Irritable bowel syndrome: Role of food in pathogenesis and management

Authors


Eamonn MM QUIGLEY, Department of Medicine, Clinical Sciences Building, Cork University Hospital, Cork, Ireland. Email: e.quigley@ucc.ie

Abstract

Patients with the irritable bowel syndrome (IBS) commonly report the precipitation of symptoms on food ingestion. Though the role of dietary constituents in IBS has not been extensively studied, food could contribute to symptom onset or even the causation of IBS through a number of mechanisms. First, the physiological response of the intestine to food ingestion could precipitate symptoms in predisposed individuals; second, there is some evidence that allergy or intolerance to a particular food can produce IBS-like symptoms, third, certain foods may alter the composition of the luminal milieu, either directly or indirectly through effects on bacterial metabolism, and thus induce symptoms and, finally, IBS may develop following exposure to food-borne pathogens. Anticipatory, psychological factors generated by previous negative experiences with food ingestion or other factors may also contribute though their contribution has been scarcely quantified. Not surprisingly, there is considerable interest in the potential roles of diet and food supplements in the therapy of IBS; for the most part, the evidence base for such recommendations remains slim though certain probiotics show considerable promise.

IBS: PREVALENCE AND PATHOGENESIS

Irritable bowel syndrome (IBS) is one of the most common disorders encountered in modern medicine: community surveys in western Europe and North America suggesting a prevalence of around 10% in the adult population.1 It should be stressed, in addition, that IBS appears to be common worldwide regardless of geography or socioeconomic status. There is no single specific diagnostic test for IBS: its definition relies, therefore, either on the exclusion of diseases that may share its symptomatology in whole or in part, or on the application of symptom-based criteria whose integrity has been validated in cross-sectional and longitudinal studies. The cardinal symptoms of IBS are abdominal pain or discomfort and bowel dysfunction. Typically, these are interrelated such that, for example, an affected patient may report that his, or more likely her, symptoms worsen when constipated, only to be relieved once a bowel movement has been achieved. In clinical research most studies apply the definitions enshrined in the Rome criteria, whose third iteration (Rome III) was released in early 2006 and defined IBS as:

Recurrent abdominal pain or discomfort (an uncomfortable sensation not described as pain) at least 3 days per month in the last 3 months associated with two or more of the following:

  • • improvement with defecation
  • • onset associated with a change in frequency of stool
  • • onset associated with a change in form (appearance) of stool.

These criteria should have been fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.2

As individual IBS symptoms are very non-specific and may occur in a host of other clinical conditions, the potential for diagnostic confusion is considerable. Furthermore, a condition such as IBS, whose definition rests exclusively on the interpretation of symptoms, is certain to encompass a heterogeneous population whose constituents may ultimately be found to have different causes for their symptoms. Not surprisingly, the search for a unifying hypothesis to explain all IBS symptoms has proven unfruitful. Several phenomena undoubtedly contribute to symptom genesis, including disordered bowel motility (spasms), visceral hypersensitivity or hyperalgesia, altered cerebral processing of gut events, environmental stressors and intrinsic psychopathology. The interplay between such gut and central nervous system factors has led to the concept of gut–brain axis dysfunction as fundamental to the induction of symptoms in IBS. According to this concept and putting it simply, the interaction or interplay between gut dysfunction and a central factor, such as stress or anxiety, leads to the development of symptoms.

Another factor, food ingestion, commonly invoked as the cause of symptoms onset, is the subject of this review. Detailed studies of relationships between diet and symptoms in IBS are surprisingly few in number and those that have been performed share some methodological limitations. This represents a glaring gap in IBS research and needs to be rectified. Furthermore, it must also be noted that the most complete dietary surveys among IBS patients in the community failed to detect any differences in dietary composition between IBS patients and community controls:3,4 why this discrepancy between what patients report, on the one hand, and dietary surveys, on the other?

