract. 2015;64(suppl 12):S16-S21.
  37. Ringel Y, Williams RE, Kalilani L, Cook SF. Prevalence, characteristics, and impact of bloating symptoms in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2009;7(1):68-72.
  38. Pimentel M, Morales W, Rezaie A, et al. Development and validation of a biomarker for diarrhea-predominant irritable bowel syndrome in human subjects. PLoS One. 2015;10(5):e0126438.
  39. Rezaie A, Park SC, Morales W, et al. Assessment of anti-vinculin and anti-cytolethal distending toxin B antibodies in subtypes of irritable bowel syndrome. Dig Dis Sci. 2017;62(6):1480-1485.
  40. Pimentel M, Morales W, Pokkunuri V, et al. Autoimmunity links vinculin to the pathophysiology of chronic functional bowel changes following Campylobacter jejuni infection in a rat model. Dig Dis Sci. 2015;60(5):1195-1205.
  41. Jee S-R, Morales W, Low K, et al. ICC density predicts bacterial overgrowth in a rat model of post-infectious IBS. World J Gastroenterol. 2010;16(29):​3680-3686.
  42. Patel P, Bercik P, Morgan DG, et al. Irritable bowel syndrome is significantly associated with somatisation in 840 patients, which may drive bloating. Aliment Pharmacol Ther. 2015;41(5):449-458.
  43. Martínez-Martínez L-A, Mora T, Vargas A, Fuentes-Iniestra M, Martínez-Lavín M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-​control studies. J Clin Rheumatol. 2014;20(3):146-150.
  44. Weinstock LB, Geng B, Brandes SB. Chronic prostatitis and small intestinal bacterial overgrowth: effect of rifaximin. Can J Urol. 2011;18(4):5826-5830.
  45. Weinstock LB, Klutke CG, Lin HC. Small intestinal bacterial overgrowth in patients with interstitial cystitis and gastrointestinal symptoms. Dig Dis Sci. 2008;53(5):1246-1251.
  46. Anbardan SJ, Daryani NE, Fereshtehnejad S-M, Taba Taba Vakili S, Keramati MR, Ajdarkosh H. Gender role in irritable bowel syndrome: a comparison of irritable bowel syndrome module (ROME III) between male and female patients. J Neurogastroenterol Motil. 2012;18(1):70-77.
  47. Carter D. The severity of symptoms related to irritable bowel syndrome is a risk factor for the misclassification of significant organic disease. J Clin Gastroenterol. 2016;50(10):899.
  48. Viberzi [package insert]. Irvine, CA: Allergan USA Inc; 2017.
  49. Lotronex [package insert]. Roswell, GA: Sebela Pharmaceuticals Inc; 2016.
  50. Shah E, Kim S, Chong K, Lembo A, Pimentel M. Evaluation of harm in the pharmacotherapy of irritable bowel syndrome. Am J Med. 2012;125(4):381-393.
  51. Zofran [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2017.
  52. Garsed K, Chernova J, Hastings M, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;​63(10):1617-1625.
  53. Ford AC, Quigley EMM, Lacy BE, et al. Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(9):​1350-1365.
  54. Shah E, Pimentel M. Evaluating the functional net value of pharmacologic agents in treating irritable bowel syndrome. Aliment Pharmacol Ther. 2014;​39(9):973-983.
  55. Xifaxan [package insert]. Bridgewater, NJ: Salix Pharmaceuticals; 2018.
  56. Ford AC, Quigley EMM, Lacy BE, et al. Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis. Am J Gastroenterol. 2014;109(10):​1547-1561.
  57. Wilson D, Evans M, Weaver E, Shaw AL, Klein GL. Evaluation of serum-derived bovine immunoglobulin protein isolate in subjects with diarrhea-predominant irritable bowel syndrome. Clin Med Insights Gastroenterol. 2013;​6:49-60.
  58. Lembo A, Pimentel M, Rao SS, et al. Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome. Gastroenterology. 2016;151(6):1113-1121.
  59. Acosta A, Camilleri M, Shin A, et al. Effects of rifaximin on transit, permeability, fecal microbiome, and organic acid excretion in irritable bowel syndrome. Clin Transl Gastroenterol. 2016;7(5):e173.
  60. Schoenfeld P, Pimentel M, Chang L, et al. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther. 2014;39(10):1161-1168.
  61. US Food and Drug Administration. Drug safety communications: FDA warns about an increased risk of serious pancreatitis with irritable bowel drug Viberzi (eluxadoline) in patients without a gallbladder. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM546542.pdf. Published March 15, 2017. Accessed March 28, 2018.
