Italian Guidelines for the Management of Irritable Bowel Syndrome Joint Consensus from the Italian Societies of: Gastroenterology and Endoscopy

Authors: Giovanni Barbara, MD, Cesare Cremon, MD, Massimo Bellini, MD, Maura Corsetti, MD, Giovanni Di Nardo, MD, Francesca Falangone, MD, Lorenzo Fuccio, MD, Francesca Galeazzi, MD, Paola Iovino, MD, Giovanni Sarnelli, MD, Edoardo Vincenzo Savarino, MD, Vincenzo Stanghellini, MD, Annamaria Staiano, MD, Cristina Stasi, MD, Cesare Tosetti, MD, Rossella Turco, MD, Enzo Ubaldi, MD, Rocco Maurizio Zagari, MD, Letizia Zenzeri, MD, Giovanni Marasco, MD, PhD.


INTRODUCTION
The irritable bowel syndrome (IBS) is a chronic and often debilitating disorder of gut-brain interaction (DGBI), formerly known as functional gastrointestinal disorders (FGID) [1]. IBS is defined by symptom-based diagnostic criteria, known as the "Rome criteria", derived by consensus from a multinational group of experts, currently in their IV iteration reported in Table 1 [1]. providing useful information about anal tone and sensitivity, and the ability to squeeze and strain, thus resulting in a firm suspicion of a functional anorectal disorder in adults [27][28][29][30][31]. However, DRE is seldomly performed in this kind of patients, even in gastroenterological referral centers [27,32]. A recent Italian survey reported that about 56.4% patients with functional constipation and IBS-C, referred to a secondary/tertiary gastroenterological center underwent a DRE [32].
Anorectal physiology tests, mainly anorectal manometry with balloon expulsion test and defecography should always be considered in adults with coexisting symptoms and signs of functional defecation disorder or fecal incontinence and/or refractory to conservative treatment, although there is limited agreement among the different tests [31]. These tests help in selecting subjects that likely benefit from a tailored pelvic floor rehabilitation which can be carried out by means of a multimodal approach, including kinesiotherapy associated with biofeedback, electrical functional stimulation and, in those with a change in rectal sensitivity, also volumetric rehabilitation [33]. The improvement in abdominal pain and bloating reported by IBS adult patients treated with a rehabilitative approach could further support this therapeutic option [34,35].
In conclusion if medical therapies have failed and/or a DRE raises the suspicion of an anorectal functional disorder, anorectal physiology tests should be considered for a tailored management of patients with IBS. Summary of evidence: celiac disease is an immune-mediated disease triggered by dietary gluten, a storage protein found in cereals such as wheat, rye, and barley. The disorder is characterized by an intestinal enteropathy leading to an extremely diversified clinical presentation ranging from no symptoms to a variety of gastrointestinal and extra-gastrointestinal manifestations [36,37]. The measurement of serum anti-tissue transglutaminase (tTG) antibodies and/or anti-endomysium are extremely sensitive and specific for the diagnosis and follow-up of CD, although at least in adults confirmation with duodenal biopsy is still mandatory. The seroprevalence of CD was recently estimated at 1.4% worldwide, ranging from 1.1 to 1.8% across geographical areas, whereas the pooled global prevalence of biopsy-confirmed CD was 0.7% (95%CI, 0.5%-0.9%) in 138,792 individuals [38].
Patients with CD often complain of abdominal pain, bloating, and/or modification in bowel habit that may be undistinguishable from IBS symptoms [39]. A gluten-free diet over a lifetime is protective, alleviates symptoms and prevents complications [36,40]. Hence, missing the diagnosis of CD in individuals reporting IBS-like symptoms might have significant potential consequences.
As demonstrated in a meta-analysis that included 36 studies with 9,275 subjects fulfilling criteria for IBS, the prevalence of abnormal serological testing for CD was significantly increased among patients fulfilling criteria for IBS irrespective of bowel habit, as compared with controls who did not have IBS [41]. In particular, the overall ORs for a positive anti-endomysium and/or tTG antibodies and biopsy-proven CD was 2.75 (95%CI 1. 35-5.61) and 4.48, (95%CI 2. 33-4.60) in patients with IBS symptoms compared with controls, respectively [41]. However, in this meta-analysis, data from North America found that a diagnosis of CD was uncommon in both IBS cases and controls without IBS. This result is consistent with another most recent study from United States (US) [42] and might be explained by a lower prevalence of CD in US compared with Europe. The OR for a positive serological test for CD was significantly higher among patients with IBS-D (OR 6.09; 95%CI 1. .7) and IBS-C (OR 4.84; 95%CI 1.32-17.7). In addition, the OR for biopsy-proven CD was consistently elevated across all IBS subtypes when compared to controls without symptoms meeting criteria for IBS. Furthermore, since immunoglobulin A (IgA) deficiency causes false-negative IgAbased celiac serology tests and 2-3% of CD patients might have IgA deficiency, CD screening should combine IgA-tTG testing with a second test such as quantitative IgA levels to avoid the underdiagnosis of CD [43].
