Dietary poorly absorbed, short-chain carbohydrates increase delivery of water and fermentable substrates to the proximal colon

Summary

Background  Functional gut symptoms are induced by inclusion and reduced by dietary restriction of poorly absorbed short-chain carbohydrates (FODMAPs), but the mechanisms of action remain untested.

Aims  To determine the effect of dietary FODMAPs on the content of water and fermentable substrates of ileal effluent.

Methods  Twelve ileostomates without evidence of small intestinal disease undertook two 4-day dietary periods, comprising diets differing only in FODMAP content in a randomized, cross-over, single-blinded intervention study. Daytime (14 h) ileal effluent was collected on day four of each diet. Patients rated effluent volume and consistency on a 10-cm visual analogue scale. The FODMAP content of the diet and effluent was measured.

Results  Ingested FODMAPs of 32% (range 6–73%) was recovered in the high FODMAP diet effluent. Effluent collection weight increased by a mean of 22% (95% CI, 5–39), water content by 20% (2–38%) and dry weight by 24% (4–43%) with the high compared to low FODMAP diet arm. Output increased by 95 (28–161) mL. Volunteers perceived effluent consistency was thicker (95% CI, 0.6–1.9) with the low FODMAP diet than with the high FODMAP diet (3.5–6.1; P = 0.006).

Conclusions  These data support the hypothetical mechanism; FODMAPs increase delivery of water and fermentable substrates to the proximal colon.

Introduction

Symptoms of abdominal pain, bloating, flatus and altered bowel habits are common complaints in gastrointestinal disorders, including irritable bowel syndrome (IBS). Barostat studies indicate that these symptoms may be induced by luminal distension in association with visceral hypersensitivity.¹ This suggests that factors that change the degree of intestinal luminal distension, by increasing water and gas volume, may be suitable targets for therapy. Likely candidates are poorly absorbed dietary components that exert an osmotic effect by virtue of a relatively small molecular size, and are fermented by intestinal bacteria, producing gas. A family of poorly absorbed, short-chain carbohydrates, recently termed FODMAPs (Fermentable Oligo-, Di-, Mono-saccharides And Polyols)² fit this profile (see Figure 1). They include (with examples) fructo-oligosaccharides (fructans; found in wheat, onion), galacto-oligosaccharides (galactans; cabbage, legumes) and polyols (sorbitol, stone fruits, mushrooms, artificial sweeteners), all of which are poorly absorbed in all people. Lactose (milk, ice-cream) and fructose (honey, apples, and high fructose corn syrup) are only considered FODMAPs (i.e. poorly absorbed) in a proportion of the population when enzyme activity or transport mechanisms are impaired.

Figure 1.  Hypothetical mode of action of FODMAPs. Ingested FODMAPs are poorly absorbed in the small intestine. Their small molecular size means that they exert an osmotic effect, drawing fluid through to the large bowel. FODMAPs are then fermented by colonic microflora producing hydrogen and/or methane gas. The increase in fluid and gas components of the bowel leads to diarrhoea, bloating, flatulence, abdominal pain and distension.

Acute ingestion of fructose,^3–9 sorbitol^{5, 7, 8, 10} and fructo-oligosaccharides^{11, 12} in pure form or incorporated into the diet of healthy volunteers and patients with IBS induce or exacerbate functional gastrointestinal symptoms. In observational studies, dietary restriction of all or major groups of FODMAPs has alleviated gastrointestinal symptoms, such as altered bowel habits (diarrhoea and/or constipation), bloating and flatulence in the majority of patients with IBS or functional bloating^13–15 and in patients with quiescent inflammatory bowel disease and functional gut symptoms.^{15, 16} The legitimacy that such symptomatic benefit was indeed as a result of restriction of FODMAPs was established in a placebo-controlled, cross-over rechallenge clinical trial in patients with IBS and fructose malabsorption who had symptom resolution on a low FODMAP diet.¹⁷ In that study, 70–80% of patients developed recurrence of abdominal symptoms such as pain, bloating and flatulence when fed a controlled diet challenged with pure forms of FODMAPs compared to 15% when fed a similar diet spiked with placebo (glucose). More recently, common foods have been analysed for their content of FODMAPs^{18, 19} and these data have enabled the construction of a low FODMAP diet for patients complaining of functional gut symptoms.²⁰

The aim of the present study was to directly test the principles upon which the hypothetical mode of action (Figure 1) is based – increased delivery of water and of fermentable substrate to the distal small bowel and proximal large bowel – and to quantify the magnitude of the effect. This was undertaken using the ileostomy model, a well-established technique to study digestion and absorption of carbohydrates.^21–24 Ileostomates were studied under controlled dietary intake to define the effect of dietary FODMAPs on the nature and volume of ileal effluent and to document perceived changes in the quality and quantity of the output.

