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Behavioral and Diet Therapies in Integrated Care for Patients with Irritable Bowel
Syndrome

W.D. Chey, L. Keefer, K. Whelan, P.R. Gibson

PII: S0016-5085(20)35281-1
DOI: https://doi.org/10.1053/j.gastro.2020.06.099
Reference: YGAST 63830

To appear in: Gastroenterology

Accepted Date: 6 June 2020

Please cite this article as: Chey W, Keefer L, Whelan K, Gibson P, Behavioral and Diet Therapies
in Integrated Care for Patients with Irritable Bowel Syndrome, Gastroenterology (2020), doi: https://
doi.org/10.1053/j.gastro.2020.06.099.

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© 2020 by the AGA Institute

 GASTRO 20-00513
Behavioral and Diet Therapies in Integrated Care for Patients with Irritable
Bowel Syndrome
WD Chey1, L Keefer2, K Whelan3, PR Gibson4
1
Division of Gastroenterology, Michigan Medicine, Ann Arbor, MI, USA,
2
Mt Sinai Medical Center, NYC, NY, USA,
3
King’s College London, Department of Nutritional Sciences, London, UK,
4
Monash University, Melbourne, AU

Corresponding Author:
William D. Chey MD, AGAF, FACG, FACP, RFF
Timothy T. Nostrant Collegiate Professor of Gastroenterology & Nutrition Sciences

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Division of Gastroenterology

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Michigan Medicine
3912 Taubman Center, SPC 5362
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Ann Arbor, MI 48105-5362
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Phone: 734-936-4780
Email: wchey@umich.edu
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Twitter: @umfoodoc
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Word Count: 7497

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Keywords: cognitive behavioral therapy, hypnosis, FODMAPs, ARFID

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Potential Conflicts of Interest:

WDC: Consultant: Allergan, Alnylam, Biomerica, IM Health, Ironwood, Phathom, QOL
Medical, Redhill, Ritter, Salix/Valeant, Takeda, Urovant. Research Funding: Biomerica,
Commonwealth Diagnostic International, QOL Medical, Salix, Vibrant, Zespri. Stock Options:
Gastro Girl, Modify Health, Ritter
LK: Consultant: Pfizer. Research Funding: Abbvie. Stock Options: metaMe Health, Trellus Health
KW: Research grants: Almond Board of California; Clasado, Danone, International Nut and
Dried Fruit Council; Consultancy: Danone; Co-inventor: mobile application to assist patients
following low FODMAP diet.
PRG: Consultant or advisory board member: Allergan, Janssen, MSD, Pfizer, Anatara, Atmo
Biosciences, Immunic Therapeutics, Novozymes and Takeda. His institution has received
speaking honoraria from Janssen, Shire, Bristol-Meyers Squibb and Pfizer. He has received
research grants for investigator-driven studies from MSD. Stock options: Atmo Biosciences.
His Department financially benefits from the sales of a digital application and booklets on
the FODMAP diet. He has published two educational/recipe books on diet.

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 All of the authors participated in drafting and critical revision of the manuscript

Abstract
Irritable bowel syndrome (IBS) is a common, symptom-based condition that has
negative effects on quality of life and costs healthcare systems billions of dollars each year.
Until recently, management of IBS has focused on over the counter and prescription
medications that reduce symptoms in fewer than half of patients. Patients have increasingly
sought natural solutions for their IBS symptoms. However, behavioral techniques and
dietary modification can be effective in treatment of IBS. Behavioral interventions include

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gastrointestinal-focused cognitive behavioral therapy and gut-directed hypnotherapy, to

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modify interactions between the gut and the brain. In this pathway, benign sensations from
the gut induce maladaptive cognitive or affective processes that amplify symptom
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perception. Symptoms occur in response to cognitive and affective factors that trigger fear
of symptoms or lack of acceptance of disease, or from stressors in the external
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environment. Among the many dietary interventions used to treat patients with IBS, a diet
low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols
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(FODMAPs) is the most commonly recommended by healthcare providers and has the most
evidence for efficacy. Patient with IBS who choose to follow the low-FODMAP diet should be
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aware of its 3 phases: restriction, reintroduction, and personalization. Management of IBS

should include an integrated care model, in which behavioral interventions, dietary
modification, and medications are considered as equal partners. This approach offers the
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greatest likelihood for success in management of patients with IBS.

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Introduction

Irritable bowel syndrome (IBS) is a symptom-based condition in which affected

patients suffer with recurrent bouts of abdominal pain and altered bowel habits (1). IBS is

important not only because it is prevalent, affecting 10-20% of the general population, but

also because of its significant impact on quality of life and overall cost to the healthcare

system and society at large (2).

Like the clinical phenotype, the pathogenesis of IBS is diverse. Over the course of the

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last 60 years, a wide range of factors have been suggested to contribute to the development

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of IBS including abnormalities in motility, visceral sensation, brain-gut interactions, the gut

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microbiota, gut permeability, immune activation, genetics, or exposure or reactions to
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psychosocial stressors (3).
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Traditionally, treatment has focused on the use of over-the-counter and prescription

medications to improve one or more IBS symptoms. Though a number of medications have
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proven more effective than placebo, most lead to clinical benefits in fewer than half of
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treated patients and yield therapeutic gains over placebo of between 7-14% (4).
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Furthermore, nearly all medications only work when taken, necessitating chronic therapy.

Medication-related adverse events and cost can also create barriers to the use of

medications for patients and providers. In aggregate, patients have increasingly challenged

the medical community to think more creatively about nonmedical solutions to address

their IBS symptoms (5).

The last 20 years has seen an explosion in our knowledge surrounding the role of

environmental variables that might be manipulated to the benefit of IBS patients (6). Chief

amongst this research are the growing recognition of food and cognitive/emotional factors

as important triggers for symptoms in IBS patients (7,8). The fact that food and stress are

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important to the illness experience of IBS patients are by no means new concepts. However,

the translation of the science to evidence-based management options for IBS patients has

largely occurred since the turn of this century. The goal of this manuscript is to review the

evidence that supports the use of behavioral therapies and a diet low in poorly absorbed,

fermentable carbohydrates in IBS and to provide a rationale for the growing adoption of

integrated care models for patients with IBS.

