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Selina R Cox, Alexis C Prince, Clio E Myers, Peter M Irving, James O Lindsay, Miranda C Lomer, Kevin Whelan, Fermentable Carbohydrates [FODMAPs] Exacerbate Functional Gastrointestinal Symptoms in Patients With Inflammatory Bowel Disease: A Randomised, Double-blind, Placebo-controlled, Cross-over, Re-challenge Trial, Journal of Crohn's and Colitis, Volume 11, Issue 12, December 2017, Pages 1420–1429, https://doi.org/10.1093/ecco-jcc/jjx073
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Abstract
Preliminary evidence suggests that fermentable carbohydrate restriction might ameliorate functional gastrointestinal symptoms [FGS] in inflammatory bowel disease [IBD]. Our aim was to determine whether fermentable carbohydrates exacerbate FGS in IBD using a randomised, double-blinded, placebo-controlled, re-challenge trial.
Patients with quiescent IBD and FGS responsive to a low FODMAP diet were allocated to a series of 3-day [d] fermentable carbohydrate challenges in random order [fructan, 12 g/d; galacto-oligosaccharides [GOS] 6 g/d; sorbitol, 6 g/d; and glucose placebo, 12 g/d], each separated by a washout period. Symptoms and stool output were measured daily during the challenges.
Thirty-two patients with IBD, fulfilling criteria for irritable bowel syndrome, functional bloating, or functional diarrhoea, were recruited and data were available for 29 patients completing all arms [12 Crohn’s disease, 17 ulcerative colitis]. Significantly fewer patients reported adequate relief of FGS on the final day day of the fructan challenge [18/29, 62.1%] compared with glucose [26/29, 89.7%] [p = 0.033]. There was greater severity of pain [1.1 vs 0.5, p = 0.004], bloating [1.3 vs 0.6, p = 0.002], flatulence [1.5 vs 0.7, p = 0.004], and faecal urgency [0.9 vs 0.4, p = 0.014] on the final day of fructan challenge compared with glucose.
At the relatively high doses used, fructans, but not GOS or sorbitol, exacerbated FGS in quiescent IBD. Further research is required to determine whether a low FODMAP diet reduces FGS in IBD and the degree of FODMAP restriction required for symptom improvement.
1. Introduction
Patients with inflammatory bowel disease [IBD] experience periods of disease remission characterised by control of intestinal inflammation and the absence of clinical manifestations of active disease. During periods of IBD remission, a significant proportion of patients continue to suffer from gastrointestinal symptoms not caused by active intestinal inflammation but which meet the criteria for a functional bowel disorder, as defined by the Rome criteria.1,2 A systematic review and meta-analysis estimated that 35% of patients with quiescent IBD meet the criteria for irritable bowel syndrome [IBS].1 These persistent functional-like gastrointestinal symptoms [FGS], which include abdominal pain, bloating, flatulence, and diarrhoea, may greatly impact on health-related quality of life.3,4 Functional-like gastrointestinal symptoms must be managed appropriately in IBD, avoiding drugs aimed at treating inflammation which will be ineffective, costly, and may be accompanied by side effects.
Dietary restriction of fermentable carbohydrates [the ‘low FODMAP diet’] is now widely implemented for the management of IBS, and is included in national guidelines.5,6 The restricted carbohydrates include oligosaccharides, disaccharides, monosaccharides and polyols [FODMAPs]. Randomised controlled trials assessing the efficacy of the low FODMAP diet have demonstrated symptom improvement in up to 70% of individuals with IBS.7–9 Some FODMAPs [eg fructose] increase small intestinal water volume whereas others [eg fructans] are incompletely digested in the small intestine and undergo bacterial fermentation in the colon leading to gas production.9–11 These processes may induce or exacerbate abdominal pain, bloating, flatulence, and diarrhoea in those with gastrointestinal hypersensitivity, such as in IBS.10,12,13
In contrast to patients with IBS who experience FGS but who do not have organic disease, the efficacy of the low FODMAP diet in patients with quiescent IBD with co-existent FGS has not been widely studied. Preliminary evidence from uncontrolled trials is promising, with the low FODMAP diet resulting in adequate relief of FGS in 56% of patients with IBD in a retrospective study14 and 78% of patients with IBD in a prospective study.15 Although any potential placebo response cannot be accounted for in uncontrolled studies of dietary interventions, these preliminary studies indicate the low FODMAP diet might represent an effective approach for the management of commonly experienced and burdensome FGS in IBD, and this requires investigation in randomised controlled studies.
It is feasible, given the complexity of foods and the high placebo response rate characteristic of functional bowel disorder trials, that a placebo response or concomitant alteration of non-FODMAP components of food may be at least partly responsible for the efficacy of the low FODMAP diet in alleviating FGS.16 A FODMAP restriction and re-challenge trial, the gold standard for diagnosing food intolerances, confirmed fructose and fructans as a cause of symptoms in some people with IBS.17 This study did not, however, investigate FODMAPs such as galacto-oligosaccharides [GOS], whose role as an inducer of FGS has yet to be confirmed. Furthermore, although the role of fructose and fructans in inducing FGS in IBS has been demonstrated, this has not been investigated in patients with IBD and co-existent FGS. A trial of prebiotics in Crohn’s disease reported increased severity of flatulence, borborygmi, and abdominal pain during 4 weeks of fructan supplementation.18 However, this was performed in active disease where the aetiology of FGS may be different, and habitual dietary intake of fructans or other FODMAPs was not restricted. The aetiology of FGS, and the role of FODMAPs in their exacerbation, may be different in IBD compared with IBS.
Therefore, our aim was to conduct a randomised, double-blind, placebo-controlled, cross-over re-challenge trial to determine whether individual fermentable carbohydrates exacerbate FGS in patients with quiescent IBD, who experience FGS.
2. Materials and Methods
This was a randomised, double-blinded, placebo-controlled, cross-over, re-challenge trial, designed to compare the effects of FODMAP challenges with placebo [glucose] on FGS in patients with quiescent IBD experiencing co-existent FGS.
2.1. Participant selection
Participants were recruited from gastroenterology clinics at Guy’s and St Thomas’ NHS Foundation Trust and Bart’s Health NHS Foundation Trust [London, UK] between March 2014 and October 2015. The inclusion criteria were: a diagnosis of IBD [CD or UC] at least 6 months before enrolment; currently in remission; and defined by Physician Global Assessment in conjunction with a faecal calprotectin concentration < 250 µg/g and serum C-reactive protein [CRP] < 10 mg/L. In addition, participants must have: been experiencing FGS that met Rome III criteria for IBS, functional bloating, or functional diarrhoea; 19 and had experienced a marked improvement following a low FODMAP diet [assessed using the Global Symptom Question]. The exclusion criteria included: a recent change in IBD medications; current steroid use; and use of antibiotics, probiotics or prebiotics in the preceding 4 weeks. Patients with concomitant comorbidities such as diabetes or cardiovascular disease and those with previous extensive gastrointestinal surgery or stenotic disease were also excluded.
Before enrolment in the study, blood and stool samples were collected to measure inflammatory markers for eligibility assessment. The blood sample was taken for CRP determination using a standard assay in the respective hospital pathology laboratories. The stool sample was collected for faecal calprotectin analysis which was measured by trained researchers using the Quantum Blue® Calprotectin Rapid lower range [30–300 µg/g] test [Bühlmann Laboratories]. The faecal calprotectin threshold of < 250 µg/g for inclusion was chosen based on a meta-analysis indicating superior sensitivity [80%] and specificity [82%] in predicting quiescent IBD20,21 compared with other thresholds.22
Participants were required to follow a low FODMAP diet and then experience adequate relief of FGS in order to be eligible for the trial. In order to do this, all patients received a 45–60 min consultation with a research dietitian with expertise in the low FODMAP diet, in which they were instructed to limit consumption of oligosaccharides [fructans and GOS], lactose, fructose, sorbitol, and mannitol, and were provided with appropriate dietary resources, as per normal clinical practice. They were required to follow a strict low FODMAP diet for at least 2 weeks and were only eligible for the current study if they provided an affirmative response to the Global Symptom Question [‘Do you currently have adequate relief of your gut symptoms?’].
Clinical data including Montreal classification and disease activity indices [Harvey-Bradshaw Index for CD, Simple Clinical Colitis Activity Index for UC] were measured based upon medical note review and assessment by the attending gastroenterologist.
2.2. Trial protocol
Eligible participants were allocated to a series of four challenges in random order, each with a duration of 3 days and separated by a washout period of at least 4 days. The four challenges were fermentable carbohydrates [fructans, GOS, sorbitol] and placebo [glucose]. Randomisation to the order of challenges was carried out using a web-based random number generator by an independent researcher not involved in the study, with all other researchers blinded to the order of challenges. Participants were instructed to follow a strict low FODMAP diet throughout the trial. The day before starting a challenge [baseline], participants completed all outcome measures and were not allowed to start a challenge period unless they reported adequate relief of gastrointestinal symptoms. The following day, participants started a challenge period, consuming a ‘challenge drink’ once daily for 3 days [Days 1–3] and recording all outcome measures. This was followed by a washout period of at least 4 days [Days 4–7] during which participants did not consume a ‘challenge drink’, and at the end of which gastrointestinal symptoms were recorded again in anticipation of starting the next challenge. On the final day of the washout period, participants were contacted by researchers and those reporting that they did not have adequate relief of gastrointestinal symptoms were instructed to prolong the washout period and delay the next challenge until they had adequate relief of symptoms.