In summary, given the increased odds of CD among patients with IBS symptoms, independent from the predominant bowel habit pattern, the significant potential consequences of missing the diagnosis of CD, the availability of highly effective treatment, and the apparent cost effectiveness of an early diagnosis [44], we recommend serologic testing with quantitative IgA levels and IgA anti-tTG to rule out CD in patients with any IBS subtype. This is mandatory, if CD prevalence in the population is >1% (as in Italy), since it has an acceptable cost and is worthwhile [44]. If tests are positive, upper endoscopy with duodenal biopsies should be performed in all adults. Summary of evidence: although symptom based criteria for IBS may miss some patients with IBD [45], the risk in patients without alarm features is very low as the prevalence of IBD in such patients is only 0.5-2%. [46,47]. The addition of non-invasive tests in the workup of patients presenting with IBS like symptoms can help identifying this marginal proportion of misdiagnosed IBD patients and should be considered in clinical practice.
Serology tests of inflammation, such as CRP, are easy to perform and inexpensive. Although these tests are non-specific for IBD, they have been largely investigated for distinguishing between IBS and IBD patients [48,49,56,57]. A meta-analysis showed that CRP ≤0,5 mg/dL yields a 1% probability of IBD among patients with IBS symptoms [56]. In conclusion, fecal calprotectin and CRP are reliable non-invasive tools that can be used for the diagnosis of IBD among patients with IBS symptoms without alarms symptoms in clinical practice. Summary of evidence: acute infectious gastroenteritis is the strongest known risk factors for the development of IBS, the so-called post-infection IBS (PI-IBS), however infection in these cases is consistently transient and stool testing for enteric pathogens in the long run is not required [58,59].
Chronic parasite gastrointestinal infections elicit a wide range of clinical manifestations ranging from asymptomatic, to severe chronic symptoms such as bloating, diarrhea, and abdominal pain. While there are data in the literature linking parasite infections with IBS, most of the literature is focused on Giardiasis. A multinational RCT found that 2% of 1452 patients with established IBS diagnosis had a positive fecal ova and/or parasite testing [60]. Tests for fecal ova and parasites are widely requested by general practitioners and community gastroenterologists as compared to IBS experts, despite the lack of evidence demonstrating a change in diagnosis or outcome [22]. However, testing is indicated in patients with risk factors for Giardiasis such as patients from developing countries, travelling to endemic areas or drinking water of poor quality. [61,62]. In summary, due to the low evidence and quality of studies available, routine testing for Giardia is not recommend in all patients with IBS, except for those at high risk. Summary of evidence: colonoscopy is frequently prescribed in patients with symptoms suggestive for IBS. However, colonoscopy should be indicated in patients with IBS symptoms and alarm features only, as well as according to local colorectal cancer-screening programs [63].
Indeed, according to several prospective and retrospective studies, in absence of alarm features the diagnostic yield of colonoscopy is low. Of note, a high heterogeneity across studies as concern design, definition of alarm features and Rome criteria used for the definition of IBS should be mentioned.
When Rome IV criteria are adopted, the range is narrowed to 0-3.5% [64,65]. In case of diarrhea as the predominant symptom, colonoscopy with biopsies should be considered in case of suspected microscopic colitis, although its prevalence is low (up to 4%) [64,66]. Summary of evidence: food intolerance can be defined as a non-immune mediated reaction to food, either secondary to the pharmacologic effects of some substances contained in foods (e.g. salicylates, vasoactive amines, caffeine, glutamate, serotonin, tyramine, and capsaicin) or, more commonly, to the effects of poorly digestible/absorbable carbohydrates, leading to alterations of bowel frequency, bloating and changes in fecal consistency [67]. Although many tests have been proposed to detect food intolerances, [e.g. serum Immunoglobulin G (IgG) panels, leukocyte activation test], they are affected by limited validation, low specificity and lack of cost-effectiveness analysis [68][69][70].
Malabsorption of certain carbohydrates (e.g., lactose, sucrose) can be detected with hydrogen breath testing. As both IBS and lactose intolerance are highly prevalent in the general population, they can be simultaneous, but not necessarily interdependent. In fact, a recent meta-analysis of 34 case series including 9041 patients with IBS, reported a prevalence of a positive lactose breath test (LBT) of 56% (95%CI: 43-69%) in South Asia, 50% (95%CI: 43%-56%) in Europe, and 21% (95%CI: 14-29%) in the USA [71]. However, the same authors, analyzing 10 case control studies, including 2008 subjects, did not find significant difference in the prevalence of lactose malabsorption in patients with IBS compared with controls (OR 1.68; 95%CI 0.95-2.94, P=0.07) [71]. No significant difference in lactose malabsorption prevalence between patients with IBS and the general population is currently available and discrepancy between the prevalence of IBS symptoms and a positive lactose hydrogen breath test has been reported [72]. Therefore, routinely carrying out a hydrogen breath test to exclude lactose intolerance in patients with IBS is not advisable. LE: unable to assess using GRADE methodology; GR: Conditional. Summary of evidence: food allergies are an immune-mediated reactions to proteins contained in foods which can be 1) related to an Immunoglobulin E (IgE)-mediated response (upon sensitization with development of specific IgE antibodies to a food allergen, e.g., nuts), 2) unrelated to IgE mechanisms (mediated by T cells, e.g., food protein-induced enterocolitis syndrome), or 3) secondary to a mixed (IgE and non-IgE) response (e.g., milk protein allergy) [37,73,74]. True food allergies are rare, as they occur in only 1%-3% of adults with the most common food allergens being related to cow's milk, soy, peanuts, eggs, seafood and wheat [74][75][76][77]. The diagnosis of a food allergy is usually clinical, when symptoms (e.g. urticaria, itching, angioedema, rhinorrhea, laryngospasm, bronchospasm, abdominal pain, nausea, vomiting and diarrhea, dizziness, tachycardia and hypotension) occur rapidly after exposure to a certain food, are absent during avoidance and are reproducible after rechallenge [73]. Unfortunately, diagnostic tests including skin prick tests or serum IgE levels yield a low sensitivity (50-75%) and do not always correlate with the intensity of the reaction [73,78,79]. Adverse reactions to food are very common in the general population (up to 20-30%) and could negatively affect quality of life and costs [75,[80][81][82]. However, even though the default interpretation is that of an allergic reaction, only 2-3% of the subjects develop recurrent symptoms when rechallenged with the offending food [82]. In fact, most adverse reactions to foods represent food intolerance or are the expression of visceral hypersensitivity [81][82][83]. Patients with IBS are more likely than the general population to report adverse reactions to food, with prevalence rates as high as 50% [73,83,84]. However, there are no case-control studies assessing the putative association between true food allergies and IBS. In conclusion, given the lack of evidence supporting an association between food allergies and IBS and the poor diagnostic performance of available tests, routine testing for food allergies in patients with IBS is not recommended, unless symptoms are reproducible after re-challenge and absent during avoidance. Summary of evidence: small intestinal bacterial overgrowth (SIBO) has been frequently reported in patients with IBS, however it remains unclear whether SIBO represents a major pathogenetic mechanism underlying IBS [85]. Results of the studies are strongly influenced by the diagnostic methods [86]. Culture of duodenal aspirates represents an invasive approach and present a risk of contamination of the samples. Breath tests are considered scarcely accurate, poorly correlated with intestinal aspiration methods and affected by a high frequency of false positives (lactulose test) and low sensitivity (glucose test) [87][88][89].