FOOD AND PHYSIOLOGY IN IBS

Many IBS patients describe the exacerbation of their symptoms immediately following food ingestion:5 the sudden onset of abdominal cramps accompanied by a striking urge to evacuate one's bowels and the need to do so as quickly as possible being a very common narrative. While many patients jump to the conclusion that this must imply a food allergy, there are, in fact, many potential explanations for such postprandial exacerbations of IBS symptoms. The most likely explanation, in most instances, is purely physiological. Given the primary function of the gut, it should come as no surprise that food ingestion is the most potent stimulus of such gastrointestinal functions as motility and secretion. The provocation of either of these could induce symptoms in IBS.

There is, indeed, a considerable amount of literature to indicate important potentiating interactions between nutrient intake, motility and visceral sensation among IBS patients, interactions that may directly lead to symptoms. Simren et al., for example, described a nutrient-dependent exaggeration of both the sensory component of the gastrocolonic response6 and of rectal sensitivity to balloon distension,7 in IBS. Other studies reported impaired small bowel gas propulsion in IBS patients with bloating during an intestinal lipid infusion administered to mimic the effects of dietary fat.8 Lipid is, indeed, an especially potent stimulant of both motor and sensory responses. In one study, intra-duodenal lipids were found to increase colonic sensitivity and alter the pattern of viscerosomatic pain referral in IBS9. In other studies, Awad et al. documented lower postprandial thresholds for sensation of gas, perception of urge and pain threshold in constipation-predominant IBS (IBS-C) patients compared with controls.10 Caldarella et al. found a similar augmentation of visceral sensitivity by intra-duodenal lipids in both diarrhea-predominant IBS (IBS-D) and IBS-C in comparison to controls.11

The mediation of these food-related effects appears to involve both vagal and endocrine components. IBS may involve an autonomic hyper-responsiveness to visceral stimuli that occurs throughout the entire gut.12 These autonomic disturbances may also have implications for changes in cellular immune functions along the neuro-endocrine-immune axis that may be relevant to the pathogenesis of IBS13. That some of these responses might be generated in the gut itself is suggested by the observation of altered autonomic responses to colonic distension in IBS. Whether such responses, in turn, generate the exaggerated reaction to food or whether postprandial events reflect an intrinsic autonomic defect or a centrally driven response must await further studies.14 A role for a centrally mediated effects is supported by one, albeit small, study that demonstrated that patients with IBS-D showed a significant postprandial increase in cortisol, a well-recognized mediator of the central stress response, which was not evident in controls or IBS-C15. The same authors also showed a significant correlation between the vagal response, assessed by heart rate variability at base line and after a meal, and the postprandial increase in gastrointestinal symptoms in IBS-D15. Other hormonal factors may also be relevant. In a study by Sjolund et al., IBS patients exhibited a stunted motilin response to both water intake and a fatty meal. In contrast, a fatty meal elicited an exaggerated and prolonged cholecystokinin release in IBS patients.16

The interplay between stress, eating behavior and symptoms is exemplified by studies of patients with eating disorders.17 For example, in one study the combination of high interpersonal perfectionism and low interpersonal self-efficacy was associated with binge dieting.18 In a small study using the perceived stress scale and the eating behavior pattern questionnaire, perceived stress was associated with haphazard planning of meals and emotional eating.19 Stress may also influence the choice of macronutrient. It has been shown, for example, that stress selectively elevated the intake of a preferred high fat intake with consequent increased IBS manifestations.20

While the physiological response to food intake in IBS remains to be completely elucidated, it is evident that food does, indeed, interact with motor and sensory factors indicted in the pathogenesis of IBS in a manner that could plausibly precipitate or exacerbate symptoms. As ever in the case of IBS, these responses cannot be viewed in isolation but must be looked at in the context of the gut–brain axis and, in particular, in the framework of the stress response.

