Inflammatory bowel disease (IBD) is characterized by inflammation

ORIGINAL ARTICLE Fermentable Carbohydrate Restriction (Low FODMAP Diet) in Clinical Practice Improves Functional Gastrointestinal Symptoms in Patients with Inflammatory Bowel Disease Alexis C. Prince, MRes, RD,*, Clio E. Myers, MRes, RD,* Triona Joyce, PhD, RD,*, Peter Irving, MD,*, Miranda Lomer, PhD, RD,*,, and Kevin Whelan, PhD, RD* Background: A significant proportion of patients with inflammatory bowel disease (IBD) experience functional-like gastrointestinal symptoms (FGS) even during remission. Research suggests that dietary restriction of fermentable carbohydrates (low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet) can improve FGS, albeit in irritable bowel syndrome. The aim of this study was to investigate the effectiveness of the low FODMAP diet delivered in routine clinical practice in patients with IBD and coexisting FGS. Methods: Gastrointestinal symptom scores were compared in consecutive patients with IBD referred for low FODMAP dietary education for symptom management (n ¼ 88). Symptoms were assessed using the Gastrointestinal Symptoms Rating Scale, and stool output was assessed using the Bristol Stool Form Scale at both baseline and follow-up (minimum of 6 weeks). Results: There was a significant and large increase in the numbers of patients reporting satisfactory relief of symptoms between baseline (14/88, 16%) and low FODMAP diet (69/88, 78%; P, 0.001). Following dietary intervention, there was also a significant decrease in severity for most symptoms and a reduction in composite symptom score (baseline mean: 1.2, SD: 0.5 versus low FODMAP diet mean: 0.7, SD: 0.5; P, 0.001). Improvements in stool consistency and frequency were observed, including an increase in normal stool form (P ¼ 0.002) and normal stool frequency (P, 0.001). Conclusions: The low FODMAP diet delivered in routine clinical practice seems effective in improving satisfaction with, and severity of, FGS in IBD. Randomized controlled trials are warranted to definitively establish effectiveness. (Inflamm Bowel Dis 2016;22:1129 1136) Key Words: inflammatory bowel disease, fermentable carbohydrates, functional gastrointestinal symptoms, low FODMAP diet Inflammatory bowel disease (IBD) is characterized by inflammation of the gastrointestinal tract driven by an abnormal immune response to luminal microbiota in genetically susceptible individuals. 1 During active disease, symptoms commonly include abdominal pain or discomfort, rectal bleeding, and a change in Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal s Web site (www.ibdjournal.org). Received for publication November 20, 2015; Accepted December 8, 2015. From the *King s College London, Faculty of Life Sciences and Medicine, Diabetes and Nutritional Sciences Division, London, UK; King s College Hospital NHS Foundation Trust, Department of Nutrition and Dietetics, London, UK; Guy s and St Thomas NHS Foundation Trust, Department of Nutrition and Dietetics, London, UK; and Guy s and St Thomas NHS Foundation Trust, Department of Gastroenterology, London, UK. Supported by a research fellowship from the National Institute for Health Research (AC Prince, CE Myers). K. Whelan is currently in receipt of research funding from a range of research councils and charities including National Institutes of Health Research (UK), Crohn s and Colitis UK, and Kenneth Rainin Foundation and industry including Clasado, Dr Scharr, and Nestle. The remaining authors have no conflict of interest to disclose. Reprints: Kevin Whelan, PhD, RD, King s College London, 150 Stamford Street, London, SE1 9NH, UK (e-mail: kevin.whelan@kcl.ac.uk). Copyright 2016 Crohn s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000708 Published online 25 February 2016. stool consistency and frequency. 2 However, a proportion of patients continue to experience gastrointestinal symptoms during remission in the absence of underlying inflammation 3,4 posing a challenge to clinicians due to a lack of effective evidencebased treatments. In the absence of any organic or inflammatory origin, these symptoms are often described as functional-like gastrointestinal symptoms (FGS). 5 Irritable bowel syndrome (IBS) is the most common cause of FGS and affects 5% to 20% adults and adolescents worldwide. 5,6 It has been suggested that FGS occur in 35% to 57% patients with quiescent IBD, 7,8 which is higher than in the general population. These symptoms impact negatively on quality of life 9,10 and, if incorrectly assumed to be caused by inflammation, may lead to the inappropriate prescription of antiinflammatory agents. Questionnaire and interview studies report that patients with IBD frequently identify foods that trigger FGS 11 and manipulate their diet to gain symptomatic control during both active and quiescent disease with potentially detrimental consequences for their nutritional status. 12 15 Gastroenterologists have expressed a lack of confidence in using dietary exclusion for management of FGS in IBD, 16 highlighting the need for further research and guidance in this area. Inflamm Bowel Dis Volume 22, Number 5, May 2016 www.ibdjournal.org 1129

