Gastrointestinal motility and absorptive disorders in patients with inflammatory bowel diseases: Prevalence, diagnosis and treatment.

FI is a commonly neglected symptom in IBD and is not infrequent to be referred as frequent bowel movements, urgency or tenesmus. FI is defined as involuntary fecal loss of liquid or stool. Several reports have shown FI to have a significant negative impact on physical, social and emotional state of IBD patients[ 84 , 85 ]. FI prevalence has been underestimated over the last decades due to social stigma, patient`s embarrassment and inadequate medical awareness. In a recent meta-analysis, we have found that pooled prevalence of FI in IBD patients is 37% (95%CI: 12%-62%). IBD patients have a higher chance of having FI as compared to non-IBD subjects (OR 7.73, 95%CI: 6.3-9.9). Rate of FI was similar among UC and CD patients. Higher risk of FI in IBD patients is likely due chronic changes in bowel habits, perianal disease/surgeries, loss of rectoanal inhibitory reflex and abnormal rectal sensation[ 86 ]. Diagnosis of FI requires a complete perianal examination, including inspection during Valsalva`s maneuvers and digital rectal exam to evaluate sphincter tone at rest and squeeze. Anorectal manometry is the gold standard to assess anorectal function, compliance, reflexes and sensation. In cases of suspected rectocele or anal sphincter defect further diagnostic testing with endoanal ultrasound and defecography might be considered[ 82 ]. Initial management includes better control of diarrhea if present. Antidiarrheal drugs such as loperamide or diphenoxylate can be used as needed. Increasing fiber intake or bulking agents in IBD may be complicated with bloating and abdominal distention. Biofeedback therapy has been proven to be effective in IBD patients. In a retrospective cohort, almost 80% of patients showed improved symptoms irrespective prior perianal fistula, IPAA or past obstetric trauma[ 87 ]. Sacral nerve stimulation is an FDA approved option for refractory FI with excellent results in non-IBD patients. Limited case series have reported positive response in IBD subjects[ 88 , 89 ]. One study has shown that concomitant treatment with infliximab and surgical repair improved and maintained long-term continence in perianal CD patients[ 90 ]. Anecdotal studies with percutaneous tibial nerve stimulation and pneumatic dilatation of the rectum have been done, but small sample size limits us to draw meaningful conclusions[ 91 , 92 ]. Injecting agents such as dextranomer gel and surgical procedures are contraindicated for IBD patients due to the risk of perianal abscess and fistula formation. Diverting loop colostomy could be acceptable when all above-mentioned therapies have failed.

SIFO was first suggested as a pathologic condition four decades ago and recently defined by excess fungi proliferation in the small bowel, particularly Candida sp. Immunocompromised patients with HIV infection, diabetes or malignancy are at higher risk for SIFO[ 67 ]. SIFO has been associated with IBS-like symptoms and its clinical presentation may be indistinguishable from SIBO. The reported prevalence of SIFO was 26% of 150 subjects evaluated for chronic GI complaints, most frequently abdominal pain, bloating, flatulence or diarrhea[ 68 ]. A prospective study has demonstrated higher rates of SIBO or SIFO in patients who had undergone previous colectomy. The most common indications for colectomy were colonic inertia, cancer, diverticular disease, bowel obstruction and CD in 6% of them (3/50). However, no significant differences were seen on symptomatology after treatment between positive and negative groups[ 69 ]. Although data are lacking, theoretically, it would be important to address SIFO in IBD patients as they are often immunosuppressed, use broad-spectrum antibiotics and commonly undergo abdominal surgery. The diagnostic workup requires an upper endoscopy with a sterile collection of small intestinal aspirate from the distal duodenum or proximal jejunum ≥ 10 3 CFU/mL of fungal growth is proposed as a positive result[ 70 ]. When the diagnosis is made, Erdogan et al[ 70 ] suggest a two to three weeks course of anti-fungal therapy ( e.g ., fluconazole). Echinocandins and amphotericin B are reserved for invasive candidiasis and for treatment of Candida glabrata and Candida krusei [ 70 ]. Future research is needed to better position SIFO into GI functional disorders.