Dietary factors in IBS

Given the aforementioned roles of motility and sensation in the pathogenesis of IBS symptoms and of the known importance of serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter in the enteric nervous system, not to mention its role in brain circuitry, one group of dietary constituents that may be of special importance to the IBS sufferer is that which includes serotonin precursors.4 About 1% of dietary tryptophan is converted to serotonin, with most of 5-HT synthesis taking place in the enterochromaffin cells of the gut. However, approximately 10–20% of serotonin biosynthesis occurs centrally once tryptophan has crossed the blood–brain barrier (BBB). The brain's storage capacity for tryptophan is limited and the central availability of tryptophan is largely determined by active transport across the BBB where it competes with other large neutral amino acids such as phenylalanine and tyrosine, in addition to its own metabolite, kynurenine. About 99% of dietary tryptophan is metabolized along the kynurenine pathway, which is regulated by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO).21 While TDO is localized to the liver and is upregulated by corticosteroids, IDO is expressed by a variety of cells and is inducible, preferentially, by the pro-inflammatory cytokine interferon-γ (IFN-γ). High cortisol levels or high levels of pro-inflammatory cytokines could influence the metabolism of tryptophan. The way in which a variety of dietary changes could affect concentrations of 5-HT in the brain and/or enteric nervous system can thus be visualized. Indeed, it has already been demonstrated that dietary manipulations to either deplete or artificially increase tryptophan levels in the blood can affect anxiety and gastrointestinal symptoms in IBS patients.22 Interestingly, a recent study showed that the activity of IDO is enhanced in IBS patients;23 though a linkage to dietary intake or to the degradation of dietary components by the microbiota has not been explored.

Food intolerance and allergy

Many IBS patients report problems with specific foods, most commonly implicating milk and wheat products, caffeine, fructose and certain meats as the offending foods.5,24Reports of specific foods inducing symptoms raise the issue of allergy and here, again, other possibilities need to be considered. First, those who are intolerant of lactose (due to lactase deficiency) or fructose or sorbitol will develop symptoms on exposure, such as abdominal cramps, urgency and diarrhea, which mimic those of IBS and need to be carefully identified and distinguished. The benefits of lactose, fructose and sorbitol exclusion among IBS subjects, in general, have been inconclusive, at best, and frankly disappointing, at worst25–34 Discrepancies between studies may reflect differences in the population prevalence of either lactase deficiency27–30 or fructose intolerance. Formal correlations between tests of tolerance and responses to exclusion have, in some hands, been unconvincing27,33 and exclusion of fructose and lactose has had highly variable effects.35 Second, the effects of some of these foods may reflect their potency as stimulants of the aforementioned physiological functions. Finally, there remains the nagging question of food allergy per se.

Poorly absorbed, highly fermentable short-chain carbohydrates and polyols (described by the acronym FODMAP: fermentable oligo-, di- and monosacharides and polyols) which include fructans, raffinose, lactose, polyols and galactans have the potential, by virtue of their osmotic effects in the distal small bowel and colon, to potentiate IBS symptoms like bloating and diarrhea. Galactans are present in such common dietary constituents as onions, legumes, cabbage and sprouts and fructans are found in wheat, onions, spring onions, shallots, leeks, artichokes and chicory. Studies of the impact of FODMAP-free diets from one research group in patients with IBS suggest that this approach may be of value in some patients.36,37

The term food allergy should be reserved for those instances where a clear allergic response to a specific food has been identified. Characteristically, these responses, which can be profoundly symptomatic, are based on the development of immunoglobulin E (IgE)-type antibodies to a food constituent (important examples here would include peanut and fish allergies). There is no consistent evidence for a role for this type of allergic response in IBS.38–42 In one study, indeed, the authors could differentiate between IBS and food allergy on the basis of symptom analysis, suggesting that they were distinct clinical entities.43 More enthusiasm has surrounded the concept that a different antibody class (IgG) may be implicated in food-related responses in IBS and two different centers have reported significant symptomatic responses among some of those IBS subjects who instituted elimination diets based on a base line IgG antibody profile.44–46 These studies need to be replicated.41

