FODMAPs and carbohydrate intolerance

Chapter 26

FODMAPs and carbohydrate intolerance Peter R. Gibson, Emma P. Halmos Department of Gastroenterology, Monash University and Alfred Health, Melbourne, VIC, Australia

Key points ●

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Indigestible dietary carbohydrates play important positive roles in laxation and in maintaining a health-promoting milieu and microbiota in the colon. Short-chain slowly absorbed and indigestible readily fermented oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) have negative effects of inducing functional bowel symptoms, particularly in the presence of irritable bowel syndrome. Carbohydrate malabsorption is a physiological, normal event but intolerance refers to the development of symptoms in association with the malabsorption. Restricting all dietary FODMAPs (the FODMAP diet) is an evidence-based approach to alleviating the abdominal symptoms in 50–85% of patients. The FODMAP diet has three phases—comprehensive restriction to assess response, reintroduction of single FODMAP groups to assess dose and tolerance, and personalized maintenance dietary program. The FODMAP diet is optimally delivered by a skilled dietitian to judge its appropriateness, to minimize over-restriction and to ensure that nutritional adequacy is maintained. There are few clinically applicable markers of the likelihood of response or lack of response. The risks are psychological (disordered eating, linear thinking), nutritional (especially meeting calcium and fiber requirements), and microbial with potentially unfavorable changes to the gut microbiome if strict restriction is maintained. Clinical strategies to restrict specific FODMAPs only such as lactose or fructose have limited evidence base. Recognition and use of therapies that restrict dietary substrates, such as sucrose or starch oligosaccharides in a minority of patients who might have brush border hydrolase deficiencies, is an area of current research.

Introduction Dietary carbohydrates have long been known to induce gastrointestinal symptoms, particularly in the setting of functional gastrointestinal disorders (FGID). Indeed, most dietary approaches to alleviating functional bowel symptoms have been centered on eliminating, reducing or even increasing specific carbohydrates that are indigestible or slowly absorbed from the small intestine by selective food choice (e.g., avoiding lactose- or fructose-containing foods) or by the taking of supplements (e.g., dietary fiber or prebiotics). This chapter will address the functional and structural heterogeneity of such carbohydrates and will concentrate on slowly-absorbed or indigestible short-chain carbohydrates and their role in carbohydrate intolerance and its management.

Heterogeneity of dietary carbohydrates Knowledge of the physiology and disposition of carbohydrates as well as their functional effects is crucial to understanding the therapeutic use of modulating their intake in patients with irritable bowel syndrome (IBS). Dietary carbohydrates are generally classified according to their molecular size and digestibility [1]. In terms of gut health, carbohydrates of specific interest can be classified into three distinct groups by their digestibility and absorptive patterns [1]. (i) Monosaccharides that are slowly absorbed: These comprise (a) fructose whose absorption when in excess of glucose in the lumen is dependent upon an active transport pathway (via GLUT5) that has low capacity and is, therefore, slow; and (b) monosaccharides (e.g., xylose) and sugar alcohols (polyols such as sorbitol and mannitol) that are passively absorbed only. The prolonged presence of these small molecules in the small intestinal lumen provides an osmotic load Clinical and Basic Neurogastroenterology and Motility. https://doi.org/10.1016/B978-0-12-813037-7.00026-1 © 2020 Elsevier Inc. All rights reserved.

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leading to increased water content in the small intestine and, if their load is high or if small intestinal transit is rapid, they may ‘spill-over’ to the fermentative environment of the colon. (ii) Digestible short-chain carbohydrates for which there are individual heterogeneity in the activity of relevant hydrolases: The expression of small intestinal lactase varies across individuals. When its activity is reduced or absent, undigested lactose will be osmotically active in the small intestinal lumen and will pass to the colon, where it is fermented by bacteria. The clinical relevance of reduced activity of other brush border hydrolases such as sucrase–isomaltase is a topic of considerable research [2] (discussed later). (iii) Indigestible carbohydrates due to the non-existence of relevant small intestinal hydrolases: These are a heterogeneous group of carbohydrates that have generally been called ‘dietary fiber’, although definitions vary. They can have chain lengths (degree of polymerization or DP) of 3–10 (oligosaccharides) to DP >10 (polysaccharides). While oligosaccharides will exert some osmotic effect in the small intestinal lumen, the greatest physiological actions of fibers are in modulating motility and the luminal contents of the large bowel, by virtue of its bulking effect and fermentation. An alternate classification of relevance to gut health is based upon their four broad functionally important properties as illustrated in Fig. 1. (i) Fiber effects associated with laxation: Indigestible carbohydrates have the potential to improve the quality of the bowel motions by bulking and subsequently promoting motility. The bulking action can result from the expansion of total bacterial content from providing fermentable substrates that promote bacterial proliferation non-specifically, and from the water-holding effects of non-fermentable fibers and from undigested food particles themselves. It is essential to understand that the ability to perform this laxation function varies considerably across non-digestible fibers [1, 3], as illustrated in Fig. 2. For instance, oligosaccharides and readily fermentable resistant starch (such as high amylose starch) alone carry little laxative effect, as shown by the minimal effect of varying their dietary intake in healthy subjects and those with IBS [1, 3]. In contrast, poorly or slowly fermentable fiber sources such as psyllium or wheat bran have excellent bulking and laxative effects. (ii) Supporting a health-promoting metabolic milieu in the colon: Carbohydrates entering the colon play key roles in producing a homeostatic environment that is of relevance to most intestinal disorders and metabolic health. The key place for colonic health of adequate short-chain fatty acid (SCFA) production from carbohydrate fermentation has been long recognized [4]. For example, butyrate has multiple effects on the colonic epithelium, being the major energy source, a differentiating agent, a suppressor of early events in carcinogenesis, and a promoter of regeneration and healing for the colonic epithelium are well-documented properties. The effects of acetate, propionate and butyrate as suppressors of inflammation both locally in the colon and systemically have more recently re-emerged. Non-fermentable fiber also has protective effects presumably via a ‘broom and mop’ action [5]. Additionally, having carbohydrate substrates for colonic microbiota to ferment will inhibit potentially hazardous protein fermentation and reduce hydrogen sulfide (H2S) production as indicated in fecal slurries [6, 7]. The relevance of all this to patients with functional bowel

Fermentation

Health-promoting metabolic milieu

FIBRE Bulking Promote motility

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cellulose PREBIOTICS hemicellulose pectins - FOS inulin glucans - GOS gums - Other brans resistant starch

FODMAPs - fructose - lactose - sugar polyols - others

Luminal distension

Gut symptoms

Laxation Selective growth of ‘good’ bacteria

Putative health benefits

FIG. 1  A functional classification of dietary carbohydrates that are of relevance to intestinal health. (Modified from Muir JG, Gibson PR. Manipulating dietary carbohydrates to treat irritable bowel syndrome. Clinical insights: irritable bowel syndrome: diagnosis and management. Future Medicine Ltd; 2013. p. 81–103.)

