The role of diet in the management of irritable bowel syndrome: a focus on FODMAPs

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1 Expert Review of Gastroenterology & Hepatology ISSN: (Print) (Online) Journal homepage: The role of diet in the management of irritable bowel syndrome: a focus on FODMAPs Russell Dolan, William D. Chey & Shanti Eswaran To cite this article: Russell Dolan, William D. Chey & Shanti Eswaran (2018): The role of diet in the management of irritable bowel syndrome: a focus on FODMAPs, Expert Review of Gastroenterology & Hepatology, DOI: / To link to this article: Accepted author version posted online: 15 May Published online: 18 May Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at

2 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY REVIEW The role of diet in the management of irritable bowel syndrome: a focus on FODMAPs Russell Dolan a, William D. Chey b and Shanti Eswaran b a Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; b Department of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA ABSTRACT Introduction: Irritable bowel syndrome is a common condition that negatively impacts quality of life and results in significant health care expenditures. The vast majority of IBS patients associate their symptoms with eating. Numerous randomized, controlled trials suggest that restriction of dietary FODMAPs improves overall symptoms, abdominal pain, bloating and quality of life in more than half of IBS sufferers. There is emerging data which suggests that other diets (gluten free, guided elimination diets) might also be of benefit to IBS patients. Areas covered: Comprehensive literature review on dietary therapies available for IBS to date and exploration into individualized dietary therapy development based on diagnostic testing. Expert commentary: FODMAP elimination identifies IBS patients who are sensitive to FODMAPs. Responders should undergo a structured reintroduction of foods containing FODMAPs to determine a patient s sensitivities. This information can then be used to create a personalized, less restrictive low FODMAP diet. Future research should focus on the identification of other effective diet therapies focusing on supplementation of functional foods in addition to elimination and the development of biomarker-based diet treatment plans which identify the right treatment for the right patient. ARTICLE HISTORY Received 11 March 2018 Accepted 9 May 2018 KEYWORDS Dietarytherapies;IBS;low FODMAP;ESP;glutenfreediet 1. Introduction and pathophysiology of IBS Irritable bowel syndrome (IBS) is the most common functional bowel disorder worldwide, affecting about 15% of the global population, with the lowest prevalence in Southeast Asia (7.0%) and the highest prevalence in South America (21%) [1]. In the United States, a recent meta-analysis estimated the prevalence of IBS to be 12% [1]. This disorder has similar impact on health-related quality of life as diabetes [2] and greater impact than gastroesophageal reflux disease or depression [3]. This contributes to a significant economic burden, and it is estimated that health care expenditures are 50% higher in IBS patients compared to matched controls without the condition [4]. Cost utilization is primarily attributed to significantly increased mean annual number of hospitalizations, ED visits, outpatient visits, and monthly (30-day) prescriptions [5]. Additionally, the workforce is significantly impacted, where individuals with IBS experience greater absenteeism, productivity loss, and activity impairment [6]. Traditional understanding of IBS has focused primarily on altered gut motility, visceral hypersensitivity, and psychosocial stressors. This construct emphasizes that IBS can arise as a consequence of multiple pathophysiologic abnormalities [7], ultimately producing abdominal pain and altered bowel habits, the cardinal clinical features of this condition according to Rome IV criteria [8,9]. It should be noted that abdominal bloating is not included in the Rome IV criteria despite being a common and bothersome complaint among IBS patients [10]. These symptoms must occur in the absence of an identifiable organic etiology, excluded by means of limited serology and endoscopy/histopathologic findings. Furthermore, there are three recognized subtypes of IBS (IBS with constipation or IBS-C, IBS with diarrhea or IBS-D, and IBS with a mixture of constipation and diarrhea or IBS-M), that exist along a spectrum from constipation to diarrhea-predominant symptoms and it is not uncommon for individuals to have instability of symptoms, migrating between classifications through time [11,12]. Although the Rome criteria will remain the primary means by which to diagnose IBS for the foreseeable future, it is tantalizing to propose that biomarkers may allow the parsing of patients on the basis of pathophysiology rather than symptoms alone [13]. For examples, post-infectious IBS patients demonstrate microbiome alterations [14] when compared to healthy