The Gut Microbiome as a Predictor of low FODMAP Diet Efficacy in Functional Bowel Disorders

Abstract

Purpose of the Review

Fermentable oligosaccharides disaccharides monosaccharides and polyols (FODMAP) dietary restriction ameliorates irritable bowel syndrome (IBS) symptoms; however, not all IBS subjects respond. Given the gut microbiome’s role in carbohydrate fermentation, investigators have evaluated whether the gut microbiome may predict low FODMAP diet efficacy.

Recent Findings

Gut microbiome fermentation, even to the same carbohydrate, is not uniform across all individuals with several factors (e.g., composition) playing a role. In both children and adults with IBS, studies are emerging suggesting the gut microbiome may predict low FODMAP diet efficacy. However, there is significant heterogeneity in the approaches (study population, microbiome assessment methods, statistical techniques, etc.) used amongst these studies.

Summary

The gut microbiome holds promise as a predictor of low FODMAP diet efficacy. However, further investigation using standardized approaches to evaluate the microbiome while concomitantly assessing other potential predictors are needed to more rigorously evaluate this area.

INTRODUCTION

Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal pain disorder; it affects up to 20% of the world’s (both adult and pediatric) population.(1) It is characterized by chronic abdominal pain related to defecation or changes in stool form or stool frequency.(1) As a functional disorder, IBS is often best viewed within the context of the biopsychosocial model.(2) As such, several potentially inter-related factors may play a role including: gut inflammation, psychosocial factors (e.g. anxiety), genetics, visceral hypersensitivity, dysbiosis (altered gut microbiome) and diet.(3) Diet is an important factor in IBS symptom generation as more than 80% of both children, adolescents, and adults with IBS identify at least one food which worsens their IBS symptoms.(4–6) In both children and adults with IBS, a higher number of perceived dietary food intolerances is associated with increased IBS symptom severity.(4, 6) Dietary components which have gained significant recent attention as potential symptom generation culprits in those with IBS are fermentable oligosaccharide disaccharide monosaccharide and polyol (FODMAP) carbohydrates.

FODMAPs

FODMAP carbohydrates include: fructose, lactose, fructans, galactans, and polyols (Table 1). FODMAP carbohydrates as a group may be malabsorbed and rapidly fermented, thereby leading to symptoms seen in functional bowel disorders including abdominal pain, bloating, and increased flatulence.(7) In both adults and children with IBS, double-blind placebo controlled trials have demonstrated FODMAPs may exacerbate IBS gastrointestinal symptoms.(8) (9) In addition, in both adults and children with IBS, a FODMAP restriction diet (or low FODMAP diet) ameliorates IBS gastrointestinal symptoms.(10, 11) However, not all subjects with IBS benefit from a FODMAP restriction diet: Studies suggest up to 50% do not benefit from this dietary intervention.(12, 13)

Table 1:

Fermentable Oligosaccharide Monosaccharide Disaccharide and Polyol (FODMAP) Carbohydrates: Type, Structure, Factors Related to Malabsorption, Example of Potentially Relevant Microbiome Enzymes/Pathways, and Examples of Common Foods Containing the Delineated FODMAP

FODMAP Carbohydrate	Structure	Factors Related to Malabsorption	Example of Associated Microbial Enzyme/Pathway	Examples of Common Foods Containing the Carbohydrate
Fructose	Monosaccharide	Passive absorption	Fructose-6-phosphate shunt	Honey, apples
Lactose	Disaccharide	Diminishing lactase enzyme expression in majority	β-galactosidase	Dairy products, milk, cheese
Fructans	Oligosaccharide – primarily fructose polymers	Lack hydrolases to metabolize	β-fructofuranosidase	Wheat, onions
Galactans	Oligosaccharide – primarily galactose polymers	Lack hydrolases to metabolize	α-galactosidase	Beans, legumes
Polyols	Sugar alcohol	Passive absorption	Sorbitol-6-phosphate dehydrogenase	Watermelon, pears