Materials and methods

Subjects

Volunteers with an ileostomy were recruited through the Ileostomy Association of Victoria and the Ostomy Association of Melbourne. Subjects were in good health and were excluded if there was evidence of small intestinal disease, if more than 10 cm of terminal ileum had been resected, if their ileostomy was formed less than 3 months previously, if they exhibited symptoms of ileostomy dysfunction or if antibiotics had been taken within the previous 6 weeks. The experimental protocol was approved by the Eastern Health Research and Ethics Committee and by the Monash University Ethics Committee. Subjects gave written, informed consent prior to participation in the study.

Experimental design

The study was a randomized, single blinded, cross-over intervention study involving diets that differed greatly in FODMAP content. Two test diets (4 days each) were used, one high in FODMAPs (HFD) and one low in FODMAPs (LFD). A washout period of at least 2 weeks separated the dietary periods to ensure that no carry-over effects occurred. Diets were matched for energy, macronutrients and fibre and provided the recommended daily requirement of micronutrients as assessed using FoodWorks food composition database (Xyris Pty Ltd, Brisbane, QLD, Australia). Fructose was balanced with glucose in the LFD for each meal and snack to maximize fructose absorption,²⁵ and was in excess for the HFD at breakfast and lunch. Resistant starch (RS) was calculated using published tables²⁶ and matched by the inclusion of high RS muffins in the LFD.

Anthropometry of the volunteers and details of physical activity were assessed to calculate estimated energy requirements. Volunteers were randomly assigned to the LFD or HFD with a minimum 2-week rest period before crossing over to the alternate diet. The diets provided to each volunteer were based on calculated energy requirements ranging from 6.6 to 13.7 MJ per day. Detailed information about the food consumed was recorded by the participants so that compliance with the protocol and the final dietary intakes could be calculated (see Table 1 for average intake on day four of each diet). All food was provided free of charge during the dietary periods.

Table 1.   Actual dietary intake on day 4 of each diet (mean ± S.E.M.)

	Low FODMAP diet	High FODMAP diet	P value
* Excess fructose = fructose minus glucose; FODMAP carbohydrates are shown in italics. † Calculated using Foodworks dietary software which uses the Australian food composition database, NUTTAB 2006. ‡ Calculated using published tables.^26, ^40 P values < 0.05 are highlighted in bold.
Energy, MJ†	9.8 ± 0.9	9.9 ± 0.6	0.926
Protein, g†	97.8 ± 9.8	101.2 ± 5.6	0.357
Fat, g†	67.9 ± 4.5	70.2 ± 6.3	0.355
Carbohydrates, g†	318.4 ± 36.3	289.6 ± 26.3	0.057
Monosaccharides	40.9 ± 7.0	159.5 ± 21.4	<0.0001
Glucose	23.4 ± 3.4	61.0 ± 9.4	<0.0001
Fructose	17.5 ± 3.7	98.6 ± 12.0	<0.0001
Excess fructose*	0	37.6 ± 2.6	<0.0001
Disaccharides	70.5 ± 8.9	56.4 ± 10.0	0.004
Sucrose	66.5 ± 8.9	31.3 ± 3.2	<0.0001
Lactose	4.1 ± 0.3	25.1 ± 6.9	<0.0001
Sugar polyols	0	3.1 ± 0.3	<0.0001
Sorbitol	0	3.1 ± 0.3	<0.0001
Mannitol	0	0.1 ± 0.0	<0.0001
Oligosaccharides	1.6 ± 0.2	27.7 ± 0.1	<0.0001
Fructans	1.3 ± 0.2	26.9 ± 0.1	<0.0001
Galactans	0.3 ± 0.1	0.8 ± 0.0	<0.0001
Starch†	159.7 ± 26.7	152.2 ± 0.4	0.383
Resistant starch‡	8.7 ± 1.5	9.3 ± 0.0	0.208
Dietary fibre†	27.8 ± 1.9	27.1 ± 0.1	0.282