Prince et al Inflamm Bowel Dis Volume 22, Number 5, May 2016 Observational studies and recent high quality randomized controlled trials have demonstrated that restriction of a group of fermentable carbohydrates is efficacious in managing FGS in patients with IBS. 17 20 This dietary intervention involves the restriction and systematic reintroduction of fermentable oligosaccharides (fructans, a-galacto-oligosaccharides), disaccharides (lactose), monosaccharides (fructose), and polyols (sorbitol, mannitol), collectively fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). 21,22 These carbohydrates are either not absorbed in humans due to a lack of digestive enzymes (fructans, a-galacto-oligosaccharides), down-regulated enzyme activity (i.e., lactase in the digestion of lactose), undergo facilitated absorption with limited capacity (fructose), or slow passive absorption (polyols). Some FODMAPs increase small intestinal water content 23,24 and others are fermented by microbiota in the colon producing hydrogen and methane gases. 23,25 This results in abdominal distension and characteristic symptoms in sensitive individuals, including pain, discomfort, bloating, diarrhea, and flatulence. 26 Approximately 70% of patients with IBS report symptom improvement or symptom relief when following a low FODMAP diet 18,19 and this dietary intervention is now recommended in guidelines for the management of IBS. 27,28 However, this intervention has not been widely studied for the management of FGS in IBD. Certain carbohydrates have been individually identified as potential triggers of FGS in IBD, including lactose 29 and fructose. 30 In a study of 72 patients with IBD who had previously received low FODMAP dietary advice, a retrospective telephone questionnaire survey found that FGS improved in 56% of patients following a low FODMAP diet, including overall symptoms, abdominal pain, bloating, flatulence, and diarrhea. 31 This was a retrospective study relying on patient recall of historic symptom improvement and generalizability is limited. Additional research is required to further evaluate the benefits of the low FODMAP diet in managing FGS in IBD. The aim of this study was to investigate the effectiveness of the low FODMAP diet delivered in routine clinical practice in patients with IBD and coexisting FGS. MATERIALS AND METHODS This study describes a case-note review of electronic medical records of all eligible patients with IBD who were referred for dietary advice for the low FODMAP diet for the management of FGS at a single U.K. tertiary IBD center between 2011 and 2015. Inclusion criteria were a diagnosis of IBD, either Crohn s disease (CD), ulcerative colitis (UC), or IBD unclassified (IBD-u), confirmed by standard endoscopic, histological, and radiological criteria, in conjunction with persistent FGS which their gastroenterologist considered to be in the absence of active inflammation or other organic cause. Exclusion criteria were the diagnosis of a medical condition that would influence symptom outcomes, including coexistent gastrointestinal disorders that might be responsible for symptoms (e.g., coeliac disease, bacterial overgrowth, bile acid diarrhea, pancreatic insufficiency, dumping syndrome). However, the presence of these was based on screening of electronic/paper medical notes, rather than prospective diagnostic exclusion for every patient. In addition, patients with missing symptom data or a duration to follow-up with the dietitian (for assessment of the study outcome) of greater than 7 months were also excluded. Study Protocol Specialist gastroenterology dietitians experienced in delivering low FODMAP dietary education administered the intervention as described previously as part of their routine clinical practice. 