Studies, often using magnetic resonance imaging, have demonstrated that FODMAPs such as fructose significantly increase small bowel water content following ingestion.(14) In contrast, FODMAPs such as fructans primarily increase colonic distention via microbial fermentation and subsequent gas production.(14) These physiologic responses were believed to be the primary mechanisms by which FODMAPs induced symptoms.(14, 15) However, investigators have not been able to differentiate those with IBS who develop symptoms vs do not develop symptoms during a FODMAP-related challenge based on these physiologic changes (e.g., gas production) alone.(9, 16) Moreover, healthy controls given FODMAPs have the same physiologic changes occur to the same degree as those with functional bowel disorders.(16) These data suggest additional mechanisms need to be determined for FODMAP induced IBS symptoms.

An additional factor which may play a role in FODMAP induced symptoms relates to visceral sensation. Visceral hypersensitivity is common in both adults and children with IBS:(17–19) For example, up to 83% of children with IBS have visceral hypersensitivity as measured by rectal barostat.(17, 20) In adults with IBS given the fermentable CHO lactulose, the presence of baseline visceral hypersensitivity predicted more severe abdominal pain after lactulose ingestion.⁸⁹ In another study in lactase deficient adults with IBS, visceral hypersensitivity (as measured via rectal barostat) was worsened by lactose ingestion.⁹⁰ An MRI-based study in adults with IBS implicated visceral hypersensitivity rather than the amount of gas produced in the induction of abdominal pain.(16)

Identifying the mechanism(s) by which FODMAPs induce functional symptoms and predicting those with IBS who may benefit from a FODMAP restriction diet has garnered significant attention.(21) In clinical practice it is recommended that the FODMAP diet be applied in three phases: comprehensive restriction (to determine efficacy of the diet), re-introduction (to determine which FODMAPs may be able to be reintroduced into the diet), and personalized maintenance.(13) Potential challenges with following a low FODMAP diet include: it does not work in all participants; education challenges such as incongruence between available dietary FODMAP-related listings; potential association with unintended weight loss; unknown long term effects given that it removes foods considered healthy (e.g., fiber, certain fruits); and initial reduction in the abundance of microorganisms associated with health (e.g., Bifidobacterium).(22–25) It is recommended that subjects with IBS implementing a FODMAP diet work with a dietitian knowledgeable about the diet to mitigate these challenges. Based in part on these challenges and lack of clear pathophysiologic factors related to FODMAP induced IBS symptoms, experts in the field of functional bowel disorders have determined that identifying the mechanism by which FODMAP carbohydrates induce symptoms as an important area for future research.(21)

Potential Role of the Gut Microbiome

One potential mechanism being actively investigated by which FODMAP carbohydrates induce IBS symptoms may be related to the gut microbiome (Figure 1). The microbiome is composed of several types of microorganisms (including bacteria, archaea, fungi, and viruses) and their genetic material.(26) Though the majority of these microorganisms cannot be cultured, new generation sequencing methods allow for culture independent elucidation of both microbial taxonomy and microbial genes (metagenomics).(27–29) Additional ‘omics technologies may provide insight into the gut microbiome activity. This includes metabolomics, which is the study of the metabolites (metabolome) in a biological sample. The gut metabolome comprises numerous small metabolites produced by the human; however, the majority of gut metabolites seen in feces are produced by the gut microbiome.(30, 31) Metabolomic studies have identified metabolites resulting from colonic microbiome metabolism of dietary products within 2 hr. of consumption(32, 33) and changes in stool metabolites within 24 hours of an antibiotic intervention.(34) These data suggest microbiome activity is readily altered by foods and/or other interventions which are ingested.