To ensure that volunteers were blinded to the nature of the test diets, meal structure was similar between the two diets, only differing by the inclusion/exclusion of high FODMAP ingredients; for example, wheat-based lasagne sheets with a sauce that included onion and garlic was used in the HFD compared with the LFD where rice and corn lasagne sheets with a sauce devoid of onions and garlic was provided. All food was prepared by the investigators, food scientists and dieticians in the kitchens of Deakin University, Melbourne, and meals were frozen in individual containers.

Ten centimetres Visual Analogue Scales (VAS) were completed following each diet, on which volunteers ranked their perceived change in output volume and consistency, as well as abdominal pain, bloating and nausea. Zero was equivalent to the absence of symptoms, while ten was equivalent to maximal severity for each symptom.

At baseline (on their usual diet) and on day four of each diet, the volunteers undertook a 24 h collection of effluent. They were provided with labelled containers and a −20 °C portable freezer. Volunteers emptied their bag in the morning prior to breakfast, discarding the contents. They were then asked to empty their ileostomy bag and decant the contents into containers every 2 h during the day for 14 h and immediately place the containers into the portable freezer. This method was enforced to minimize fermentation of the carbohydrates of interest ex vivo, and to ensure that the majority of digestion and absorption of all meals consumed within that day was complete (long chain FODMAPs are detected in their highest concentrations in ileal effluent 3 h after a meal).²⁴ Output collection continued overnight, but strict timings were not enforced. The ileostomy effluent was weighed and collated into daytime and overnight collections for each individual and frozen at −40 °C. A 20 mL sample from each daytime and overnight collection was thawed and warmed to 37 °C after which, pH was measured using a protein-resistant electrode. Changes in pH were used as a marker of fermentation and this was used to monitor compliance to the effluent collection protocol. The remainder of the effluent samples were freeze-dried (Operon Freeze-drier, Gimpo-City, Korea) to constant dry weight so that wet and dry weight could be determined.

Analysis of FODMAP content

Prior to the study, each meal and snack, including drinks were separately analysed for their content of fructose, sucrose, glucose, maltose, lactose, sorbitol, mannitol, raffinose, stachyose, kestose, nystose, galactose and total fructans according to the methods established in our laboratory. Total fructans were measured using an AOAC-approved commercially available, enzymatically based assay kit (Megazyme International Ireland Ltd, Wicklow, Ireland), as per manufacturer’s instructions. Individual FODMAPs were measured by high performance liquid chromatography (HPLC) as previously described.^{18, 19} Assessment of carbohydrate absorption was undertaken by analysing the effluent daytime collections using the methods described above and comparing the content to the level of ingested FODMAPs (Table 1) in the diet on day four (effluent collection day). Starch in the effluent samples was measured using the Megazyme Total Starch assay (Megazyme International Ireland Ltd).

Statistical evaluation

The results were analysed on a per-protocol basis. All statistical tests were performed using graphpad prism (version 3.00 for Windows, GraphPad Software, San Diego, CA, USA). Results are presented as mean (95% confidence interval) unless otherwise stated. Unpaired t test was used to compare the two test diets. Paired t test was used to compare the normally distributed pH data, whereas Wilcoxon signed rank test was used to compare results between LFD and HFD for output and symptoms. Correlation of FODMAP intake with water output was determined using Spearman calculation. A P value of ≤0.05 was considered significant.

Results

Subjects

Of the twelve recruited subjects, the results from two were withheld from analysis. The first was excluded for violation of protocol because fluid intake was highly variable between the diets. The second patient was withdrawn when he developed a marked reduction in ileostomy output with abdominal distension on day two of the low FODMAP diet and was unable to complete that arm. Thus, results from 10 subjects were evaluated, four men with mean age 55 (range 31–78) years. An ileostomy had been created in the subjects because of ulcerative colitis in eight and Crohn’s disease in two and the surgery had been performed a mean of 14 (range 1–33) years prior to the study. Neither subject with Crohn’s disease had a history of small bowel involvement. All subjects were asymptomatic before entering the study with a baseline 24 h effluent collection weight of 757 (500–1015) g on their normal diets.

