Accepted Manuscript. Prebiotics Versus Low Fodmap Diet: An Interpretative Nightmare. Jane Varney, Jane G. Muir, Peter R. Gibson

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1 Accepted Manuscript Prebiotics Versus Low Fodmap Diet: An Interpretative Nightmare Jane Varney, Jane G. Muir, Peter R. Gibson PII: S (18) DOI: Reference: YGAST To appear in: Gastroenterology Accepted Date: 18 October 2018 Please cite this article as: Varney J, Muir JG, Gibson PR, Prebiotics Versus Low Fodmap Diet: An Interpretative Nightmare, Gastroenterology (2019), doi: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Letter: PREBIOTICS VERSUS LOW FODMAP DIET: AN INTERPRETATIVE NIGHTMARE Jane Varney, Jane G. Muir, Peter R Gibson Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Victoria Australia Corresponding author: Professor Peter Gibson Department of Gastroenterology, Alfred Hospital, 99 Commercial Road, Melbourne, Victoria 3004, Australia E: peter.gibson@monash.edu T: Conflicts of interest: Monash University markets a digital application, booklets and online education on the low FODMAP diet and funds raised from these are reinvested in to research. PRG has published a book on the low FODMAP diet. 1

3 Editors The concept that prebiotics may assist in the management of functional gastrointestinal symptoms has appeal, and the results and conclusions of a recent clinical trial by Huanan et al claim to support the use of a synthetic prebiotic supplement, β-galacto-oligosaccharide (GOS), for symptom alleviation and microbiota enrichment in patients with chronic functional gastrointestinal symptoms [1]. The study was intended to compare the effects of a low FODMAP diet with prebioticsupplemented support. However, major issues with study design and interpretation require exploration before the results and conclusions are accepted. The first issue concerns the choice of placebos - a Mediterranean diet and a xylose supplement. A Mediterranean diet typically encourages the consumption of foods rich in natural prebiotics (fructans and GOS), such as legumes, nuts and wholegrain breads and cereals [2], and contrasts the intervention diet (a low FODMAP diet) that restricted these (and other) foods. As the nutritional analysis of the habitual diet of the subjects was not provided, it is unknown whether the placebo diet provided increased amounts of natural prebiotics (including GOS). Furthermore, there is indirect evidence for an association of the Mediterranean diet and reduced chance of functional gastrointestinal symptoms [3]. Thus, attribution of the effects on the increased abundance of Bifidobacteria and alleviation of symptoms specifically to the prebiotic supplement seems highly speculative. The authors also chose a placebo supplement (2.4 g xylose per day) that is arguably, not a placebo. Xylose is a slowly absorbed, readily fermented sugar [4], and is, by definition, a FODMAP. It is not included in the standard FODMAP compositional lists because the amount found naturally in food and consumed in the diet is very small. Xylose is, however, less likely to be prebiotic. Hence, the low FODMAP arm, for which nutritional analysis was not presented, could not really be low in FODMAPs, 2

4 although probably is low in prebiotics. Perhaps symptomatic effect of both interventional arms represented placebo response. We also question their conclusion regarding the therapeutic advantage of prebiotic supplementation owing to the sustained, symptomatic benefits that persisted for 2 weeks after the treatment period, unlike the benefits of a low FODMAP diet, which were lost upon treatment withdrawal. However, having not measured or compared dietary intake in the post-treatment period, it cannot be ruled out that differences in dietary prebiotic intake accounted for the apparent lasting effects of prebiotic supplementation. The conclusion also reflects a misunderstanding regarding the intended use of the FODMAP diet approach. A FODMAP diet is not intended as a 4-week diet, at the end of which patients return to their habitual diet and expect to see a sustained improvement in symptoms. Instead, the diet involves 3 steps, which together allow patients to identify and reintroduced foods and FODMAPs that they tolerate, while restricting those that trigger symptoms [5]. Thus, a limited degree of ongoing FODMAP restriction is required to observe lasting symptom relief. Our take-home message from the study of Huaman et al is that a xylose (FODMAP)-supplemented, low FODMAP diet and a prebiotic supplemented, prebiotic-rich Mediterranean diet are equally effective in terms of symptom control. However, these effects cannot be separated from placebo responses. The findings that the abundance of Bifidobacteria was stimulated with prebiotic supplementation/mediterranean diet and reduced on a low FODMAP diet are not new. In all, the insights from this study are of limited value in clinical practice and serve only to confuse. REFERENCES 1. Human JW, et al. Gastroenterology 2018;155: Trichopoulou A, et al. BMC Med 2014;12: Zito FP, et al. World J Gastrointest Pharmacol Ther. 2016;7:

5 4. Levitt MD, Donaldson RM. J Lab Clin Med 1970;75: Barrett JS. J Gastroenterol Hepatol 2017;32(Suppl 1):