Gastrointestinal symptoms and stool output were recorded by participants the day before each challenge [Day 0] and daily during the 3-day challenge period [Days 1–3]. Adequate relief was assessed using the Global Symptom Question, a validated dichotomous outcome for assessing global gastrointestinal symptoms in IBS, which has been used in a variety of pharmaceutical trials23,24 and is widely recommended for use in clinical trials of functional bowel disorders.25 Incidence and severity of 11 individual gastrointestinal symptoms, plus overall symptoms, were measured daily during the challenges, using the validated Gastrointestinal Symptom Rating Scale [GSRS] and a four-point Likert scale [absent = 0, mild = 1, moderate = 2, severe = 3].26 In addition, a composite symptom score was calculated as the average severity score of all 11 individual symptoms. Stool frequency and consistency were recorded using the Bristol Stool Form Scale.27 Participants were also asked to record adherence to the low FODMAP diet and challenge drinks on each day of the 3-day challenge.
Following completion of all four challenges and the final 4-day washout period, participants returned to the hospital clinic and gastrointestinal symptom incidence and severity, and stool consistency and frequency were recorded. Repeat blood samples were collected for CRP determination, and stool samples were provided for faecal calprotectin analysis, as previously described.
2.3. Challenges
Participants were allocated to consume four challenges in random order. The FODMAP challenges were 12 g/d of fructans [Beneo Orafti® P95 95% oligofructose; average degree of polymerisation 4; molecular weight 666.58 g/mol], 6 g/d of GOS [Hunan NutraMax Inc 98% soybean oligosaccharide; composed of stachyose ≥ 55–65%, raffinose ≥ 14–18%, verbascose ≥ 16–20%; average molecular weight 738.64 g/mol], 6 g/d of sorbitol [Roquette Pharma Neosorb P 60 W; molecular weight 182.17 g/mol], and 12 g/d of glucose [Thornton and Ross dextrose; molecular weight 180.16 g/mol]. Glucose was chosen as the placebo as it is efficiently absorbed in the small intestine and therefore would not be expected to induce gastrointestinal symptoms. The FODMAPs were chosen as they have not been investigated as inducers of FGS in patients with IBD. The doses of FODMAPs were chosen to reflect realistic quantities consumed in a UK diet, with fructans typically being consumed in greater quantities than GOS or sorbitol.7,28
The challenges were provided in identical opaque containers labelled only with the participant ID and the order [day, week] in which it was to be consumed, therefore blinding participants to their allocation. Challenges were provided in powder form and reconstituted with up to 100 ml of water by the participant before consumption. Participants were instructed to consume the ‘challenge drink’ before 11:00 h on each of the 3 days of the challenge, with or without food.
2.4. Ethical considerations
This trial was approved by the London-Camberwell St Giles Research Ethics Committee. Participants provided written informed consent before the collection of any research data. The trial was registered on a trial registry before recruitment of any participants [http://www.isrctn.com/ISRCTN98226923].
2.5. Sample size
The sample size estimation was calculated for the primary outcome and was based upon a previous FODMAP re-challenge trial in IBS.17 During a high-dose fructan challenge [19 g/d], 23% of patients with IBS reported adequate relief of gastrointestinal symptoms, compared with 86% during placebo challenge [20 g/d glucose]. The effect size in the current study was expected to be smaller since a lower fructan dose [12 g/d] was used to reflect intakes achievable in the normal diet. Therefore it was estimated that 50% of participants would report adequate relief of gastrointestinal symptoms during the fructan challenge and 86% during the placebo challenge. Sample size estimation revealed that with α level of 5%, β [power] 80% and an assumed attrition rate of 15%, 32 participants were required to detect such a difference in adequate relief of symptoms.
2.6. Statistical analysis
The primary endpoint was the proportion of participants reporting adequate relief of gastrointestinal symptoms following the FODMAP challenges [ie on the final day, Day 3] compared with placebo [glucose]. Secondary outcomes included the proportion of patients with adequate relief on all 3 days of the FODMAP challenges, and the mean number of days of adequate relief during the FODMAP challenges, compared with placebo [glucose]. Further secondary outcomes included gastrointestinal symptoms, stool frequency and consistency measured on the final day and during all 3 days of the FODMAP challenges compared with placebo [glucose], and the differences in concentrations of faecal calprotectin and CRP between baseline and follow-up.
All statistical analyses were performed using SPSS v.22. Baseline demographic data were compared between CD and UC using an independent t test for continuous variables or a χ2 test for categorical variables. The normality of continuous data was determined using Shapiro-Wilk test. Paired analyses were performed to compare data between FODMAP challenges and placebo [glucose], either parametric [repeated-measures ANOVA with Bonferroni post hoc adjustment] or non-parametric [Friedman test for four group comparisons, and where this was significant, Wilcoxon signed rank test with Bonferroni post hoc adjustment for two group comparisons] as appropriate, depending on data distribution. Values for CRP and faecal calprotectin were compared at the start and the end of the study using paired t tests. Differences were considered significant when p < 0.05. Data were analysed on all patients providing data for each challenge.
3. Results
3.1. Participants
A total of 32 patients with IBD were recruited [14 CD, 18 UC]. One participant exited the trial before the first challenge due to personal commitments, and one due to a subsequent raised serum CRP after randomisation. One exited the trial before the final challenge due to developing pneumonia and requiring a course of antibiotics. Trial data were not available for these three withdrawals and therefore data for 29 participants who completed all arms were analysed [12 CD, 17 UC] [Figure 1]. Baseline demographic characteristics and disease phenotype are provided in Table 1. Participants were aged 22–69 years (median 39 years, interquartile range [IQR] 19.5), and 11 [34.4%] participants were male. All participants met Rome III criteria for either IBS [n = 12], functional bloating [n = 12], or functional diarrhoea [n = 5]. Mean CRP and faecal calprotectin at baseline were 2.4, standard deviation [SD] 1.7 mg/L and 30.2, SD 29.9 µg/g, respectively. Patients with CD and UC did not differ significantly in any baseline characteristics, except for a significantly greater proportion of patients with UC taking 5-aminosalicylic acid [5-ASA] [15/17, 88.2% vs 3/12, 25.0%, P = 0.002] [Table 1].