32 At the initial appointment (baseline), all patients underwent standard dietetic assessment, including medical history, relevant medications, nutritional status, and baseline dietary intake. Patients subsequently received initial low FODMAP dietary advice either in a 45-minute one-to-one appointment or during a group session (specifically for patients with IBD and FGS) provided by gastroenterology dietitians trained in this approach. Certain aspects of the diet were tailored to each individual based on an assessment of their usual eating habits, as is normal dietetic practice. All patients were advised to restrict fructans (e.g., wheat products, onion, garlic), a-galacto-oligosaccharides (e.g., beans, pulses), and polyols (e.g., artificial sweeteners, prunes). Lactose (e.g., milk) and fructose (e.g., honey) were restricted if, based on symptom history and dietary assessment, it was suspected that they may contribute to symptoms, in line with normal practice. Dietary education was supported with detailed written FODMAP patient resources detailing suitable and unsuitable foods, information regarding suitable and unsuitable processed foods and brands, food product packaging, recipes and meal planning, and strategies for eating out. Patients were advised to follow the diet for a minimum of 6 weeks and were offered a 30-minute one-toone follow-up appointment at which symptom response was reviewed and reintroduction education provided. Outcome Data Collection All outcome data (i.e., FGS, stool output) was recorded prospectively using standardized, validated questionnaires at the time of the patients baseline appointment (immediately before dietary advice) and at their follow-up appointment (having followed low FODMAP diet) and recorded in their medical/dietetic records as part of routine clinical practice. Between March 2014 and January 2015, a case-note review of electronic medical records was undertaken to collate all data from patients whose consultations were between January 2011 and January 2015. Demographic and clinical characteristics included age, sex, diagnosis, IBD phenotype (categorized using the Montreal classification), 33 and treatment history. The primary outcome measure was assessment of satisfactory relief of FGS measured using the global symptom question (Do you currently have satisfactory relief of your gut symptoms?), the recognized standard for evaluating outcomes in FGS trials. 34 1130 www.ibdjournal.org

Inflamm Bowel Dis Volume 22, Number 5, May 2016 Low FODMAP Diet in IBD In addition, individual symptoms were assessed using the Gastrointestinal Symptom Rating Scale 35 consisting of 11 symptoms scored on a 4-point Likert scale with qualifiers (0 ¼ none, no symptoms or very rarely; 1 ¼ mild, occasional or mild symptoms; 2 ¼ moderate, frequent symptoms that affect some social activities; 3 ¼ severe, continuous symptoms that affect most social activities). Calculating the mean of the 11 individual symptom scores resulted in a mean composite symptom score. Typical current stool consistency was assessed using the validated Bristol Stool Form Scale. 36 Stool types 3, 4, and 5 are considered normal consistency. 36 Typical current stool frequency was assessed on a seven-point scale (once a week, once every 4 to 6 days, once every 2 to 3 days, once a day, 2 to 3 times a day, 4 to 6 times a day, 7 or more times a day), with once every three days to three times a day considered normal. 5 Ethical Considerations The hospital advised that ethical approval was not required for this case-note review and so this was registered as a service evaluation (reference GSTT-3763). 37 Patient confidentiality and anonymity were maintained at all times. Statistical Analyses All statistical analyses were performed using SPSS v.20.0 software. To minimize data entry bias, a process of double data entry was undertaken. Demographic and clinical data were analyzed descriptively. Continuous data (e.g., age) are presented as mean (SD) and categorical data (e.g., diagnosis) as frequencies and percentages. Where possible, differences between subgroups (e.g., CD versus UC) were analyzed using an unpaired t test or 1- way analysis of variance. Dichotomous data, including responses to the global symptom question, were compared between baseline and follow-up using McNemar s test. Individual symptom scores were recoded as a dichotomous score, either none or mild or moderate or severe, and compared between baseline and follow-up using McNemar s test. This recoding enabled the clinically meaningful differentiation between no/mild FGS and moderate/severe FGS. A composite mean symptom severity score was calculated and compared between baseline and follow-up using a paired samples t test. Stool consistency was reclassified into normal (Bristol Stool Form types 3, 4, or 5) and abnormal (Bristol Stool Form types 1, 2, 6, or 7) and analyzed as dichotomous data. Mean Bristol Stool Form scores were calculated and analyzed as continuous data. P, 0.05 was considered statistically significant. RESULTS Demographic and Clinical Characteristics Data