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Highly fermentable short-chain

Highly fermentable fibre

Intermediate fermentable fibre

Slowly fermentable fibre

Non-fermentable fibre

wheat bran, psyllium, flax

cellulose, sterculia, methylcellulose

Bulking Transit time Prebiotic SCFA production Gas production Specific fibre types

Oligosaccharides (FOS, GOS)

Resistant starch Oats pectin, guar Resistant starch + wheatbran

FIG. 2  Heterogeneity of effects of different dietary fibers, related in part to their fermentability and molecular size. SCFA, short-chain fatty acids; FOS, fructo-oligosaccharides; GOS, galacto-oligosaccharides, RS, resistant starch. (Modified from Eswaran S, Muir J, Chey WD. Fiber and functional gastrointestinal disorders. Am J Gastroenterol 2013;108(5):718–27. For comprehensive understanding of the role of fibre in gastroenterology.)

d­ isorders goes beyond just maintaining good health. Butyrate promotes motility and may reduce visceral sensitivity, while H2S contributes to malodorous flatus, may increase visceral sensitivity and, in higher amounts, may contribute to mucosal inflammation. The optimal situation is to have fermentation evenly distributed around the colon, as reviewed in detail elsewhere [1, 8]. Delivery of mainly readily fermented carbohydrates leads to predominant fermentation in the proximal colon that has two potential consequences. First, it may be injurious to the colonic mucosa, presumably related to the load of SCFA produced locally. Butyrate and other SCFA are toxic to cells at high concentrations. Indeed, large delivery of lactulose or fructo-oligosaccharides (FOS) to the caecum of rats leads to increased permeability and susceptibility to experimental Salmonella infection. Whether such deleterious effects occur in humans is uncertain due to the inaccessibility to the caecum for suitable measurements. The second consequence is the exhaustion of carbohydrates available for fermentation in the more distal colon and the subsequent increase in potentially deleterious protein fermentation and possibly H2S production. The way to spread the fermentation more evenly around the colon is to combine readily fermented with slowly fermented fiber. Indeed, in rats, pigs and humans, this was achieved with wheat bran and high amylose starch (rich in resistant starch) [1]. Thus, the fermentation was reduced proximally (measured only in experimental animals), and evidence of greater carbohydrate and reduced protein fermentation in the distal colon was observed with the combination of fibers compared with those of either alone. These results underline the importance of understanding the regional dynamics of fiber utilization and the heterogeneity of fibers when dietary carbohydrate is being modulated. (iii) Prebiotic effects associated with health-promoting effects on microbial composition: An important effect of specific carbohydrates is their ability to promote growth of bacteria with putative health-promoting properties with concomitant relative suppression of other bacteria. These so-called ‘prebiotic’ effects are different to the non-specific promotion of microbial growth by the provision of energy substrates, in that the utilization of the substrate has specific preferences. This effect has been best demonstrated with fructo-, galacto- and xylo-oligosaccharides and inulin, although the health benefits for gut disorders largely remain to be proven (see Chapter 42). (iv) FODMAP effects associated with induction of functional gut symptoms: FODMAP is an acronym that refers collectively to Fermentable Oligo-, Di- and Mono-saccharides and Polyols [8]. The FODMAP concept was developed to link multiple short-chain carbohydrates that can induce gastrointestinal symptoms by virtue of common physiological effects comprising increasing small intestinal water content (osmotic effect) and increasing colonic gas production (fermentative effect) with the consequent distension of the intestinal wall (Fig. 3). All carbohydrates had previously been documented to induce functional-like bowel symptoms when ingested in large amounts alone [11]. It was hypothesized that, when presented to the gut in smaller amounts in normal dietary intake that are less likely to induce symptoms, they would have additive effects and subsequently induce symptoms by the stimulation of mechanoreceptors via the stretching the intestinal wall. It was also hypothesized that patients with visceral hypersensitivity will develop symptoms with much lower intake of FODMAPs than asymptomatic people. Indeed, the hypothesis is now strongly supported (see below).

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FIG. 3  The concept of FODMAPs. Individually, all short-chain carbohydrates outlined can cause physiological changes to the intestines of increasing small intestinal water (as shown by MRI studies [9]) and generation of gases from bacterial fermentation (as shown by breath hydrogen analysis [10]). At high intakes, individual carbohydrates can alone induce IBS-like symptoms. When considered collectively, the effects are additive and smaller amounts of each will additively contribute to the induction of symptoms via stretching of the intestinal wall and activating mechanoreceptors. In the presence of visceral hypersensitivity, amounts found in the normal diet will induce symptoms. (Data reproduced with permission from Murray K, Wilkinson-Smith V, Hoad C, et al. Differential effects of FODMAPs (fermentable oligo-, di-, mono-saccharides and polyols) on small and large intestinal contents in healthy subjects shown by MRI. Am J Gastroenterol 2014;109:110–119.)