controls or IBS patients with no antecedent history of GI infection. Additionally, the host metabolome and immune system activation at both the mucosal and systemic levels [15] are now thought to contribute to the complex pathogenesis of IBS. The vast majority of patients perceive their symptoms as related to either specific foods or meal intake in general [16 18]. While many patients jump to the conclusion that this implies a food allergy, there are, in fact, many potential explanations for such postprandial exacerbations of IBS symptoms, most of which represent activation of physiologic rather than allergic responses [19]. Given the primary function of the gut, it should come as no surprise that food ingestion is the most potent stimulus of gastrointestinal functions including motility and secretion. Postprandial symptoms in IBS patients can arise as a CONTACT Russell Dolan rdolan@med.umich.edu Department of Internal Medicine, University of Michigan, 3116 TC, SPC E. Medical Center Dr., Ann Arbor, MI , USA 2018 Informa UK Limited, trading as Taylor & Francis Group

3 2 R. DOLAN ET AL. Figure 1. Food effects on production of IBS symptoms. Primary and secondary effects of hosts response to food can trigger exaggerated physiologic responses in patients with IBS. consequence of triggering exaggerated physiologic responses, such as a hyperactive gastrocolonic response, with or without amplified sensory responses to normal or exaggerated physiology [20,21]. These abnormal postprandial symptom responses should be looked at within the context of IBS pathophysiology and disordered gut brain signaling (Figure 1). This represents a huge gap in IBS research given the high prevalence of postprandial exacerbations of IBS symptoms, and the difficulties in managing these symptoms. Given the heterogeneous factors contributing to the pathophysiology of IBS, there currently exists no single therapy to improve symptomatology in these individuals. Patients are most likely to experience benefit with tailored, individualized, multi-dimensional treatment plans, and this has led to focus on dietary manipulation as a primary strategy to improve symptom severity and quality of life in IBS individuals. This review explores the available literature on dietary therapy implementation as a means to improve IBS symptomatology and provides insight and recommendations into future directions toward implementing individualized interventions. 2. Low FODMAP diet in IBS 2.1. Low FODMAP diet mechanism of action The most well-studied of the dietary therapies to date focuses on reducing consumption of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, known as the low FODMAP diet [22 24]. Much of this is due to increased recognition of the prevalence of short-chain carbohydrates across Western diets and their association with gastrointestinal symptomatology [25,26]. These short-chain carbohydrates consist of increased concentration of fructose in excess of glucose (apples, pears), lactose (dairy products), fructans (wheat, onions), polyols (artificial sweeteners and sorbitol), and galacto-oligosaccharides (GOSs; legumes, cabbage), all of which are poorly absorbed from the gastrointestinal lumen [27]. Owing to small size, FODMAPs are osmotically active and rapidly fermented by the luminal microbiome [28], thereby precipitating luminal distension through water secretion and gas production [29]. By reducing consumption of these short-chained carbohydrates, alleviating symptoms of abdominal pain, bloating, and flatus production, in particular, are primary goals in IBS patients when implementing the low FODMAP diet. Most recently, improvement in diseasespecific quality of life has also been demonstrated, improving the recognition of the true impact of the low FODMAP diet [30]. The capacity of malabsorbed carbohydrates to undergo rapid fermentation by the gut microbiome and to induce a laxative effect has been known for greater than 20 years [31]. However, it was not until 2005 when Shepherd and Gibson proposed the hypothesis that a diet high in FODMAPs might perpetuate GI symptoms in patients with Crohn s disease[32]. This was soon followed by extrapolation to IBS patients in an uncontrolled study, demonstrating the potential benefits from fructose and fructan restriction in individuals with IBS and fructose malabsorption [33]. While fermentation is likely the main mechanism by which FODMAPs cause symptoms, several other pathways may also play a role. Host immune regulation is also likely affected by the low FODMAP diet, with studies having demonstrated decreased urinary histamine (recognized in pathogenesis of IBS) [34] and production of pro-inflammatory cytokines in IBS patients [35]. Additionally, the various FODMAPs are likely to exert differential effects on the GI tract. Using fmri, investigators from the UK showed differential effects of fructose and fructans in the small intestine and colon in healthy volunteers and IBS patients [36]. Further evidence is required to understand true implications of these factors on syndrome pathogenesis Evidence supporting the low FODMAP diet for IBS In the last 10 years, retrospective and randomized studies of dietary FODMAP restriction have reported symptomatic improvement in 50 76% of IBS patients [37 44], leading to widespread adoption of this approach in clinical practice. The low

