**5. Role of meals in the generation of symptoms in functional dyspepsia**

Epidemiologic studies, both in the USA and Europe, have shown that 50 to 80% of subjects with functional dyspepsia indicate that their symptoms are meal-related [5]. Meal ingestion is associated with diverse changes in the environment of the gastrointestinal lumen, the gastro‐ intestinal function and potential physiopathological mechanisms. The two most cited causes of pathology are delayed gastric emptying and visceral hypersensitivity. After ingestion of a meal, patients with functional dyspepsia experience a marked rise in the intensity of their symptoms (epigastric burning, epigastric pain, fullness, bloating, nausea and belching) that persists for 4 hours [14]. Postprandial fullness is the most severe symptom that a meal aggravates.

How Food Triggers Gastrointestinal Symptoms?

of the balloon during barostat studies).

abnormal motility responses may ensue.

hypersensitivity, and with abdominal pain [23,24].

dietary manipulation.

The enteric nervous system is a major controller of multiple gut functions, such as secretion, motility, blood flow and mucosal growth. In a normal situation, low intensity stimuli from the lumen have few discernible effects on motility (as occurs in association with minimal inflation

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In most patients with functional gastrointestinal disorders, there is a change in relationship between stimulus intensity and perception (the hallmark of visceral hypersensitivity) and efferent motility response. These people experience pain in response to low intensity stimuli;

Luminal events may be initiated via two main stimuli: mechanical (associated with distention of the gut wall) and chemical stimuli. Chemical stimuli trigger specific enteroendocrine cells of the gut, releasing serotonin, which stimulates primary afferents of the enteric nervous system [21]. There is also evidence that some enteric neurons might directly respond to mechanical stimuli: the transient receptor potential (TRP) cation channels seem to be involved in most levels of control of gastrointestinal function, including visceral hypersensitivity [22]. The TRPV1 (vanilloid) channels appear to be central to the initiation and persistence of visceral hypersensitivity in an animal model. Increased expression of TRPV1 channels in neurons of the gut has been observed in patients with IBS; such expression correlates with visceral

Food stimulates the gut through the release of enteric hormones and particularly via the enteric nervous system. A primary trigger is luminal distention, which results from the physical act of ingesting food and from secondary events such as gas production (especially bacterial fermentation). Food also contains potent chemicals. If the food constituents that stimulate the enteric nervous system were to be identified, then these would become obvious targets for

On the basis of these concepts (luminal distention, visceral hypersensitivity and chemical stimuli of the enteric nervous system), three specific areas of proven or suspected food-induced gut symptoms in patients with functional GI symptoms are important: a. FODMAPs (fer‐ mentable oligo-, di- and monosaccharides and polyols) that include luminal distention; b. food chemicals (salicylates, amines) that potentially stimulates the enteric nervous system (ENS),

Carbohydrates occur across a range of foods regularly consumed including grains such as wheat and rye, vegetables, fruit and legumes. Short-chain carbohydrates with chain lengths up to 10 sugars vary in their digestibility and subsequent absorption. Those that are poorly absorbed exert osmotic effects in the intestinal lumen increasing its water volume. They are also rapidly fermented by bacteria yielding consequent gas production. These two effects may underlie many of the gastrointestinal symptoms that follows their ingestion. Only monosac‐ charides (glucose, galactose) can be actively absorbed across the small intestinal epithelium.

and c. gluten that may trigger symptoms by as yet unknown mechanisms.

**a.** *Targeting luminal distention: The FODMAP approach*

Disturbances in upper gastrointestinal motor functions in FD have received considerable attention. Not surprisingly, current treatments such as prokinetics are primarily directed to these abnormalities. Therapies for visceral hypersensitivity remain difficult to establish. Factors such as eating patterns (meal size and frequency, nutrient composition, overall energy intake) and intolerances to specific foods or food groups have received little attention so far.

## **6. Dietary factors in functional dyspepsia**

#### **6.1. Eating patterns**

Patients with functional dyspepsia frequently report that they are able to tolerate only small quantities of food [15], suggesting that their eating patterns differ from healthy subjects [8]. As a result of eating smaller quantities of food with lower energy intake, over half of FD patients experience weight loss even with a tendency to snack [16]. Despite eating fewer meals and consuming less total energy and fat, patients with FD experience fullness that is directly related to the amount of fat ingested and overall energy intake, while inversely related to the amount of carbohydrates ingested. Management of FD patients therefore might be improved by consuming smaller meals with reduced fat content [17,18].

#### **6.2. Food intolerances**

Patients with functional dyspepsia appear to exhibit more food intolerances than healthy persons, although studies are limited.