FODMAPs comprise ●

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Slowly absorbed monosaccharides, most notably fructose in excess of glucose and polyols (such as sorbitol, mannitol, xylitol). Non-digestible oligosaccharides, most commonly in the diet being FOS (also known as oligofructose and fructans when DP ≤10) and galacto-oligosaccharides (GOS, most commonly stachyose and raffinose). Di- and oligosaccharides that are inadequately digested by brush border hydrolases, notably lactose in those with hypolactasia, and potentially sucrose, maltose and dextrins in those with low activity of sucrase-isomaltase. Other natural FODMAPs that are not usually found in clinically relevant concentrations might include xylose and xylo-oligosaccharides. FODMAPs used to supplement food or as therapeutic agents, including various oligosaccharides used as prebiotics or lactulose used therapeutically as a laxative. Inulin that is commonly added to foods has a DP >10 so does not strictly fit the definition of a FODMAP. However, the DP of inulin is not reported on food labels and its physiological behavior is FODMAP-like, particularly in inducing rapid colonic fermentation. Hence, it is usually considered under the banner of ‘FODMAPs’.

Concepts of short-chain carbohydrate malabsorption and intolerance In order to understand the utility of manipulating carbohydrates in the dietary management of patients with FGID, the meaning of terms used is essential as they are often incorrectly used interchangeably. ●

Malabsorption: This refers to the delivery of FODMAPs to the colon. In other words, absorption in the small intestinal has not occurred or is incomplete. By definition, the vast majority of FODMAP oligosaccharides are delivered to the colon in everyone. A small consumption within the small intestine might be related to their utilization by small intestinal bacteria or the sugar–sugar bonds being broken by sheer forces. Thus, malabsorption is a normal event. For fructose and polyols, the delivery of a small percentage to the colon is a normal event. When large doses (35–50g) are administered

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orally, similar proportion of patients with FGID and healthy subjects will have positive breath hydrogen tests, indicating delivery of fructose to the colon (see Chapter 22) [12]. Whether such absorption occurs or not will depend upon the dose and the small intestinal transit. There are few data on the variation of intrinsic ability of individuals to absorb free fructose, but, since an active transporter is involved, it would not be surprising that its efficiency will vary. Patients with Crohn’s disease or ulcerative colitis, but not celiac disease, have a higher chance of malabsorbing a fructose load of 35g [12]. In terms of passively absorbed monosaccharides and polyols, absorption may be affected by mucosal disease; sorbitol absorption is elevated in patients with untreated celiac disease [13]. Nevertheless, malabsorption of all FODMAPs is a normal event and its demonstration per se provides no useful clinical information about the individual’s capability of coping with FODMAP intake. Intolerance: This refers to the induction of gut symptoms upon ingestion of the sugar of concern. For fructose and polyols, the induction of symptoms bears no relationship to whether they were malabsorbed during a breath test. Symptoms can be induced by small intestinal distension due their osmotic effect, irrespective of whether some is malabsorbed. The concept is that the induction of symptoms is a reflection of visceral hypersensitivity not of abnormal handling of the sugar concerned and this has recently been strongly supported [14]. The corollary of this is that breath hydrogen responses to a sugar load define the physiology at the point of time the test was performed, but do not inform with regards to the likelihood of specific dietary approaches being of therapeutic benefit. The symptom response to the sugar load theoretically is more informative, but when the symptoms should be assessed (the tests are not standardized) and how the nocebo effect can be addressed have not been resolved. Furthermore, supra-dietary doses are typically used for breath tests, e.g., 50g lactose equivalent more than 1L of milk and 35g fructose is equivalent to the consumption of more than nine pears in one sitting, so the clinical relevance of the malabsorption is questionable.

Clinical approach to restricting dietary short-chain carbohydrates in IBS Using an evidence-based approach in patients with IBS, the starting point should be reducing FODMAP intake.

The FODMAP diet The general principle of the FODMAP diet is to follow an ‘elimination diet’-type protocol with three phases [15, 16] as illustrated in Fig. 4. Details of its implementation are outlined in Table 1. The full program is recommended to educate and empower the patient, to minimize the psychosocial effects of a restrictive diet, and to avoid potential adverse effects of strict FODMAP restriction (described later).

Evidence-base for the FODMAP dietary program Phase 1 has been subject to multiple randomized controlled trials. A blinded cross-over feeding study in which a low FODMAP diet was compared with a typical Australian FODMAP diet provided proof for the concept [20]. A series of

FIG. 4  The three phases in delivering the FODMAP diet.

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TABLE 1  The educative process for the FODMAP diet Phase 1: Comprehensive restriction

Phase 2: Rechallenge

Aims

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To determine if comprehensive reduction of FODMAPs will improve symptoms (stop if not) • To initiate empowerment of the patient to use the Monash University low FODMAP app or food lists wisely, and to gain a basic knowledge of food content

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To enable recognition of the specific FODMAPs that induce symptoms • To recognize the dose that induces symptoms

To enable the patient to: • Liberalize food choice with continuing symptomatic benefit • Make self-dietary manipulations of the level of restriction according to current IBS status • Understand when dietary indiscretions may have induced more severe symptoms • Build confidence in making food choices with minimization of nocebo effects

How it is done

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Educate re pathophysiology of IBS, FODMAP concept and mechanisms by diet might work • Asked to restrict foods high in FODMAPs and replace them with foods low in FODMAPs. (Table 2 for examples)

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Reintroduce specific foods in which a single FODMAP group predominates (e.g., mango for fructose) [15]. A low dose is started and increased over a few days if well tolerated • Another FODMAP group is then tested, and so on • As nocebo effects can influence this process, recommended that re-challenge with poorly tolerated foods be repeated at future dates as confidence grows

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Tools to assist

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•

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Diagrams, access to explanatory videos, web information, booklets • Accurate food lists. The Monash University Low FODMAP diet Smartphone application [18] is gold standard and travels with the patient • Beware of inaccurate information [19]

Diaries to facilitate documentation of food rechallenge results have been developed specifically for this process—in paper form or contained within a digital application such as the Monash University low FODMAP diet app