. | Total IBD [n = 29] . | Crohn’s disease [n = 12] . | Ulcerative colitis [n = 17] . | p-Valuec . |
---|---|---|---|---|
Male, n [%] | 11 [34.4] | 4 [33.3] | 7 [41.2] | 0.668a |
Age [y], median [IQR] | 39.0 [19.5] | 40.5 [25.0] | 32.0 [19.5] | 0.661b |
Disease duration [y], mean [SD] | 12.8 [13.0] | 15.6 [15.8] | 10.9 [10.6] | 0.346b |
Time since last flare, n [%] | 0.060a | |||
≤ 1 year | 15 [46.9] | 3 [25.0] | 12 [70.6] | |
1–5 years | 8 [25.0] | 6 [50.0] | 2 [11.8] | |
6–10 years | 3 [9.4] | 1 [8.3] | 2 [11.8] | |
> 10 years | 3 [9.4] | 2 [16.7] | 1 [5.9] | |
Montreal classification, n [%] | - | Location L1, ileal: 3 [25] L2, colonic: 5 [42] L3, ileocolonic: 4 [33] Behaviour B1, nonstricturing, nonpenetrating: 10 [83] B3, penetrating: 2 [17] P, perianal disease: 2 [17] | Extent E1, proctitis: 9 [53] E2, left-sided: 3 [18] E3: pancolitis: 5 [29] | - |
CRP [mg/L], mean [SD] | 2.4 [1.7] | 2.3 [1.3] | 2.5 [2.0] | 0.741b |
Faecal calprotectin [µg/g], mean [SD] | 30.2 [29.9] | 19.8 [12.2] | 37.6 [36.3] | 0.116b |
Disease activity score, mean [SD] | HBI score 2.3 [3.3] | SCCAI score 1.8 [1.9] | - | |
FBD category, n [%] | 0.596a | |||
IBS | 12 | 4 | 8 | |
Functional bloating | 12 | 5 | 7 | |
Functional diarrhoea | 5 | 3 | 2 | |
Previous surgery, n [%] | 2 [6.3] | 2 [16.7] | 0 [0] | - |
Medications, n [%] | ||||
5-ASA | 18 [56.3] | 3 [25.0] | 15 [88.2] | 0.002a |
Thiopurines | 10 [31.3] | 6 [50.0] | 4 [23.5] | 0.280 |
Biologics | 3 [9.4] | 3 [25.0] | 0 [0] | 0.119 |
Other | 8 [25.0] | 3 [25.0] | 5 [29.4] | 1.000 |
. | Total IBD [n = 29] . | Crohn’s disease [n = 12] . | Ulcerative colitis [n = 17] . | p-Valuec . |
---|---|---|---|---|
Male, n [%] | 11 [34.4] | 4 [33.3] | 7 [41.2] | 0.668a |
Age [y], median [IQR] | 39.0 [19.5] | 40.5 [25.0] | 32.0 [19.5] | 0.661b |
Disease duration [y], mean [SD] | 12.8 [13.0] | 15.6 [15.8] | 10.9 [10.6] | 0.346b |
Time since last flare, n [%] | 0.060a | |||
≤ 1 year | 15 [46.9] | 3 [25.0] | 12 [70.6] | |
1–5 years | 8 [25.0] | 6 [50.0] | 2 [11.8] | |
6–10 years | 3 [9.4] | 1 [8.3] | 2 [11.8] | |
> 10 years | 3 [9.4] | 2 [16.7] | 1 [5.9] | |
Montreal classification, n [%] | - | Location L1, ileal: 3 [25] L2, colonic: 5 [42] L3, ileocolonic: 4 [33] Behaviour B1, nonstricturing, nonpenetrating: 10 [83] B3, penetrating: 2 [17] P, perianal disease: 2 [17] | Extent E1, proctitis: 9 [53] E2, left-sided: 3 [18] E3: pancolitis: 5 [29] | - |
CRP [mg/L], mean [SD] | 2.4 [1.7] | 2.3 [1.3] | 2.5 [2.0] | 0.741b |
Faecal calprotectin [µg/g], mean [SD] | 30.2 [29.9] | 19.8 [12.2] | 37.6 [36.3] | 0.116b |
Disease activity score, mean [SD] | HBI score 2.3 [3.3] | SCCAI score 1.8 [1.9] | - | |
FBD category, n [%] | 0.596a | |||
IBS | 12 | 4 | 8 | |
Functional bloating | 12 | 5 | 7 | |
Functional diarrhoea | 5 | 3 | 2 | |
Previous surgery, n [%] | 2 [6.3] | 2 [16.7] | 0 [0] | - |
Medications, n [%] | ||||
5-ASA | 18 [56.3] | 3 [25.0] | 15 [88.2] | 0.002a |
Thiopurines | 10 [31.3] | 6 [50.0] | 4 [23.5] | 0.280 |
Biologics | 3 [9.4] | 3 [25.0] | 0 [0] | 0.119 |
Other | 8 [25.0] | 3 [25.0] | 5 [29.4] | 1.000 |
IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; IQR, interquartile range; SD, standard deviation; y, years; FBD, functional bowel disorder; 5-ASA, 5-aminosalicylate; HBI, Harvey-Bradshaw Index; SCCAI Simple Clinical Colitis Activity Index.
aChi square test.
bIndependent samples t test
cCD vs UC.
. | Total IBD [n = 29] . | Crohn’s disease [n = 12] . | Ulcerative colitis [n = 17] . | p-Valuec . |
---|---|---|---|---|
Male, n [%] | 11 [34.4] | 4 [33.3] | 7 [41.2] | 0.668a |
Age [y], median [IQR] | 39.0 [19.5] | 40.5 [25.0] | 32.0 [19.5] | 0.661b |
Disease duration [y], mean [SD] | 12.8 [13.0] | 15.6 [15.8] | 10.9 [10.6] | 0.346b |
Time since last flare, n [%] | 0.060a | |||
≤ 1 year | 15 [46.9] | 3 [25.0] | 12 [70.6] | |
1–5 years | 8 [25.0] | 6 [50.0] | 2 [11.8] | |
6–10 years | 3 [9.4] | 1 [8.3] | 2 [11.8] | |
> 10 years | 3 [9.4] | 2 [16.7] | 1 [5.9] | |
Montreal classification, n [%] | - | Location L1, ileal: 3 [25] L2, colonic: 5 [42] L3, ileocolonic: 4 [33] Behaviour B1, nonstricturing, nonpenetrating: 10 [83] B3, penetrating: 2 [17] P, perianal disease: 2 [17] | Extent E1, proctitis: 9 [53] E2, left-sided: 3 [18] E3: pancolitis: 5 [29] | - |
CRP [mg/L], mean [SD] | 2.4 [1.7] | 2.3 [1.3] | 2.5 [2.0] | 0.741b |
Faecal calprotectin [µg/g], mean [SD] | 30.2 [29.9] | 19.8 [12.2] | 37.6 [36.3] | 0.116b |
Disease activity score, mean [SD] | HBI score 2.3 [3.3] | SCCAI score 1.8 [1.9] | - | |
FBD category, n [%] | 0.596a | |||
IBS | 12 | 4 | 8 | |
Functional bloating | 12 | 5 | 7 | |
Functional diarrhoea | 5 | 3 | 2 | |
Previous surgery, n [%] | 2 [6.3] | 2 [16.7] | 0 [0] | - |
Medications, n [%] | ||||
5-ASA | 18 [56.3] | 3 [25.0] | 15 [88.2] | 0.002a |
Thiopurines | 10 [31.3] | 6 [50.0] | 4 [23.5] | 0.280 |
Biologics | 3 [9.4] | 3 [25.0] | 0 [0] | 0.119 |
Other | 8 [25.0] | 3 [25.0] | 5 [29.4] | 1.000 |
. | Total IBD [n = 29] . | Crohn’s disease [n = 12] . | Ulcerative colitis [n = 17] . | p-Valuec . |
---|---|---|---|---|
Male, n [%] | 11 [34.4] | 4 [33.3] | 7 [41.2] | 0.668a |
Age [y], median [IQR] | 39.0 [19.5] | 40.5 [25.0] | 32.0 [19.5] | 0.661b |
Disease duration [y], mean [SD] | 12.8 [13.0] | 15.6 [15.8] | 10.9 [10.6] | 0.346b |
Time since last flare, n [%] | 0.060a | |||
≤ 1 year | 15 [46.9] | 3 [25.0] | 12 [70.6] | |
1–5 years | 8 [25.0] | 6 [50.0] | 2 [11.8] | |
6–10 years | 3 [9.4] | 1 [8.3] | 2 [11.8] | |
> 10 years | 3 [9.4] | 2 [16.7] | 1 [5.9] | |
Montreal classification, n [%] | - | Location L1, ileal: 3 [25] L2, colonic: 5 [42] L3, ileocolonic: 4 [33] Behaviour B1, nonstricturing, nonpenetrating: 10 [83] B3, penetrating: 2 [17] P, perianal disease: 2 [17] | Extent E1, proctitis: 9 [53] E2, left-sided: 3 [18] E3: pancolitis: 5 [29] | - |
CRP [mg/L], mean [SD] | 2.4 [1.7] | 2.3 [1.3] | 2.5 [2.0] | 0.741b |
Faecal calprotectin [µg/g], mean [SD] | 30.2 [29.9] | 19.8 [12.2] | 37.6 [36.3] | 0.116b |
Disease activity score, mean [SD] | HBI score 2.3 [3.3] | SCCAI score 1.8 [1.9] | - | |
FBD category, n [%] | 0.596a | |||
IBS | 12 | 4 | 8 | |
Functional bloating | 12 | 5 | 7 | |
Functional diarrhoea | 5 | 3 | 2 | |
Previous surgery, n [%] | 2 [6.3] | 2 [16.7] | 0 [0] | - |
Medications, n [%] | ||||
5-ASA | 18 [56.3] | 3 [25.0] | 15 [88.2] | 0.002a |
Thiopurines | 10 [31.3] | 6 [50.0] | 4 [23.5] | 0.280 |
Biologics | 3 [9.4] | 3 [25.0] | 0 [0] | 0.119 |
Other | 8 [25.0] | 3 [25.0] | 5 [29.4] | 1.000 |
IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; IQR, interquartile range; SD, standard deviation; y, years; FBD, functional bowel disorder; 5-ASA, 5-aminosalicylate; HBI, Harvey-Bradshaw Index; SCCAI Simple Clinical Colitis Activity Index.
aChi square test.
bIndependent samples t test
cCD vs UC.
3.2. Adherence to protocol and adverse events
Data on adherence to the low FODMAP diet and the challenge drinks were available for all participants. All participants reported high adherence to the low FODMAP diet during all of the challenges [defined as ≥ 75% adherence on all 3 challenge days]. The numbers of participants consuming all of the carbohydrate drink on all 3 days of the challenge were high during the fructan [97%], GOS [93%], sorbitol [100%], and glucose [97%] challenges [p = 0.392].
Data were included in the analysis for all patients completing the trial irrespective of compliance to the low FODMAP diet and the challenge drinks.