Chronic intestinal pseudo-obstruction (CIPO) is a severe motility disorder characterized by obstructive symptoms in an otherwise patent GI tract[ 93 ]. Although rare, the early recognition of its clinical presentation might provide safe and effective therapeutic measures to improve the quality of life. In a large cohort of CIPO patients, 84% of them required surgery, 76% were dependent on home parenteral nutrition and the survival rate was 68% in over a ten-year period of follow-up[ 94 ]. Non-specific symptoms such as abdominal pain or distension are the most frequently reported at initial stage and it is not uncommon for patients to be misdiagnosed with IBS. Nausea, vomiting, constipation and malabsorption occur with disease progression, whereas diarrhea is generally a consequence of superimposed SIBO. The pathophysiology generally includes myopathy, neuropathy or dysfunctional interstitial cells of Cajal[ 95 , 96 ]. Apart from neurologic and autoimmune diseases, small bowel CD is an important underlying cause of CIPO and should be ruled out prior to establishing proper treatment. There are few case reports in the literature of CD mimicking CIPO. These patients presented with refractory diarrhea, electrolyte disturbances and malnourishment[ 97 , 98 ]. Diagnosis of CIPO can be challenging. Laboratory tests may distinguish primary from secondary causes, while upper endoscopy and colonoscopy assess mechanical obstruction. Computed tomography or magnetic resonance can elaborate dilation of bowel loops. Antroduodenal manometry can confirm myogentic/neurogentic dysmotility, although access is limited and is only available in selected centers[ 99 ]. Effective treatments for CIPO are lacking. Nutritional support is required and patients should be advised to increase protein. Elemental diet and enteral nutrition might also be needed. Pharmacological therapy with prokinetics such as erythromycin, domperidone or prucalopride may be effective but should be dis-continued if it fails after a short trial. Peripherally acting mu-opioid receptor antagonist, gabapentin, pregabalin, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors can be prescribed for pain control with con-siderable side effects. Opioids should be avoided. Treating concomitant SIBO may improve diarrhea and distension[ 100 , 101 ]. Surgery is no longer indicated and refractory patients might benefit from percutaneous endoscopic gastro-jejunostomy (PEG-J). A pilot study has evaluated the efficacy of PEG-J decompression in 7 patients diagnosed with CIPO and found a marked improvement in serum albumin, oral intake and abdominal symptoms. No major adverse events were reported, except for reflux chemical dermatitis[ 102 ]. Intestinal transplant (isolated or multivisceral) is considered a salvage therapy for intractable CIPO and CD patients who present with complications of parenteral nutrition. Up until 2015, over 2500 patients had undergone intestinal transplant worldwide with a survival rate of 76% and 43% in one and ten years, respectively[ 103 ]. Despite transplant, a subgroup of patients with dysmotility might still requires end ileostomy for symptomatic improvement[ 104 ].

Motility and absorptive disorders are highly prevalent in IBD patients, particularly in those with persistent GI symptoms despite quiescent disease. Timely diagnosis and appropriate treatment of these conditions significantly improves care and well-being of IBD patients. Despite the high prevalence and significant impact of these disorders in IBD patients, evidence in diagnosis and treatment is critically lacking. Future controlled studies are needed to address motility and absorptive disorders specially in IBD patients.

An IBD flare may be recognized when patients present with rectal bleeding, mucus or tenesmus; however, non-specific GI symptoms such as diffuse abdominal pain or altered bowel habits do not always reflect a flare. Fecal calprotectin has been used as a surrogate biomarker for active inflammation in IBD and it is considered a reasonable instrument to predict response to therapy[ 6 , 7 ]. Despite a 97% positive predict value to rule-in a flare, a negative result does not necessarily diagnose IBS or any other specific superimposed disease[ 8 ]. Active small bowel inflammation can account for up to 10% of CD patients[ 9 ]. Enteric stenosis and fistulas are not diagnosed by a routine colonoscopy and in these scenario non-invasive tests such as C-reactive protein and fecal calprotectin are not considered reliable markers. Current guidelines recommend cross-sectional imaging as magnetic resonance enterography, when available[ 10 ]. Treatment for active disease demands therapy optimization either