Phase 3: Personalized (maintenance) diet

Construct a catalogue of well tolerated foods, moderately tolerated foods to use at lower amounts or occasionally. Poorly tolerated foods restricted to patient’s choice • Repeat challenges of poorly tolerated foods, particularly when the IBS is quiescent • Provide education on multiple areas of relevance to long term management, e.g., maintenance of nutritional, strategies for eating out and when traveling, tricks in food preparation and the use of supplemental enzymes (lactase when hypolactasic, α-galactosidase of GOS-sensitive [17]) Various tools available, including booklets, apps and internet sites; e.g., the Monash University Low FODMAP Diet app contains useful tips in all of the relevant areas

r­andomized, controlled studies in which the diet was taught to patients, including one where the comparator was a true placebo diet, also showed efficacy [21–26], as outlined in Table 3. The only negative study compared a low FODMAP diet with a ‘standard’ diet modeled on recommendations from the National Institute of Heath and Care Excellence (NICE) of the UK, but with additional reduction of flatulogenic foods (that are high in FODMAP content) [21]. Response rates for both were similar and relatively low (about 50%). This may have related to the fact that the FODMAP intake in the subjects’ habitual diets was already quite low and the small increment of FODMAP intake achieved, according to reported intakes by the investigators [29]. Recent meta-analysis has supported the efficacy of the elimination phase of the low FODMAP diet, but has indicated that, relative to classic drug–trial methodology, the quality of the evidence is low [30]. However, achieving high quality on these criteria is challenging for dietary studies [31]. Real-world experience has mirrored the results of the controlled studies in that around 70% of patients respond to the diet [32]. The re-challenge phase is less amenable to controlled studies. However, prospective observation of patients who were taught the phase 2 re-challenge indicate that the majority do reintroduce successfully with ongoing symptomatic benefit in maintenance [27, 28, 33–37] (Table 4). A minority remain strictly low FODMAP.

FODMAPs and carbohydrate intolerance Chapter | 26  377



TABLE 2  Some foods high in FODMAPs and alternative low FODMAP foods Food type

High FODMAP foods

Low FODMAP foods

Vegetables

Onions, garlic, asparagus, artichokes, legumes/pulses, sugar snap peas, cauliflower, mushrooms

Alfalfa, bean sprouts, green beans, bok choy, capsicum (bell pepper), carrot, chives, fresh herbs, choy sum, cucumber, lettuce, tomato, zucchini

Fruit

Apples, pears, mango, nashi pears, watermelon, nectarines, peaches, plums

Orange, mandarin, grapes, blueberries, strawberries, kiwifruit

Dairy foods

Milk (cow, goat, sheep), yoghurt, fresh cheese, cream, custard, ice cream

Lactose-free milk, lactose-free yoghurts, Ripened cheese

Breads and cereals

Rye, wheat-containing breads, Wheat-based cereals with dried fruit, Wheat pasta

Gluten-free bread, sourdough spelt bread, ice bubbles, oats, gluten-free pasta, rice, quinoa

Snacks

Rye crackers, wheat-based biscuits

Gluten-free biscuits, rice cakes, corn thins

Nuts and seeds

Cashews, pistachios

Pumpkin seeds, peanuts, walnuts

From Monash University low FODMAP diet app Monash University. The low FODMAP diet. 2018. Available from: monashfodmap.com.

Who should deliver the FODMAP diet The FODMAP diet involves explanation of IBS and the genesis of symptoms, assessment of nutritional status and dietary intake and patterns, education in the composition and identification of foods, reading of food labels, and a 3-phase specific process that requires teaching, support and feedback. Hence, it is almost axiomatic that a dietitian who understands IBS and is FODMAP-trained is most likely to optimally deliver the FODMAP diet [38]. Most, but not all, prospective studies have involved dietitian-led education of the patients. However, in selected patients, group education by a dietitian can be as effective as individual teaching in the short-term [39] and other healthcare professionals can achieve good response rates [40]. It should be noted, however that, while direct teaching of complete details of the full FODMAP approach may not be needed to improve symptoms in many patients, it is likely, though not proven, that education in all of the issues in addition to food composition might lead to more optimal results. Unfortunately, FODMAP-educated dietitians are not available in many parts of the world, due to the lack of trained dietitians and/or funding for their services. Patients who are self-taught, at times on the direction of healthcare practitioners incapable of providing the necessary background education, are at heightened risk of inappropriate, unnecessary or long-term dietary restriction with sub-optimal outcomes, and of disordered eating and nutritional inadequacy. It behooves healthcare professionals who are delivering such dietary advice to up-skill in delivering the FODMAP diet or to refer patients to those who are.

Relevance across the world There is considerable heterogeneity of eating styles, food choice and food supply across the world. However, onions, garlic and wheat flour (sources of fructans) are staple ingredients in most parts of the world, legumes (source of GOS) are important particularly in South Asian cultures, and lactose is relevant across the majority of the adult population in the world [41, 42]. Hence, the FODMAP approach is of relevance widely and efficacy has been reported in South Asia, Malaysia, China, Korea, and Central and South America in addition to European, North American and Australasian countries. The key issue is, however, how to make the appropriate food choices since the index food database predominantly refers to foods sourced in Australia, and the quality and details in food labelling of processed foods varies from country to country. These issues are being addressed by the ongoing assessment of food ingredients from across the world, the evaluation of FODMAP content of manufactured processed foods by certification systems, and the expansion of languages used in the Monash University FODMAP Diet app.

Predictors of response and non-response Since the application of the FODMAP diet requires time, energy and input from both healthcare professionals and patients alike, identifying those who are very unlikely to respond would be very useful. While abdominal pain and bloating are the symptoms that seem to best respond to the FODMAP diet, such observations do not guide who should not be offered the diet. In patients with IBS, the predominant bowel habit is a poor predictor of response, even though some studies have

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TABLE 3  Evidence based studies for efficacy of Phase 1 (strict low FODMAP) of the FODMAP diet Findings (low FODMAP vs comparator)

Author (year)

Country

How diet delivered

Staudacher [25]

UK

Dietitian

Habitual diet

4 weeks

35

IBS-D

Overall symptoms 68% vs 23% (P=0.005)

Halmos [20]

Australia

Food supplied

Typical diet (cross-over)

3 weeks

30

All sub-types

Significantly different overall (P=0.001) and individual symptoms (bloating, gas, satisfaction with stool symptoms)

Bohn [21]

Sweden

Dietitian

Modified NICE

4 weeks

67

All sub-types

Improvement: 50% vs 47%

Comparator

Duration

Number

IBS type

All improved vs baseline Eswaran [22]