4 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 3 FODMAP diet has been compared to a variety of interventions: placebo/sham diet, high FODMAP diet, habitual diet, and other active dietary interventions (Table 1). Although there is mounting evidence that restricting dietary FODMAP intake reduces IBS symptoms (particularly abdominal pain and bloating), not all patients experience improvement to a similar degree [36], much in line with the heterogeneous pathophysiology of IBS Placebo/sham diet comparator In comparison to placebo/sham diet, the low FODMAP diet has demonstrated improved management of IBS symptoms. In a randomizedstudybyshepherdetal,ibspatientsunderwent symptom assessment after randomization to drinks spiked with FODMAPs (fructose, fructan, both) or placebo (glucose) [45]. Overall symptom severity was statistically significantly higher in subjects consuming the drinks containing FODMAPs compared to the placebo drink [45]. This study was the first to clearly demonstrate that FODMAPs, individually or in combination, can trigger symptoms in IBS patients. Staudacher et al recently published a placebo-controlled dietician-led trial which used a 2 2 factorial design in which IBS patients received either low FODMAP diet or a meticulously designed placebo/sham diet along with a probiotic supplement or identical placebo [37]. In a per-protocol analysis of low FODMAP diet compared to sham diet, a statistically significant greater proportion of individuals achieving adequate relief of symptoms was seen in intervention group (IBS-Symptom Severity Score (SSS) lower 177 ± 95) than sham diet (224 ± 89; p =0.001)[37] Real-world diet comparator There has been a total of three recent randomized controlled diets comparing the low FODMAP diet to real-world dietary intervention [38,40,46]. In a crossover study comparing a low FODMAP diet to a typical Australian diet wherein food was supplied to subjects with IBS for 3 weeks, the low FODMAP diet led to statistically significantly lower overall IBS symptoms as well as the individual symptoms of abdominal pain, bloating, and passage of wind (flatulence) [38]. Overall symptoms reported on the Visual Analog Scale were halved when undergoing the low FODMAP diet compared to typical Australian diet (22.6 mm; 95% CI mm vs 44.9 mm; 95% CI mm; p < 0.001)[38]. When compared to standard dietary advice for IBS patients (i.e. focus on eating behaviors such as regular meal pattern, avoidance of large meals, caffeine, fat or insoluble fibers), the beneficial effects of low FODMAP diet have been less robust. In a study from Sweden, IBS patients receiving either a dietician led low FODMAP diet or a diet based upon the NICE guidelines for 4 weeks showed statistically significantly reduced overall symptoms from baseline; however, there was no statistically significant difference in the magnitude of benefit between the treatment groups [46], with similar reductions in individual IBS symptoms (bloating, abdominal pain). It is notable than in both groups, there was a heterogeneous response among subjects, with about half of individuals being identified as responders that experienced significantly greater relief compared to peers in the same study arm [46]. Another randomized, controlled trial from the United States compared a dietician led low FODMAP diet to usual dietary recommendations for IBS in 92 IBS-D subjects over a 4-week period [40]. This study differed from the Swedish study in that the control diet was careful to avoid the exclusion of foods containing FODMAPs. Though there was a therapeutic gain of 11% favoring the low FODMAP diet for the primary end-point of adequate relief of IBS symptoms, this difference failed to reach statistical significance (52% vs 41%, p = 0.31)[40]. However, for several key IBS symptoms including pain, bloating, and stool frequency, there were significant improvements in the low FODMAP group compared to usual dietary advice. Further, the low FODMAP diet led to significantly greater improvements in disease-specific quality of life and anxiety than usual dietary recommendations for IBS [47] High FODMAP diet comparator Recently, four randomized controlled trials have demonstrated consistent and significant improvement in symptom control Table 1. Randomized controlled trials of the low FODMAP diet stratified by comparators. Study (Year) Design Comparator Outcome Comments Shepherd et al (2008) [45] Double-blinded, quadruple arm re-challenge with fructose and fructan supplement 25 IBS patients Glucose supplement Overall symptom worsening with FODMAPs compared with comparator All subjects had fructose malabsorption