from 88 patients with IBD (39 CD, 38 UC, and 11 IBDu; 70.5% female, mean age, 40; age range, 20 80 years) who received low FODMAP dietary advice were analyzed. Demographic and clinical characteristics are shown in Table 1. Males (45.3 years, SD: 13.9) were older than females (35.6, SD: 11.9; P ¼ 0.001). No other demographic or clinical differences between gender and diagnostic groups were found at baseline. Of the 88 TABLE 1. Demographic and Clinical Characteristics Characteristics Crohn s Disease (n ¼ 39) Ulcerative Colitis (n ¼ 38) IBD-u (n ¼ 11) Total IBD (n ¼ 88) Age (yr), mean (SD) 40 (13) 41 (14) 41 (14) 40 (13) Sex Female, n (%) 31 (79) 26 (68) 5 (45) 62 (70) Male 8 (21) 12 (32) 6 (55) 26 (30) Age at diagnosis, mean (SD) 29 (12) 32 (13) 33 (16) 31 (13) Age at baseline, mean (SD) 38 (13) 39 (14) 38 (14) 38 (13) Disease duration (yr), mean (SD) 11 (11) 9 (8) 7 (6) 10 (10) Previous surgery, n (%) 10 (26) 2 (5) 0 (0) 12 (14) Montreal classification, n (%) Location Extent (n ¼ 37) L1, ileal: 12 (31) E1, proctitis: 14 (38) L2, colonic: 11 (28) E2, left-sided: 19 (51) L3, ileocolonic: 16 (41) E3, pancolitis: 4 (11) Behavior B1, nonstricturing, nonpenetrating: 26 (67) B2, stricturing: 9 (23) B3, penetrating: 4 (10) P, perianal disease: 6 (15) www.ibdjournal.org 1131

Prince et al Inflamm Bowel Dis Volume 22, Number 5, May 2016 patients, 75 (85%) received dietary advice in a one-to-one appointment and 13 (15%) during a group appointment. Mean duration between the initial dietetic appointment (baseline) and follow-up appointment (low FODMAP diet) was 2.6 months (SD: 1.4). Satisfactory Relief of Symptoms Paired global symptom question data were analyzed for all 88 patients. There was a significant increase in the proportion with satisfactory relief of their FGS following a low FODMAP dietary intervention. At baseline, 14/88 (16%) reported satisfactory symptom relief, compared with 69/88 (78%) at follow-up (P, 0.001; Fig. 1). Similar findings were observed for CD (P, 0.001), UC (P, 0.001), and IBD-u (P ¼ 0.004). Symptom Response Abdominal pain (75/88, 85%), bloating (84/88, 95%), flatulence (80/88, 91%), urgency (73/88, 83%), and lethargy (79/88, 90%) were the most commonly reported symptoms of any severity at baseline. Data for the number of patients reporting each of the symptoms as absent, mild, moderate, and severe at baseline and following the low FODMAP diet are presented as Supplemental Digital Content (http://links.lww.com/ibd/b231). At follow-up, when data were dichotomized into presence or absence of symptoms, there was a significant reduction in the number of patients reporting symptoms of any severity (mild, moderate, or severe) for abdominal pain (P, 0.001), bloating (P, 0.001), flatulence (P ¼ 0.041), belching (P ¼ 0.001), incomplete evacuation (P ¼ 0.012), nausea (P ¼ 0.011), and heartburn (P ¼ 0.035) (data not shown). However, given their greater impact on patients lives, data were analyzed for the effect of the low FODMAP diet specifically on moderate and severe symptoms. A significant reduction was observed in the number of patients reporting moderate or severe symptoms for all symptoms, with the exception of heartburn, which only a minority of patients experienced at either baseline or follow-up (Table 2). When analyzed separately, following the low FODMAP diet, there was a significant reduction in the number of patients with CD with moderate or severe abdominal pain (P ¼ 0.002), FIGURE 1. Frequency of patients reporting satisfactory relief of FGS at baseline and following the low FODMAP diet. TABLE 2. Number (%) of Patients with IBD Reporting Moderate or Severe Symptoms (Gastrointestinal Symptom Rating Scale) at Baseline and Following the Low FODMAP Diet Symptom IBD, n (%) (n ¼ 88) Baseline Low FODMAP Diet P a Abdominal pain 38 (43) 16 (18),0.001 Bloating 61 (69) 17 (19),0.001 Flatulence 53 (60) 17 (19),0.001 Belching 22 (25) 7 (8) 0.001 Borborygmi 37 (42) 12 (14),0.001 Fecal urgency 51 (58) 24 (27),0.001 Incomplete evacuation 29 (33) 16 (18) 0.007 Nausea 15 (17) 3 (3),0.001 Heartburn 9 (10) 6 (7) 0.549 Acid regurgitation 14 (16) 6 (7) 0.021 Lethargy 53 (60) 34 (39) 0.001 a Analyzed using McNemar s test. bloating (P, 0.001), flatulence (P ¼ 0.031), and nausea (P ¼ 0.016) and in the number of patients with UC with moderate or severe abdominal pain (P ¼ 0.021), bloating (P, 0.001), flatulence (P, 0.001), belching (P ¼ 0.004), borborygmi (P, 0.001), fecal urgency (P, 0.001), incomplete evacuation (P ¼ 0.004), and lethargy (P ¼ 0.022). In the small number of patients with IBD-u, there was a significant reduction in numbers with moderate or severe flatulence (P ¼ 0.016). Overall, individual symptom severity