Figure 1:

Hypothetical Framework of the Potential Role of Microbiome Composition and/or Microbiome Activity (Metabolite Production) as it Relates to Fermentable Oligosaccharide Disaccharide Monosaccharide and Polyol (FODMAP) Carbohydrate Metabolism and Subsequent Symptom Development in Functional Bowel Disorders

The intestinal microbiome contains over 9 million genes: This number significantly outnumbers the number of human genes.(35) These microbial genes allow the microbiome to serve essential functions in maintaining human health. One important health related gut microbiome function includes the colonic fermentation of dietary carbohydrates – traditionally believed to be of great importance for energy salvage.(36) Though humans may lack the necessary enzymes to hydrolyze the bonds within certain FODMAP carbohydrates (e.g., fructans), microbial genes allow the microbiome to metabolize malabsorbed carbohydrates such as FODMAPs (Table 1).(37)

When comparing IBS subjects vs. healthy subjects, microbiome composition differences have been identified; however, the same differences have not been consistently identified across all studies.(38, 39) In children with IBS, using a combination of microbiome composition, microbiome metabolic pathways, and fecal metabolites may help differentiate children with IBS from healthy controls with high accuracy.(40) These types of alterations in microbiome composition (dysbiosis) may be relevant with FODMAPs as microbiome composition determines how luminal polysaccharides are degraded based on the interactions between microorganisms.

Microorganisms have several interactions with each other when metabolizing substrates such as malabsorbed (FODMAP) carbohydrates including: competition, syntrophy, and cross-feeding relationships.(36) These microbial interactions determine the availability of both the FODMAP carbohydrate itself and its subsequent metabolites. In addition, these interactions amongst microorganisms may influence how a microorganism metabolizes a FODMAP carbohydrate. For example, archaea may stimulate bacterial fermentation: Bacteroides thetaiotamicron expresses more fructofuranosidases (capable of metabolizing fructans) when co-cultured with the archaeal organism M. smithii - resulting in an increase in acetate production.(41) Another example can be seen in a humanized gnotobiotic rodent study where evaluation of three different human-derived gut microbiome communities of different composition resulted in markedly different responses in both magnitude and type of microbiota-derived metabolites.(42)

FODMAPs, once consumed, also modulate both microbial composition and microbial fermentation.(9, 15) These gut microbial responses, even to the same carbohydrate, are not uniform across all individuals with variations in both subsequent composition changes and fermentation byproducts. In one study in healthy adults receiving agave inulin (a type of fructan) supplementation the majority of subjects had a subsequent increase in Bifidobacterium; however, a sizeable subset ~ 25% had a decrease in Bifidobacterium. Even those who had an increase in Bifidobacterium with the supplementation had different amounts (percentages) of increase.(43) In a separate study evaluating production of short-chain fatty acids in healthy adults to different fibers (including inulin), the composition of an individual’s microbiota was an important factor in determining the production identified.(44) Ultimately, microbial fermentation response to CHO ingestion appears to be strongly influenced by an individual’s gut microbiome composition.(37, 42, 44)

Fermentation metabolites resulting from FODMAP metabolism may include (amongst many): short chain fatty acids (e.g. acetate), lactate, hydrogen, methane, hydrogen sulfide, and amines.(38) Though further studies are needed, these metabolites may alter the colonic environment or affect colonic physiology in such a manner as to lead to an exacerbation in IBS symptoms. For example, production of fermentation metabolites (e.g., short chain fatty acids) may lead to increased luminal acidity. In one rodent model of visceral sensation, intraluminal colonic acidic hypertonic saline (akin to what may occur in the setting of carbohydrate malabsorption) infusions increased visceral hypersensitivity.(45) Visceral hypersensitivity related to FODMAP intake has also been associated with increased gut immune activation with one rodent study associating this increase with increased intestinal SCFA production.(46) However, increases in gut immune activation from FODMAP carbohydrates are not uniformly seen in all rodent models.(47) Further investigation is needed to determine the potential role of microbiome-derived metabolites on FODMAP induced symptoms.