at baseline Halmos et al (2014) [37] Bohn et al (2015) [47] Eswaran et al (2016) [39] McIntosh et al (2017) [34] Staudacher et al (2017) [46] Tuck et al (2017) [50] Crossover 30 IBS Patients 8 healthy controls Comparative efficacy trial 75 IBS patients Comparative efficacy trial 92 IBS-D patients Controlled single-blind study 40 IBS patients 2x2 factorial design 104 IBS patients 3-day LFD run-in 3-day trial period 31 IBS patients Typical Australian diet NICE diet Modified NICE diet Low FODMAP diet v High FODMAP diet Sham diet (placebo) Placebo, probiotic High FODMAP diet with galactosidase supplementation Overall symptoms improved with LFD over comparator Significant improvement with both dietary interventions Significant improvement with both dietary interventions Significant improvement w/lfd No significant benefit of LFD compared to placebo diet (sham) High FODMAP diet increased symptoms that were mitigated by enzyme LFD: Low FODMAP diet; VAS: Visual Analog Scale; NICE: National Institute for Health and Care Excellence. All food provided to subjects Greater benefit of LFD for abdominal pain and bloating compared to mnice Urine metabolic profiling (i.e. histamine) Single-blinded Per-protocol analysis: significant improvement w/lfd compared to placebo (sham) All subjects were GOS-sensitive

5 4 R. DOLAN ET AL. when comparing the low FODMAP diet to a high FODMAP diet [34,45,48,49]. In a Canadian study, the proportion of patients defined as responders (IBS SSS reduction 50) was significantly greater in the low FODMAP group (72%; 13/18) compared with the high FODMAP group (21%; 4/19; p < 0.009), with the primary benefit derived through reduction in abdominal pain intensity and frequency [34]. Finally, a recent study reported that symptom burden associated with the ingestion of galacto- GOS could be mitigated by administration of alpha-galactosidase enzyme supplements in a subset of IBS individuals found to be GOS sensitive [49]. The primary mechanism is thought to be due to enzymatic reduction of GOS, decreasing its availability for fermentation by the colonic microbiome. This interesting finding reaffirms the known heterogeneity among the IBS population and provides evidence that reintroduction of FODMAP components after the elimination phase may lead to improved tolerance when paired with enzyme supplementation Low FODMAP diet plan: think ESP The low FODMAP diet is composed of three distinct phases: elimination, determination of sensitivities, and personalization [50,51]or ESP for short (Figure 2).Thus far,the majority of research supporting the low FODMAP diet has focused on the elimination phase, which typically lasts about 2 6 weeks, after which symptom improvement is determined. If a therapeutic response is achieved, patients then undergo a structured reintroduction phase (optimally with the help of a dietitian) to determine their sensitivities and tolerances. This information can then be used to create a personalized version of the low FODMAP diet. As will shortly be discussed, potential drawbacks of the low FODMAP diet such as nutritional inadequacy and luminal microbiota alterations may be partially offset by structured, personalized reintroduction of some higher FODMAP dietary components, based on patient tolerance. While standardized protocols for reintroduction (dose, duration, type of FODMAP) are in development, dietitians reintroduce singular FODMAP components sequentially to assess patient response [52]. In doing so, dietary restrictions are able to become less burdensome and nutritional adequacy more likely to be maintained, thereby improving tolerance. Given the mosaicism of the pathophysiology of IBS, the personalization phase proves crucial in successful dietary therapy implementation Criticisms of low FODMAP diet As our understanding of the complex pathophysiology of IBS evolves, so does the recognition of potential pitfalls to the low FODMAP diet. Given that the diet comprises an initial elimination phase (of high FODMAP foods) that can be viewed as somewhat restrictive, concerns have been raised regarding the potential development of nutrient deficiencies [53], especially pertinent given that the excluded foods are nutrient-rich. While there is evidence to suggest that the elimination phase is associated with a decrease in certain micronutrients [44,54], the short duration of the elimination phase (2 4 weeks) suggests that the diet can be implemented without nutritional concern for long-term inadequacies. Furthermore, a recently published follow-up study evaluating IBS patients after the reintroduction period demonstrated no nutritional adequacies for patients on an adapted FODMAP diet [55]. Additionally, given the increased recognition of dysbiosis in IBS patients [14,56] and that dietary composition profoundly influences the gut microbiome, there is concern about the effect of dietary interventions on the host microbiome and Figure 2. Low FODMAP plan ESP (elimination, sensitivities, personalization phases).