scores decreased following low FODMAP diet with the greatest reductions in score observed for bloating and flatulence, followed by abdominal pain and lethargy (Fig. 2). Similar patterns were observed for CD, UC, and IBD-u subgroups. Individual scores for each of the 11 FGS were combined into a mean composite symptom severity score. This score was significantly lower at follow-up compared with baseline for all IBD (P, 0.001) and for all IBD subgroups (Table 3). Stool Output More patients reported normal consistency stools (types 3, 4, or 5) at follow-up (55/88, 63%) compared with baseline (36/88, 41%; P ¼ 0.002), with the greatest decrease being in mixed consistency stools (any stool form) and loose stools (types 6 and 7; Fig. 3). When analyzed by IBD subgroup, the findings were nonsignificant, although in patients with CD, there was a trend toward greater numbers with normal stool consistency at follow-up (P ¼ 0.057). The mean (SD) Bristol Stool Form Score at baseline was 4.4 (1.3) and following low FODMAP diet was 4.2 (1.3), although this was not statistically significant (P ¼ 0.077). 1132 www.ibdjournal.org

Inflamm Bowel Dis Volume 22, Number 5, May 2016 Low FODMAP Diet in IBD FIGURE 2. Change in symptom severity scores for 88 patients with IBD at baseline and following the low FODMAP diet. Bars represent mean (SEM) change in symptom severity scores between baseline and following the low FODMAP diet. Symptom severity scores were measured using the Gastrointestinal Symptom Rating Scale where 3 ¼ severe, 2 ¼ moderate, 1 ¼ mild, and 0 ¼ absent. More patients reported normal-frequency stools (once every 3 days to 3 times a day) following the low FODMAP diet (71/88, 81%) compared with baseline (53/88, 60%; P, 0.001; Fig. 4). Similar findings were observed for the UC subgroup (P ¼ 0.004) and a trend toward significance observed for CD (P ¼ 0.065). The greatest decrease was in the number of patients reporting highfrequency stools (4 or more times a day). DISCUSSION FGS cause significant distress for patients with IBD and pose a dilemma for treating clinicians in the absence of effective management strategies. They may also be mistaken for symptoms of active disease resulting in the inappropriate use of antiinflammatory medication thereby exposing the patient to the risk of side effects without any benefit. Fermentable carbohydrate restriction (low FODMAP diet) has been shown to reduce symptoms of IBS 19 and when patients responding to a low FOD- MAP diet are challenged with individual fermentable carbohydrates, symptoms return. 17 Research investigating the low FODMAP diet in IBD is limited to 1 retrospective telephone survey showing an improvement in symptoms in CD and UC 31 and 1 randomized controlled trial as yet only published as a conference abstract. 38 The latter reported a nonblinded randomized controlled trial in which 89 patients with IBS-like symptoms on a background of quiescent IBD or those with mild to moderate disease activity were randomized to either a low FODMAP diet or a normal diet. There was a greater reduction in IBS severity scoring system in the low FODMAP diet group compared with the control diet group between baseline and week 6 of the trial. 38 In this study, we aimed to investigate the effectiveness of the low FODMAP diet in clinical practice in patients with IBD and coexisting FGS. Patients were more likely to report satisfactory control of symptoms following dietary intervention, and reducing dietary FODMAPs resulted in a reduction in the number of patients with an array of FGS. This reflects previous findings in IBS 18,19,32 in which symptoms shown to improve following a low FODMAP diet have included abdominal pain, flatulence, 18,20,39 bloating, 18 20,39 diarrhea, borborygmi, urgency, and lethargy, 19,39 whereas in IBD, the symptoms most likely to respond are abdominal pain, diarrhea, bloating, and flatulence. 31 We demonstrated improvements in a wider variety of symptoms in IBD than was seen in the study by Gearry et al, 31 which may be related to the prevalence of baseline symptoms in our population and the fact that data were collected prospectively enabling greater accuracy in assessing and recording symptoms and thus eliminating the risk of recall bias. Mechanisms for the reduction in symptoms were not assessed in this study. However, randomized controlled crossover trials have demonstrated that FODMAPs exhibit varying absorption, 24,40,41 are osmotically active in the gastrointestinal lumen 24 and, once fermented by colonic microbiota, increase gas production to a greater degree in patients with FGS than in healthy controls. 