  62. Cash BD, Epstein MS, Shah SM. A novel delivery system of peppermint oil is an effective therapy for irritable bowel syndrome symptoms. Dig Dis Sci. 2016;61(2):560-571.
  63. EnteraGam [package insert]. Ankeny, IA: Entera Health Inc; 2016.
  64. Good L, Rosario R, Panas R. New therapeutic option for irritable bowel syndrome: serum-derived bovine immunoglobulin. World J Gastroenterol. 2015;​21(11):3361-3366.
  65. Weinstock LB, Jasion VS. Serum-derived bovine immunoglobulin/protein isolate therapy for patients with refractory irritable bowel syndrome. Open J Gastroenterol. 2014;4(10):329-334.
  66. Imodium A-D [package insert]. Fort Washington, PA: Johnson & Johnson Consumer Inc; 2016.
  67. Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J Med. 2016;374(3):242-253.
  68. Wade PR, Palmer JM, McKenney S, et al. Modulation of gastrointestinal function by MuDelta, a mixed μ opioid receptor agonist/ μ opioid receptor antagonist. Br J Pharmacol. 2012;167(5):1111-1125.
  69. Mawe GM, Hoffman JM. Serotonin signalling in the gut—functions, dysfunctions and therapeutic targets. Nat Rev Gastroenterol Hepatol. 2013;10(8):​473-486.
  70. Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002;122(4):1140-1156.
  71. Laird KT, Tanner-Smith EE, Russell AC, Hollon SD, Walker LS. Short-term and long-term efficacy of psychological therapies for irritable bowel syndrome: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2016;14(7):937-947.e4.
  72. Weinstock LB. Long-term outcome of rifaximin therapy in non-constipation irritable bowel syndrome. Dig Dis Sci. 2011;56(11):3389-3390.
  73. Pimentel M, Morales W, Chua K, et al. Effects of rifaximin treatment and retreatment in nonconstipated IBS subjects. Dig Dis Sci. 2011;56(7):2067-2072.
  74. Pimentel M. Review article: potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea. Aliment Pharmacol Ther. 2016;43(suppl 1):37-49.
  75. DuPont HL. Therapeutic effects and mechanisms of action of rifaximin in gastrointestinal diseases. Mayo Clin Proc. 2015;90(8):1116-1124.
  76. Pimentel M, Lembo A, Chey WD, et al; TARGET Study Group. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364(1):22-32.
  77. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;​372(16):1539-1548.
  78. Zaura E, Brandt BW, Teixeira de Mattos MJ, et al. Same exposure but two radically different responses to antibiotics: resilience of the salivary microbiome versus long-term microbial shifts in feces. MBio. 2015;6(6):e01693-​e01615.
  79. Rashid M-U, Zaura E, Buijs MJ, et al. Determining the long-term effect of antibiotic administration on the human normal intestinal microbiota using culture and pyrosequencing methods. Clin Infect Dis. 2015;60(suppl 2):​S77-S84.
  80. Pimentel M, Cash BD, Lembo A, Wolf RA, Israel RJ, Schoenfeld P. Repeat rifaximin for irritable bowel syndrome: no clinically significant changes in stool microbial antibiotic sensitivity. Dig Dis Sci. 2017;62(9):2455-2463.
  81. DuPont HL, Wolf RA, Israel RJ, Pimentel M. Antimicrobial susceptibility of Staphylococcus isolates from the skin of patients with diarrhea-predominant irritable bowel syndrome treated with repeat courses of rifaximin. Antimicrob Agents Chemother. 2016;61(1):e02165-e02116.
  82. Chey WD. Food: the main course to wellness and illness in patients with irritable bowel syndrome. Am J Gastroenterol. 2016;111(3):366-371.
  83. Petschow BW, Burnett B, Shaw AL, Weaver EM, Klein GL. Serum-derived bovine immunoglobulin/protein isolate: postulated mechanism of action for management of enteropathy. Clin Exp Gastroenterol. 2014;7:181-190.
  84. Roberts LM, McCahon D, Holder R, Wilson S, Hobbs FDR. A randomised controlled trial of a probiotic ‘functional food’ in the management of irritable bowel syndrome. BMC Gastroenterol. 2013;13:45.
  85. Gracie DJ, Ford AC. Symbiotics in irritable bowel syndrome—better than probiotics alone? Curr Opin Clin Nutr Metab Care. 2015;18(5):485-489.
  86. Houghton LA, Heitkemper M, Crowell M, et al. Age, gender and women’s health and the patient. Gastroenterology. 2016;150(6):1332-1343.e4.