Characteristics of the ileostomy effluent

For the pooled daytime samples, the mean pH was 7.3 (95% CI; 7.0–7.5) for the LFD and 7.1 (6.7–7.5) for the HFD (P = N.S.; paired t test). This is comparable with expected luminal pH 6.5–7.5²⁷ and indicates that the freezing regimen and compliance with it were good since reduction in pH would indicate carbohydrate fermentation ex vivo in the ileostomy effluent. In contrast, when strict timings were not enforced, as was the case with the overnight samples, the pH fell and was significantly lower in the HFD effluent [6.2 (5.7–6.7)] compared with the LFD [6.8 (6.2–7.4); P = 0.04].

The measured FODMAP content in ileal effluent differed between the diets. The breakdown of the mean weight of individual short-chain carbohydrates measured in the effluent is shown in Table 2. The major FODMAP contributors to effluent output weight were fructans and sorbitol, equating to 32% of both ingested fructans (7–78%) and sorbitol (0–70%) escaping digestion during the HFD (Figure 2). Four volunteers demonstrated lactose malabsorption with 0.1–3.2% ingested lactose evident in their HFD effluent. Fructose malabsorption was minimal in all patients with less than 4% of ingested excess fructose recovered in the effluent. An average of only 0.01 g galactans was detected in the effluent following each diet due to the minimal galactan content of the test diets.

Table 2.   Recovery of short-chain carbohydrates (mean ± S.E.M.) in the ileostomy effluent

Carbohydrate, g	Amount recovered in effluent (g)		P value
	Low FODMAP diet	High FODMAP diet
P values < 0.05 are highlighted in bold.
Monosaccharides	1.71 ± 0.63	1.55 ± 0.47	0.610
Glucose	1.31 ± 0.58	1.00 ± 0.39	0.213
Fructose	0.40 ± 0.14	0.56 ± 0.11	0.138
Disaccharides	0	0.10 ± 0.09	0.125
Sucrose	0	0	N.S.
Lactose	0	0.10 ± 0.09	0.125
Maltose	0.06 ± 0.04	0.05 ± 0.02	0.813
Sugar polyols	0.28 ± 0.10	0.96 ± 0.22	0.014
Sorbitol	0.04 ± 0.02	0.75 ± 0.21	0.004
Mannitol	0.25 ± 0.08	0.20 ± 0.08	0.641
Oligosaccharides	0.90 ± 0.26	8.48 ± 1.74	0.002
Fructans	0.89 ± 0.26	8.47 ± 1.74	0.002
Galactans	0.01 ± 0.00	0.01 ± 0.01	0.125
Mucus sugars	0.20 ± 0.06	0.45 ± 0.11	0.020
Fucose	0.10 ± 0.05	0.19 ± 0.07	0.109
Galactose	0.10 ± 0.04	0.25 ± 0.07	0.027
Resistant starch	6.61 ± 1.16	9.27 ± 0.60	0.098

Figure 2.  Proportion of FODMAPs recovered in the ileostomy effluent expressed as a percentage of the estimated intake of FODMAPs on the high FODMAP diet.

In addition to FODMAPs, other carbohydrates were measured in the effluent. Glucose and maltose were detected in similar proportions following each diet. Galactose and fucose, the mucous sugars, were found in significantly greater amounts following the HFD [0.45 (0.20–0.69) g vs. 0.20 (0.06–0.34) g on LFD; P = 0.02].

The composition of the daytime ileostomy effluent differed between the two diets. As shown in Figure 3, the mean effluent weight was significantly less during the LFD (409 ± 65 g) compared with the HFD (504 ± 51 g; P = 0.01; Wilcoxon signed rank test). This represented a reduction of 22 (5–39) % or, in terms of volume, 95 (28–161) mL over the day. Water content of the effluent was 20 (2–38) % or 58 ± 17 mL less on the LFD (mean ± S.E.M.; P = 0.013). Dry weight also was 24 (4.0–43.4) % less or 37 ± 15 g during the LFD (P = 0.028).