25 Individual FODMAPs also have different effects on gastrointestinal physiology. Intestinal water content increases to a greater extent following a fructose challenge, whereas inulin increases colonic hydrogen production, 23 which in the context of visceral hypersensitivity results in FGS. 42 Following a low FODMAP diet, patients reported improvements in stool consistency (higher proportion indicating normal stool form, fewer reporting loose stools) and stool frequency TABLE 3. Mean (SD) Composite Symptom Severity Scores at Baseline and Following the Low FODMAP Diet Diagnosis Baseline Low FODMAP Diet Mean (SD) 95% CI Mean (SD) 95% CI P a IBD, n ¼ 88 1.20 (0.48) 1.10 1.31 0.75 (0.46) 0.65 0.85,0.001 CD, n ¼ 39 1.27 (0.51) 1.12 1.44 0.91 (0.52) 0.74 1.08,0.001 UC, n ¼ 38 1.15 (0.40) 1.02 1.28 0.66 (0.34) 0.55 0.77,0.001 IBD-u, n ¼ 11 1.15 (0.63) 0.72 1.57 0.48 (0.35) 0.24 0.71 0.001 Composite symptom severity scores were measured using the scale where 3 ¼ severe, 2 ¼ moderate, 1 ¼ mild, and 0 ¼ absent. a Analyzed using paired t test. www.ibdjournal.org 1133

Prince et al Inflamm Bowel Dis Volume 22, Number 5, May 2016 FIGURE 3. Stool consistency categories at baseline and following the low FODMAP diet. (higher proportion indicating normal frequency, fewer reporting high stool frequency). This is as would be expected as a reduction in fructose results in reduced small bowel water content. 23,24,43 Strengths and Limitations Defining improvement in FGS in clinical studies is problematic. In this evaluation, we examined a range of data, including the global symptom question (suggested by the Rome foundation as the primary outcome measure in trials of FGS), and the severity of individual and overall symptoms, enabling a more thorough evaluation of symptomatic change following treatment. The observational design carries a number of limitations. In the absence of a control group, a placebo effect cannot be excluded. This is particularly relevant given the intensive nature of the dietary consultation and of following the diet itself, both of which may augment the placebo effect, in view of which a definitive cause-effect relationship cannot be ascribed here. However, it is important to note that placebos controls for dietary advice are very difficult to design and apply. Referral bias may lead to patients most likely to respond positively to treatment being referred for dietary advice, whereas excluding those lost without follow-up data risks, selection bias as patients who responded positively may be more likely to attend follow-up FIGURE 4. Stool frequency categories at baseline and following the low FODMAP diet. appointments. The design did not allow for formal capture or analysis of potentially confounding variables, such as fluctuations in disease course, medication changes, dietary intake, and dietary adherence. Efforts were made to include only patients in remission; however, changes in disease activity may have occurred undetected. Quiescent disease was not defined using endoscopic or inflammatory markers (e.g., fecal calprotectin), but rather based on the clinical judgment of the referring gastroenterologist. Furthermore, changes in disease activity were not monitored using these objective markers during dietary intervention, again in line with routine clinical practice. Therefore, changes in disease activity may have occurred, although given that patients were judged to be in remission at baseline, any changes would likely have been a worsening of disease activity, which if resulting in mild/moderately active disease would likely have been detected using symptom data. Despite these limitations, the strength of the design of this study is that it examines clinical data in a real-life setting, reflecting patient outcomes that would be expected in clinical practice, rather than when participating in a prospective clinical trial as a research participant. Previous research found that the effectiveness of the low FODMAP diet is associated with dietary adherence in both IBD 31 and IBS. 39 Although we did not formally measure adherence to the diet in this study, the symptom response suggests that adherence was not a significant factor for most patients. Dietetic consultation may also lead to fundamental changes in an individual s usual eating habits and inadvertent restriction of other dietary components, resulting in symptom improvement that cannot be excluded as a confounding effect in this study. 