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Integrated Care is Becoming the Rule Not the Exception for IBS

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The main goals of treating IBS patients are to improve their overall symptoms, sense

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of wellbeing, and quality of life. Frustratingly, there is often discord between GI symptom
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alleviation and improvements in quality of life. For instance, satisfaction with bowel
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movements is often not associated with objective change in the appearance or water

content of feces (9). Likewise, reducing stool frequency with loperamide in IBS-D patients
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has a poor record of improving overall wellbeing (10). Perhaps related is that IBS patients
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often endorse symptoms extending beyond abdominal pain and altered bowel habits. For
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example, a recent population based study of over 71,000 US citizens found that 10-50% of

people with lower GI symptoms also reported upper GI symptoms such as heartburn,

dysphagia, or nausea (11). Similarly, a substantial proportion of IBS patients endorse non-GI

complaints such as fatigue, insomnia, depression, and anxiety (12 – 14), all of which are

known to negatively impact upon quality of life. Thus, it follows that behavioral therapy

within a gastroenterology clinic for patients with functional GI disorders led to considerable

improvement and satisfaction in patients compared with those not receiving it, even though

gastrointestinal symptom severity was unchanged (15).

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In several other chronic conditions, such as diabetes or arthritis, collaborative or integrated

management, defined as care that strengthens and supports self-care while assuring that

effective medical, preventive and health maintenance interventions take place, is associated

with improved outcomes (16). Likewise, IBS is a chronic condition of diverse pathogenesis.

That said, with few exceptions, the current medical model of gastroenterologist-only

specialist care fails to deliver such collaborative management. Indeed, in the few outcome

evaluations of the traditional Western management model, quality of life of patients was

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unchanged (17, 18) and rates of patient dissatisfaction were high (19). Limitations of the

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current Western medical model include lack of time for providers to take a more holistic

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approach to care, a focus on pharmacological management, inadequate training, and lack of
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access to specific dietary, psychological and other management strategies. It is logical that
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involvement of other health professionals with greater time available, with skills in other

therapeutic techniques, and with training in behavioral techniques to improve self-care will
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improve outcomes for IBS patients. Furthermore, the ability to share the burden of
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management may also reduce burnout amongst physician providers.

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Hence, integrated care models, in which multi-disciplinary teams that work

collaboratively have been developed by an ever increasing number of GI practices to more

effectively manage their patients with IBS. However, to date, credible evidence of improved

outcomes with such models is scant (20, 21). Limited data from studies which evaluated

nurse or dietitian-led clinics with strict entry criteria have reported high rates of satisfaction

for patients with functional GI symptoms (21-23). Nurse-led clinics for patients with chronic

constipation or fecal incontinence achieved excellent outcomes, but these programs

involved institution of specific treatment algorithms (24, 25). When psychological services

are integrated into the clinic, benefits have been described in two prospective cohorts (15,

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26). Patients who persisted with psychological interventions had fewer subsequent medical

procedures in one study, and improvements in psychological status and quality of life

without alteration in severity of abdominal symptoms was observed in another. The use of a

3-hour educational program delivered by an allied health team in addition to standard

gastroenterologist-delivered care was associated with improved alleviation of symptoms

(27).

Four different approaches have recently been evaluated in Australia. First, a pilot

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study in family physicians, which utilized an algorithmic approach that avoided specialist

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involvement and provided pathways for multidisciplinary management, was well accepted

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and improved outcomes (28). Secondly, a structured multidisciplinary program showed
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benefit over standard care (29). Thirdly, a nurse-led multidisciplinary individualized program
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showed improved quality of life and symptoms, as well as reduced investigation and costs in

a case-control study (30). Perhaps the most persuasive data to date comes from an un-
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blinded, randomized study of 188 IBS patients in which a gastroenterologist-led integrated,

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multidisciplinary care model showed improved clinical outcomes, quality of life,

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psychological health, and cost effectiveness compared to standard care (31). It is notable

that gastroenterologists in the standard care arm were permitted to order consultations

with a dietitian or behavioral therapist outside of their hospital while gastroenterologists

working in the integrated care group had immediate access to on-site services from a

dietitian or behavioral therapist. Patients in the integrated care group were significantly

more likely to be seen by a dietitian or behavioral therapist. For the primary outcome, 84%

of IBS patients in the integrated care arm reported a significant improvement in global IBS

symptoms vs. 57% in standard care arm (p<0.001). This study suggests that a team-based,

collaborative care model offers measurable benefits over simply having access to a dietitian

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or behavioral therapist. This may be because open communication between team members

enables shared identification and decision making of important clinical issues. For example,

hypervigilance and disordered eating behaviors are ideally addressed jointly by all members

of the collaborative team. In other words, the whole of the integrated team is greater than

the sum of its parts.

In the following sections, we will critically review the strengths and weaknesses of

behavioral and diet based therapies for IBS.

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Behavioral Therapies

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Brief behavioral therapies, offered in conjunction with medical therapies, appear to
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be effective in reducing abdominal pain and improving satisfaction with bowel habits in a
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subset of patients for whom stress, hyper-arousal, anxiety, fear or maladaptive thoughts

drive symptoms. GI behavioral therapies were adapted from highly effective behavioral
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therapies used to treat anxiety and chronic pain to more specifically address dysregulation
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of the brain-gut axis (Table 1). Adaptation focuses on 2 primary pathways through which
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behavior modification, and hence, GI symptom reduction, could occur. Techniques with

potential to modify dysregulated (ascending) gut-to-brain pathways leverage established

behavioral techniques focused on re-interpreting benign sensations in the body, in this case

from the gut, that could trigger maladaptive cognitive or affective processes in the brain.