Relations between IBS and one of the most common and well-defined disorders based on an immunological response to a food constituent, namely celiac disease, have also come under the microscope of late. As the true prevalence of celiac disease comes to be recognized and as the breadth of the spectrum of symptoms associated with this disorder is appreciated, the potential for overlap between IBS and celiac symptomatologies has increasingly emerged. Nowadays it has become common to identify celiac disease among individuals presenting with relatively vague abdominal symptoms that may, in the past, have been dismissed as IBS.47–52 This has led to the recommendation that serological testing for celiac should be performed among all newly presenting IBS subjects in populations where the prevalence of IBS is known to be high.50 IBS-type symptoms may persist among celiac patients following the institution of a gluten-free diet even when compliance is apparently complete.48 Does this represent the coincident occurrence of two common disorders, IBS and celiac disease or is there a real association? Could the persistence or occurrence of IBS-type symptoms in this context represent the effects of persistent low-grade inflammation or merely reflect the impact of unrecognized or inadvertent non-compliance? These issues remain unresolved.

What of the IBS patient who protests wheat intolerance but in whom celiac serology and small intestinal biopsies are normal? Until recently this association would have been passed off as imagined; now comes intriguing data to suggest that those IBS patients with wheat intolerance and who possess the genotype most closely associated with celiac disease (HLA DQ2 or DR3) but who do not have overt evidence of the disorder (as evidenced by typical serological markers and appropriate changes in small intestinal histology) can be shown to exhibit other immunological evidence of gluten reactivity and to respond to a gluten-free diet.53 Is there a state of gluten sensitivity which does not fulfill the current criteria for celiac disease?54 The plot thickens!

Food and the enteric flora: potentially interrelated factors in IBS

Recently, a new twist has been added to the IBS story with reports from a number of laboratories of potentially related phenomena, namely, subtle alterations in immune function and disturbances in the composition of the intrinsic bacterial population of the gut (the enteric flora or microbiota). The possibility that the enteric flora, or microbiota, could play a role in the pathogenesis of IBS has only very recently begun to attract concerted scientific attention though evidence to suggest a link has been extant for some time and contains several distinct strands:

  • • epidemiological evidence that antibiotic use may predispose to IBS or to exacerbations55
  • • epidemiological, clinical and experimental evidence for the existence of post-infectious IBS.
  • • evidence, both experimental and clinical, for a role for low grade inflammation (perhaps triggered by luminal bacteria) in IBS,
  • • the suggestion that IBS may be associated with small intestinal bacterial overgrowth, or qualitative or quantitative changes in the colonic flora (dysbiosis),
  • • evidence to indicate that the manipulation of the gut flora by antibiotics or probiotics may ameliorate symptoms in IBS.

Of these two issues, namely, post-infectious IBS and the use of probiotics to treat IBS are of particular relevance to the topic at hand, given that some of the former instances have been related to food-borne infections. To date, the possibility that antibiotic residues contained in food could disturb the microbiota and contribute to IBS symptoms has not been addressed.

POST-INFECTIOUS IBS

We are now beginning to see real data to directly support the concept of post-infectious or post-dysenteric IBS.56 First reported by McKendrick and Read,57 the occurrence of IBS following episodes of bacteriologically-confirmed gastroenteritis has now been documented in several studies.58–68 Some of these episodes have been directly and exclusively linked to food-borne pathogens.64 Thabane et al. recently performed a systematic review and concluded that the overall risk for the development of IBS was increased six-fold following an episode of bacterial gastro-enteritis with younger subjects, those who have prolonged fever during the episode of gastroenteritis and those who suffer from anxiety or depression being at greatest risk.69 In individual studies, being female, having a more severe initial illness and possessing premorbid psychopathology predicted those most at risk.65–68 The nature of the infectious agent does not appear to confer additional risk. These symptoms are not transient; in a Scandinavian study in which 12% of their subjects had IBS within 3 months of gastroenteritis, 9% still had symptoms five years later.66 Neal et al. documented similar recovery rates for post-infectious and non-post-infectious IBS in a six-year follow-up study.70