with escalation of anti-inflammatory drugs, such as immunomodulators and biologic agents or surgery. There are several conditions that should be excluded in an IBD patient presenting with persistent diarrhea despite relative control of inflammation. (Table 1 summarizes clinical presentations and Table 2 outlines the diagnostic and therapeutic approaches) Common symptoms of overlapping gastrointestinal disorders in inflammatory bowel disease patients Causes of irritable bowel syndrome-like symptoms in inflammatory bowel disease patients False-positive results are observed in liquid stools. CD: Crohn’s disease; 75 SeHCAT: Selenium-75-homocholic acid taurine scan; CFU: Colony-forming unit; H1: Histamine 1 receptor; H2: Histamine 2 receptor; EGD: Esophagogastroduodenoscopy. Celiac disease is more prevalent in IBD patients than in general population. A large systematic review with over 41000 patients from 17 studies has shown a 2-fold increase risk for Celiac disease. Overall, in IBD patients the prevalence of Celiac disease was 1110/100000 [95% confidence interval (CI), 1010-1210/100000] as compared to 620/100000 (95%CI, 610-630/100000) in general population[ 11 ]. Screening is based on IgA anti-tissue transglutaminase, anti-endomysial antibodies and serum total IgA concentration. Both children and patients with total IgA deficiency should be tested with IgG anti-tissue transglutaminase or deamidated gliadin peptide. Positive serology can be further assessed with upper endoscopy with duodenal biopsies to evaluate villous atrophy and degree of inflammation[ 12 ]. The standard therapy is a lifelong gluten-free diet[ 13 ]. In underdeveloped countries giardiasis should be also ruled out, as a common parasitic infection which might mimic Celiac disease by causing diarrhea and bloating[ 14 ]. Treatment is based on nitroimidazoles derivates drugs or nitazoxanide[ 15 ]. Bile acid malabsorption (BAM) is another cause of persistent diarrhea especially in ileal CD or in patients with previous terminal ileal resection[ 16 , 17 ]. Although not approved in United States, 75 selenium homotaurocholic acid test remains the gold standard for diagnosis of BAM. When available, other tests such as serum 7 α-hydroxy-4-cholesten-3-one (C4) and a 48-h fecal measurement of chenodeoxycholic and deoxycholic acids may be helpful for diagnostic workup[ 18 ]. Indeed, in a pediatric IBD cohort, 23% (10/44) of CD patients with persistent non-bloody diarrhea had higher serum C4-concentrations when compared to controls[ 19 ]. A short course of cholestyramine as a diagnostic tool to diagnose BAM is a reasonable approach when the above noted tests are not available. Treatment consists of bile acid sequestrants such as cholestyramine, colestipol, or colesevelam and a low-fat diet. Novel therapeutic targets as farsenoid X agonist have been studied with promising results, however randomized controlled trials are still lacking[ 20 ]. While bile acid binders such as cholestyramine are the mainstay of treatment of BAM, caution should be used in IBD patients. They are known to block absorption of concomitant medications, which might be a concern for patients on 5-aminosalicylic acid, immunosuppressant or Janus kinase inhibitor therapies. Moreover, they can decrease serum liposoluble vitamins levels and fat absorption leading to worsening abdominal distention/bloating, steatorrhea and malnutrition. Undiagnosed exocrine pancreatic insufficiency can also lead to diarrhea and fat malabsorption in IBD patients. Exocrine dysfunction should be considered at any age even in elderly, as older age correlates directly with reduced exocrine pancreatic function[ 21 ]. In a cross-sectional study, the estimated incidence of exocrine pancreatic insufficiency in IBD patients, considering the cut-off of fecal elastase-1 level < 200 µg/g, was 14% in CD and 22% in UC. Compared to controls, the odds ratio of exocrine pancreatic insufficiency was 8.34 (95%CI: 1.34-37.89) for CD and 12.95 (95%CI: 2.91-57.58) for UC patients. The risk was higher in patients with more than three bowel movements per day[ 22 ]. Although uncommon, type-2 autoimmune pancreatitis has been also associated with IBD, which can lead to exocrine insufficiency[ 23 ]. According to the International Consensus Diagnostic Criteria the diagnosis is based on imaging findings such as enlargement of the pancreas or narrowing of the main pancreatic duct, the presence of granulocyte epithelial lesions in histology, frequent association with extra-pancreatic involvement and considerable response to steroids. In contrast with type-1 autoimmune pancreatitis, serum IgG4 is not elevated[ 24 ]. From the clinical perspective, steatorrhea is expected