Secondly, techniques that potentially modify dysregulated (descending) brain-to-gut

pathways, in which GI symptoms occurred in response to cognitive and affective triggers

arising from the fear of symptoms, lack of acceptance of disease, or from stressors in the

external environment may also offer benefit to some IBS patients. Below, we describe a

practical approach to implementation of the behavioral techniques most commonly

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employed in brain-gut psychotherapies, although efficacy data on specific techniques is

limited (Figure 1)

Gut-to-brain behavioral techniques

Established alterations in the hypothalamo-pituitary-adrenal (HPA) axis in IBS can

explain the stress-sensitive nature of symptom induction. IBS patients have been shown to

have heightened sympathetic nervous system arousal, lower heart rate variability/vagal

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tone (32, 33) and higher levels of circulating stress hormones (cortisol, corticotropin-

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releasing hormone) than healthy controls (34). These altered processes can in turn lead to

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mechanical and chemical stimulation of the colon and activation of the emotional motor
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system (perception of normal gut signals as painful) under real or perceived stress.
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Furthermore, IBS patients have been shown to have reduced thickness of the pre-frontal

cortex, limiting their ability to ignore sensations arising from the gut (35) and that altered
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resting-state functional connectivity may make them more susceptible to visceral

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hypersensitivity, attentional bias, and hypervigilance (36, 37). A recent behavioral therapy
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trial for IBS demonstrated improvements in functional connectivity after gut-directed

hypnotherapy (38); the changes were associated with IBS symptom improvement, further

supporting the impact of these therapies on the pathophysiology of IBS.

Behavioral techniques focused on the reduction of baseline arousal of the

sympathetic nervous system as well as strategies to pro-actively activate the

parasympathetic nervous system under acute stress are well-justified and a core component

of most brain-gut psychotherapies. Type of relaxation technique is chosen by the therapist

in collaboration with the patient based on patient preference, motivation and context in

which symptoms occur. Acknowledging that levels of evidence vary, common techniques

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include diaphragmatic breathing, heart-rate-variability biofeedback (through digital apps),

progressive muscle relaxation, guided imagery, and mindfulness based stress reduction.

Gut-directed hypnotherapy also leverages relaxation techniques to induce the hypnotic

state, prior to the delivery of potent suggestions focused on restoring brain-gut regulation.

Optimizing a patient’s social support, especially if interpersonal difficulties are identified,

can also improve baseline sympathetic nervous system arousal and buffer against the

negative effects of stress (39). Of the behavioral interventions, modification of arousal likely

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has the most immediate impact on bowel symptoms in IBS.

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Relaxation techniques paired with symptom onset or in advance of a setting in which

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symptoms might occur (e.g., before a meal) can also disrupt the interpretation of benign,
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visceral signals from the gut as painful at the level of the brain. In this case, relaxation
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techniques such as diaphragmatic breathing can be used to de-condition attentional bias

towards gut signals or potential gut signals, as well as hypervigilance towards symptoms and
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the settings in which they occur. In gut-directed hypnotherapy, hypervigilance and

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attentional bias are remediated through subconscious, post-hypnotic suggestions focused

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on the re-interpretation of visceral signals arising from the gut as natural, comfortable, and

un-important during routine activities such as digestion. Mindfulness-based stress reduction

programs have also been shown to be effective in women with moderate to severe IBS

symptoms (40). While not previously evaluated, in cases of post-infection IBS, in which

visceral hypersensitivity arises after acute infection or injury to the colon, relaxation

techniques focused on reduced hypervigilance and attentional bias, including hypnotherapy,

can be particularly effective.

Interoceptive exposure, which is first-line behavioral therapy for panic disorder, has

also been shown to modify gut-brain pathways including visceral sensitivity, hypervigilance

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and attentional bias towards gut sensations in IBS patients (41). Stemming from

psychological literature on experiential avoidance, (42, 43), the underlying assumption

behind interoceptive exposure for IBS is that attempts to emotionally or behaviorally avoid

gut signals paradoxically amplifies the symptom experience and reinforces avoidance. Fear

and avoidance of symptoms lead to a perpetual cycle of anxiety, depression and other

psychological comorbidities which in turn exacerbate IBS symptoms through the HPA axis

and centrally-mediated targets (discussed later). In interoceptive exposure-based therapies,

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patients are asked to purposely activate visceral gut sensations such as abdominal

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discomfort or fullness (tightening a belt), altered motility (eating an avoided food), or

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withholding a bowel movement to amplify cramping or urgency. The goal of doing so is to
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reduce cognitive and behavioral avoidance of these gut sensations and drive habituation to
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the sensations so that they carry less perceived threat at the level of the brain. Exposure for

IBS may or may not be paired with mindfulness (44), and is often used in conjunction with
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other CBT techniques. Finally, patients with co-morbid somatization and extra-intestinal
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symptoms such as low back pain, fatigue, and fibromyalgia often benefit from these arousal
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and avoidance techniques as well. Gut-to-brain behavioral techniques often complement

dietary intervention.

Brain-to-gut behavioral techniques

As seen in Figure 1, alterations in the downregulation of brain signals in the setting

of IBS symptoms as well as in response to environmental triggers is another well-established

target of brain-gut psychotherapies. IBS patients, when compared experimentally to healthy

controls, have reduced activity in the limbic system, or emotional response network of the

brain (e.g., amygdala, hippocampus and anterior cingulate gyrus) (45), supporting the notion

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of ineffective downregulation of gut signals and the resulting amplification of abdominal

pain. Further, treatment-seeking IBS patients have demonstrated reduced gray matter

density and altered resting state (35), both of which have been associated with pain

catastrophizing and negative prediction/probability overestimation in several chronic

syndromes (46), and explain the benefit of modern GI-CBT which focuses primarily on these

two particular cognitive errors (47). Abnormalities in the emotional response system in the

brain is also seen among patients with psychiatric disorders and may explain the large

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subset of IBS patients who exhibit comorbid depression and anxiety (48). Pain

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catastrophizing, or the combination of magnifying the seriousness of pain and other

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symptoms simultaneously with a sense of helplessness is associated with more severe IBS
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symptoms (49). CBT has been shown to be the most effective behavioral therapy in this
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brain-to-gut domain, with techniques such as cognitive reframing, de-catastrophizing,

evidence-based logic, perspective-taking and challenging underlying schemas such as

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perfectionism, approval-seeking and over-responsibility enhancing the patient’s ability to

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downregulate pain pathways and reduce avoidance/isolation associated with symptoms,

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and hence symptom reporting. Pain catastrophizing has also been shown to improve with

gut-directed hypnotherapy (50), when suggestions are focused on this particular cognitive

process.