6 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 5 metabolome. Indeed, it has been demonstrated that bifidobacteria [44,57] and Faecalibacterium prausnitzii [57], species considered beneficial for host health, are reduced in IBS patients taking a low FODMAP diet, perhaps as a consequence of reducing an important source of dietary prebiotics. The fact that the abundance of several bacteria (F. prausnitzii, Actinobacteria, and Bifidobacterium) rebounded after 10 days of FOS supplementation is reassuring [35]. Recent evidence suggests dietary supplementation with probiotics may offset loss of bifidobacteria abundance when undergoing the low FODMAP diet [37]; however, further investigations to determine the clinical significance of these changes in the microbiome are needed. Finally, there have been correlations between microbial alterations and clinical phenotypes (stool frequency, anxiety, depression, abdominal pain, and discomfort) [56], which may help explain the clinical improvements in mood in addition to improvements in clinical symptoms [30] Quality of evidence evaluating low FODMAP diet to date The low FODMAP diet is now widely regarded as an effective intervention for IBS patients [58], with some experts suggesting the intervention should be considered first-line [38], or at least second-line therapy [59]. Indeed, recent meta-analyses find that the low FODMAP diet positively impacts overall IBS symptoms [60] and most notably, abdominal pain and bloating [61]. However, several shortcomings regarding the quality of evidence have been raised. Recent reviews have highlighted challenges inherent to diet studies which are less of an issue in trials evaluating drugs [62]. Krogsgaard et al illuminated the persistent risk of performance bias in recent studies primarily due to both reliance on subjective outcomes and difficulties with blinding diet intervention trials [63]. Additionally, it was noted that trial control groups were exposed to controlled diets where FODMAP components were higher than traditional IBS diets [63]. In conjunction with the recognized notable placebo response associated with therapies directed at IBS [64], future investigation needs to actively address these shortcomings to determine the true efficacy of specific diets in IBS individuals. 3. Gluten free diet Non-celiac wheat sensitivity (NCWS), often referred as non-celiac gluten sensitivity or gluten intolerance, is characterized by intestinal and extra-intestinal symptoms related to the ingestion of wheat-containing food, in subjects in whom celiac disease or wheat allergy has been excluded [65,66]. Several studies have demonstrated significant improvements in IBS symptoms after the avoidance of gluten/wheat [67 71]. Though symptoms have traditionally been closely tied to gluten, symptom generation may be due to the ingestion of other wheat-related components such as fructans (which are FODMAPs), wheat germ agglutinins, and/or amylase alpha-trypsin inhibitors [72]. Potential mechanisms by which wheat-related components might lead to IBS-type symptoms include inducing low grade inflammation, altering barrier function, and the consequences of fermentation [73,74]. A 2011 double blind RCT demonstrated that individuals with NCWS experienced significant worsening of their IBS symptoms when exposed to gluten compared to a gluten free diet [70]. Building on this study, investigators demonstrated increased stool frequency and increased intestinal permeability in IBS-D patients receiving gluten compared to a gluten free diet, an effect that was more pronounced in HLA-DQ2/DQ8 positive patients [68,75]. However, Biesiekierski et al. demonstrated that once patients were on a low FODMAP diet, symptoms worsened during the study period to a similar degree regardless of how much gluten (0, 2, or 16 g) was added to their diets (p =0.001) [69]. The results of this study suggested that the fructan/ FODMAP content of wheat may be more important to the generation of IBS symptoms than gluten, contradicting the conclusions drawn in previous studies and lending credence to the notion of wheat sensitivity rather than gluten sensitivity. In general, the data supporting the notion of NCWS have not been consistent, perhaps due to an inconsistency in study design and quality. The Salerno experts have advocated a double-blind, placebo-controlled (DBPC), crossover, gluten challenge as the gold standard test to discriminate true NCGS patients, along with several other recommended criteria [65]. A recent systemic review found considerable heterogeneity and flaws in methodology in published studies even among DBPC trials [76]. They also demonstrated a 40% nocebo response during re-challenge (similar or increased symptoms in response to placebo), casting doubt on gluten as the true villain in patients with presumptive NCWS. 4. Guided elimination diets There is currently no accepted diagnostic approach for patients with suspected food intolerances, including NCWS, but these patients represent an important subgroup of IBS patients, as their condition could be effectively treated with dietary