In conclusion, patients with IBS were more likely to have a positive test for SIBO as compared with healthy subjects. However, although a difference in the prevalence of SIBO was found between patients with IBS and healthy controls and SIBO may be an explanation for IBS symptoms for some patients, available data do not support the routine testing for SIBO in both adult and pediatric patients with IBS.  The LFD, usually recommended as a second-line diet consisting in the reduction of highly fermentable carbohydrates [98,99]. Several trials enrolling a total of 658 subjects have compared a LFD with other therapeutic choices, mainly dietary interventions [94][95][96][97][100][101][102][103][104][105][106] showing that the LFD was associated with a reduction in the risk of remaining symptomatic [Risk Ratio (RR)=0.71; 95%CI 0.61-0.83]. Among these studies, trials comparing the LFD with the TDA showed the least heterogeneity and magnitude of effect when pooled together and no difference in the efficacy between the two dietary intervention (RR=0.82, 95%CI 0.67-1.01) [107]. A recent systematic review and metanalysis reported that LFD is able to reduce gastrointestinal symptoms and to improve quality of life [108]. However, evidence concerning the efficacy of most trials involving LFD and other dietary options is very scarce. In fact, most studies do not meet the GRADE guidelines level for high quality evidence [98,109]. Moreover, most trials reported the results at the end of the starting of the elimination phase, the so called "strict LFD", usually lasting 4-6 weeks. Up to now only four studies have reported results in the medium-long term (6-44 months) of an adapted LFD, (i.e. only excluding trigger foods) showing symptom improvement in up to 60% of patients with IBS [103,[110][111][112].
However, the complexity of the low FODMAP diet, its potential for nutritional deficiencies and the risk for the development of restrictive eating habit, which require counselling by a specialist dietician, led to the recommendation of LFD as a second-line approach in this guideline and others [93,107] A recent meta-analysis, including 11 trials (three prospective studies, six RCTs, one retrospective study and one study in the pediatric population) stated that gluten might contribute to the occurrence of gastrointestinal symptoms in patients with IBS [113]. However, improvement reported by some patients on a GFD could be due also to the reduction of the fructans contained in wheat, which are FODMAPs, rather than to the withdrawal of gluten. In clinical practice some patients with IBS report an improvement of symptoms and QoL when adopting a GFD [114]. In 2018, a systematic review and meta-analysis by Dionne et al. [109] identified two RCTs including 111 IBS subjects [115,116]. The GFD was not associated with a significant improvement in global IBS symptoms in comparison with a control gluten containing diet (RR=0.42, 95%CI 0.11-1.55). Therefore, as for now there is too little evidence to suggest the adoption of a GFD in patients with IBS. Summary of evidence: intake of 25-35 g of fiber per day is usually recommended due to general health benefits [117,118]. Different types of fiber can be distinguished based on their solubility, viscosity, and ability to resist fermentation in the colon, with different effects on gut microbiome, metabolism, transit time, stool consistency, bile acid absorption, immune-mediated and antiinflammatory pathways [118,119]. Insoluble fiber (e.g., wheat bran) undergoes little physical change as it passes through the gut, bulks stools, and increases stool water content, with the potential to accelerate intestinal transit times [120]. Soluble fibers form a gel that interacts with gut bacteria, resulting in the production of metabolites, including short-chain fatty acids and secondary bile acids [118,120]. Soluble fiber is found in ispaghula husk/psyllium, oat bran, barley, and beans. The major adverse effects of fiber intake are bloating, abdominal distension, and flatulence [121], which however, are less prominent with soluble than with insoluble fibers [119].
A systematic review and meta-analysis on fiber in IBS [68]  Due to the effect on intestinal transit, the use of fibers could potentially be useful in patients with IBS and constipation. A systematic review was unable to perform a meta-analysis due to study heterogeneity and methodological quality. However, fiber was beneficial in all the three studies [122].