Centrally-mediated targets

Unfortunately, in cases where early, effective therapies, medical or otherwise, are

lacking for IBS, symptoms progress and become less and less associated with visceral

triggers (food, menstruation, stress) and more centrally-mediated, resulting in hyperalgesia

(increased sensitivity to pain signals). At this point, brain-gut psychotherapies must focus

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more broadly on normalizing pain thresholds, as seen in gut-directed hypnotherapy,

mindfulness-based stress-reduction programs and acceptance-based therapies that focus on

living a meaningful, value-based life despite chronic pain (51). Psychodynamic interpersonal

psychotherapy, another evidence-based behavior therapy for IBS, can also be leveraged in

these cases to address broader issues of somatization, early trauma (52) and personality

characteristics such as neuroticism and alexithymia (53 - 55). Neuromodulators may also be

helpful in conjunction with brain-gut psychotherapy in cases where IBS pain is believed to

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be centrally mediated (56).

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Complex Behavioral Targets -p
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A detailed discussion of complex clinical situations including trauma and early life
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adversity, opioid seeking behavior, disordered eating and toileting behaviors among others

is beyond the scope of this review. These behaviors often respond to a combination of
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personalized techniques and are best delivered by a health psychologist in a

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multidisciplinary setting.
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Safety, tolerability and efficacy of brain-gut psychotherapies

Evidence supporting the safety, tolerability and clinical benefit of brain-gut

psychotherapies has become increasingly robust over the last decade. Notably, most of the

evidence for behavioral therapies have been tested in conjunction with medical therapies,

rather than as an alternative, stand-alone form of treatment. Level 1 evidence (high quality,

randomized controlled trial/s (RCT)) supports the use of brain-gut psychotherapies,

particularly GI-CBT and gut-directed hypnotherapy, with a number-needed-to-treat

between 3 and 4 (57, 58) and long-term maintenance of efficacy (59), up to 2 years for GI-

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CBT (60) and 6 years for gut-directed hypnotherapy (61), including when delivered in groups

(62). Level 2 evidence (lesser quality RCTs, cohort studies) has demonstrated that these

therapies can be delivered across multiple modalities, including in groups (63), online (64),

over the phone (65) and with minimal therapist contact (47). Less is known about which

therapies are best for which patients because there is a lack of comparative effectiveness

research in this area. However, an RCT from Australia evaluated the comparative

effectiveness of gut-directed hypnotherapy and a low FODMAP diet (66), and is discussed

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later in this review. Notably, when behavioral therapies are evaluated using the same

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domains as medication trials, they are criticized for methodological weaknesses such as lack

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of blinding (which is not possible). When evaluating the rigor of behavioral clinical trial
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methodology going forward, it could be useful to consider the gold-standard of trial design
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and conduct in behavioral interventions guidelines for chronic pain (67).

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Implementation of behavioral therapies

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Access to qualified professionals experienced in brain-gut psychotherapies are the

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primary barrier to their widespread use. However, there are several ways in which to

integrate brain-gut psychotherapy services into GI practice regardless of whether your

practice is in an academic medical setting or community practice. First and foremost, the

uptake of these therapies is highest when patients are referred to a behavioral therapist by

a knowledgeable provider who has mastered patient-friendly language around the brain-gut

connection and the primary behavioral approaches available (68). Table 2 identifies some

considerations for ideal and poor candidates for brain-gut psychotherapies.

Models of GI behavioral care

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 Several academic GI Divisions have hired full-time GI health psychologists who are

available by referral from their GI colleagues for management of IBS. Most of these

practices require IBS patients to be referred from an on-staff provider and do not accept

outside referrals given both volume and need to collaborate in real-time with the GI

provider; however, in these settings, insurance typically covers these services as it would a

medical visit. Another group of hospital-based practices have partnered with their

department of psychiatry or psychology and utilize a co-located GI psychologist or

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psychiatrist on a part-time basis, usually on days when there is a high volume of patients

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with disorders of gut-brain interactions (DGBI), seen by 1-2 GI providers; often times these

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patients end up following up with the mental health provider in their own hospital-based
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psychiatry practice or clinic, which can be a viable alternative to an integrated program.
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Many hospital-based practices, along with their community based colleagues will also

identify 1-2 local providers trained in behavior therapies for chronic medical conditions
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(sometimes with experience in GI) and create a collaborative pathway through which IBS
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patients can be managed (www.romegipsych.org). In these cases, GI providers must be

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sensitive to local practitioners’ preferred patient types, insurance panels, communication

preferences and location. Finally, advanced-practice providers and physicians are eligible to

undergo training and certification in hypnotherapy through national organizations

(www.asch.net) and then utilize existing gut-directed hypnotherapy protocols in practice.

CBT principles are being increasingly taught to advanced practice providers as well.

Future Directions for behavioral therapies

The future of behavioral therapies for IBS is bright, with an increased focus on the

training and supervision of qualified professionals in the evidence-based practices described

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above. In the US, UK and Australia, GI psychologists can offer their services via telemedicine,

which allows for a convenient onsite consult during a GI visit, followed by remote sessions

over telemedicine. Similarly, several GI behavioral scientists have begun to commercialize

their behavior therapy approaches with digital therapeutics to improve accessibility and

reduce cost of these interventions to patients and payers. There has also been growing

interest in the application of newer behavior therapies in the treatment of IBS, including

acceptance and commitment therapy, applied positive psychology and mindfulness-based

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cognitive therapy (69, 51, 70). Comparative effectiveness studies, including comparing

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behavioral therapies with each other, as well as with medical therapies would be of value.