USA

Dietitian

Modified NICE

4 weeks

84

IBS-D

Adequate relief: 52% vs 41% (P=0.31) Individual symptoms significantly better; abdominal pain 51% vs 23% (P=0.008)

McIntosh [24]

Canada

Dietitian

High FODMAP

3 weeks

37

All subtypes

Reduction in composite (P<0.001)

Staudacher [26]

UK

Dietitian

Placebo diet

4 weeks

104

Non-C

Adequate relief: 58% vs 38% (P=0.051); individual symptoms significantly improved

Hustoft [23]

Norway

Dietitian

Re-challenge with FOS/ placebo

6 weeks ­re-challenge

20

Non-C

All responded to diet Re-challenge: 30% with FOS vs 80% with placebo

Peters [27]

Australia

Dietitian

Gut-directed hypnotherapy

6 weeks

49

All subtypes

Overall symptom improvement 72% vs 71%

Schumann [28]

Germany

Not stated

Hatha yoga

12 weeks

59

Not stated

Adequate relief 79% vs 82%

Variable end-points were applied.

t­ argeted non-constipated patients. Fecal water content changes little from habitual to low in FODMAP diet [43]. This would be different if large amounts of fructose and sorbitol, for example, were being consumed as the doses that induce diarrhea are usually much higher than those in found in the diet. Likewise, lactose induces diarrhea when consumed in large amounts and lactulose therapeutically has a threshold dose before inducing diarrhea [44]. It has been proposed that the complete absorption of variably absorbed FODMAPs, specifically fructose, sorbitol or mannitol, after a large oral load is given in a breath hydrogen test would indicate that that sugar does not need to be restricted for symptomatic benefit. This premise is flawed as malabsorption poorly correlates with symptoms, which are also generated in the small intestine due to osmotic effects independent of whether the sugar is malabsorbed [9, 45, 46]. The lack of symptoms generated by a sugar during a breath tests has been suggested as predictive of non-response to restriction

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TABLE 4  Efficacy of the FODMAP diet in the longer term Author (year)

Country

Setting

Number

De Roest [33]

New Zealand

Prospective observational

90

Staudacher [37]

UK

Retrospective observational

Peters [27]

Australia

Maagard [35]

Duration of follow up

Reintroduction

Sustained relief

Mean 16 months

No

72%

43

9 months

No

76%

Prospective follow-up

25

6 months

Yes in 92%

82%

Denmark

Retrospective observational

131

Median 15 months

Yes in 84%

70% satisfaction

Harvie [34]

New Zealand

Prospective follow-up

50

6 months

Yes

‘vast majority’

O’Keefe [36]

UK

Prospective observational

103

6–18 months

Yes in 82%

57%

Schumann [28]

Germany

Prospective follow up

29

6months

Yes

79%

of that sugar, but the value of this feature has yet to be validated in this way and the concept is generally contrary to the FODMAP hypothesis (e.g., additive effects of several FODMAPs). Furthermore, reproducibility of the breath tests is poor [46]. In repeat testing in 30 patients whose index breath test showed malabsorption after a 35g load, 30% were negative. Since fermentative activity of gut microbiota is at least partly responsible for the genesis of symptoms due to FODMAPs, characterization of fecal microbiota has been proposed as a predictor of response [47]. Indeed, a greater relative abundance of fermentative bacteria was predictive of response of abdominal pain in children in one study, and two further studies have shown the pattern of bacterial DNA compared with that from a small cohort of healthy Scandinavian controls, creating a so-called ‘dysbiosis index’, was predictive of response. However, with the considerable overlap with the patterns of the non-responders, the test could not be used in clinical practice to exclude specific patients. An alternative approach is to assess the chromatographic pattern of volatile organic compounds released from the feces. Algorithms were developed that could completely separate responder and non-responders from a controlled trial [48], but prospective application of that algorithm other cohorts is needed to determine its validity. Hence, contraindications to the low FODMAP diet currently remain the only true exclusions. Those who refuse to entertain altering their diet would be an absolute contraindication, in addition to those with an active eating disorder where dietary restriction would affect them psychologically and potentially nutritionally. Those whose nutrition is already impaired and those at-risk of disordered eating should be regarded as relative contraindications to the FODMAP diet. In such situations, the diet should only be applied under direct supervision of the relevant healthcare professionals (dietitian and/or psychologist/psychiatrist).

Reasons for and approach to non-response Non-response or insufficient response to a low FODMAP diet may be due to many factors as shown in Table 5. Consideration to the diagnosis, to the patient’s underlying physiology and psychology, and to the patient’s understanding of and adherence to the diet are needed. Alternative therapeutic approaches are clearly needed. The key is that FODMAP restriction is not continued if it has not impacted symptoms. There are no reports of the success of strategies to deal with these scenarios.

Risks of a FODMAP diet Like all therapies offered to patients, there are risks to changing the dietary patterns and food choice of patients. This seems seldom considered by many lay proponents of diets and healthcare providers, many of whom are antagonistic towards pharmacological agents, in which adverse effects are well described. However, the risks of diets are less easily documented, as they involve psychological issues, nutritional risks and changes to the gut microbiota.

Psychological risks The first risk is that the individual might develop or be encouraged to continue linear thinking, in which IBS is caused by food. When one diet does not work, then that person then seeks another or additional restriction in order to define the

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TABLE 5  Some reasons for failure of failure of phase 1 (‘elimination’ phase) of the FODMAP diet to adequately alleviate symptoms Reason

Description

Diagnosis incorrect

Celiac disease, inflammatory bowel disease and microscopic colitis can mimic IBS and have specific, effective therapies

Inappropriate scenario

Symptomatic episodes with extended asymptomatic periods between

Poor adherence to the diet

Inability to follow instructions Inadvertent intake of FODMAPs (inaccurate advice, hidden sources, poor food choice)

Low FODMAP intake in habitual diet

Incremental reduction in intake too small to achieve differences in physiology

Physiology unsuitable

Visceral hypersensitivity not present Central sensitization syndrome

Psychology unsuitable

Unrealistic expectation of response such as complete resolution of symptoms Major co-morbid psychopathology

offending food. Characteristically, there is accumulation of diets rather than replacement, despite lack of efficacy of them all. Such disordered eating patterns require psychological intervention to assist in broadening rather than further restricting the diet. Screening for risk of disorder eating has been suggested [47]. Secondly, orthorexia, a fixation on righteous eating, might be stimulated if not already present or further encouraged. The additional pressure that this may exert on psychosocial functioning may increase rather than alleviate the burden of the patient’s symptoms. Thirdly, imposing a restrictive diet on a patient with a past history of an eating disorder is hazardous and should only be contemplated by experienced dietitians in conjunction with a mental health professional.