One of these studies went on to establish a direct link between prior exposure to an infectious agent, persisting low grade inflammation and IBS.61 In this study, an increase in the number of chronic inflammatory cells in the rectal mucosa was seen only among those exposed patients who had developed IBS. Others have demonstrated a persisting increase in rectal mucosal enteroendocrine cells, T lymphocytes and gut permeability in patients with post-dysenteric IBS.62,63 These observations are important as they indicate a relationship between perturbations of the microbiota, mucosal inflammation and IBS, a hypothesis that is amply supported by data from studies in experimental animal models.

A number of parasites, such as Dientamoeba fragilis, Blastocystis hominis and Giardia have been associated with the development of chronic gastrointestinal symptoms which may mimic IBS71,72 whether parasitic infections can trigger IBS, per se, is unknown. Very recently, an outbreak of food-borne viral gastroenteritis was associated with the new onset of an IBS-type syndrome in 24% of affected subjects when interviewed three months later; subsequent follow suggested that post-viral IBS was more transient than its bacterial counterpart.73

Post-infectious IBS may explain only a minority of cases of IBS {1-6.7% in one recent study74} but it does represent a clear link between exposure to an environmental agent, such as a food-borne pathogen, inflammation and IBS in predisposed individuals.

PROBIOTICS AND PREBIOTICS IN IBS; POTENTIAL MODULATORS OF DYSBIOSIS AND IMMUNE DYSFUNCTION?

For some time various studies have suggested the presence of qualitative changes in the colonic flora (dysbiosis) in IBS patients; a relative decrease in the population of bifidobacteria being the most consistent finding.75–77 It should be noted, however, that these findings have not always been reproduced and the methods employed have been subject to question. More recent studies using molecular techniques have confirmed the presence of an altered flora in IBS though the precise nature of these changes remains to be defined.77–79 Nevertheless, qualitative changes in the colonic flora, be they primary or secondary, could lead to the proliferation of species that produce more gas and short chain fatty acids and are more avid in the deconjugation of bile acids. With regard to the former, the displacement of gas-forming species could result in local changes in gas production, a development that may be poorly tolerated by IBS patients who seem to have difficulties with the transport of gas along the intestine80 and to be overly sensitive to gas-induced distension.81 Here again there is potential for an interaction with food. One can readily visualize how the ingestion of poorly digested or indigestible carbohydrates, by acting as substrates for the colonic flora, could exacerbate this situation further. The excess production of short chain fatty acids and deconjugated bile salts could, in turn, lead to clinically significant changes in water and electrolyte transport in the colon and affect colonic motility and/or sensitivity.