exclusion. Assessing specific food intolerance in clinical practice is challenging, and while the DBPC food challenge is the gold standard for diagnosis [77], it is difficult to operationalize in clinical trials and impractical for routine use in clinical practice [78,79]. Understanding the mechanisms by which specific foods lead to symptoms is crucial, and a number of commercially available diagnostic modalities are predicated on the belief that symptoms are generated from food-based immunologic reactions in the GI tract. This is the rationale for leukocyte activation testing (LAT) [80], basophil activation testing [81], IgE/IgG based assays [82], mediator release testing, and confocal light microscopy guided testing [83] Leukocyte activation testing LAT utilizes flow cytometry to detect in vitro morphological changes in leukocytes after exposure to food extracts. This information can then be used to create a personalized elimination diet based upon a patient s specific food intolerances. A recently reported, small, controlled trial assessed clinical response in 58 participants with IBS [80]. Subjects were randomized to a dietician taught exclusion diet that either restricted foods which led to leukocyte activation or a sham diet which excluded foods that did not lead to leukocyte activation over 4 weeks. Dieticians providing education to study participants were blinded to LAT results. The LAT diet

7 6 R. DOLAN ET AL. resulted in a statistically significantly greater benefit to GI Symptom Score compared to the sham diet at 4 weeks with a mean between-group difference equal to 0.86 (p = 0.04, 95% CI ). Both the intervention and sham diet groups demonstrated significant improvements from baseline in IBS- SSS, with the intervention group experiencing significantly larger improvements (mean between-group difference in change since baseline at 4 weeks (p = 0.04, 95% CI 4.43 to ) [80] Confocal laser endomicroscopy Confocal laser endomicroscopy (CLE) is a magnification endoscopic imaging tool that enables visualization of gut epithelium at a cellular level and enables visualization of altered mucosal barrier function in real time. A 2014 study aimed to identify specified food sensitivities in IBS patients based upon this technique [83]. After the administration of food antigens to the duodenal mucosa of sensitive patients, CLE demonstrated an increase in the number of intraepithelial lymphocytes, epithelial shedding and breaks followed by leaks with secretion of fluorescein into the lumen, and edema with increased inter-villous spaces. Characteristic mucosal changes after administration of a wheat suspension were seen in 13 and after administration of milk, soy, and yeast in another 9 of 36 IBS patients. Dietary elimination of the identified triggers resulted in a long-term improvement of symptoms. While potentially offering a powerful tool for the diagnosis of food sensitivities in IBS patients, it should be noted that these results have not been replicated to date. Additionally, CLE requires considerable training and capital investment as well as prolonged endoscopy time for the patient. increasingly require an integrated, holistic approach which incorporates diet, lifestyle, complementary/alternative therapies, as well as medications. There are a variety of research gaps which remain for the low FODMAP diet. Further research is needed to better understand the most efficient way by which to reintroduce foods containing FODMAPs. Long-term adherence, effectiveness, and safety data are also needed. Perhaps the most compelling clinical research will focus on the identification of biomarkers which help providers to choose the right diet therapy for the right patient. Recent studies have opened the door to the possibility of leveraging the gut microbiome [84,85], metabolome [34], volatile organic compounds [86], or physiologic pathways known to be relevant to the pathogenesis of IBS [87] to identify patients who are more or less likely to respond to the low FODMAP diet. Another interesting and important line of research will be to identify the causes and solutions for patients with meal related symptoms who fail to improve with the low FODMAP diet. Recent studies identifying a greater likelihood of sucrose isomaltase SNPs in IBS patients create some interesting hypotheses in this regard [88,89]. While the low FODMAP diet has stolen the spotlight for IBS patients in recent years, it should be viewed as a solution for a subset of IBS sufferers, not the solution for all IBS patients. This should come as no surprise given the pathophysiologic and clinical heterogeneity of IBS. It is also quite likely that the current focus on identifying and eliminating culprit foods will expand to include supplementation of functional foods which promote health benefits. As this review illustrates, creative thinking and rigorous clinical research will help other diet therapies transform from interesting hypotheses to evidencebased treatment options. 