At present the evidence suggests that only soluble (e.g., ispaghula husk/psyllium) but not insoluble (e.g., wheat bran) fibers have a significant effect for the treatment of IBS symptoms. The low cost and lack of significant side effects makes soluble fiber a reasonable first-line therapy for patients with IBS. While the results of meta-analysis and RCTs suggest that probiotics as a group may be effective in the management of global IBS symptoms, specific recommendations cannot be given due to different study design (including different comparators, inclusion criteria, comorbidity, outcomes and endpoints), various strains, formulation, combination, or mixture of probiotics assessed, and heterogeneity among studies. Summary of evidence: polyethylene glycol (PEG) is a minimally adsorbed osmotically acting laxative, commonly used to manage constipation in both adults and children. PEG exerts its laxative action by increasing water content of stools due to its ability to interact with water molecules [134].
The clinical effectiveness of PEG in the management of constipation in adults has been confirmed in a recent meta-analysis. The NNT with osmotic laxatives was 3 (95%CI 2-4) [135]. PEG is well tolerated with most adverse events being mild to moderate in severity, including abdominal pain, diarrhea, loose stools, nausea and abdominal distension, mostly occurring in a dose-dependent manner [136][137][138]. In chronic constipation patients older than 70 years of age, long-term PEG was well tolerated without nutritional deficiencies or biochemical abnormalities [139]. PEG has been evaluated in 2 RCTs recruiting patients with IBS-C. One was a mechanistic study that evaluated 47 patients with IBS-C according to Rome II criteria. The primary endpoint was the effects of PEG 3350 over fasting and post prandial (PP) recto-anal tone and sensitivity before and at the end of 30 days of treatment with PEG 3.45 g t.i.d., p.o. or placebo. No changes in fasting and PPpost prandial rectal tone and thresholds for first sensation, gas sensation, urge to defecate, and pain was observed with PEG. However, PEG improved stool consistency. The second study was a multicenter RCT that studied 139 patients with IBS-C for 28 days. The primary endpoint, that was the mean number of spontaneous bowel movements (SBMs) per day in the last treatment week, was met. Abdominal discomfort/pain, the secondary endpoint, however, was not improved in PEG treated patients compared with placebo. Moreover, in the post-hoc analysis when compared with placebo, PEG did not demonstrate a significant lower failure rate of symptom relief using the modified FDA responder definition (patients with pain reduction of >30%, >3 SBMs per week, and an increase of 1 SBM per week) (RR=0.9; 95%CI, 0.66-1.2) [140]. The most common treatment-emergent adverse events were abdominal pain and diarrhea and were more frequent in patients treated with PEG compared with placebo, but most of these were mild or moderate. An American College of Gastroenterology monograph in 2014 concluded that there is no evidence that PEG formulations alleviate pain or provide overall symptom relief in IBS [6] and, no other RCTs were conducted.
In summary, the 2 RCTs that studied the beneficial effect of PEG in IBS-C patients were heterogeneous in trials design and endpoint and were only 4 weeks duration, thus there is no evidence that PEG alone alleviates neither abdominal pain or global symptoms in patients with IBS-C. PEG should be considered for the treatment of constipation in people with IBS-C acting as osmotic laxative. The dose should be titrated according to stool consistency. The side effect of abdominal pain should be taken into account and the long-term efficacy in IBS-C is unknown. have been studied and approved by the FDA for the treatment of IBS-C, but only linaclotide has been authorised by EMA for this indication and is available in Italy.
Lubiprostone is an activator of chloride type 2 channels in the intestine and was approved by FDA in 2008 for the treatment of adult women with IBS-C at a dosage of 8 mg twice daily. The efficacy and safety of lubiprostone has been assessed in 3 RCTs [141,142] In particular, the most robust data derive from a combined analysis of two different phase-3 RCTs (registration IDs NCT00380250, NCT00399542) [142]. These studies involved 1,171 patients meeting Rome II criteria for IBS-C who were randomized to receive 8 mg of lubiprostone or placebo twice daily for 12 weeks. The primary endpoint, i.e., the total number of overall responders, was achieved by 17.9% in the lubiprostone group as compared with 10.1% in the placebo group (P<0.0001), In addition, secondary endpoints demonstrated a significant efficacy of the active treatment in the improvement of abdominal pain/discomfort, bloating, straining, stool frequency, and consistency. In a post-hoc analysis based on 2012 FDA updated guidance document recommending composite endpoints (with both abdominal pain and stool frequency), lubiprostone was significantly more effective than placebo in improving composite end-points, abdominal pain, bloating and stool frequency [143]. High quality systematic reviews/meta-analyses confirmed that lubiprostone was more effective than placebo for overall IBS-C symptoms. Differently from other secretagogues, nausea but not diarrhea is the most frequently reported side effect with this treatment.
Linaclotide is a guanylate-cyclase agonist which activates human guanylate cyclase-C, a transmembrane protein located in the intestinal epithelium, that in turn increases fluid secretion.