Nutritional risks Restrictive diets impose risks of nutritional inadequacy if wise food choices are not made [49]. Care should be exercised when attributing nutritional inadequacy on the new dietary approach as pre-existing nutritional inadequacy due to poor dietary patterns and food choice in their habitual diet may be a culprit. This was exemplified by a study of patients with newlydiagnosed celiac disease in whom most of nutritional inadequacies of the gluten-free diet after 12 months were also present in their pre-celiac diet [50]. There is no theoretical reason why nutritional inadequacy should occur with the FODMAP diet since no food group is excluded and multiple low FODMAP alternatives are available for every high FODMAP food restricted (Table 1). Nevertheless, two key nutrients that have been identified [49]. First, calcium intake may be low, often because of the restriction of dairy foods that contain lactose. Secondly, dietary fiber may be reduced, largely related to the limitation of wheat-based foods. Alternatives for both are readily available in the form of foods (e.g., lactose-free milk, oats) or dietary supplements (calcium tablets, manufactured low FODMAP fibers such as hydrolyzed guar gum).

Risks to the structure and function of the microbiota There is currently a huge focus on the gut microbiome and changes that might be favorable or deleterious to health. Unfortunately, current concepts about this are crude and naïve, but this does not inhibit paranoia about actions we take that might lead to significant shifts in the structure of the microbiota. Since carbohydrates have a great influence on the structure and function of the gut microbiota, both as metabolic substrates and in the prebiotic effects of some, the FODMAP diet has been attacked as ‘hazardous’ with respect to this aspect. It is not surprising that strict adherence to a low FODMAP diet during the elimination phase is associated with changes in the absolute and relative bacterial abundance in fecal microbiota. Some of the effects observed are as follows: ●

●

No effect on bacterial diversity: This has consistently been shown in patients with IBS, as well as in smaller healthy cohorts and in patients with Crohn’s disease in whom a low FODMAP diet was instituted [47]. Since reduced bacterial diversity currently carries negative health connotations, these observations are very important. Absolute abundance of bacteria falls when FODMAPs are restricted: This has been shown in human feeding studies in healthy subjects and in patients with IBS and Crohn’s disease [51, 52]. Furthermore, large differences in the content bacterial lipopolysaccharide (LPS) in fecal water when diets that differ in FODMAP content are found in both patients

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●

●

with IBS and in rats. In the rat studies, increased LPS load associated with high FODMAP intake was causally linked to the development of mild inflammation and mast cell activation in the rat colonic mucosa [53]. This effect was mimicked when fecal water from patients involved in a clinical trial of the FODMAP diet was infused into the rat colon. Thus, a reduced total abundance may be favorable. Consistent effects on specific functional groups, genera or species occur when FODMAP intake differs: Bifidobacteria are generally believed to be health-promoting, but their relative abundance has been reduced in many, but not all studies [47]. Probiotic supplementation corrected this change in one study [26]. Bacteria that are prominent in saccharolytic fermentative (especially butyrate-producing) activities are reduced in most studies in conjunction with restriction of FODMAP intake. Likewise, bacteria that have putative roles in the mucosa-associated microbiota were consistently altered by different intakes of FODMAPs in a feeding study in patients with IBS and Crohn’s disease and in healthy controls; the relative abundance of Akkermansia muciniphila, which converts acetate to butyrate and is believed to be health-promoting, is reduced in the feces while that of some Ruminococci, which consume mucus without known benefits, is increased [51, 52]. Such changes may be potentially hazardous for health. However, what was missed by many observers in this study was that the effects on relative and not absolute abundance related more to changes induced by the control diet compared with the relative abundance in association with the habitual diet [51]. Because there was a small increase in oligosaccharide content compared to that of the subjects’ habitual diet, at least some of the changes may have reflected prebiotic effects of additional oligosaccharides, rather than the loss of prebiotic effects. No aberration in fecal microbiota are yet evident in the maintenance/personalized phase: The limited studies available examining longer-term effects on fecal microbiota during the personalized phase of the diet have shown no aberration of relative abundance of specific bacteria compared with that when on their habitual diet [34]. More data are needed in this area.

Perhaps a more physiologically relevant way of examining the health aspects of the relationship between the colonic microbiota and diet is by examining the luminal concentrations or production of key metabolites related to health of the colon. As outlined above, it is believed favorable to have higher levels of SCFA production and concentrations, lower pH, minimization protein fermentation and lower levels of H2S production. Unfortunately, there are currently no available methodologies to measure these critical indices in the colon. Most data have come from studies of freshly-passed feces, which is a poor surrogate for what is happening in the proximal colon. As found in experimental studies, altering FODMAP intake alone has in most studies not changed fecal SCFA output or concentrations [21, 51]. The exception is where reduced fecal SCFA concentrations and evidence of increased protein fermentation in response to a low FODMAP diet were observed [23, 54]. However, both of these findings are manifestations of reducing fermentable long-chain fiber in the diets used, and dietary fiber content was neither measured nor controlled in that study. It is clear from metabolomic analysis of the urine of patients who were treated with high and low FODMAP diets that the pattern of metabolites differs considerably between those FODMAP intakes [24]. One interesting finding was that, in responders to the diet, urinary histamine was considerably reduced. In light of activation of mast cells by high FODMAP diet in the rat study discussed above [53], this is consistent with a mast cell effect. However, it could also relate to metabolic changes in the gut microbiota. This study did not, however, shed light on whether colonic metabolome when FODMAPs are reduced or increased might be detrimental to health.