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Diet Therapies: Focus on the Low FODMAP Diet
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A number of diet interventions are utilized by IBS patients and healthcare providers

in the hope of improving symptoms and quality of life (71). Limited numbers of studies with
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small numbers of patients with IBS have evaluated the effectiveness of a gluten-free diet
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(72) and elimination diets based upon IgG antibody testing (73), leukocyte activation testing
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(74) and confocal laser endo-microscopy after food challenges (75). Of the available diet

options for IBS patients, the low FODMAP (fermentable oligosaccharides, disaccharides,

monosaccharides and polyols) diet is currently the most commonly recommended by

healthcare providers (71) and the most evidence-based (72). That said, it is important for

providers recommending this diet to be aware of the strengths and weaknesses of the

available literature and possess a full understanding of proper implementation to ensure

optimum effectiveness and patient safety.

FODMAPs can trigger GI Symptoms

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 Several short-chain carbohydrates commonly found in the diet are slowly absorbed

or non-digestible in the small intestine, which increases small intestinal water content via

osmotic effects, and increases gas and other metabolite production from fermentation by

colonic bacteria. Abdominal symptoms occur in subjects with IBS when challenged with

individual carbohydrates usually at high doses relative to the amount usually consumed in

food (73). There is evidence that their effects are additive; for example, greater symptoms

were experienced when lactose and fructans were consumed together compared those

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when consumed alone in lactose malabsorbers (74). However, with the exception of lactose,

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their dietary restriction did not penetrate clinical practice due both to the lack of quality

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evidence for efficacy and to the fact that much lower amounts were present in the habitual
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diet than in the challenge experiments.
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Given the likelihood that they had additive effects, these short-chain carbohydrates

were collectively termed FODMAPs (75). Diets that differed in FODMAP content had
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significant differences in ileostomy water output (76), were associated with marked
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differences in breath hydrogen content in healthy subjects and IBS patients (77), and altered
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the symptom burden of a cohort of IBS patients, but not healthy subjects (77). Thus, the

effects observed for high doses of individual FODMAPs were mimicked by combinations of

FODMAPs often found in the diet.

The principal reason for the rapid induction of symptoms after ingestion of a large

dose of dietary FODMAPs and the relief of symptoms that occurs within days of starting a

diet low in FODMAPs is likely to be altered mechanoreceptor stimulation from luminal

distension. The relative specificity of symptom induction in patients with functional bowel

disorders lies in the heightened response of the enteric nervous system to

mechanoreceptor stimulation (i.e., visceral hypersensitivity) and not to different

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physiological effects of a given dose of FODMAPs. This was elegantly shown in experiments

utilizing magnetic resonance imaging in healthy subjects and patients with IBS (78).

This mode of action is, however, relatively unsatisfactory in explaining longer term

observations that at least 75% of patients with IBS who respond to the initial strict FODMAP

restriction can maintain alleviation of symptoms with only mild FODMAP dietary restriction

(79). There are several reasons possible for this. First, it might reflect the fluctuating natural

history of IBS, but the proportions observed to maintain symptom control seem too large

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for this to be the only explanation. Secondly, the broad and relatively strict restriction of

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FODMAPs might not have been needed in the first place. A comparison of a top-down

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approach with a graded step-up in restriction may answer this question (80). Thirdly,
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changes in gut microbiology and physiology resulting from chronic restriction of FODMAPs
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or the lack of episodic high FODMAP intake might have altered the response to

mechanoreceptor activation (81). In this way, FODMAP intake might have a pathogenic role
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in the underlying pathophysiology of IBS, not just the genesis of symptoms.

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The most consistent changes in the gut microbiota associated with FODMAP
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restriction is reduced density (absolute abundance) of bacteria. This has been documented

in the feces (82-85), but probably also occurs in the small intestine and proximal colon due

to the reduction of favored substrates (particularly oligosaccharides) for bacterial growth.

The other consistent microbial effect of altering FODMAP intake is to change the relative

abundance of Bifidobacteria, this being suppressed by reduction of FODMAPs (84- 88) and

increased by their supplementation (86). There is evidence that neither scenario has

beneficial or deleterious effects in patients with IBS; correction of reduced Bifidobacteria

with probiotic supplementation had no impact on symptoms (86). Thus, loss of a prebiotic

effect associated with low FODMAP intake has, as yet, no clearly defined health-related

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consequences. Multiple other changes to microbial communities have been reported (81),

but the lack of consistency of findings might suggest that the effects may not be specifically

related to FODMAPs.

The effects of boosting FODMAP intake has been studied in humans and

experimental animals, either by increasing FODMAP-rich foods in the diet or by

supplementing the diet with specific FODMAPs above the amounts usually consumed (89.

90). Such an approach has been associated with a variety of intestinal pathologies that have

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included increased mucosal inflammation, mast cell infiltration, visceral hypersensitivity,

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barrier dysfunction and increased susceptibility to Salmonella infection, as recently

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reviewed (81). A few underlying mechanisms have been implicated. First, in a pig model,
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excessive fermentation and its subsequent high output of organic acids with lowering of
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proximal colonic pH, compromised barrier function and epithelial integrity, and increased

visceral sensation at a cecal pH ≤ 5.0 (91). This may have relevance in humans since, in a
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study of 16 subjects with IBS using a wireless motility-pH capsule, approximately half of IBS
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patients exhibited cecal pH below 5.0 (92). Secondly, a high FODMAP diet in rats increased
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fecal endotoxin (lipopolysaccharide) levels and this was associated with inflammatory

changes in the colon and increased visceral sensitivity, an effect that could be blocked by

antibodies to endotoxin (93). The same authors also showed that the endotoxin content of

feces of IBS patients consuming their habitual diet was elevated and that infusion of fecal

water from these patients into the colon of rats induced the same effects (93). In both

patients and rats, a diet low in FODMAPs reduced the content of fecal endotoxin and the

colonic effects did not occur. Thirdly, glycation end-products were implicated in a rat study

in which dietary fructo-oligosaccharide-induced mast cell activation in the colon and visceral

sensitivity were inhibited by a drug that specifically blocks glycation (94). While many of

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these findings require translation from animal to human biology, the mounting evidence

would suggest that higher-than-usual intake of FODMAPs might be pathogenically related to

visceral hypersensitivity and the types of colonic inflammation observed in many patients

with IBS. Such effects are not necessarily restricted to FODMAPs; they may also occur with

longer-chain carbohydrates that are readily fermentable, such as resistant starch (95), or

potentially with other readily fermented hydrocolloids that are being included in the

Western diet. Further research is required to put such observations into clinical perspective.