44 46 Randomized controlled studies are required to overcome these limitations, in which intervention and control groups consume diets differing only in FODMAP content. Outcome data were collected and documented prospectively at the time of patient contact removing recall bias. Data collection relied on accurate and consistent recording, and the standardized symptom questionnaires helped to achieve this. Although at baseline dietary advice was provided in a group setting for a minority of patients (n ¼ 13), we have previously shown that this does not impact on the effectiveness of the diet in terms of symptom relief and response. 47 Whether FGS in IBD are truly functional or are simply caused by subclinical inflammation has been debated, 7 and there is evidence of increased colonic permeability and changes in the acute inflammatory phase that persist even during remission. 48,49 As such, the categorization of these symptoms is challenging without endoscopic assessment, which is expensive, not without risk and burdensome for patients. Furthermore, in the clinical setting, gastrointestinal symptoms in IBD may seem to be functional-like but may actually have an organic origin, such as bacterial overgrowth, bile acid malabsorption, adhesions, short bowel syndrome, and dumping syndrome. No patients in the current analysis were diagnosed with such organic disorders, but that 1134 www.ibdjournal.org

Inflamm Bowel Dis Volume 22, Number 5, May 2016 Low FODMAP Diet in IBD these may be the cause of gastrointestinal symptoms in a minority of patients cannot be ruled out. Accordingly, it is not possible from the nature of this study design to know how much the FGS were exacerbated by fermentable carbohydrates and how much they were caused by subclinical inflammation or other organic cause. The low FODMAP diet is deemed to be safe in the shortterm in IBS and is nutritionally adequate if education is provided by a registered dietitian experienced in low FODMAP education. 19,32 Assessment of nutritional adequacy over the longer term has also found no difference between IBS and control groups for macronutrients and overall energy intake. 50 There is no safety or nutritional adequacy data in IBD. Furthermore, we do not have data on body weight in this study and nor do previous published reports. 31,38 Therefore, it is recommended that researchers and clinicians monitor nutritional adequacy and nutritional status when intervening with the low FODMAP diet in patients with IBD. A further area for inquiry is the impact of FODMAP restriction on the gastrointestinal microbiota. Fructans and a-galacto-oligosaccharides are prebiotics that stimulate the growth of colonic bifidobacteria. 51 Patients with quiescent IBD have similar intakes of fructans as healthy controls 52 and reducing the consumption of these may therefore have implications for the diversity and composition of the microbiota. For example, controlled trials have reported that FODMAP restriction reduces bifidobacteria 19,53 and immunoregulatory Faecalibacterium prausnitzii 53 in IBS. The gastrointestinal microbiota is already altered in IBD 54 and prebiotics may influence inflammation through modulation of microbiota and inflammatory cytokines. 55 Therefore, research is required to examine the impact of FODMAP restriction on the gastrointestinal microbiota and inflammation in IBD. CONCLUSIONS Restriction of dietary FODMAPs may offer an effective therapeutic option for patients with IBD and coexistent FGS. Randomized controlled trials are warranted to confirm a causal relationship between fermentable carbohydrates and FGS and to assess the impact of FODMAP restriction on FGS, dietary adequacy, gastrointestinal microbiota, and disease activity. ACKNOWLEDGMENTS The authors thank patients at Guy s and St Thomas NHS Foundation Trust for reporting symptom data and Jo Felton, Dearbhaile O Hanlon, Dr Steven Fong, and Dr Ben Warner for their support with data collection. Author contributions: A. C. Prince contributed to the design, data collection and input, statistical analyses, and writing of the manuscript. T. Joyce, C. E. Myers, and M. Lomer contributed to data collection and input. P. Irving and MCL contributed to study design and data interpretation. K. Whelan contributed to the study design, data interpretation, and writing of the manuscript. All authors commented critically on the manuscript and approved the final manuscript for submission. REFERENCES 1. Sartor RB. Mechanisms of disease: pathogenesis of Crohn s disease and ulcerative colitis. Nat Clin Pract Gastr. 2006;3:390 407. 2. Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2011;60:571 607. 3. Bayless TM, Harris ML. Inflammatory bowel disease and irritable bowel syndrome. Med Clin N Am. 1990;74:21 28. 4. Camilleri M. Managing symptoms of irritable bowel syndrome in patients with inflammatory bowel disease. Gut. 2011;60:425 428. 5. 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