Moreover, guanylate cyclase-C activation led to the production and release of cyclic guanosine-3',5'monophosphate (cGMP) which may act in the extracellular compartment inhibiting nociceptors, thereby reducing nociception.. Linaclotide was approved by the FDA and EMA in 2012 for the symptomatic treatment of adults with moderate-to-severe IBS-C. The efficacy and safety of linaclotide was assessed in 3 North American phase IIb/III trials [144][145][146] and later evaluated in several systematic reviews/meta-analyses. In particular, a phase 3 RCT (Trial 31, NCT00948818) [146] was performed in 800 patients with IBS-C and assessed the efficacy and safety of 290 μg linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal period [146]. Linaclotide significantly improved abdominal pain and bowel symptoms for at least 12 weeks (primary endpoint achieved in 33.6% of patients treated with linaclotide as compared with 21.0% of placebo-treated patients, P<0.0001). During the withdrawal period, patients remaining on linaclotide showed sustained symptom improvement, while patients passing from linaclotide to placebo showed return of symptoms to baseline level without worsening. A similar phase 3 study (Trial 302, NCT00938717) [145] was performed in 804 adult patients with IBS-C and showed that linaclotide 290 μg once daily significantly improved abdominal and bowel symptoms over 26 weeks of treatment (primary end-point achieved in 33.7% of patients treated with linaclotide as compared with 13.9% of placebo-treated patients, P<0.0001). These trials, although conducted in the US and Canada between July 2009 and September 2010, were designed in accordance with both FDA and EMA guidelines for the treatment of patients with IBS-C. Also applying the pre-specified EMArecommended co-primary endpoints, linaclotide significantly improved abdominal pain/discomfort and degree-of-relief of IBS-C symptoms over 12 and 26 weeks [147]. In both the pivot studies, diarrhea was the most common adverse event, resulted in discontinuation of about 5% of linaclotide patients.
Plecanatide is another guanylate cyclase-C agonist that has been approved in 2017 by FDA for the treatment of IBS-C (at the dosage of 3 mg). The efficacy and safety of this agent has been evaluated in 3 individual phase IIb/III studies. In particular, the 2 identical phase 3 studies involved a total of 2189 Rome III IBS-C patients randomized to placebo or plecanatide (3 or 6 mg) for 12 weeks [13].
Both doses showed superior efficacy when compared to placebo as concern the achievement of the study primary end point [148,149]. Similarly, all secondary end points (stool frequency/consistency, straining, abdominal symptoms) showed statistically significant improvements after the active treatment as compared with placebo. Similar to other secretagogues, diarrhea was the most frequently reported side effect.
Tenapanor, recently approved by FDA for IBS-C, is a first in class inhibitor of the sodium/hydrogen exchanger isoform 3 that reduces intestinal sodium and phosphate absorption. A phase 3, doubleblind study in patients with IBS-C according to Rome III criteria, included a total of 610 patients in the safety analysis, of whom 309 received tenapanor 50 mg two per day and 301 received placebo [150]. In the intention-to-treat analysis, a significantly greater proportion of patients treated with tenapanor showed a reduction in average weekly worst abdominal pain of ≥30.0% and an increase of complete spontaneous bowel movements ≥1 per week from baseline than placebo group at 6/12-week (27.0% vs 18.7%, P=0.020) and at 9/12-week (13.7% vs 3.3%). During the 12-week treatment period, treatment with tenapanor compared with placebo resulted in significantly higher durable abdominal pain responder (P=0.006) and durable complete SBMs responder rates; diarrhea was the most commonly reported adverse event, confirming a safety profile for this new treatment option for patients with IBS-C. Similar results were obtained in a more recent RCT showing that tenapanor 50 mg b.i.d. improved IBS-C symptoms over 26 weeks [151].
A network meta-analysis by Black et al. [149] compared the efficacy of the four secretagogues Summary of evidence: 5-HT4 receptors play a key role in the modulation of human gut motility and have been the target of drug development in both chronic constipation and IBS-C since long time [152]. Only two drugs of this class, tegaserod and prucalopride, are currently approved for the treatment respectively of IBS-C in USA and chronic idiopathic constipation both in Europe and USA.
A meta-analysis [154] has evaluated all the 11 RCTs including 9242 patients conducted in the past with tegaserod with dose ranging from 0.5 to 12 mg bid. Eight of these enrolled only IBS-C while the others excluded IBS-D but not IBS-M. All the studies used as endpoint the global or overall relief of IBS-C symptoms. Tegaserod resulted more effective than placebo in in treating IBS-C symptoms (RR of symptoms persisting=0.85, 95%CI 0.80-0.90) [154]. Most common treatment-emergent adverse event was diarrhea (RR of diarrhea=3.60, 95%CI 2.45 -5.30).
However, the drug was withdrawn by the company in 2007 because of a small increased risk of cerebrovascular and cardiovascular ischemic events [155]. In 2019, after a re-evaluation of the safety data and a post-hoc analysis conducted according to the recent FDA composite endpoints, FDA has reintroduced the drug [155]. As all confirmed cardiovascular ischemic events occurred in patients with risk for these, the current indication is for females IBS-C, <65 years old, without pre-existing cerebrovascular and cardiovascular disease [155]. Tegaserod has not been re-introduced by EMA.