Microbiome Composition and Predicting FODMAP Diet Efficacy (Table 2)

Table 2:

Characteristics and Findings of Studies Evaluating Gut Microbiome Composition as a Predictor of low Fermentable Oligosaccharide Disaccharide Monosaccharide and Polyol diet efficacy for Irritable Bowel Syndrome

Reference	IBS Population studied	Study Design	Diet Responder Definition	Microbiome Analysis	Discriminant Analysis	Key Baseline Microbiome Findings
Chumpitazi et al.12	Children (ages 7–17 years), n=8	Open-label: low FODMAP × 1 week	≥50% decrease in abdominal pain frequency from baseline	16s rRNA pyro-sequencing	Yes: LEfSE	Responders (n=4) enriched in Sporobacter, Subdoligranulum, Alistipes, and an unclassified Ruminococcaceae. Non-responders (n=4) enriched in Bacteriodes, unclassified Bacteriodales, and a different unclassified Ruminococcaceae.
Halmos et al.10	Adults, n=30	Cross-over RCT (low FODMAP vs. Australian diet) × 21 days	10 mm decrease in visual analogue scale	Select PCR probes of total bacteria and 9 specific targets	No	No differences between Responders (n=21) vs. Non-responders (n=9).
Chumpitazi et al.11	Children, n=33	Cross-over RCT Low FODMAP vs. Typical American childhood diet × 48 hours	50% decrease in abdominal pain frequency during the low FODMAP diet alone.	16s rRNA pyro-sequencing	Yes: LEfSE	Responders (n=8) were enriched in 63 microbial OTUs including: Bacteriodes, Ruminococcaceae, F. prausnitzii, Dorea and Clostridiales. Nonresponders (n=15) were uniquely enriched in Turicibacter. Placebo-responders (n=10) not included.
Bennet et al.49	Adults, n=31 placed on low FODMAP	Parallel group RCT (low FODMAP vs. traditional IBS diet) × 4 weeks	Reduced IBS-Symptom Severity Score by ≥ 50	54 DNA probes targeting ≥ 300 bacteria. Calculation of Dysbiosis Index.	Yes: Multivariate factor orthogonal partial least square discriminant analysis	No bacteria found to be enriched in Responders (n=19). Nonresponders (n=12) enriched in several bacteria including Bacteroides stercoris, Parabacteriodes, Bacillus, Pseudomonas, Acineteobacter, Desulfitispora, Streptococcus, Dorea, Ruminococcus gnavus. Nonresponders had a higher dysbiosis index score at baseline.
Valeur et al.48	Adults, n=61	Open-label, 4 week FODMAP restriction	50% reduction in IBS-Symptom Severity Score	54 DNA probes targeting ≥ 300 bacteria. Calculation of Dysbiosis Index.	No	Responders (n=32) were enriched in Bacteroides fragilis, Acinetobacter, Ruminiclostridium, Streptococcus, and Eubacterium. Nonresponders (n=29) were enriched in Clostridia, Negativicutes, Bacilli; Actinomycetales, Anaerotruncus; Clostridiales; and Shigella, Escherichia. No difference in dysbiosis index between Responders and Nonresponders.

IBS= irritable bowel syndrome; RCT = randomized controlled trial; LEfSE= Linear Discriminant Analysis Effect Size; OTU = operational taxonomic unit

Given the role of the microbiome in determining the metabolism and subsequent metabolite production with carbohydrate ingestion, several investigators have evaluated whether microbiome composition prior to starting a low FODMAP diet (baseline) may predict low FODMAP diet efficacy (Table 1). These investigations have been relatively heterogeneous in methodology in several areas including: study design (e.g. randomized control trial vs. open-label); population included (e.g., children vs. adults with IBS), number of subjects; method used to determine microbiome composition (e.g., select DNA probes vs. 16S rRNA sequencing); definition of clinical response (responder vs. non-responder) to a low FODMAP diet; and the statistical analyses (e.g., whether a discriminant analysis was conducted and if so, what type) employed.

With this heterogeneity amongst studies in mind, it is not surprising that the results have not been consistent amongst them. Nevertheless, four of the five studies identified microbiome signatures differentiating low FODMAP diet responders vs. non-responders. Two studies identified that those who responded to a low FODMAP diet had a microbiome composition enriched in bacteria with an increased ability to metabolize carbohydrates (saccharolytic).(11, 48) One study identified increased dysbiosis in those who did not respond to a low FODMAP diet; however, another study using a similar microbiome analysis technique did not identify dysbiosis as a contributing factor.(48, 49) Though promising, future studies which are larger and use more uniform design and microbiome evaluation approaches are needed to definitively determine if baseline microbiome composition may predict low FODMAP diet efficacy.