Two adverse events were reported during the trial. One participant reported dizziness and severe faecal incontinence during the fructan challenge, which resolved on the same day. This was not thought to require further investigation and the participant chose to continue the trial. One patient developed pneumonia following the GOS challenge, not suspected to be related to the trial, and was withdrawn due to antibiotic prescription.
3.3. Gastrointestinal symptoms
There was a significant difference in the proportion of participants reporting adequate relief of gastrointestinal symptoms on the final day [‘Day 3’] of each challenge, across the challenges [p = 0.033] [Table 2]. Post hoc correction revealed that significantly fewer participants reported adequate relief on the final day of the fructan challenge [18/29, 62.1%] than the glucose [placebo] challenge [26/29, 89.7%] [p = 0.033] but no significant differences were found between GOS [22/29, 75.9%] or sorbitol [23/29, 79.3%] compared with glucose [placebo] [Figure 2]. The difference in the number of days of adequate relief across the challenges approached significance [p = 0.057], with the lowest incidence being for fructans [mean 2.1, SD 1.2] [Table 2].
. | Fructan . | GOS . | Sorbitol . | Glucose . | p-Value . | p-Value for challenge vs glucosec . | ||
---|---|---|---|---|---|---|---|---|
Fructan . | GOS . | Sorbitol . | ||||||
Participants with adequate relief, n [%] | ||||||||
Final day of the challenge | 18 [62.1] | 22 [75.9] | 23 [79.3] | 26 [89.7] | 0.033a | 0.033 | 0.306 | 0.771 |
All 3 days of the challenge | 15 [51.7] | 20 [69.0] | 21 [72.4] | 23 [79.3] | 0.070a | - | - | - |
Number of days of adequate relief during the 3-day challenges, mean [SD] | 2.1 [1.2] | 2.4 [1.0] | 2.5 [1.0] | 2.7 [0.8] | 0.057b | - | - | - |
. | Fructan . | GOS . | Sorbitol . | Glucose . | p-Value . | p-Value for challenge vs glucosec . | ||
---|---|---|---|---|---|---|---|---|
Fructan . | GOS . | Sorbitol . | ||||||
Participants with adequate relief, n [%] | ||||||||
Final day of the challenge | 18 [62.1] | 22 [75.9] | 23 [79.3] | 26 [89.7] | 0.033a | 0.033 | 0.306 | 0.771 |
All 3 days of the challenge | 15 [51.7] | 20 [69.0] | 21 [72.4] | 23 [79.3] | 0.070a | - | - | - |
Number of days of adequate relief during the 3-day challenges, mean [SD] | 2.1 [1.2] | 2.4 [1.0] | 2.5 [1.0] | 2.7 [0.8] | 0.057b | - | - | - |
GOS, galacto-oligosaccharide; IBD, IBD, inflammatory bowel disease; SD, standard deviation.
aFriedman test across four challenges
bRepeated-measures ANOVA across four challenges
cEach challenge compared with placebo [glucose] using Wilcoxon signed rank test with Bonferroni correction for multiple comparisons.
. | Fructan . | GOS . | Sorbitol . | Glucose . | p-Value . | p-Value for challenge vs glucosec . | ||
---|---|---|---|---|---|---|---|---|
Fructan . | GOS . | Sorbitol . | ||||||
Participants with adequate relief, n [%] | ||||||||
Final day of the challenge | 18 [62.1] | 22 [75.9] | 23 [79.3] | 26 [89.7] | 0.033a | 0.033 | 0.306 | 0.771 |
All 3 days of the challenge | 15 [51.7] | 20 [69.0] | 21 [72.4] | 23 [79.3] | 0.070a | - | - | - |
Number of days of adequate relief during the 3-day challenges, mean [SD] | 2.1 [1.2] | 2.4 [1.0] | 2.5 [1.0] | 2.7 [0.8] | 0.057b | - | - | - |
. | Fructan . | GOS . | Sorbitol . | Glucose . | p-Value . | p-Value for challenge vs glucosec . | ||
---|---|---|---|---|---|---|---|---|
Fructan . | GOS . | Sorbitol . | ||||||
Participants with adequate relief, n [%] | ||||||||
Final day of the challenge | 18 [62.1] | 22 [75.9] | 23 [79.3] | 26 [89.7] | 0.033a | 0.033 | 0.306 | 0.771 |
All 3 days of the challenge | 15 [51.7] | 20 [69.0] | 21 [72.4] | 23 [79.3] | 0.070a | - | - | - |
Number of days of adequate relief during the 3-day challenges, mean [SD] | 2.1 [1.2] | 2.4 [1.0] | 2.5 [1.0] | 2.7 [0.8] | 0.057b | - | - | - |
GOS, galacto-oligosaccharide; IBD, IBD, inflammatory bowel disease; SD, standard deviation.
aFriedman test across four challenges
bRepeated-measures ANOVA across four challenges
cEach challenge compared with placebo [glucose] using Wilcoxon signed rank test with Bonferroni correction for multiple comparisons.
Symptom incidence and severity were not significantly different between CD and UC at baseline, preceding the fermentable carbohydrate challenges. There were also no significant differences in the severity of any symptoms across the challenges on the day before beginning challenges [‘Day 0’] [data not shown].
There were significant differences in incidence of moderate or severe pain [p = 0.006], bloating [p < 0.001], flatulence [p = 0.001], and overall symptoms [p = 0.021] across the challenges [Table 3]. Following post hoc correction comparing differences between each FODMAP challenge and glucose [placebo], there were significantly greater numbers of days of moderate or severe pain [0.9, SD 1.1 vs 0.2, SD 0.6, p = 0.014], bloating [1.0, SD 1.0 vs 0.3, SD 0.7, p = 0.017], and flatulence [1.2, SD 1.2 vs 0.4, SD 0.7, p = 0.034] during the fructan challenge compared with the glucose placebo only [Table 3].
. | Incidence [number of days] of moderate or severe symptoms during the 3-day challenges, mean [SD] . | Severity of symptoms on final day of challenge, mean [SD]b . | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
. | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . |
Abdominal pain | 0.9 [1.1]* | 0.4 [0.8] | 0.6 [0.9] | 0.2 [0.6] | 0.006 | 1.1 [0.8]* | 0.8 [0.9] | 0.7 [0.9] | 0.5 [0.6] | 0.006 |
Bloating | 1.0 [1.0]* | 0.2 [0.6] | 0.6 [1.1] | 0.3 [0.7] | < 0.001 | 1.3 [0.9]* | 0.6 [0.7] | 0.8 [0.8] | 0.6 [0.7] | < 0.001 |
Flatulence | 1.2 [1.2]* | 0.6 [1.0] | 0.2 [0.5] | 0.4 [0.7] | 0.001 | 1.5 [0.8]* | 0.9 [1.0] | 0.7 [0.6] | 0.7 [0.7] | < 0.001 |
Belching | 0.3 [0.7] | 0.1 [0.4] | 0.1 [0.4] | 0.1 [0.4] | 0.095 | 0.3 [0.7] | 0.3 [0.7] | 0.3 [0.6] | 0.2 [0.4] | 0.751 |
Borborygmi | 0.3 [0.9] | 0.2 [0.6] | 0.0 [0.2] | 0.2 [0.7] | 0.239 | 0.7 [0.9] | 0.4 [0.8] | 0.3 [0.5] | 0.3 [0.5] | 0.036 |
Faecal urgency | 0.7 [1.1] | 0.4 [0.9] | 0.4 [0.9] | 0.2 [0.7] | 0.055 | 0.9 [1.1]* | 0.7 [1.0] | 0.5 [0.7] | 0.4 [0.6] | 0.011 |
Incomplete evacuation | 0.4 [0.9] | 0.1 [0.3] | 0.1 [0.4] | 0.1 [0.4] | 0.158 | 0.6 [0.7] | 0.3 [0.5] | 0.2 [0.6] | 0.2 [0.5] | 0.026 |
Nausea | 0.1 [0.4] | 0.0 [0.2] | 0.1 [0.6] | 0.1 [0.3] | 0.699 | 0.2 [0.5] | 0.2 [0.5] | 0.2 [0.5] | 0.2 [0.4] | 0.987 |