Prucalopride is selective for 5-HT4 receptors approved by EMA for the treatment of chronic idiopathic constipation not responding to laxatives [152], with a low affinity for hERG potassium channel (relevant to cisapride-induced arrhythmias), thus minimizing potential cardiac side effects both in animal and human studies [152]. Mechanistic studies both in healthy subjects and constipated patients have shown that prucalopride stimulates gastric emptying, small bowel and colonic transit time [152]. A recent network meta-analysis [156] has evaluated 8 RCTs assessing the effectiveness of prucalopride in patients with chronic idiopathic constipation, finding that 2 mg daily was more effective than placebo, both at 4 and 12 weeks. The most common treatment-emergent adverse events of prucalopride are nausea, diarrhea and headache (RR=1.20, 95%CI 1.08-1.34) [156]. So far there have been no RCTs of prucalopride in patients with IBS-C.  [157]. A meta-analysis based on 6 studies [158] showed that the 75-selenium homocholic acid taurine test (SeHCAT) testing was positive for bile acid malabsorption (BAM) in 28.1% (CI 22.6%-34%) of patients with IBS-D. Bile acid sequestrants, including colestyramine, colestipol, and colesevelam, binding bile acids in the intestinal lumen, were developed initially to lower hypercholesterolemia. Subsequently, they were shown to relieve diarrhea in patients with ileal resection and associated BAM [159]. An open-label single-center trial in 12 patients with IBS-D showed that 1.875 mg of colesevelam daily determined a modest reduction in the Bristol Stool Score (P=0.043) [6]. On the other hand, a randomized, double-blind, placebo-controlled study [163] in 24 patients with IBS-D showed that colesevelam at dose of 1.875 mg b.i.d. was associated with a greater ease of stool passage (P=0.048) and firmer stool consistency [163].
Given the fact that there is limited evidence on randomized controlled trials evaluating the utility of tests to diagnose BAM in patients with IBS-D nor the usefulness of empirical therapy with bile acid sequestrants in these patients, the recommendation to use bile acid sequestrants can be advised but is based on low quality of evidence. showing that rifaximin 550 mg t.i.d. for 2 weeks improved global symptoms in 40.7% of patients compared to 30.7% of patients receiving placebo [168].
The same group subsequently analyzed the response to rifaximin retreatment in IBS-D patients with clinical relapse after the first treatment. Among relapsing patients, 38.1% responded to a second treatment with rifaximin, vs 31.5 % receiving placebo [169]. In the same study, abdominal pain improvement was observed in 1384 patients (56.8%). In the long-term follow-up after treatment, 35% of patients were still pain-free [170]. In a secondary analysis on the open label arm of the study, rifaximin could also ameliorate quality of life [169]. Also, in a study including 93 IBS-D patients, a higher response rate (56%) was observed in patients with a positive vs negative LBT (59.7% vs 25.8%, OR 4.3, 95%CI 1.5-12.7, p=0.002), suggesting that altered baseline microbiota might predict rifaximin response [171].
Risks of adverse events of rifaximin have been reported in a meta-analysis of 5 studies involving 1187 patients, showing not significant risks compared with placebo, with a number needed to harm (NNH) of 8971 and a pooled of RR=1.01, 95%CI 0.5-2.02 [172]. In a post hoc analysis from the phase 2b-phase 3 trials, patients were followed-up to 12 weeks, showing similar incidence of adverse events in patients treated with rifaximin or placebo. In addition, no case of C. difficile colitis or deaths were described [173]. Rifaximin also showed the best safety profile compared with other treatment for IBS, such as alosetron, ramosetron and eluxadoline [174].
Furthermore, no effect of rifaximin on stool microbial susceptibility was observed [175]. There are very few data on the effect of rifaximin in IBS-C: a small study found that rifaximin in combination with neomycin significantly improved constipation, bloating and straining but not pain compared with neomycin alone, and the effect as accompanied by a reduction in breath methane [176].
In conclusion, data from the literature in adults support the beneficial effect of rifaximin on IBS without constipation, being the treatment both effective and safe. Further studies are needed to confirm the efficacy of rifaximin in the pediatric population. Alosetron was withdrawn from the market in 2001 due to reports of ischemic colitis [179]. It was however reintroduced in the US via a risk evaluation and mitigation strategy, at a lower dose of 0.5 mg b.i.d., for women with severe IBS-D. At these doses, the rates of ischemic colitis were no higher than those expected in female patients with IBS [180].
Ramosetron is associated with a low incidence of adverse events, such as abdominal distension and hard stools, and is unlikely to cause ischemic colitis. Based on the above, ramosetron is considered safe for treating IBS without constipation. However, clinical research on ramosetron was conducted in Japan and Korea, therefore these findings cannot be generalizable to Western populations.
Alosetron and ramosetron remain unavailable in many countries [181].
Ondansetron, a widely available 5-HT3 receptor antagonist with a good safety profile, has been evaluated in several trials. A small crossover trial of ondansetron, titrated from 4 mg up to 8 mg t.i.d., showed significantly higher rates of improvement in urgency, bloating and stool consistency, but not abdominal pain [182]. A subsequent RCT of 12 mg once a day of bimodal release ondansetron also demonstrated superiority over placebo in improving stool consistency, but not abdominal pain [183].
Constipation was the most reported side effect.
However, there are noticeable individual differences in 5-HT3 receptor antagonists' responsiveness which have been correlated with common polymorphisms in key genes regulating the synthesis and reuptake of 5-HT, as well as the structure of the 5-HT receptors. Therefore, the sensitivity to 5-HT3 receptor antagonists, such as ondansetron, might be partly dependent on genetic variability due to polymorphisms in these genes. In 2019 Gunn et al., [184] carried out a randomized, placebocontrolled, cross-over trial of 5 weeks of ondansetron versus placebo in 125 IBS-D patients. IBS-D patients had significant abnormalities in mucosal 5-HT metabolism and those with the lowest concentration of 5-HT in rectal biopsies showed the greatest responsiveness to ondansetron.