only at end-stage pancreatic insufficiency. Less severe disease usually manifests as watery diarrhea and weight loss. The diagnosis relies on the clinical suspicion and on the determination of indirect pancreatic function tests. Fecal elastase is widely accessible, easy to perform and recommended by the American Pancreatic Association for diagnosis[ 25 ]. This test has been shown to have a pooled sensitivity of 77% and 88% of specificity when compared to secretin stimulation test in a recent meta-analysis[ 26 ]. However, false-positive results are observed in patients with chronic watery diarrhea and, therefore, this test might not be as reliable for the IBD population[ 26 ]. A trial of pancreatic enzyme replacement is reasonable and safe option for treatment in the context of exocrine dysfunction in IBD. Although IBD associated inflammation can potentially lead to decreased mucosal disaccharidases, data on the true rate of sucrose/lactose intolerance in IBD patients is scarce. Physicians should be vigilant about possibility of carbohydrate intolerance ( i.e ., lactose, sucrose and fructose) in IBD patients. Apart from correlation of dietary items with symptoms, hydrogen breath testing can be used to make the diagnosis[ 27 ]. Presence of small intestinal bacterial overgrowth (SIBO) must be ruled-out prior to breath testing for carbohydrate malabsorption as SIBO leads to a positive fructose/sucrose/lactose breath test in up to one third of patients[ 27 ]. Treatment is instituted by avoiding the carbohydrate, preferable with the help of a dietician. Mast cell activation syndrome (MCAS) is a chronic multisystem disease of abnormal mast cell degranulation secondary to regulatory gene mutations leading to inappropriate release of mast cell mediators. MCAS has been described recently in 2007 and our understanding on how to diagnose and treat the disease is rapidly evolving[ 28 ]. MCAS can affect multiple organs including cardiovascular, GI, dermatologic, hepatic, neurologic and musculoskeletal systems. GI manifestations include nausea, heartburn, abdominal pain, and altered bowel habits[ 29 ]. If suspected, treatment with antihistamines (H1 and H2 blockers), cromolyn sodium or disodium cromoglycate may be beneficial, however, referral to an allergist or hematologist familiar with treatment of MCAS is indispensable in management of these patients[ 30 ]. Eosinophilic gastroenteritis is a rare Th2-type mediated disease which is believed to be induced by food or environmental allergens[ 31 , 32 ]. To the best of our knowledge there is no data in the literature that have addressed primary eosinophilic gastroenteritis in IBD. Nonetheless, in general population the estimated prevalence is 5 in 100000 inhabitants and it appears to be more frequent in males and young adults[ 33 ]. Symptomatology may range from abdominal pain, bloating or diarrhea to protein losing enteropathy and malnourishment[ 34 ]. The presence of GI symptoms and histopathological findings of a dense eosinophilic infiltration, eosinophilic cryptitis or abscesses confirms the diagnosis[ 35 ]. Peripheral eosinophilia is commonly observed despite not being mandatory for diagnosis. In addition, some reports have documented anecdotal cases of eosinophilic gastroenteritis induced by anti-tumor necrosis factor in IBD patients[ 36 , 37 ]. Amongst first-line therapeutic options are a short trial of elemental diet (with the goal of eliminating food antigen exposure) and systemic corticosteroids[ 31 ]. Recently, Grandinetti et al[ 38 ] have reported promising histological improvement in refractory patients treated with vedolizumab, a monoclonal antibody against α4β7 integrin. However, further evidence of clinical efficacy is needed. Intra-abdominal adhesions are highly prevalent in IBD daily practice as colectomy and small bowel resections are required in up to 10% of UC and approximately 30% of CD patients during the lifetime[ 39 , 40 ]. Furthermore, adhesions caused by fistulas, endometriosis and non-GI abdominal surgeries can also occur in IBD patients. The estimated prevalence of intra-abdominal adhesions in IBD population is lacking. Postprandial abdominal pain, bloating, distension, nausea and alternating bowel habits are the most common clinical presentation[ 41 ]. A past medical history of abdominal surgery heightens a diagnostic suspicion of adhesions. Conservative management with fasting, intravenous hydration and/or a nasogastric tube is generally the first choice of treatment, whereas surgical lysis should be indicated for refractory cases[ 42 ]. IBS, SIBO and small intestinal fungal overgrowth (SIFO) can also lead to chronic diarrhea, which are described in detail below.