Based on the aforementioned disturbances in the enteric flora, as well as on the potential for certain probiotics to exert anti-inflammatory effects and to thereby reverse the immunological changes described above, there has been, of late considerable interest in the use of probiotics in IBS. Given their safety profile, probiotics, if effective, would at first sight also appear to be a more attractive than antibiotics as potential manipulators of the gut flora in IBS. Are probiotics effective in IBS? Several factors complicate the interpretation of clinical trials of probiotics preparations in IBS. Many studies have been underpowered and some earlier studies were even uncontrolled and not blinded. Furthermore, results between studies are difficult to compare because of differences in study design, the use of non-validated and differing end points, and variations in probiotic dose and strain. Nevertheless, there has been some, but by no means consistent, evidence of symptom improvement.82–104 More recent reviews105,106 have explored the scientific rationale behind the use of probiotics in IBS and reviewed the clinical results from studies performed over the past two decades. Outcomes continue to be variable. Some studies report little evidence of efficacy while others document responses only for specific symptoms or in selected populations. It is noteworthy that flatulence, bloating and distension, common and distressing symptoms in IBS,107 seem especially responsive to probiotic therapy. Indeed, a recent study using objective methods demonstrated the ability of one probiotic to reduce abdominal distension and accelerate colonic transit.108 In another study probiotic administration was shown to reduce bacterial fermentation with an associated improvement in flatulence.101 Furthermore, other studies have employed probiotic cocktails rather than single isolates, rendering it difficult to deduce what were the active moieties.97–99 Nevertheless, the conclusion of a number of systematic reviews has been that probiotics, in general, have a beneficial effect in IBS.109–112 One particular probiotic, Bifidobacterium infantis 35624 appears to have more global effects in IBS.113 In the first of two studies with this organism, this strain of Bifidobacterium was found to be superior to both a Lactobacillus and placebo for each of the cardinal symptoms of the irritable bowel syndrome (abdominal pain/discomfort, distension/bloating and difficult defecation), as well as for a composite score.114 More recently these results were replicated in a much larger, dose-ranging, primary care-based study involving 360 IBS patients, where Bifidobacterium infantis, in an encapsulated format and in a dose of 108 was associated with significant improvements in the cardinal symptoms of IBS as well as in the patients' global assessment of all symptoms. At the study end, over 60% of patients randomized to the Bifidobacterium felt better than before therapy; a therapeutic gain of over 20% over placebo.115

To date, most studies of probiotics in IBS have been short term, though two studies of 5 and 6 months in duration, respectively,94,97 suggest that continued use is associated with sustained efficacy.

An alternative approach to the manipulation of the microbiota is to administer a prebiotic preparation to promote the growth of selected species such as Bifidobacteria or Lactobacilli. Indeed, a number of substances that have been used in IBS-C in particular, such as fiber and lactulose, can be regarded as exerting prebiotic effects. While there have been as yet relatively few studies of prebiotics, either alone116 or in combination with a probiotic,117 in IBS, there is, at least, the suggestion that this strategy may also have some efficacy.

The interactions between food and the microbiota may extend far beyond the well-defined prebiotic effect and could involve the release of a variety of biologically active compounds into the intestinal lumen that could exert effects on the mucosa, the immune compartment and neuro-enteric apparatus of the gut wall and well beyond to influence, either beneficially or negatively, symptoms in the IBS patient.

For all these reasons, food and functional foods, in particular, have emerged as potential therapies for IBS but in a very new and very different context; one in which IBS is viewed as a disorder of immune regulation118 related, perhaps, to disturbances in the interaction between the flora and the host.

DIETARY RECOMMENDATIONS

Apart from the various dietary restrictions that have been discussed above, a variety of other dietary recommendations are commonly given to the IBS patient or sufferer. Most have no basis in science or clinical evidence. Furthermore, a component of IBS dietary advice that had become enshrined in the IBS therapeutic armamentarium, namely supplemental fiber, has recently come under fire. Quite simply, the evidence that dietary fiber alleviates any symptom of IBS other than constipation, or contributes to general well-being, is simply not there!119–123 Indeed, in some patients, fiber, perhaps through its stimulation of bacterial fermentation,124 may exacerbate rather than relieve symptoms.125 Can we translate this information into useful clinical advice for our patients? While it has been traditional to instruct IBS patients on a variety of food management strategies and restrictions, there is no validated data on which to base these recommendations. We simply do not have enough information on the role of diet and its various and highly complex constituents in IBS, in general, or in a specific subgroup.126,127 The knowledge gap here is Grand Canyonesque in its proportions.

CONCLUSIONS

Food, diet and food supplements are an important, but poorly studied, aspect of IBS. Food undoubtedly precipitates symptoms in many IBS patients; the precise mode of this effect remains unclear and may vary from one individual to another. The role of food as an inducer of allergic or inflammatory responses in IBS deserves further study. While a sheer lack of good data currently precludes the provision of evidence-based dietary advice to an individual IBS patient, recent studies provide good evidence for a role for certain specific probiotics in the management of IBS.

Ancillary