Heartburn | 0.1 [0.4] | 0.0 [0.2] | 0.0 [0.0] | 0.0 [0.2] | 0.179 | 0.2 [0.5] | 0.2 [0.5] | 0.1 [0.3] | 0.0 [0.2] | 0.273 |
Acid regurgitation | 0.0 [0.2] | 0.0 [0.2] | 0.0 [0.2] | 0.0 [0.0] | 0.596 | 0.1 [0.4] | 0.1 [0.3] | 0.1 [0.3] | 0.1 [0.4] | 0.505 |
Lethargy | 0.6 [1.1] | 0.3 [0.8] | 0.4 [0.9] | 0.4 [0.9] | 0.159 | 1.0 [1.0] | 0.6 [0.8] | 0.8 [0.9] | 0.8 [1.0] | 0.068 |
Overall | 0.8 [1.1] | 0.3 [0.6] | 0.3 [0.6] | 0.3 [0.6] | 0.021 | 1.1 [0.9] | 0.7 [0.8] | 0.6 [0.7] | 0.7 [0.6] | 0.006 |
. | Incidence [number of days] of moderate or severe symptoms during the 3-day challenges, mean [SD] . | Severity of symptoms on final day of challenge, mean [SD]b . | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
. | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . |
Abdominal pain | 0.9 [1.1]* | 0.4 [0.8] | 0.6 [0.9] | 0.2 [0.6] | 0.006 | 1.1 [0.8]* | 0.8 [0.9] | 0.7 [0.9] | 0.5 [0.6] | 0.006 |
Bloating | 1.0 [1.0]* | 0.2 [0.6] | 0.6 [1.1] | 0.3 [0.7] | < 0.001 | 1.3 [0.9]* | 0.6 [0.7] | 0.8 [0.8] | 0.6 [0.7] | < 0.001 |
Flatulence | 1.2 [1.2]* | 0.6 [1.0] | 0.2 [0.5] | 0.4 [0.7] | 0.001 | 1.5 [0.8]* | 0.9 [1.0] | 0.7 [0.6] | 0.7 [0.7] | < 0.001 |
Belching | 0.3 [0.7] | 0.1 [0.4] | 0.1 [0.4] | 0.1 [0.4] | 0.095 | 0.3 [0.7] | 0.3 [0.7] | 0.3 [0.6] | 0.2 [0.4] | 0.751 |
Borborygmi | 0.3 [0.9] | 0.2 [0.6] | 0.0 [0.2] | 0.2 [0.7] | 0.239 | 0.7 [0.9] | 0.4 [0.8] | 0.3 [0.5] | 0.3 [0.5] | 0.036 |
Faecal urgency | 0.7 [1.1] | 0.4 [0.9] | 0.4 [0.9] | 0.2 [0.7] | 0.055 | 0.9 [1.1]* | 0.7 [1.0] | 0.5 [0.7] | 0.4 [0.6] | 0.011 |
Incomplete evacuation | 0.4 [0.9] | 0.1 [0.3] | 0.1 [0.4] | 0.1 [0.4] | 0.158 | 0.6 [0.7] | 0.3 [0.5] | 0.2 [0.6] | 0.2 [0.5] | 0.026 |
Nausea | 0.1 [0.4] | 0.0 [0.2] | 0.1 [0.6] | 0.1 [0.3] | 0.699 | 0.2 [0.5] | 0.2 [0.5] | 0.2 [0.5] | 0.2 [0.4] | 0.987 |
Heartburn | 0.1 [0.4] | 0.0 [0.2] | 0.0 [0.0] | 0.0 [0.2] | 0.179 | 0.2 [0.5] | 0.2 [0.5] | 0.1 [0.3] | 0.0 [0.2] | 0.273 |
Acid regurgitation | 0.0 [0.2] | 0.0 [0.2] | 0.0 [0.2] | 0.0 [0.0] | 0.596 | 0.1 [0.4] | 0.1 [0.3] | 0.1 [0.3] | 0.1 [0.4] | 0.505 |
Lethargy | 0.6 [1.1] | 0.3 [0.8] | 0.4 [0.9] | 0.4 [0.9] | 0.159 | 1.0 [1.0] | 0.6 [0.8] | 0.8 [0.9] | 0.8 [1.0] | 0.068 |
Overall | 0.8 [1.1] | 0.3 [0.6] | 0.3 [0.6] | 0.3 [0.6] | 0.021 | 1.1 [0.9] | 0.7 [0.8] | 0.6 [0.7] | 0.7 [0.6] | 0.006 |
GOS, galacto-oligosaccharide; IBD, inflammatory bowel disease; SD, standard deviation.
aRepeated-measures ANOVA across four challenges.
bSeverity scoring system: 0 = absent, 1 = mild, 2 = moderate, 3 = severe.
*Significantly different from placebo [glucose] on post hoc analysis with Bonferroni correction for multiple comparisons.
. | Incidence [number of days] of moderate or severe symptoms during the 3-day challenges, mean [SD] . | Severity of symptoms on final day of challenge, mean [SD]b . | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
. | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . |
Abdominal pain | 0.9 [1.1]* | 0.4 [0.8] | 0.6 [0.9] | 0.2 [0.6] | 0.006 | 1.1 [0.8]* | 0.8 [0.9] | 0.7 [0.9] | 0.5 [0.6] | 0.006 |
Bloating | 1.0 [1.0]* | 0.2 [0.6] | 0.6 [1.1] | 0.3 [0.7] | < 0.001 | 1.3 [0.9]* | 0.6 [0.7] | 0.8 [0.8] | 0.6 [0.7] | < 0.001 |
Flatulence | 1.2 [1.2]* | 0.6 [1.0] | 0.2 [0.5] | 0.4 [0.7] | 0.001 | 1.5 [0.8]* | 0.9 [1.0] | 0.7 [0.6] | 0.7 [0.7] | < 0.001 |
Belching | 0.3 [0.7] | 0.1 [0.4] | 0.1 [0.4] | 0.1 [0.4] | 0.095 | 0.3 [0.7] | 0.3 [0.7] | 0.3 [0.6] | 0.2 [0.4] | 0.751 |
Borborygmi | 0.3 [0.9] | 0.2 [0.6] | 0.0 [0.2] | 0.2 [0.7] | 0.239 | 0.7 [0.9] | 0.4 [0.8] | 0.3 [0.5] | 0.3 [0.5] | 0.036 |
Faecal urgency | 0.7 [1.1] | 0.4 [0.9] | 0.4 [0.9] | 0.2 [0.7] | 0.055 | 0.9 [1.1]* | 0.7 [1.0] | 0.5 [0.7] | 0.4 [0.6] | 0.011 |
Incomplete evacuation | 0.4 [0.9] | 0.1 [0.3] | 0.1 [0.4] | 0.1 [0.4] | 0.158 | 0.6 [0.7] | 0.3 [0.5] | 0.2 [0.6] | 0.2 [0.5] | 0.026 |
Nausea | 0.1 [0.4] | 0.0 [0.2] | 0.1 [0.6] | 0.1 [0.3] | 0.699 | 0.2 [0.5] | 0.2 [0.5] | 0.2 [0.5] | 0.2 [0.4] | 0.987 |
Heartburn | 0.1 [0.4] | 0.0 [0.2] | 0.0 [0.0] | 0.0 [0.2] | 0.179 | 0.2 [0.5] | 0.2 [0.5] | 0.1 [0.3] | 0.0 [0.2] | 0.273 |
Acid regurgitation | 0.0 [0.2] | 0.0 [0.2] | 0.0 [0.2] | 0.0 [0.0] | 0.596 | 0.1 [0.4] | 0.1 [0.3] | 0.1 [0.3] | 0.1 [0.4] | 0.505 |
Lethargy | 0.6 [1.1] | 0.3 [0.8] | 0.4 [0.9] | 0.4 [0.9] | 0.159 | 1.0 [1.0] | 0.6 [0.8] | 0.8 [0.9] | 0.8 [1.0] | 0.068 |
Overall | 0.8 [1.1] | 0.3 [0.6] | 0.3 [0.6] | 0.3 [0.6] | 0.021 | 1.1 [0.9] | 0.7 [0.8] | 0.6 [0.7] | 0.7 [0.6] | 0.006 |
. | Incidence [number of days] of moderate or severe symptoms during the 3-day challenges, mean [SD] . | Severity of symptoms on final day of challenge, mean [SD]b . | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
. | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . |
Abdominal pain | 0.9 [1.1]* | 0.4 [0.8] | 0.6 [0.9] | 0.2 [0.6] | 0.006 | 1.1 [0.8]* | 0.8 [0.9] | 0.7 [0.9] | 0.5 [0.6] | 0.006 |
Bloating | 1.0 [1.0]* | 0.2 [0.6] | 0.6 [1.1] | 0.3 [0.7] | < 0.001 | 1.3 [0.9]* | 0.6 [0.7] | 0.8 [0.8] | 0.6 [0.7] | < 0.001 |
Flatulence | 1.2 [1.2]* | 0.6 [1.0] | 0.2 [0.5] | 0.4 [0.7] | 0.001 | 1.5 [0.8]* | 0.9 [1.0] | 0.7 [0.6] | 0.7 [0.7] | < 0.001 |
Belching | 0.3 [0.7] | 0.1 [0.4] | 0.1 [0.4] | 0.1 [0.4] | 0.095 | 0.3 [0.7] | 0.3 [0.7] | 0.3 [0.6] | 0.2 [0.4] | 0.751 |
Borborygmi | 0.3 [0.9] | 0.2 [0.6] | 0.0 [0.2] | 0.2 [0.7] | 0.239 | 0.7 [0.9] | 0.4 [0.8] | 0.3 [0.5] | 0.3 [0.5] | 0.036 |
Faecal urgency | 0.7 [1.1] | 0.4 [0.9] | 0.4 [0.9] | 0.2 [0.7] | 0.055 | 0.9 [1.1]* | 0.7 [1.0] | 0.5 [0.7] | 0.4 [0.6] | 0.011 |
Incomplete evacuation | 0.4 [0.9] | 0.1 [0.3] | 0.1 [0.4] | 0.1 [0.4] | 0.158 | 0.6 [0.7] | 0.3 [0.5] | 0.2 [0.6] | 0.2 [0.5] | 0.026 |
Nausea | 0.1 [0.4] | 0.0 [0.2] | 0.1 [0.6] | 0.1 [0.3] | 0.699 | 0.2 [0.5] | 0.2 [0.5] | 0.2 [0.5] | 0.2 [0.4] | 0.987 |
Heartburn | 0.1 [0.4] | 0.0 [0.2] | 0.0 [0.0] | 0.0 [0.2] | 0.179 | 0.2 [0.5] | 0.2 [0.5] | 0.1 [0.3] | 0.0 [0.2] | 0.273 |
Acid regurgitation | 0.0 [0.2] | 0.0 [0.2] | 0.0 [0.2] | 0.0 [0.0] | 0.596 | 0.1 [0.4] | 0.1 [0.3] | 0.1 [0.3] | 0.1 [0.4] | 0.505 |
Lethargy | 0.6 [1.1] | 0.3 [0.8] | 0.4 [0.9] | 0.4 [0.9] | 0.159 | 1.0 [1.0] | 0.6 [0.8] | 0.8 [0.9] | 0.8 [1.0] | 0.068 |
Overall | 0.8 [1.1] | 0.3 [0.6] | 0.3 [0.6] | 0.3 [0.6] | 0.021 | 1.1 [0.9] | 0.7 [0.8] | 0.6 [0.7] | 0.7 [0.6] | 0.006 |
GOS, galacto-oligosaccharide; IBD, inflammatory bowel disease; SD, standard deviation.