FODMAP diet in the management algorithms for IBS IBS is a multifactorial condition and, while the FODMAP dietary approach has a high level of efficacy across all Rome subtypes, it is only one of the therapeutic strategies for patients with IBS. There are limited studies comparing its efficacy with that of other broad-spectrum strategies. Gut-directed hypnotherapy and traditional hatha yoga seem to have comparable durable benefits [27, 28]. Hence, there are now choices in initial approaches. The pathway taken, particularly in the patient with more difficult problems, will be dependent upon the patient’s scenario, the doctor’s biases and the available expertise. It should be remembered that optimal implementation depends upon skills of the healthcare practitioners, reiterating the issue that adequate training in whatever therapies are instituted, including dietary therapy, is paramount to best outcomes.

Other indications for a FODMAP diet To date, the vast majority of evidence for efficacy of the FODMAP diet has been restricted to adult patients with IBS. However, there is emerging evidence that it is applicable in other situations: ●

Children with functional bowel disorders: A brief (2-day) cross-over feeding study demonstrated benefit of the low FODMAP diet in a subset of children with abdominal pain [55]. A 3-day placebo-controlled cross-over challenge with

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●

●

●

●

fructans (vs maltodextrins) identified fructan sensitivity in at least one half of the 23 children evaluated [56], suggesting that the more comprehensive approach to FODMAP restriction is indicated, rather than just restricting fructose. However, nutritional adequacy and general good eating behavior is of more concern in children and the implementation of the FODMAP should be supervised by a dietitian in this group [57]. Functional bowel symptoms in patients with IBD: Functional bowel symptoms are common in patients with IBD and may or may not relate to ongoing inflammation in the intestine [58]. There is now accumulating evidence from prospective observations and randomized controlled trials that reducing FODMAPs can successfully alleviate functional gut symptoms in the majority of patients with quiescent IBD [59]. However, this patient group are at-risk of nutritional inadequacy and it is recommended that institution of a FODMAP diet be delivered under the supervision of a dietitian. Functional dyspepsia: Reducing FODMAPs appears to have benefited many patients with FGID not classified as IBS, including those with functional dyspepsia [60]. Interventional studies are needed to determine the place of the diet in management of this patient group. Mothers with colicky infants: Anecdotal reports and a prospective observational study have suggested that reducing the FODMAP content of breastfeeding mothers reduces infant colic [61]. A subsequent randomized controlled cross-over study confirmed this observation, although the mechanisms of action have not been identified [62]. Other: Observational experience has suggested that lowering of FODMAP intake will alleviate exercise-induced gastrointestinal syndrome in endurance sports, persistent symptoms in celiac disease despite gluten-free diet, fibromyalgia in patients with concomitant with gut symptoms and radiation enteritis. Further evaluation in these areas are warranted.

Where reducing FODMAP intake is of no value is in healthy subjects. The diet is not one for ‘good health’ and altering the amount consumed does not change gastrointestinal symptoms [20].

Consideration of specific short-chain carbohydrates Fructose and sorbitol intolerance Fructose intolerance, as reviewed in detail [63], was first recognized a ‘fruit-juice diarrhea’ in a cohort of children. Fructose in excess of glucose is slowly absorbed in the small intestine and exerts a considerable osmotic effect. A variable proportion of it is malabsorbed. Symptoms are often exacerbated by its frequent co-existence with sorbitol, such as in apples and pears. Observational studies suggested that fructose restriction in patients with fructose malabsorption and IBS or functional bloating responded well [64]. Unfortunately, the nature of dietary restriction was not outlined in those studies and patients without malabsorption were not similarly reported. A subsequent study of patients with IBS and fructose malabsorption also showed good resolution of symptoms, but the diet also restricted fructans [65], and a subsequent randomized cross-over re-challenge study showed both fructose and fructans, alone and additively in combination, induced symptoms more than did glucose as placebo [66]. Again patients without fructose malabsorption were not offered the therapy in those studies. As outlined earlier, the detection of fructose malabsorption on breath hydrogen testing may be a normal event and does not, therefore, represent a ‘diagnosis’. In a study from New Zealand, the presence of fructose malabsorption (breath hydrogen response after 35g fructose) predicted a better response to a low FODMAP diet than those without [33], but this observation does not translate to a clinical application; those without fructose malabsorption at the test should still be offered a FODMAP diet including restriction of free fructose. Thus, it is difficult to define a reason for fructose breath testing or to utilize a low fructose diet, although all experts do not agree [67].

Brush border hydrolase deficiencies Starch and dietary disaccharides are hydrolyzed by enzymes in the brush border of the small intestinal epithelial cells (Fig. 5). Absent or reduced activity of these will potentially lead to maldigestion and manifestation so carbohydrate intolerance. Hypolactasia is common and well understood, but there has been recent increasing interest in other brush border hydrolases.

Lactase deficiency Small intestinal lactase activity reduces markedly within 3–20 years after weaning in at least two thirds of the world population, particularly in Asia, South America and Africa [68]. Whether this manifests as lactose intolerance depends upon how much lactose is ingested and what the response is to malabsorbed lactose. Small doses might induce bloating and discomfort whereas larger doses will have greater osmotic effects and cause diarrhea. There is wide variations in tolerance



FODMAPs and carbohydrate intolerance Chapter | 26  383

FIG. 5  Digestion of starch and disaccharides ingested in food in the luminal phase (amylase from salivary glands and pancreas) and at the brush border.

to ­malabsorbed lactose and this is likely to depend upon factors that include the presence of visceral hypersensitivity [69]. Dietary management comprises a lactose-reduced diet since the majority of patients with lactose intolerance can tolerate small to moderate amounts of lactose in one sitting. This is reported to be 12–15g (equivalent to 300mL of milk) [68]. Of importance is that the diet is not lactose-free and that small amounts found in medications, for instance, will not induce symptoms. It is also important that the diet is not ‘dairy-free’ as butter and ripened cheeses contain minimal lactose, but some are excellent sources of calcium. Lactose-free products in which the lactose is hydrolyzed by β-galactosidase (lactose) are available in some countries. The ingestion of lactase with foods can also be efficacious, unless the lactose load is very high. While lactose restriction is very effective in reducing symptoms associated specifically with ingestion of moderate amounts of lactose, its benefit to patients with IBS depends largely on observational studies of cohorts with IBS who had positive tests for lactose malabsorption and reported good response to lactose-reduced diets both in short and longer term. However, there was no placebo group and those with negative tests were not offered the diet. In other words, the specific (as opposed to placebo) benefit of pursuing lactose malabsorption and placing such patients on a lactose-free diet remains uncertain.