Microbiome Metabolic Pathways/ Metabolites and Predicting Low FODMAP diet Efficacy

In addition to microbiome composition, investigators have evaluated both microbiome metabolic potential and fecal metabolites which may be produced by the microbiome as a potential means to predict low FODMAP diet efficacy. In a short-term low FODMAP randomized controlled crossover trial, we identified two carbohydrate related metabolic pathways enriched in the gut microbiome of low FODMAP responders: LacI family transcription regulators and Alpha-N-arabinofuranosidase.(11) LacI family transcriptional regulators regulate microbiome carbohydrate utilization genes and facilitate expression of these genes depending on environmental/substrate availability. Alpha-N-arabinofuranosidase enzymes metabolize arabinogalactans which are a type of FODMAP found in wheat flour.(11) These data suggest microbial genetic potential to metabolize FODMAP carbohydrates may predict FODMAP diet efficacy. However, to date, additional studies investigating gut microbial genes/metabolic pathways and their relationship to the FODMAP diet remain to be completed.

With respect to microbial-derived metabolites, a small open-label pilot feasibility trial using a global metabolomics approach in children with IBS identified several fecal metabolites enriched in low FODMAP diet responders including: gamma-tocopherol, alpha-ketoglutarate, and 1,3,7-trimethylurate.(12) In contrast, non-responders were enriched in several fecal metabolites at baseline including asparagylleucine, urobilinogen, and methylsuccinate.(12) Using a more focused fecal metabolite evaluation, Rossi et al. identified that baseline fecal volatile organic compound (VOCs) profiles differentiate low FODMAP responders vs. non-responders with a high accuracy.(50) The specific VOCs within the profiles which differentiated responders from non-responders VOCs are gaseous carbon based compounds: There are approximately 101 fecal VOCs in stools from healthy individuals.(51) VOCs are believed to be reflective, in part, of microbial composition and fermentation of dietary components such as carbohydrates and proteins.(51) Though these data suggest there are potential baseline differences in baseline microbiome activity differentiating responders vs. non-responders, further work clarifying the specific VOCs playing a role and/or other associated fecal metabolites which may predict low FODMAP diet response are needed.

Conclusion

FODMAP dietary restriction ameliorates IBS gastrointestinal symptoms in both children and adults with IBS. However, not all IBS subjects respond and there may be challenges with implementing a low FODMAP diet. The mechanism(s) by which FODMAP carbohydrates induce IBS symptoms is under active investigation. Given the role of the microbiome in fermenting malabsorbed carbohydrates and the individualized microbiome response (e.g., production of metabolites) which may occur based on an individual’s microbiome composition, there has been increasing attention on the potential role of the gut microbiome in predicting low FODMAP diet efficacy. In both children and adults with IBS, heterogeneous studies suggest that both microbiome composition and microbiome-related metabolomic profiles may predict FODMAP restriction efficacy. However, further investigation utilizing consistent and rigorous methodologic approaches and ideally incorporating other potential factors (e.g., visceral sensation) are needed to further elucidate the role of the gut microbiome as a baseline predictor of low FODMAP diet efficacy in functional bowel disorders.

KEY POINTS.

1. Gut microbiome fermentation, even to the same carbohydrate, is not uniform across all individuals with several factors (e.g., composition) playing a role.

2. In both children and adults with IBS, studies are emerging suggesting the gut microbiome may predict low FODMAP diet efficacy.

3. However, there is significant heterogeneity in the approaches (study population, microbiome assessment methods, statistical techniques, etc.) used amongst these studies.

4. Further investigation using standardized approaches to evaluate the microbiome while concomitantly assessing other potential predictors are needed to more rigorously evaluate this area.

Abbreviations

FODMAP

fermentable oligosaccharides disaccharides monosaccharides and polyols

IBS

irritable bowel syndrome

VOCs

volatile organic compounds

RCT

randomized controlled trial

LEfSE

Linear Discriminant Analysis Effect Size

OTU

operational taxonomic unit