Dyssynergic defecation (DD) is a well-known cause of chronic constipation; however, in IBD patients it can also manifests with rectal discomfort, sensation of incomplete evacuation, diarrhea or FI[ 80 ]. DD is characterized by the discoordination between the contraction of abdominal wall and pelvic floor muscles that prevents adequate evacuation. IBD patients have an increased risk of DD due to chronic changes in bowel habits, perianal disease and surgical procedures[ 81 ]. Previous studies have reported IBD to be associated with sensorimotor anorectal function, increased anal pressure, increased rectal sensitivity and absent rectoanal inhibitory reflex[ 81 , 82 ]. In a recent meta-analysis we have found a high prevalence rate from 45% to 97% in 2 studies with 182 IBD patients with ongoing GI symptoms[ 83 ]. Diagnosis of DD in IBD patients is generally made based on anorectal manometry with a balloon expulsion test. Magnetic resonance/barium defecography and anal sphincter electromyography can also be utilized[ 83 ]. For the last three decades biofeedback has been the standard treatment for DD and previous studies have reported high symptomatic response, reduced healthcare utilization and improved overall quality of life. We have shown a response rate of 86% and 70% in patients with and without ileal pouch anal anastomosis (IPAA), respectively[ 83 ]. IBD patients with anal stricture, fissure and stenosis may have limited benefit from biofeedback therapy. Invasive procedures such as botulinum toxin injection are not recommended for IBD patients considering the increased risk of perianal fistula and FI.

The prevalence of constipation in IBD patients appears to be similar to the general population[ 71 ]. Farrokhyar et al[ 72 ] assessed 149 patients with inactive IBD and found that constipation was present in 10.7% of patients. UC patients had higher rate of constipation as compared to CD (25% vs 5.7%). Assessment of constipation involves a comprehensive review of medical history and current medications to exclude secondary causes. In IBD patients, colorectal cancer is major a concern when addressing recent-onset constipation. Non-pharmacological interventions such as exercise, increased fluid intake or soluble fiber have modest efficacy in general population and may be considered in IBD patients. Polyethylene glycol, an osmotic laxative, is the first line drug to treat constipation. Prucalopride and tegaserod are selective serotonin type 4 agonists which are recently approved/reintroduced by FDA for treatment of constipation[ 73 ]. Safety of these medications is yet to be determined in the IBD population[ 74 ]. Secretagogues are also effective in treatment of constipation. In a recent meta-analysis, linaclotide, lubiprostone and plecanatide were all shown to be superior to placebo in treatment of constipation. The most common side effects were diarrhea and nausea[ 75 ]. Experimental studies have suggested that some prosecretory agents exhibit anti-inflammatory properties and could potentially be candidates for the treatment of IBD. Plecanatide and dolcanatide, both guanylyl cyclase C agonists, improved colitis in mice by downregulation of pro-inflammatory cytokines and their effect was comparable to 5-amino salicylic acid[ 76 ]. Moreover, a small trial with 28 subjects found that lubiprostone, a chloride channel activator, decreased intestinal permeabitily in healthy volunteers[ 77 ]. Potential anti-inflammatory effects of segretogogues make them an intriguing option for treatment of constipation in IBD patients. One other differential diagnosis to consider for constipation and IBS-like symptoms in IBD patients is Ehlers-Danlos Syndrome (EDS). EDS is a heterogeneous group of heritable connective tissue disorders and are grossly underdiagnosed. EDS type III (hypermobility type) is the most common type and is associated with significant GI symptoms such as constipation, straining, abdominal pain, nausea, distention, pelvic floor dysfunction, heartburn, and IBS-like symptoms[ 78 ]. Diagnosis of EDS III is entirely clinical without any objective or genetic testing[ 79 ]. The pathophysiology of GI symptoms in EDS patients remains unknown but visceroptosis, defined as prolapse of abdominal organs below their natural position, has been proposed as the cause of GI symptoms in EDS. Therapy is symptom-directed and involves a multidisciplinary approach. Physiotherapy and promotility drugs have been indicated to treat GI symptoms in these groups of patients but clinical trials are lacking.