Deficiency of other brush border hydrolases in the small intestine Reduced activities of any of the other brush border hydrolases will potentially result in maldigestion of dietary disaccharides, and of maltose and dextrins from amylase-mediated digestion of starch. Congenital deficiencies of sucrase–­ isomaltase and trehalase are well described, being relatively common in Greenland and Alaska, but not in USA or Europe, and result in gastrointestinal symptoms consistent with those induced by carbohydrate malabsorption [70]. There is a current wave of interest in whether reduced activities of other brush border hydrolases are clinically relevant in adolescents and adults with IBS. If so, their detection may extend the list of FODMAPs in some individuals to include sucrose or starch, and may be one explanation for incomplete or lack of response to a FODMAP diet. Pediatric studies indicate that hydrolase activities are not uncommonly reduced in duodenal biopsies [71] and this has led to claims that maldigestion of the relevant disaccharide substrates causes the symptoms in such patients. While this notion is appealing, evidence supporting it is limited and mostly extrapolated from experience with lactose. How measured enzymatic activity correlates with actual maldigestion and symptoms has not been established and the evidence that dietary restriction is beneficial is unconvincing. Supplementation with exogenous sucrosidase appears to have benefits when sucrase activity is minimal (congenital deficiency of sucrase–isomaltase) [71], but studies are lacking in the adults where duodenal sucrase activity is reduced. In other

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words, what is needed in adults with IBS is the translation of finding a physiological state (e.g., low duodenal sucrase activity) to a therapeutic benefit (e.g., symptoms response to reducing sucrose intake). The breakthrough in this area has come from studying polymorphisms for which the expressed enzyme has reduced activity in large populations. Indeed, the presence of such polymorphisms of sucrase–isomaltase are more common in patients with non-constipation-predominant patients with IBS with Odd’s Ratio of 1.36 for the more common 15Phe variant [2]. To translate such seminal observations into clinical practice, diagnostic criteria that reliably predict clinical relevance of reduced enzyme activity need to be refined, perhaps with the use of genetic testing, possibly breath testing with strict control over confounders (as previously discussed) and enzymatic activities in duodenal biopsies, together with evidence that dietary strategies designed according to the deficiencies found are efficacious. The dietary challenge for sucrase–­isomaltase and maltase–glucoamylase includes the fact that starch, which makes up about 60% of dietary carbohydrate intake, may well need to be restricted.

Conclusions Slowly absorbed and indigestible short-chain carbohydrates (FODMAPs) are frequent inducers of symptoms in patients with IBS. The use of single FODMAP-group dietary restriction has little evidence-based role in patients with IBS. The genesis of symptoms from the monosaccharides fructose and polyols does not necessarily depend upon their malabsorption and fermentation in the colon due to their strong osmotic effects in the small intestine. In contrast, non-digestible oligosaccharides are likely to have colonic fermentation as a major component of their contribution to symptom genesis and this will depend upon the microbiota of the individual. Thus, there is heterogeneity in the clinical effects of FODMAP groups. The use of comprehensive FODMAP restriction is highly effective in the majority of, but not all, patients with IBS, and its initial application as a ‘top-down’ approach offers the opportunity to determine if this dietary approach is efficacious. If it is, then a program of re-challenge of foods rich in individual FODMAP groups followed by reconciliation into a maintenance, personalized diet has become the recommended approach. This strategy provides the setting for patient empowerment, limited restriction with improved food-related quality of life, low risk of nutritional inadequacy, reduced risk of disruption of the gut microbiome and ongoing symptom control. To achieve this, healthcare professionals (or their referral base) need to enhance their knowledge of dietary carbohydrates and up-skill their ability to deliver dietary advice so that they can achieve optimal efficacy and safety in the appropriate patients.

Acknowledgments Nil

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Review article: implementation of a diet low in FODMAPs for patients with irritable bowel syndrome-directions for future research. Aliment Pharmacol Ther 2019;49(2):124–39. Implementation of a FODMAP diet in IBS and gaps in knowledge. [48] Rossi M, Aggio R, Staudacher HM, et al. Volatile organic compounds in feces associate with response to dietary intervention in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2018;16(3):385–91. [49] Staudacher  HM. Nutritional, microbiological and psychosocial implications of the low FODMAP diet. J Gastroenterol Hepatol 2017;32 (Suppl. 1):16–9. [50] Shepherd SJ, Gibson PR. Nutritional inadequacies of the gluten-free diet in both recently-diagnosed and long-term patients with coeliac disease. J Hum Nutr Diet 2013;26(4):349–58. [51] Halmos  EP, Christophersen  CT, Bird  AR, et  al. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut 2015;64:93–100. [52] Halmos EP, Christophersen CT, Bird AR, et al. Consistent prebiotic effect on gut microbiota with altered FODMAP intake in patients with Crohn's disease: a randomised, controlled cross-over trial of well-defined diets. Clin Transl Gastroenterol 2016;14(7):e164. [53] Zhou SY, Mr G, Wu X, et al. FODMAP diet modulates visceral nociception by lipopolysaccharide-mediated intestinal inflammation and barrier dysfunction. J Clin Invest 2018;128(1):267–80. [54] Valeur J, Røseth AG, Knudsen T, et al. Fecal fermentation in irritable bowel syndrome: influence of dietary restriction of fermentable oligosaccharides, disaccharides, monosaccharides and polyols. Digestion 2016;94(1):50–6. [55] Chumpatazi BP, Cope JL, Hollister EB, et al. Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome. Aliment Pharmacol Ther 2015;42(4):418–27. [56] Chumpitazi  BP, McMeans  AR, Vaughan  A, et  al. 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