aRepeated-measures ANOVA across four challenges.
bSeverity scoring system: 0 = absent, 1 = mild, 2 = moderate, 3 = severe.
*Significantly different from placebo [glucose] on post hoc analysis with Bonferroni correction for multiple comparisons.
In addition, across the challenges there were significant differences in the severity [absent = 0, mild = 1, moderate = 2, severe = 3] of pain [p = 0.006], bloating [p < 0.001], flatulence [p < 0.001], borborygmi [p = 0.036] faecal urgency [p = 0.011], incomplete evacuation [p = 0.026], and overall symptoms [p = 0.006] on the final day of the challenge [Table 3]. Following post hoc correction, there was significantly greater severity of pain [1.1, SD 0.8 vs 0.5, SD 0.6, p = 0.004], bloating [1.3, SD 0.9 vs 0.6, SD 0.7, p = 0.002], flatulence [1.5, SD 0.8 vs 0.7, SD 0.7, p = 0.004], and faecal urgency [0.9, SD 1.1 vs 0.4, SD 0.6, p = 0.014] on the final day of the fructan challenge compared with the glucose [placebo] only [Table 3].
A composite symptom severity score was calculated as the mean severity of all 11 gastrointestinal symptoms [absent = 0, mild = 1, moderate = 2, severe = 3] on the final day of the challenges. There was a significant difference across the challenges in the composite score on the final day of the challenges [p < 0.001], with post hoc correction revealing a significantly greater composite score on the final day of the fructan challenge [0.72, SD 0.49] compared with glucose [placebo] [0.39, SD 0.33] [p = 0.002]. There was no significant difference in any of the individual scores or in the composite score on the final day or all 3 days of the GOS or sorbitol challenges compared with glucose [placebo].
3.4. Stool frequency and consistency
Stool frequency and consistency were assessed using the Bristol Stool Form Scale on each day of the challenges [Table 4]. There was a significant difference in daily stool frequency across the challenges [p = 0.026], although this did not reach significance between any of the fermentable carbohydrate challenges compared with glucose [placebo] following post hoc adjustment. In light of the finding that significantly fewer patients reported adequate relief on Day 3 of the fructan challenge compared with glucose [placebo], stool frequency on Day 3 of the challenges was compared to explore a possible cumulative or delayed effect of the fermentable carbohydrates. This revealed no significant difference across the challenges [p = 0.412] [Table 4].
Mean [SD] . | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . | p-Value challenge vs glucoseb . | ||
---|---|---|---|---|---|---|---|---|
Fructan . | GOS . | Sorbitol . | ||||||
Stool frequency [per day] | ||||||||
Final day of challenge | 2.3 [1.8] | 2.1 [1.4] | 2.1 [1.6] | 1.9 [1.3] | 0.412 | - | - | - |
All 3 days of the challenge | 2.4 [1.4] | 2.1 [1.2] | 2.1 [1.5] | 1.9 [1.2] | 0.026 | 0.067 | 1.000 | 0.986 |
Stool consistency [BSFS] | ||||||||
Final day of challenge | 4.9 [1.2] | 4.3 [1.1] | 4.1 [1.3] | 4.0 [1.2] | 0.017 | 0.070 | 1.000 | 1.000 |
All 3 days of the challenge | 4.2 [1.3] | 4.0 [1.0] | 3.8 [1.2] | 3.5 [1.0] | 0.010 | 0.007 | 0.033 | 0.247 |
Proportion of stools of normal consistency [%] | ||||||||
Final day of challenge | 48.8 [42.3] | 71.0 [40.1] | 63.4 [43.3] | 66.1 [45.9] | 0.141 | - | - | - |
All 3 days of the challenge | 71.0 [33.5] | 78.5 [30.0] | 74.3 [34.5] | 66.6 [32.6] | 0.273 | - | - | - |
Mean [SD] . | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . | p-Value challenge vs glucoseb . | ||
---|---|---|---|---|---|---|---|---|
Fructan . | GOS . | Sorbitol . | ||||||
Stool frequency [per day] | ||||||||
Final day of challenge | 2.3 [1.8] | 2.1 [1.4] | 2.1 [1.6] | 1.9 [1.3] | 0.412 | - | - | - |
All 3 days of the challenge | 2.4 [1.4] | 2.1 [1.2] | 2.1 [1.5] | 1.9 [1.2] | 0.026 | 0.067 | 1.000 | 0.986 |
Stool consistency [BSFS] | ||||||||
Final day of challenge | 4.9 [1.2] | 4.3 [1.1] | 4.1 [1.3] | 4.0 [1.2] | 0.017 | 0.070 | 1.000 | 1.000 |
All 3 days of the challenge | 4.2 [1.3] | 4.0 [1.0] | 3.8 [1.2] | 3.5 [1.0] | 0.010 | 0.007 | 0.033 | 0.247 |
Proportion of stools of normal consistency [%] | ||||||||
Final day of challenge | 48.8 [42.3] | 71.0 [40.1] | 63.4 [43.3] | 66.1 [45.9] | 0.141 | - | - | - |
All 3 days of the challenge | 71.0 [33.5] | 78.5 [30.0] | 74.3 [34.5] | 66.6 [32.6] | 0.273 | - | - | - |
GOS, galacto-oligosaccharide; IBD, inflammatory bowel disease; BSFS, Bristol Stool Form Scale.
aRepeated-measures ANOVA across four challenges.
bEach challenge compared with placebo [glucose] using paired t test with Bonferroni post hoc correction for multiple comparisons.
Mean [SD] . | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . | p-Value challenge vs glucoseb . | ||
---|---|---|---|---|---|---|---|---|
Fructan . | GOS . | Sorbitol . | ||||||
Stool frequency [per day] | ||||||||
Final day of challenge | 2.3 [1.8] | 2.1 [1.4] | 2.1 [1.6] | 1.9 [1.3] | 0.412 | - | - | - |
All 3 days of the challenge | 2.4 [1.4] | 2.1 [1.2] | 2.1 [1.5] | 1.9 [1.2] | 0.026 | 0.067 | 1.000 | 0.986 |
Stool consistency [BSFS] | ||||||||
Final day of challenge | 4.9 [1.2] | 4.3 [1.1] | 4.1 [1.3] | 4.0 [1.2] | 0.017 | 0.070 | 1.000 | 1.000 |
All 3 days of the challenge | 4.2 [1.3] | 4.0 [1.0] | 3.8 [1.2] | 3.5 [1.0] | 0.010 | 0.007 | 0.033 | 0.247 |
Proportion of stools of normal consistency [%] | ||||||||
Final day of challenge | 48.8 [42.3] | 71.0 [40.1] | 63.4 [43.3] | 66.1 [45.9] | 0.141 | - | - | - |
All 3 days of the challenge | 71.0 [33.5] | 78.5 [30.0] | 74.3 [34.5] | 66.6 [32.6] | 0.273 | - | - | - |
Mean [SD] . | Fructan . | GOS . | Sorbitol . | Glucose . | p-Valuea . | p-Value challenge vs glucoseb . | ||
---|---|---|---|---|---|---|---|---|
Fructan . | GOS . | Sorbitol . | ||||||
Stool frequency [per day] | ||||||||
Final day of challenge | 2.3 [1.8] | 2.1 [1.4] | 2.1 [1.6] | 1.9 [1.3] | 0.412 | - | - | - |
All 3 days of the challenge | 2.4 [1.4] | 2.1 [1.2] | 2.1 [1.5] | 1.9 [1.2] | 0.026 | 0.067 | 1.000 | 0.986 |
Stool consistency [BSFS] | ||||||||
Final day of challenge | 4.9 [1.2] | 4.3 [1.1] | 4.1 [1.3] | 4.0 [1.2] | 0.017 | 0.070 | 1.000 | 1.000 |
All 3 days of the challenge | 4.2 [1.3] | 4.0 [1.0] | 3.8 [1.2] | 3.5 [1.0] | 0.010 | 0.007 | 0.033 | 0.247 |
Proportion of stools of normal consistency [%] | ||||||||
Final day of challenge | 48.8 [42.3] | 71.0 [40.1] | 63.4 [43.3] | 66.1 [45.9] | 0.141 | - | - | - |
All 3 days of the challenge | 71.0 [33.5] | 78.5 [30.0] | 74.3 [34.5] | 66.6 [32.6] | 0.273 | - | - | - |
GOS, galacto-oligosaccharide; IBD, inflammatory bowel disease; BSFS, Bristol Stool Form Scale.