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In any individual, there is heterogeneity of sensitivity to specific FODMAPs. In other

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words, different FODMAPs may exert different physiologic and clinical effects in different

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IBS patients. This has become most evident during reintroduction phase of the 3-step low
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FODMAP diet program. Reasons for such heterogeneity have not been defined, but there
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are a few possibilities. Exposure to specific FODMAP groups in the habitual diet might play a

role; for example, the intake of galacto-oligosaccharides in an Australian population is lower

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than in the UK (82-84). There are physiological differences between FODMAP groups. For
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instance, fructose and polyols are smaller molecules than the oligosaccharides, and
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consequently have greater osmotic effects (96), which might generate more symptoms than

fermentation owing to variable malabsorption. Conversely, fermentation is likely to be a key

pathogenic event for oligosaccharides, given their reduced osmotic effect and greater

delivery to the colonic microbiota. The handling of FODMAPs by colonic microbiota is also

heterogeneous as shown by variability of breath hydrogen responses to FODMAP

challenges. It seems reasonable to assume that such heterogeneity underlies differing

sensitivities to individual FODMAPs in IBS patients. This is supported by a recent study in

which a third of a small cohort of IBS patients had no demonstrable sensitivity to dietary

galacto-oligosaccharides (97).

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Evidence supporting clinical benefits

Evidence of benefit of dietary FODMAP restriction comes from blinded re-challenge

studies, RCTs comparing strict dietary FODMAP restriction to some comparator,

comparative effectiveness studies, real-world experience and, in the longer term, FODMAP

personalization. In this section, we will help readers to understand the strengths and

weaknesses of the available evidence from clinical trials.

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Blinded, randomized, placebo-controlled re-challenge with individual FODMAPs in

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patients who had responded to overall FODMAP restriction is one way to prove cause and

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effect between FODMAP restriction and improved IBS symptoms. Such information is
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essential as it is often difficult to alter a diet in specific ways without changing other
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features of the diet – the problem of collinearity (98). At present, there are limited data

from rigorous re-challenge studies. In patients with IBS who responded to restriction of
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fructose and fructans, blinded challenge with fructose and fructans alone or in combination
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reproduced symptoms in the vast majority and to a significantly greater extent than
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challenge with glucose (as placebo) (99). In a cohort of patients with functional bowel

symptoms and inactive inflammatory bowel disease (normal calprotectin) whose symptoms

had responded to a low FODMAP diet, challenge with fructans, but not other FODMAPs or

glucose, significantly induced similar symptoms (100).

The best quality evidence supporting the clinical benefits of dietary FODMAP

restriction comes from a growing number of RCTs, all of which have focused on the clinical

benefits derived from short-term dietary FODMAP restriction. Several meta-analyses

summarizing the data on the low FODMAP diet for IBS have recently been published (101-

105). One recent meta-analysis reported that the low FODMAP diet reduced overall IBS

20
symptoms with a risk reduction of remaining symptomatic on a low FODMAP diet of 0.69

(95% CI 0.54 to 0.88) with a NNT was 5 (95% CI 3 to 11) (72). Relevant to patients with IBS-D,

a recent cohort study reported that the low FODMAP diet may reduce episodes of fecal

incontinence in patients with loose stools (106).

However, the quality of the data has been considered very low for three main

reasons - heterogeneity of the comparator diet, small numbers of patients and concern

regarding the success of blinding (72). Unfortunately, methodological problems are inherent

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to dietary interventional trials. For the comparator diet, the difference in symptom control

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may be exaggerated if it has a higher FODMAP content than the participant’s habitual diet

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(as seen for a high FODMAP (85) or investigator-created typical FODMAP containing diets
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(80), or if the low FODMAP diet is being compared with a participant’s habitual diet (107),
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and will be minimized if the comparator diet also reduces FODMAP content (108). The low

FODMAP diet may be less effective if sub-optimally delivered, as may have been the case in
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a study which provided only limited teaching in an attempt to maintain blinding of a placebo
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diet (86,109). The baseline/habitual diet may influence response if it is already low in
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FODMAPs such that the increment achieved is small as occurred in one study where lactose

was considered erroneously as a FODMAP in a population with a low prevalence of

hypolactasia (108,110). Nevertheless, the findings overall in RCTs have mimicked those

observed in real-world cohorts with 2-3 out of 4 patients responding to strict reduction in

FODMAP intake (101).

Determining the long-term effectiveness associated with FODMAP personalization in

initial responders to full FODMAP restriction is difficult, if not impossible, to assess in RCTs.

Rather, the long-term effectiveness of personalization has been inferred from prospective

and retrospective real-world cohorts. This has recently been systematically reviewed (79).

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There have been 6 studies in which reintroduction was attempted involving more than 300

patients from 5 countries over a follow up of 6-18 months. Continuation of strict FODMAP

restriction occurred in 2-18% of patients. Maintenance of symptom amelioration was

achieved 57-82% of patients, although only 29% reached full effectiveness at follow up in a

Danish study. Quality of life scores, whether assessed via an IBS-specific or generic tool,

improved in all studies, but the increment varied considerably. Healthcare utilization was

evaluated in only one study, in which no change was observed (111). The disparity of

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success across studies might relate to methods of teaching the dietary reintroduction as

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there is currently no standardized protocol and/or other factors associated with the model

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Full FODMAP restriction has been compared with gut-directed hypnotherapy (66)
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and yoga (112) in randomized, comparative effectiveness studies. In a study from Australia,

both hypnosis and a low FODMAP diet led to statistically significant improvement in IBS
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symptoms compared to baseline a 6 weeks and 6 months and the magnitude of benefit was
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similar for the two interventions (66). In another trial, yoga and the low FODMAP diet both
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improved IBS symptoms compared to baseline at 3 and 6 months with no different in the

magnitude of benefit between interventions (112). Comparison of the low FODMAP diet

with other active dietary interventions have been less easy to interpret. A Swedish study

compared full FODMAP restriction to what was considered the standard dietary approach

for IBS (108). The comparator diet was based upon the NICE recommendations, but also

included recommendations to avoid a number of high FODMAP foods. There was no

difference in clinical outcomes after the two diet interventions, but benefits of the low

FODMAP diet may have been obscured by the elimination of some FODMAPs in the

comparator diet (110). In a US study in IBS-D patients, a diet using the NICE principles, but

22
without eliminating foods containing FODMAPs, was compared to full FODMAP restriction.