Ondansetron is a safe 5-HT3 receptor antagonist and worldwide available, which could improve mild to moderate IBS-D symptoms. These data suggest either that access to existing, licensed 5-HT3 antagonists should be improved, or large trials of older 5-HT3 antagonists, such as ondansetron, are needed in patients with IBS-D and IBS-M. bloating, nausea and constipation may limit tolerability. These effects can be mitigated by titrating the dose. However, the risk of prolonged QTc suggests caution, particularly for chronic use with high doses in patients with long QT or in comedication with other drugs prolonging QT [185]. Another randomized-controlled study by Cann et al. [186], showed that loperamide improved daily stool frequency compared with placebo after 5 weeks of treatment (1.3 versus 1.9 stools/day, respectively).
Moreover, patients reported a significant reduction in the percentage of loose stools (P<0.01), and incidence of urgency (P <0.001) [186]. Taken together, these data suggest that loperamide may be effective in the treatment of diarrhea in patients with IBS-D, although its chronic use should be avoided due to poor tolerability and the risk of tachyphylaxis and serious adverse events.
Eluxadoline is a peripherally acting, mixed mu-and kappa-opioid receptor agonist/delta-opioid receptor antagonist, effective in slowing intestinal transit and reducing visceral hypersensitivity [187]. A recent metanalysis including 3122 patients from four RCT studies [174] demonstrated that eluxadoline, (both 75 mg b.i.d. and 100 mg b.i.d.) was superior to placebo in improving IBS-D symptoms as assessed by the FDA-approved composite endpoints. Moreover, eluxadoline 100 mg b.i.d. was also superior to placebo in improving abdominal pain. Adverse events included constipation, nausea and headache, and adverse events leading to drop out were significantly higher with active drug than placebo. In addition, serious adverse events, including pancreatitis and sphincter of Oddi spasm, occurred in 0.5% of patients included in these trials [188]. For this reason, the drug is contraindicated in patients with prior sphincter of Oddi problems or in presence of cholecystectomy, alcohol abuse, pancreatitis or severe liver impairment. Although EMA approved for IBS-D, eluxadoline is currently unavailable in European countries. with IBS [58]. In addition, gut microbiota has been shown to be altered in patients with IBS, and certain microbial signatures have been associated with the severity of IBS symptoms [189,190].
In the last decade, fecal microbiota transplantation (FMT), namely the process of transferring fecal bacteria and other microbes from a healthy individual into another individual, has been investigated in the context of IBS.
Two meta-analyses did not observed a clear benefit of FMT for the relief of IBS symptoms [191,192].
Of note, over 90% of patients had IBS-D or IBS-M. Myneedu et al. [192] [191]. Interestingly, FMT from donor stool via naso-jejunal tube showed a trend towards a benefit over autologous stool in one trial (RR=0.69, 95%CI 0.46-1.02). However, none of the studies included showed a low risk of bias, thus precluding definitive conclusions.
In addition, a recent RCT carried out on 49 patients with IBS (51% IBS-D) using FMT via colonoscopy, failed in achieving a reduction in the IBS-SSS throughout the 52-week follow-up period [193]. In another RCT [194], FMT from a single healthy, well-characterized donor was administered via gastroscope in 164 patients with IBS. This study found that patients who received placebo, 30 g FMT or 60 g FMT were responders in 23.6%, 76.9% (p<0.0001) and 89.1% (p<0.0001), respectively.
Future studies should test FMT in IBS to understand its efficacy, determine the optimal donor and delivery formulation and technique. Summary of evidence: antispasmodics are among the most frequently used treatments for IBS although their availability in the different countries is very diversified. The rationale for using these drugs is based on the fact that that some IBS symptoms are believed to be the result of gastrointestinal spasm and dysmotility [195]. Antispasmodics are an heterogeneous group of substances that include direct smooth muscle relaxants (e.g.papaverine, mebeverine), anticholinergic agents (e.g., butylscopolamine, hyoscine, cimetropium bromide, pirenzepine) and calcium channel blockers (e.g., alverine citrate, otilonium bromide, pinaverium bromide, peppermint oil). For some of these molecules the pharmacological action is not fully known and the mechanisms are often mixed [196].
Data on the efficacy of antispasmodics were analyzed in a meta-analysis that included 26 RCTs, evaluating 2811 patients with IBS. Thirteen different antispasmodics were compared with placebo [68]. Antispasmodic therapy had a statistically significant effect in improving global IBS symptoms (RR of IBS symptoms not improving=0.65, 95%CI 0.56-0.76) and the NNT was 5 (95%CI 4-8). The overall rates of adverse events were significantly higher with antispasmodics compared with placebo, most notably dry mouth, visual disturbance and dizziness, essentially linked to the anticholinergic effects, but no serious adverse events were reported. Statistically significant effect on improving global IBS symptoms were demonstrated for cimetropium (NNT=3), dicyclomine (NNT=4), drotaverine (NNT=2), hyoscine (NNT=3), otilonium (NNT=5), pinaverium (NNT=4), but not for mebeverine, trimebutine, pirenzepine, alverine, rociverine, prifinium, and propinox. In a Cochrane review, trimebutine was effective for abdominal pain, pinaverium for abdominal pain, global assessment and IBS symptom score, cimetropium/dicyclomine for global assessment, while no statistically significant effect was reported for mebeverine and scopolamine derivatives [197]. In a pooled analysis comprising 3 clinical trials, otilonium bromide demonstrated a significant reduction of intensity and frequency of abdominal pain and of severity of bloating at 10 and 15 weeks of treatment. No significant effect was observed in stool frequency and consistency [198].