aRepeated-measures ANOVA across four challenges.
bEach challenge compared with placebo [glucose] using paired t test with Bonferroni post hoc correction for multiple comparisons.
There was a significant difference in stool consistency across the challenges [p = 0.010] and post hoc correction revealed a significantly greater Bristol Stool Form Scale score [representing softer stools] during the fructan [4.2, SD 1.3, p = 0.007] and GOS [4.2, SD 1.3, p = 0.033] challenges compared with glucose [placebo] [3.5, SD 1.0]. There was also a significant difference in stool consistency on Day 3 of the challenge across the challenges [p = 0.017]; however, post hoc correction revealed no significant differences between any of the fermentable carbohydrates compared with glucose [placebo]. Across the challenges, there was no significant difference in the proportion of stools that were of normal consistency [Bristol Stool Form Scale type 3, 4, or 5] during the challenges [p = 0.273] or on the final day of the challenges [p = 0.141] [Table 4].
3.5. Inflammatory markers
Start and end of trial CRP concentrations were available for 27 participants [10 CD, 17 UC], and faecal calprotectin concentrations for 24 participants [10 CD, 14 UC] [Table 5]. There was no significant difference in CRP between the start and end of trial [p = 0.797]. However, faecal calprotectin increased significantly between baseline and end of trial [29.5 µg/g, SD 31.0 vs 72.9 µg/g, SD 82.1, p = 0.018]. When sub-group analyses were performed individually for CD and UC, the difference in faecal calprotectin was significant only for CD between baseline and end of trial [16.8 µg/g, SD 5.7 vs 46.4 µg/g, SD 32.8, p = 0.026]. However, only two participants [8%] had a faecal calprotectin > 250 µg/g at end of trial.
Mean [SD] . | Baseline . | End of trial . | p-Valuea . |
---|---|---|---|
CRP [mg/L] | |||
All participants [n = 27] | 2.3 [1.8] | 2.4 [1.7] | 0.797 |
CD [n = 10] | 2.1 [1.3] | 2.6 [2.2] | 0.487 |
UC [n = 17] | 2.5 [2.0] | 2.3 [1.3] | 0.624 |
Faecal calprotectin [µg/g] | |||
All participants [n = 24] | 29.5 [31.0] | 72.9 [82.1] | 0.018 |
CD [n = 10] | 16.8 [5.7] | 46.4 [32.8] | 0.026 |
UC [n = 14] | 38.6 [38.3] | 91.9 [101.3] | 0.083 |
Mean [SD] . | Baseline . | End of trial . | p-Valuea . |
---|---|---|---|
CRP [mg/L] | |||
All participants [n = 27] | 2.3 [1.8] | 2.4 [1.7] | 0.797 |
CD [n = 10] | 2.1 [1.3] | 2.6 [2.2] | 0.487 |
UC [n = 17] | 2.5 [2.0] | 2.3 [1.3] | 0.624 |
Faecal calprotectin [µg/g] | |||
All participants [n = 24] | 29.5 [31.0] | 72.9 [82.1] | 0.018 |
CD [n = 10] | 16.8 [5.7] | 46.4 [32.8] | 0.026 |
UC [n = 14] | 38.6 [38.3] | 91.9 [101.3] | 0.083 |
SD, standard deviation; CRP, C-reactive protein; CD, Crohn’s disease; UC, ulcerative colitis.
a Paired t test comparing baseline and end of trial.
Mean [SD] . | Baseline . | End of trial . | p-Valuea . |
---|---|---|---|
CRP [mg/L] | |||
All participants [n = 27] | 2.3 [1.8] | 2.4 [1.7] | 0.797 |
CD [n = 10] | 2.1 [1.3] | 2.6 [2.2] | 0.487 |
UC [n = 17] | 2.5 [2.0] | 2.3 [1.3] | 0.624 |
Faecal calprotectin [µg/g] | |||
All participants [n = 24] | 29.5 [31.0] | 72.9 [82.1] | 0.018 |
CD [n = 10] | 16.8 [5.7] | 46.4 [32.8] | 0.026 |
UC [n = 14] | 38.6 [38.3] | 91.9 [101.3] | 0.083 |
Mean [SD] . | Baseline . | End of trial . | p-Valuea . |
---|---|---|---|
CRP [mg/L] | |||
All participants [n = 27] | 2.3 [1.8] | 2.4 [1.7] | 0.797 |
CD [n = 10] | 2.1 [1.3] | 2.6 [2.2] | 0.487 |
UC [n = 17] | 2.5 [2.0] | 2.3 [1.3] | 0.624 |
Faecal calprotectin [µg/g] | |||
All participants [n = 24] | 29.5 [31.0] | 72.9 [82.1] | 0.018 |
CD [n = 10] | 16.8 [5.7] | 46.4 [32.8] | 0.026 |
UC [n = 14] | 38.6 [38.3] | 91.9 [101.3] | 0.083 |
SD, standard deviation; CRP, C-reactive protein; CD, Crohn’s disease; UC, ulcerative colitis.
a Paired t test comparing baseline and end of trial.
4. Discussion
Functional-like gastrointestinal symptoms are experienced by many patients with IBD in remission and have a significant impact on health-related quality of life,3 and therefore effective management of the symptoms is essential. A re-challenge trial demonstrated that fructans induce gastrointestinal symptoms in patients with IBS while following a strict low FODMAP diet.17 This is the first randomised, placebo-controlled, cross-over re-challenge trial to investigate the effect of fermentable carbohydrate challenges in patients with IBD and FGS.
It is important to determine whether a low FODMAP diet could be an effective strategy for managing FGS in IBD. However, dietary intervention studies [eg low FODMAP diet] are fraught with challenges, including the notorious difficulty in controlling for changes in dietary components other than those under investigation and the placebo response that may be as high as 84% in functional bowel disorder trials.16,29 In order to address these difficulties in dietary trial design, a re-challenge trial to establish whether exacerbation of FGS in IBD occurred during challenge with pure FODMAP compounds was warranted.
Significantly fewer participants reported adequate relief of gastrointestinal symptoms on the final day of the fructan challenge compared with placebo [glucose]. There was also a greater incidence of moderate or severe abdominal pain, bloating, and flatulence during the fructan challenge compared with placebo [glucose] and greater severity of abdominal pain, bloating, flatulence, and faecal urgency on the final day of the fructan challenge compared with placebo [glucose]. These statistically significant findings for fructans compared with placebo were not observed during the GOS and sorbitol challenges.
The reduced incidence of adequate relief and increase in FGS during the fructan challenge is consistent with the proposed mechanisms of FODMAPs in FGS exacerbation. Fructans are a heterogeneous group of linear or branched fructose oligosaccharides, which undergo minimal digestion in the small intestine due to a lack of enzymes capable of hydrolysing the β-[2-1] fructosyl-fructose glycosidic bonds. Research using ileostomy models and aspiration of distal ileal contents indicate that the majority of ingested fructans are recovered from the small intestine [87–89%] and are therefore available for colonic bacterial fermentation and the associated gas production.30–32 A high FODMAP diet has previously been shown to increase breath hydrogen [a marker of colonic gas production] in both healthy volunteers and patients with IBS, but only induced gastrointestinal symptoms in those with IBS,11 a finding that has recently been confirmed during fructan challenges using functional MRI.13 Therefore, the worsening of symptoms attributable to colonic gas volume [pain, bloating, and flatulence] in the current study is supported, whereas the lack of impact on other symptoms [eg nausea, heartburn, acid reflux] implies that the effects of fructans are specific to increased colonic gas volume and that they do not include generalised gastrointestinal effects. This finding also reflects those of a randomised controlled trial in which patients with active Crohn’s disease experienced a worsening of abdominal pain, flatulence, and borborygmi during fructan supplementation, whereas acid reflux was not affected.18
Although the number of patients with adequate relief was lower on the final day of the fructan challenge compared with placebo, there was no difference in the number of days of adequate relief during the whole 3-day challenge. This might be the result of a cumulative effect of the fructan challenge, with a peak in symptoms on the final day, not reflected when presenting an average over the 3 days.