There was no statistically significant difference in the proportion of patients reporting the

primary end-point of adequate relief of IBS symptoms (52% vs. 41%, p=0.31). However, the

low FODMAP diet led to statistically significant benefits in abdominal pain, bloating, and

quality of life (113,114). Overall, these studies suggest that full FODMAP restriction offers

similar benefits to properly-administered psychotherapeutic techniques and that the style

of eating might offer benefits additional to avoiding high FODMAP foods.

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Implementation of low FODMAP diet

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For any healthcare provider recommending the low FODMAP diet to patients, it is
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critically important to recognize and embrace that proper dietary counselling should consist
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of three phases:
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Phase one (Full FODMAP Restriction) in which total FODMAP intake is markedly reduced,
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ideally to below the patient’s tolerance threshold. Phase one of the low FODMAP diet plan
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is the beginning NOT the end of the plan. It should be viewed as a diagnostic test to identify

patients who are sensitive to FODMAPs. Patients who do not respond after 4-6 weeks of

FODMAP restriction should be transitioned to another intervention for their IBS symptoms.

Only patients who respond to Phase one progress to Phase two (FODMAP Re-Introduction)

in which the full low FODMAP diet is continued and a series of challenges is performed

whereby foods containing a single FODMAP are consumed in increasing quantities over a 3-

day period to detect the tolerance threshold to that FODMAP.

23
In Phase three (FODMAP Personalization), the information gained from phase two is utilized

to liberalize FODMAP intake and develop a personalized version of the low FODMAP diet for

long-term use (115) (Figure 2). It is very important for providers to utilize all three phases of

the low FODMAP diet plan, in order to limit the impact on dietary variety, nutrient intake

and potentially, on the gut microbiome.

The low FODMAP diet is a complex dietary plan requiring significant changes to

shopping, food preparation and eating behavior. Clinical trials of the low FODMAP diet in IBS

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largely consist of dietary counselling provided by a registered dietitian. While expert dietetic

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support may not be available in every gastroenterology clinic, there is as yet limited

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evidence of the effectiveness of alternative models of dietary counselling, monitoring, and
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follow-up. Education sessions consisting of one dietitian counselling between four and
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twelve patients in a group have also been shown to be as clinically effective as one-to-one

dietetic counselling in selected patients, but at lower cost (116). Additional educational
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materials are frequently provided to support patients in clinical practice, including online
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and written literature and mobile apps (115). The use of these educational materials alone,
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without counselling from a dietitian, has not been rigorously investigated. Meanwhile, a

qualitative interview study of patients who had received low FODMAP dietary education

from a family physician or gastroenterologist, but not a dietitian, reported the advice to be

too simplistic with little personalization and requiring substantial interpretation (117).

Indeed, in a retrospective analysis of dietary change in patients prescribed a low FODMAP

diet, education by a dietitian achieved the goals of the dietary strategy to a significantly

greater extent than non-dietitian education where poor implementation led to incomplete

FODMAP restriction and unsuccessful or absent reintroduction and personalization (118).

These are likely to reduce the chance of achieving optimal clinical benefit and patient self-

24
empowerment. Alternatively, there is also the chance of excessive restriction of dietary

intake with consequent nutritional inadequacy and impaired food-related quality of life

(119).

The low FODMAP diet restricts consumption of fermentable carbohydrates from a

range of food groups including cereals (including some fortified breakfast cereals), grains,

legumes, dairy products and many fruits and vegetables, and there is potential risk of

nutritional inadequacy. One analysis has shown FODMAP restriction reduced diet quality

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scores, but did not result in lower intakes of most nutrients compared with controls,

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although many people with IBS already failed to meet recommended intakes of key

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nutrients (120). Another analysis showed that IBS-D patients’ habitual diet quality was quite
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poor and that overall diet quality improved after consultation with a GI dietitian, regardless
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of whether they were counselled on a low FODMAP diet or usual dietary recommendations.

Full FODMAP restriction reduced intakes of energy, carbohydrate, thiamine, riboflavin,

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calcium and sodium (121). In the longer term, one study reported those who had undergone
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FODMAP personalization and were now following an adapted low FODMAP diet did not
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have lower intakes of key nutrients compared with those who had returned to their habitual

diet (111). Patients should be advised to follow national recommendations for intakes of

nutrients, as well as for specific food groups such as fruits and vegetables, acknowledging

that low-FODMAP versions should be encouraged.

The major changes in shopping, food preparation and eating behavior required

during the low FODMAP diet can be challenging for patients to incorporate into their daily

lives. Even in the longer term, the vast majority of patients following a personalized, low

FODMAP diet considered it more expensive and experienced difficulty eating when at

restaurants, at family or friends’ houses and whilst traveling (111). These issues should be

25
expected and addressed during dietary consultations. The greater expense often relates to

the higher cost of wheat-free foods such as wheat-free breads and pastas (122).

As the popularity of the low FODMAP diet and other exclusion diets increases in IBS

patients, it is important for providers to be aware of eating disorders that might be

encountered in patients with meal-related GI symptoms. Most providers are familiar with

legacy eating disorders such as anorexia nervosa or bulimia nervosa (123). However, other

eating disorders may not be as familiar and may actually be more common in GI practices.