Figure 3.  Weight of daytime effluent output on the fourth day of the high and low FODMAP diets. The high FODMAP diet resulted in a significantly greater output compared with the low FODMAP diet (P = 0.013).

There was a positive correlation between the output water volume and the total FODMAP content of the output (Spearman r = 0.6848, P = 0.035) (Figure 4).

Figure 4.  Correlation between FODMAPs recovered and water content of ileostomy output, Spearman r = 0.6848, P = 0.035.

Perceptions of the subjects

As shown in Figure 5a, the subjects perceived a significantly thicker effluent consistency (VAS; 0 = solid, 10 = liquid) with the LFD [2.3 (0.9–3.7) vs. 4.8 (3.5–6.1) on HFD; P = 0.005]. Their perception of the volume (VAS: 0 = no output, 10 = excessive) of the ileostomy output was also less while consuming the LFD [4.2 (2.7–5.6) vs. 5.6 (4.4–6.7) on HFD], but this failed to reach statistical significance (P = 0.066; Figure 5b).

Figure 5.  Perceived characteristics of the ileostomy output as reported by the subjects on the fourth day of a low and high FODMAP diet using the 10 cm Visual Analogue Scale. (a) Consistency (P = 0.005) and (b) Volume (P = 0.066).

Four subjects experienced moderate-to-severe (VAS > 3 cm) abdominal symptoms of pain, bloating and nausea during the LFD, with two of these four subjects also experiencing symptoms on the HFD (Figure 6). Examination of the baseline characteristics of these four patients identified that they had a lower baseline 24 h collection output [459 (223–695) g] than those who were symptom-free during both dietary periods [954 (461–1447) g; P = 0.067].

Figure 6.  Symptoms reported by individual patients via a Visual Analogue Scale during the high and low FODMAP diets.

Discussion

Multiple studies have now shown that ingestion of FODMAPs, either as a pure liquid^{3, 4, 8, 10–12, 28, 29} or together with¹⁷ or as part of food,³⁰ induce gastrointestinal symptoms. In examining FODMAPs as a group, provided in meals across the day, an increase in total effluent output, including effluent water volume (measured and noted by the participants and correlated with FODMAP recovery), confirms that FODMAPs as part of the diet are osmotically active and that their poor absorption gives rise to their potential fermentation and associated gas production. Concurrent increase in gas production from carbohydrate fermentation and increased fluid load will lead to luminal distension in the distal small bowel and proximal colon, and these may, in the presence of visceral hypersensitivity, lead to symptoms of bloating, wind and abdominal pain. Secondary motility responses to luminal distension may lead to changes in bowel habit that might be constipation, diarrhoea, both or neither. Increased fluid delivery to an intact bowel may also contribute to diarrhoea, as would an osmotic laxative, although a previous study of the subsequent handling of short-chain carbohydrates after entering the colon indicated that the fermentative rather than osmotic effects predominated in most people.³¹

Recovery of FODMAPs following the HFD revealed that a mean of 32% of ingested fructans were poorly absorbed compared with 86–89% in previous studies when fructans were consumed as a liquid³² or a single food source (artichokes).³³ An additional distinction from the current investigation was that, in the previous studies, fructan content was measured in samples of intestinal contents aspirated directly from the ileum rather than from a stoma bag and these were snap-frozen. In the current study, fructans were ingested within a normal diet with whole foods incorporated into meals, and ileostomy effluent was collected two-hourly and placed into a portable freezer at −20 °C. The lower recovery indicates that fermentation was taking place prior to the freezing of the ileostomy effluent. As sugars and oligosaccharides are rapidly fermented when exposed to intestinal flora, some fermentation was likely to be occurring in the terminal ileum³³ and within the ileostomy bag. The latter was clearly evident by examination of effluent pH in the overnight samples and those collected during the day. Furthermore, not all fructans may have traversed the small intestine before the overnight collection commenced as set meal times were not enforced. This may account for the lower average fructan output as well as the significant inter-individual variation of recovered fructans (range 7–78%). Similar variations were seen for the malabsorption of polyols (range 0–70%) with the same reasons applicable to explain the discrepancy from previous studies demonstrating that 25–40% of ingested polyols are malabsorbed.²⁴