Inflammatory bowel diseases (IBD) including Crohn’s disease (CD) and ulcerative colitis (UC) are chronic relapsing disorders that often require long-term therapy and follow up[ 1 , 2 ]. They are recognized for their complex pathophysiology that involves innate immune system deregulation and altered microbiome in genetically predisposed individuals[ 3 ]. Despite adequate treatment, a subgroup of IBD patients exhibit persistent gastrointestinal (GI) symptoms such as abdominal pain, dyspepsia, diarrhea, urgency, fecal incontinence (FI), constipation and bloating that are not always related to mucosal damage. In this setting, it is crucial to exclude superimposed conditions before reassessing degree of inflammation with further invasive diagnostic testing or escalating potentially harmful anti-inflammatory treatments. GI motility disorder and IBD specialists are falling short of staying up-to-date in each field due to exceedingly sub-specialized nature of these disciplines as the two fastest growing fields of luminal gastroenterology. GI motility disorders are observed in more than one third of IBD patients, which significantly impair overall quality of life[ 4 , 5 ]. Herein, we describe the prevalence, diagnosis and management of the most common GI motility disorders associated with IBD.

Irritable bowel syndrome (IBS) is one of the most prevalent differential diagnoses in IBD population with refractory symptoms which significantly impact patient-reported outcomes. A number of studies have demonstrated higher prevalence of IBS in quiescent IBD patients than general population. The largest published meta-analysis, including over 1700 subjects, estimated a 4-fold increase in prevalence of IBS in IBD patients when compared to the general population (OR 4.39; 95%CI 2.24-8.61). The pooled prevalence of IBS in both UC and CD patients during clinical remission was 31% and 41%, respectively. There was significant heterogeneity between the studies with various criteria used to define remission and IBS[ 43 ]. Moreover, the majority of these studies did not vigorously rule-out alternative causes of IBS-like symptoms, therefore the exact prevalence of IBS in IBD patients remains unclear. The current accepted hypothesis states that IBD-IBS patients exhibit an enhanced neuronal responsiveness due to chronic inflammation with subsequent visceral hypersensitivity, hyperalgesia, allodynia, dysmotility and altered intestinal secretions[ 44 ]. Vivinus-Nebot et al[ 45 ] found that IBS symptoms in quiescent IBD subjects are associated with ongoing microscopic inflammation, increased paracellular permeability, intraepithelial lymphocytosis and high TNF-α levels. Conversely, tight junctions’ proteins such zonulin and alfa-cathenin were decreased. Akbar et al[ 46 ] have demonstrated that IBS symptoms were secondary to prior inflammatory changes as shown by the correlation of abdominal pain scores with the upregulation of visceral hypersensitivity receptor in IBD-IBS patients. As the Rome criteria for diagnosis of IBS are based on clinical symptoms, they may not serve as an appropriate diagnostic tool in IBD patients which may exhibit similar symptoms[ 47 ]. Biomarkers are desperately needed to objectively rule-in IBS. Recently, Pimentel et al[ 48 ] have validated two autoantibodies derived from the underlying pathophysiology of post-infectious IBS. In a large cohort of 2823 patients, higher levels of anti- cytolethal distending toxin B (CdtB) and anti-vinculin were detected in IBS patients as compared to IBD patients and healthy controls. Anti-CdtB had a specificity and sensitivity of 91.6% and 43.7% and anti-vinculin showed specificity and sensitivity of 83.8% and 32.6%, respectively to rule-in IBS as compared to IBD. Given the high specificity but modest sensitivity of these tests, a positive result rules in post-infectious IBS but a negative result does not rule out IBS. The role of these biomarkers in IBD patients with overlapping IBS is yet to be determined. A comprehensive multi-disciplinary treatment approach includes a combination of enhanced physician-patient relationship, dietary changes and medications[ 49 , 50 ]. A meta-analysis has demonstrated significant benefit of low-FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet in improving functional GI symptoms in IBS and IBD patients[ 51 ]. If this diet is initiated, it is crucial to reintroduce FODMAPs foods after 4-6 wk to achieve a less restrictive personalized diet[ 52 ]. Neuromodulators and behavioral therapies have been advocated in treatment of IBS symptoms[ 53 ]; however, the role of these interventions is yet to be elucidated in IBD-IBS overlap. Currently, lubiprostone, plecanatide and linaclotide are approved for treatment of IBS-Constipation while rifaximin, eluxadoline and alosetron are approved for IBS-D by Food and Drug administration (FDA) in the United States[ 54 ]. It should be noted that IBD patients were excluded from the trials assessing these drugs. While alosetron is contraindicated in patients with IBD, eluxadoline is contraindicated in patients with previous cholecystectomy and can cause pancreatitis, which limits their use in IBD population[ 55 , 56 ].