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It is common for patients with meal-related GI symptoms to restrict the intake of suspected

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culprit foods. It can be difficult to distinguish between patients who appropriately restrict

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foods which trigger their GI symptoms and those patients who inappropriately restrict foods
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as a consequence of fear or anxiety that a type of food might trigger their GI symptoms.
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Every gastroenterologist has encountered the IBS patient who is suspiciously more than a

picky eater, limiting their diet to only a handful of foods. Avoidant/Restrictive Food Intake
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Disorder (ARFID) is a newly described eating disorder where the consumption of certain
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foods is limited because of appearance, smell, taste, texture, brand, presentation, or a past
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negative experience. ARFID patients should have weight loss, nutritional deficiency,

dependency on a feeding tube or dietary supplements, and/or significant psychosocial

interference (124). Emerging evidence suggests that 6-19% of patients with GI symptoms

exhibit characteristics of ARFID (125). In a recent retrospective analysis of 223 patients seen

in GI clinics at a single US, tertiary care center, 12.6% met clinical criteria for ARFID. ARFID

and non-ARFID patients were clinically indistinguishable based on gender, body-mass index

or GI diagnosis. Somewhat surprisingly, ARFID patients were less likely to be using

psychotropic agents, reported lower body image concerns and increased frustration with

not being able to eat food than non-ARFID patients. Of concern, in over 70% of patients who

26
screened positive for ARFID, a low FODMAP diet was recommended by their GI provider

who was unaware of the screening survey results (126). Though an ARFID screening

questionnaire is available, it has yet to be validated in patients with GI conditions (127). The

development and validation of such a GI-specific screening tool will be important to help

providers to identify patients in which restrictive diets should be avoided.

Future directions for low FODMAP diet

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The observations that the low FODMAP diet results in symptom amelioration in

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approximately half to three quarters of IBS patients still means that up to half will not

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benefit from the diet, and yet will still be exposed to some of its disadvantages including
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alterations to the microbiome and the extensive changes to eating behavior that can be
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challenging for some. It would therefore be attractive to identify biomarkers which identify

patients who are more or less likely to improve with a low FODMAP diet. Several studies
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suggest that baseline (pre-low FODMAP diet) stool microbiome profiling could serve as such
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a biomarker. In one study, non-responders had more abundant Streptococcus, Dorea and
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Ruminococcus gnavus (128). Another study identified profiles of fecal volatile organic

compounds released from stool samples could predict response or lack of response to the

low FODMAP diet with at least 97% accuracy (129). However, at this time, measures of the

stool microbiome and their metabolites as a biomarker of response to the low FODMAP diet

should be considered exploratory and requires additional clinical validation.

Another recent observation provides insight into IBS patients who are less likely to

improve with a low FODMAP diet. Sucrase-isomaltase is the brush border dissacharidase

responsible for the digestion of sucrose and some starches, which comprise the majority of

carbohydrates in the western diet. Recent studies have found that IBS patients are more

27
likely than controls to harbor sucrase-isomaltase gene mutations (130). As the low FODMAP

diet does not restrict sucrose intake, IBS patients with sucrase-isomaltase deficiency may be

less likely to improve with a low FODMAP diet than those without sucrase-isomaltase

deficiency. Indeed, a recent post-hoc analysis from a randomized, controlled trial in IBS-D

patients confirmed this hypothesis, finding that response to a low FODMAP diet was

significantly reduced in those with vs. those without sucrase-isomaltase gene mutations

(131). In aggregate, these studies suggest that in the future, biomarkers may allow providers

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to identify the right IBS patients for which to recommend a low FODMAP diet. These data

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also make clear that while the low FODMAP diet can provide a solution for some IBS

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patients, neither it, nor any other diet, should be expected to provide the solution for all IBS
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patients. It is clear that further high quality research is needed to find additional evidence-
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based dietary solutions for IBS patients.

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Future Directions for Integrated Care

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There is a growing body of evidence that supports the benefits of behavioral and diet
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interventions in patients with IBS. It is important for providers to understand the

indications, benefits and potential risks of these interventions. Questions around the

effectiveness of these treatments are giving way to practical questions regarding proper

implementation. In particular, access to adequately trained psychogastroenterologists and

GI dietitians, as well as reimbursement for their services, are important barriers to the

broad dissemination of integrated care models for IBS patients. There is now sufficient

evidence to suggest that integrated models of care improve clinical outcomes, satisfaction

and quality of life of IBS patients. The modern gastroenterology practice model for patients

with IBS and other functional GI disorders should, at a minimum, include access to expert

28
nursing support as well as nutrition and behavioral counselling (Figure 3). An idealized

tertiary care team might include a nurse-specialist, dietitian, psychologist, psychiatrist,

physiotherapist, exercise physiologist, and complementary and alternative medicine

provider working collaboratively with the gastroenterologist. Such a multi-disciplinary

approach would enable the therapeutic strategy to be individualized and may better

empower patients to more effectively engage in self-care. Telehealth and virtual care

platforms offer the possibility of widespread access to nutrition and behavioral health

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services. Further data addressing the benefits of such care models are sorely needed and

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eagerly awaited.

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Table Legends:

Table 1: Behavioral Therapies for Irritable Bowel Syndrome

Table 2: Which IBS patients should be referred for Behavioral Therapy?

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Figure Legends:

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Figure 1: Behavioral therapy options and targets
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Figure 2: The three stages of the low FODMAP diet: Restriction, Re-Introduction, Personalization
(taken with permission from Whelan et al, 2018) .
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Prior to dietary counselling from a dietitian, FODMAP intake in the habitual diet varies from day to
day but is above the FODMAP tolerance threshold leading to gut symptoms. (i) During FODMAP
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Restriction, total FODMAP intake is dramatically reduced to below the tolerance threshold and
symptoms respond in 50-80% of patients. (ii) During FODMAP Re-introduction, whilst continuing
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restriction of other FODMAPs, food containing individual FODMAPs are used as challenges.
Challenge foods are consumed in increasing amounts over a 3-day period during which symptoms
are monitored, with each 3-day period separated by at least 1-2 days depending upon symptom
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provocation. (iii) During FODMAP Personalization, FODMAP-containing foods that were successfully
challenged can be reintroduced into the diet over the long-term in order to increase dietary variety,
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while keeping the type and total amount of FODMAP intake below the tolerance threshold for that
patient.

Figure 3: Key components of integrated care for IBS patients

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