Peppermint oil is used in the treatment of IBS symptoms due to its main action as a calcium channel blocker, but several other physiological effects are reported. In Ford's meta-analysis it is suggested a benefit of peppermint oil for overall symptom improvement in IBS patients and, in a subsequent meta-analysis, it is reported a NNT=3 for overall IBS symptoms and NNT=4 for abdominal pain [199]. Peppermint oil was well tolerated but some patients experienced heartburn probably due to relaxation of the lower esophageal sphincter. In a recent RCT, small bowel release peppermint oil led to significant improvements in the secondary outcomes including abdominal pain, discomfort and IBS severity, compared with placebo [200]. The results obtained in these studies cannot be extended to many products containing Peppermint oil, variously formulated, and enteric-coated formulations must be used to minimize heartburn. In conclusion, published studies support the use of antispasmodics to treat global and troublesome IBS symptoms. However, published data mainly came from small sample size and dated studies, with bias in selection of patients and variability in end points. Also, no data on head-to-head efficacy are available. In Italy, medications registered for use in patients with IBS include cimetropium, hyoscine, mebeverine, otilonium, pinaverium, trimebutine, and peppermint oil, while other compounds (e.g., prifinium, dicycloverine, drotaverine) are marketed, alone or in combination, in many over-the-counter products.

Summary of evidence: a recent Rome Foundation Working Team Report has recommended
replacing the term antidepressants with that of gut-brain neuromodulators [201]. This has been motived by two main reasons. The first is that it is now recognized that gut-brain interaction plays a relevant role in the pathophysiology of functional bowel disorders. This means that clinicians need to be aware these medications are not prescribed only to treat psychological factors like anxiety and depression in IBS. Second but maybe more relevant reason is that the term "antidepressants" associates with a stigma that has profound implication in clinical practice and is responsible for emotional distress, medication non-adherence and increase in symptoms [202]. Different classes of neuromodulators exist but only TCAs, SSRIs and gabapentin have been applied in RCTs in IBS. The most accepted mechanism of action of TCA and SSRI at central level is through the modulation of three main monoamines: serotonin, noradrenalin, and dopamine [201].
A recent metanalysis have evaluated the RCTs conducted with these medications in patients with IBS and has identified 12 studies with TCA (including a total of 787 patients) and 7 with SSRI (including a total of 356 patients) [203]. The study endpoints were mainly relief of global symptoms.
Only in four studies, the duration of treatment was longer than 2 months, and the maximum duration was 12 weeks [203]. SSRI resulted more effective than placebo in treating IBS symptoms (RR=0.68, 95%CI 0.51-0.91). Although not always reported, adverse events were not serious and drowsiness and dry mouth were more frequent in patients treated with TCAs. These medications need to be started at low dosage and titrated according to the patients' symptoms response and tolerability.
A recent study has evaluated the efficacy and safety of pregabalin in IBS including all the different subtypes [204]. Pregabalin is a calcium channel α2δ ligand previously demonstrated to act on visceral hypersensitivity in IBS [204]. Pregabalin 225 mg was found to be more effective than placebo in reducing the average pain score (25 vs 42, P=0.008) and overall severity score (26 vs 42, P=0.009) as measured by Bowel Symptoms Scale in 85 patients with IBS over 12 weeks treatment. Most common adverse events were blurred vision, dizziness and altered sensation. 1.13-2.49, I 2 =63%) was superior to placebo. Healing therapies based on body and energy also demonstrated no significant benefit over placebo or sham for abdominal pain or overall response [212]. Not all studies reported adverse effects (AEs), and many reported AEs overlapped with IBS symptoms. No major AEs were reported, suggesting that overall, CAM therapies show a reasonable safety profile in IBS.
In addition, a recent meta-analysis [213] assessed the efficacy of Western herbal medicines in the treatment of IBS. Several herbal medicines were effective in relieving IBS symptoms. Aloe vera and asafoetida were proven effective in reducing global IBS symptoms in meta-analyses. Herbal formulations such as STW 5, STW 5-II and Carmint, along with Ferula assa-foetida, Pimpenella anisum oil, the combination of Curcumin and Foeniculum vulgare oil, and the blend of Schinopsis lorentzii, Aesculus hippocastanum and peppermint essential oil, were also effective. In conclusion, many herbal medicines show promise in the treatment of IBS. However, with the exception of peppermint essential oil, Aloe vera, and asafoetida, none of the positive trials have been replicated.
Therapy options should also align with patients' preferences, who in many cases may be willing to and interested in exploring CAM. CAM may also serve as a useful aid for patients refractory to traditional approaches. The downside is that the strength of the evidence is low and additional high quality RCTs are needed. Moving forward, future studies on CAM therapy in IBS should adopt the FDA's guidance on pharmaceutical treatments for IBS to provide more rigorous quality evidence. months [216] compared with treatment as usual (TAU). This approach has also been shown to be cost-effective [217].
The randomized trial Irritable Bowel Syndrome Outcome Study (IBSOS) [218]    We recommend for the use of opioid agonists to manage diarrhea in IBS-D. 1  We recommend for the use of opioid agonists to manage diarrhea in IBS-D. 1 We recommend for the use of mixed opioid agonists/antagonists to treat global symptoms in IBS-D We recommend for the use of psychologically directed therapies for the treatment of global symptoms in patients with IBS.

Yes
Low Strong 100% Abbreviations: PICO: patient, intervention, control, and outcome. NA: not available: unable to assess using GRADE methodology. IBS: Irritable Bowel Syndrome. IBD: inflammatory bowel disease.