The lack of symptom exacerbation following GOS and sorbitol is interesting given that, like fructans they are incompletely digested and undergo bacterial fermentation. A soybean-derived α-GOS was chosen in this study to mimic GOS found in the diet [eg pulses, grains, and nuts]. Mammals lack the α-galactosidase enzyme required for hydrolysis of α-1,6 linkages within α-GOS, therefore it is assumed that dietary α-GOS is not digested,33 with one small study reporting 88% of ingested raffinose reaches the colon intact and is available for bacterial fermentation.34
The GOS dose chosen in this study may have been inadequate to generate symptoms. Additionally, it could be that FODMAPs have an additive effect, as has been demonstrated in a FODMAP re-challenge trial in IBS, in which a mixture of fructans and fructose induced gut symptoms to a greater degree than these fermentable carbohydrates in isolation.17 It may be possible to accommodate luminal distension following isolated FODMAP challenges, but when several FODMAPs are combined within foods administered throughout the day, a significant worsening of symptoms may occur. However, this would not explain the inconsistency in exacerbation of symptoms by fructans, but not GOS or sorbitol in the current study.
Since polyols increase small bowel water content,35 it could be hypothesised that a sorbitol challenge would result in looser stools. This was not observed during the sorbitol challenge in this study, and could potentially be explained by the dose of sorbitol administered. A study in healthy volunteers in which mannitol was shown to significantly increase small bowel water [measured using MRI] used a 40-g dose of mannitol,35 in contrast to the 6 g/day used in this study. The limited duration of the challenges and variable baseline stool frequency and consistency might also explain the lack of effect of the sorbitol challenge on stool frequency and consistency.
Sorbitol and mannitol challenges have previously been shown to exacerbate gastrointestinal symptoms in IBS.36 Although an ileostomy study demonstrated incomplete intestinal absorption of 15 g orally administered sorbitol,37 malabsorption of polyols may not be required for symptom generation.38 This previous study administered 10-g doses of sorbitol and mannitol and, therefore, the discrepancy in results with the current study in terms of gastrointestinal symptom exacerbation may, again, relate to differences in the dose of polyol administered. In addition, in the aforementioned study, patients took the polyol challenges after an 8-h fast, in contrast to the current study in which patients were permitted to take the challenge drink with food in the context of an ongoing low FODMAP diet. Gastrointestinal physiology and symptom responses may vary depending on whether the carbohydrate is taken with or without food, given the complex mixture of nutrients and fibre that are present in whole foods.
This study was designed to assess the impact of FODMAPs consumed within a standard diet. Therefore, the doses of the challenges used were chosen to reflect realistic UK intakes based upon our own dietary intake survey data in healthy people, IBS, and IBD.7,28,39 It should be noted that the doses chosen in this study likely reflect the extremes of dietary FODMAP intake [although are not unrealistic] and therefore caution should be used in extrapolating the current findings to clinical practice. That said, patients in this trial were instructed to follow a strict low FODMAP diet during the challenges, and the 12 g/day provided during the fructan challenge likely still represents a relatively typical overall FODMAP intake.7 Furthermore, the dose of fructans chosen in this study was lower than the 19 g/d of fructans used in the only other challenge trial of this nature.40
Fructan intakes in a typical UK diet are considerably greater than for GOS or sorbitol and therefore a higher dose was selected for fructans [12 g/d] compared with GOS or sorbitol [6 g/d].7 Providing equal doses of 12 g/d for all challenges would be the equivalent of challenging with 2.5 cans [c. 1 kg] of chickpeas for GOS or eight plums for sorbitol.36,41 It was therefore not considered appropriate to use equal doses for the different carbohydrate challenges. This does however mean that the exacerbation of symptoms during only the fructan challenge may be partially explained by the greater dose compared with GOS and sorbitol [where no symptom exacerbation was observed]. Further studies would be required to elucidate whether symptom induction is specific to fructans in this group of patients.
Additionally, since the quantity of carbohydrate in the carton was greater during the fructan challenge, a greater ‘nocebo’ response might be anticipated. This was minimised by delivering the challenges in opaque cartons in order to mask differences in powder volume. Furthermore, the placebo [glucose] challenge was provided in the same dose as fructans [12 g/d], and yet a large majority of participants [26/29, 90%] reported adequate relief of symptoms following the placebo [glucose] challenge, implying that a larger dose of powder was not sufficient to induce a substantial ‘nocebo’ effect on FGS, which reflects the findings of a previous glucose challenge in IBS [86% participants reporting adequate relief].40
Faecal calprotectin was significantly elevated at the end of the trial compared with baseline, in particular in those with CD. Any trial recruiting patients with IBD in remission is susceptible to participants entering spontaneous relapse. It is unclear, given the study design described, whether the increase in faecal calprotectin at the end of the trial was the result of the low FODMAP diet, the FODMAP challenges, or spontaneous fluctuations in this inflammatory marker. The low FODMAP diet restricts fructans and GOS, which are dietary prebiotics that have indirect effects on immune function through the stimulation of immune-modulatory gut bacteria such as bifidobacteria and Faecalibacterium prausnitzii,18,42–44 as well as direct effects through interaction with pattern-recognition receptors on gut immune and epithelial cells.45 Although patients enrolled in this trial were asked to follow the low FODMAP diet, it might be expected that the FODMAP challenges would restore any alterations in microbiota. The potential explanations for an elevated faecal calprotectin remain elusive and the effects of the low FODMAP diet on gut microbiota, inflammation, and faecal calprotectin in IBD require further investigation.
The low FODMAP diet significantly reduces gastrointestinal symptoms in patients with IBS,9 and retrospective and prospective uncontrolled evidence has shown that it may alleviate FGS in IBD.14,15 A randomised controlled trial reported a significant improvement in gastrointestinal symptom severity following a 6-week low FODMAP diet compared with a habitual diet in patients with quiescent or mildly active IBD.46 However, this trial was not placebo controlled and further research is needed to establish the efficacy of the diet in IBD, which differs substantially from IBS in terms of pathophysiology and clinical presentation.
The lack of significant symptom exacerbation following the GOS and sorbitol challenges raises questions regarding whether the low FODMAP diet as currently implemented in clinical practice is overly restrictive in terms of GOS and sorbitol, especially given that the doses were at the higher end of typical dietary intake. However, this trial was designed to measure the effect of pure carbohydrate challenges on symptom induction following previous resolution on a low FODMAP diet. This differs substantially from intervention trials involving dietary restriction of all FODMAPs or specific FODMAPs in food form. Therefore, whereas the findings of this trial cannot be directly extrapolated to use of the low FODMAP diet in clinical practice, trials to investigate the effect of individual, or indeed less strict, FODMAP restriction are now warranted in IBD.
This re-challenge trial identified that fructans, but not GOS and sorbitol [at the doses given] induced gastrointestinal symptoms in patients with quiescent IBD. Further investigation will be required to establish the effects of different types and doses of FODMAPs on FGS in patients with IBD, and the effect of a low FODMAP diet and the degree of FODMAP restriction required for gastrointestinal symptom improvement in patients with quiescent IBD.
Funding
This work was supported by National Institute of Health Research fellowships [ACP, CEM] and by King’s College London.
Conflict of Interest
KW and MCL are co-inventors of a mobile app regarding the low FODMAP diet. KW, MCL, and PMI have received research funding from Clasado Ltd.
Author Contributions
KW and ACP formulated the research question and designed the study; ACP, CEM, SRC, PMI, JOL, and MCL recruited participants and performed all measurements; SRC and KW analysed data; SRC and KW wrote the manuscript; all authors critically commented on and approved the final manuscript.
Footnotes
Conference presentation: This work was presented at the 11th Congress of ECCO [European Crohn’s and Colitis Organisation] 2016 [poster number P476] and at the XVII International Congress of Dietetics 2016 [poster number P-040].
Acknowledgments
The authors thank patients who participated in this study at Guy’s and St Thomas’ NHS Foundation Trust and at Bart’s Health NHS Trust.
References
Author notes
SRC, ACP, CEM made equal contributions and are joint first authors.
- carbohydrates
- crohn's disease
- glucose
- inflammatory bowel disease
- diarrhea
- diet
- flatulence
- feces
- glasgow outcome scale
- oligosaccharides
- randomization
- signs and symptoms, digestive
- sorbitol
- fructans
- irritable bowel syndrome
- abdominal bloating
- symptom aggravating factors
- fermentable, oligo-, di-, monosaccharides, and polyols