None of the participants exhibited evidence of fructose malabsorption. As fructose is well absorbed in the presence of equimolar glucose, the potential for malabsorption is restricted to free fructose (or that in excess of glucose).²⁵ The likelihood of fructose malabsorption depends upon the dose; at a challenge dose of 25 g, 53% of people malabsorb fructose compared with 73% in those challenged with 50 g.³ In the present study, the HFD contained fructose in excess of glucose at breakfast and lunch (9.82 g and 12.46 g respectively) because of the inclusion of apple juice and soft drink. Only 1.3–5.3% of this free fructose was detected in the ileal effluent. This represents efficient fructose absorption via GLUT5 transporters and/or low bacterial content in the ileum because of the ileostomy.³⁴ The small amount of fructose detected in the effluent could also be a result of polysaccharide breakdown rather than incomplete absorption.^21–23

Similar assessment can be made for lactose absorption, with lactose detected in the effluent of only four volunteers, and only in small amounts. It has been demonstrated that symptoms only occur in lactose malabsorbers when lactose is ingested in quantities in excess of seven grams as most people have some degree of lactase activity.³⁵ The diet in the current study only provided this amount at two intervals, breakfast and afternoon tea (7 g and 10 g, respectively). It is not surprising therefore that the lactose malabsorbers only had small amounts of lactose in the ileal effluent.

Effluent maltose and glucose are starch breakdown products. The total weight of these products was 1.04 g in the daytime samples, representing 0.65% of ingested starch, consistent with Englyst and Cumming’s work²³ where again 0.65% of ingested starch was detected as effluent glucose and maltose. The level of mucous sugars measured in the effluent of the diets was also comparable to previous ileostomy studies where 0.1–1.5 g galactose and fucose have been recovered.^{21, 22, 33} Interestingly, there was a significantly greater level of effluent mucous sugars, particularly galactose, in association with the HFD. Whether this observation is causally related to the FODMAPs themselves remains unknown, but a thicker mucous layer has been demonstrated in the colon in response to another fermentable substrate, resistant starch.³⁶ Such a potential association warrants further evaluation.

There is little doubt that the FODMAPs delivered to the distal small bowel and more particularly to the bacteria-rich proximal colon would result in considerable luminal gas production. Fermentation did occur in the ileostomy bag as shown by the lower pH in ileostomy effluent collected overnight in the HFD compared with the LFD arm, and it could be inferred that already some fermentation had occurred in the distal small intestine by the degree of fructan recovery as discussed above, that intestinal gas production does indeed occur in association with FODMAPs incorporated into the diet has been recently shown via breath hydrogen analysis in a recent preliminary report.³⁰

The osmotic activity of FODMAPs has previously been demonstrated using the ileostomy model, but only when subjects were challenged with individual FODMAPs, such as polyols, in pure form.^{24, 37} The current data present further evidence for the osmotic nature of pooled FODMAPs seen in a normal diet, as confirmed by the correlation between increasing water output and FODMAP recovery. This provides a physiological explanation, in addition to the fermentative effects on luminal distension, for the efficacy of the LFD in managing the subset of patients with diarrhoea,^{16, 17} although its relative importance may be small.³¹

In conclusion, the present study provides evidence that FODMAPs might induce symptoms related to intestinal luminal distension via increasing delivery of water and rapidly fermentable substrates to the proximal colon. This physiological mechanism supports the use of an LFD for people experiencing functional gastrointestinal symptoms such as altered bowel habits, bloating, wind and abdominal pain.

Acknowledgements

Declaration of personal interests: SJS has published four cookbooks directed towards issues of coeliac disease and FODMAPs. RBG was supported by Pharmatel Fresenius Kabi IBD Fellowship and the New Zealand Society of Gastroenterology-Ferring Pharmaceuticals Fellowship. Declaration of funding interests: This study was funded by project grants from the International Organisation of Inflammatory Bowel Disease and the National Medical & Research Council of Australia. JSB was in receipt of a Sir Robert Menzies Memorial Research Scholarship in the Allied Health Sciences and received support from a Monash University Postgraduate Publications Award. Food donations were provided by Coles, Changs, Liddells, San Remo, Fantastic Snacks, Country Life, Freedom Foods, Heinz, Parmalat Australia Ltd, Sanitarium and Ingham.