5. Expert commentary It is now clear that diet therapies should be considered in the treatment plan of most IBS patients. Of the diet therapies available, the low FODMAP diet has the largest evidence base, acknowledging the shortcomings already discussed. Going forward, it will be important to develop strategies and tactics to help physicians and other health care providers to administer the low FODMAP diet in a medically responsible manner. This will require universal recognition that the elimination phase is not intended to serve as a long-term solution for IBS patients. Rather, the elimination phase should be viewed as a diagnostic test to identify IBS patients with FODMAP sensitivities and in patients who respond, as the entry point into the 3-part ESP plan. It will be very helpful to develop high quality print, web, and mobile application-based teaching materials to address the wide range of learning preferences of IBS patients. Unfortunately, physicians have neither the training nor time to appropriately educate IBS patients on the low FODMAP diet. Thus, efforts to increase the number of appropriately trained GI dieticians will facilitate proper administration of diet therapies and in so doing, improve clinical outcomes. With a growing body of evidence also supporting behavioral therapies such as cognitive behavioral therapy and hypnosis, the care of patients with moderate-to-severe IBS will 6. Five-year view The current literature has contributed in developing a broad spectrum of dietary management approaches for IBS; however, it has also provided insight that current understanding is likely the tip of the iceberg. Driven by increased recognition that not all IBS individuals respond similarly to particular treatments, the next steps in IBS therapies will include further tailoring individualized therapy by clinical features and biomarker testing. The concept of individualized medicine has been bolstered by expanding practices across medical subspecialties, perhaps most notably in oncology but an early example of this in IBS could be with further study of the aforementioned sucrose isomaltase SNPs, or elimination diets guided by testing (see section 4.0, above). Beyond individualized testing, dietary therapy implementation strategies will continue to evolve and expand upon the current ESP strategy being used for the low FODMAP diet. Particularly during the elimination phase, potential micronutrient deficits as well as gut microbiota alterations will continue to become clear. Long-term nutrient inadequacies such as vitamin B12, vitamin D, folate, fiber, and iron have been demonstrated in other dietary therapies such as the gluten free diet practiced in those with celiac disease [90]. Given the lack of understanding whether prolonged implementation of personalized low FODMAP diets leads to sustained nutritional

8 EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY 7 inadequacies, this will further be explored in the coming years. Similarly, altered gut microbiota has been detected in IBS patients on the low FODMAP diet; however, long-term implications of this are yet to be revealed. In response, replacement with micronutrient supplementation or probiotics will likely be studied in attempt to offset any recognized deficits during the elimination phase. As every novel has a number of different chapters, the low FODMAP diet represents a compelling first chapter, one which has drawn in providers and patients alike. In the years to come, other chapters will take shape and science will write their stories. Hopefully this book will prove to be a page turner which ends up on the best seller s list. Key issues IBS is a heterogeneous disease attributed to numerous codependent variables (altered motility, visceral hypersensitivity, early adverse life events, psychological distress, altered alimentary microbiota, immune dysregulation, food intolerances), which leads to a variable response to existing therapies. The majority of patients believe their symptoms are related to eating, making dietary therapies a particularly attractive treatment approach. There is mounting evidence to support the use of dietbased treatments, especially for the low FODMAP diet. Though double-blind, placebo-controlled trials are the gold standard in dietary studies, the placebo and nocebo effects of food are difficult to control. Future research should emphasize identification of novel effective diet therapies focusing on supplementation of functional foods in addition to elimination and the development of biomarker-based diet treatment plans identify patient-specific therapies. Funding This paper was not funded. Declaration of interest W. Chey has acted as a consultant for Nestle, Ritter and Bionorica; has received a research grant from Nestle and owns stocks in True Self and Ritter. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. References Papers of special note have been highlighted as either of interest ( ) or of considerable interest ( ) to readers. 1. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012;10(7): e El-Serag KO HB, Bjorkman D. Health-related quality of life among persons with irritable bowel syndrome: a systematic review. 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