The belief that food is causing or at least triggering gut symptoms has led to the application of investigations purporting to guide dietary design. Various tests for food "intolerances" are widely available, such as skin prick (allergy) tests and assays for food specific immunoglobu‐ lins, but their value is unknown. Furthermore, various diets including wheat-free, anticandida, carbohydrate-free, and other complex exclusions diets are touted in books and on the internet but evidence for any benefit is lacking.[19] The exception is the gluten-free diet, which will be discussed later in the chapter.

Alternative health practitioners and some nutritionists have advocated many such diets and intolerance-testing.

Therefore, gastroenterologists often are left with a defensive role when patients request dietary interventions. Although gastroenterologists may appreciate that food is an undoubted trigger, it is difficult to recognize the specific food item. Tests designed to this have a poor predictive value, while the resulting diets are often overly restrictive with the potential to render the patient nutritionally compromised [20].

#### How Food Triggers Gastrointestinal Symptoms?

meal, patients with functional dyspepsia experience a marked rise in the intensity of their symptoms (epigastric burning, epigastric pain, fullness, bloating, nausea and belching) that persists for 4 hours [14]. Postprandial fullness is the most severe symptom that a meal

Disturbances in upper gastrointestinal motor functions in FD have received considerable attention. Not surprisingly, current treatments such as prokinetics are primarily directed to these abnormalities. Therapies for visceral hypersensitivity remain difficult to establish. Factors such as eating patterns (meal size and frequency, nutrient composition, overall energy intake) and intolerances to specific foods or food groups have received little attention so far.

Patients with functional dyspepsia frequently report that they are able to tolerate only small quantities of food [15], suggesting that their eating patterns differ from healthy subjects [8]. As a result of eating smaller quantities of food with lower energy intake, over half of FD patients experience weight loss even with a tendency to snack [16]. Despite eating fewer meals and consuming less total energy and fat, patients with FD experience fullness that is directly related to the amount of fat ingested and overall energy intake, while inversely related to the amount of carbohydrates ingested. Management of FD patients therefore might be improved

Patients with functional dyspepsia appear to exhibit more food intolerances than healthy

The belief that food is causing or at least triggering gut symptoms has led to the application of investigations purporting to guide dietary design. Various tests for food "intolerances" are widely available, such as skin prick (allergy) tests and assays for food specific immunoglobu‐ lins, but their value is unknown. Furthermore, various diets including wheat-free, anticandida, carbohydrate-free, and other complex exclusions diets are touted in books and on the internet but evidence for any benefit is lacking.[19] The exception is the gluten-free diet, which

Alternative health practitioners and some nutritionists have advocated many such diets and

Therefore, gastroenterologists often are left with a defensive role when patients request dietary interventions. Although gastroenterologists may appreciate that food is an undoubted trigger, it is difficult to recognize the specific food item. Tests designed to this have a poor predictive value, while the resulting diets are often overly restrictive with the potential to render the

**6. Dietary factors in functional dyspepsia**

98 Dyspepsia - Advances in Understanding and Management

by consuming smaller meals with reduced fat content [17,18].

aggravates.

**6.1. Eating patterns**

**6.2. Food intolerances**

intolerance-testing.

persons, although studies are limited.

will be discussed later in the chapter.

patient nutritionally compromised [20].

The enteric nervous system is a major controller of multiple gut functions, such as secretion, motility, blood flow and mucosal growth. In a normal situation, low intensity stimuli from the lumen have few discernible effects on motility (as occurs in association with minimal inflation of the balloon during barostat studies).

In most patients with functional gastrointestinal disorders, there is a change in relationship between stimulus intensity and perception (the hallmark of visceral hypersensitivity) and efferent motility response. These people experience pain in response to low intensity stimuli; abnormal motility responses may ensue.

Luminal events may be initiated via two main stimuli: mechanical (associated with distention of the gut wall) and chemical stimuli. Chemical stimuli trigger specific enteroendocrine cells of the gut, releasing serotonin, which stimulates primary afferents of the enteric nervous system [21]. There is also evidence that some enteric neurons might directly respond to mechanical stimuli: the transient receptor potential (TRP) cation channels seem to be involved in most levels of control of gastrointestinal function, including visceral hypersensitivity [22]. The TRPV1 (vanilloid) channels appear to be central to the initiation and persistence of visceral hypersensitivity in an animal model. Increased expression of TRPV1 channels in neurons of the gut has been observed in patients with IBS; such expression correlates with visceral hypersensitivity, and with abdominal pain [23,24].

Food stimulates the gut through the release of enteric hormones and particularly via the enteric nervous system. A primary trigger is luminal distention, which results from the physical act of ingesting food and from secondary events such as gas production (especially bacterial fermentation). Food also contains potent chemicals. If the food constituents that stimulate the enteric nervous system were to be identified, then these would become obvious targets for dietary manipulation.

On the basis of these concepts (luminal distention, visceral hypersensitivity and chemical stimuli of the enteric nervous system), three specific areas of proven or suspected food-induced gut symptoms in patients with functional GI symptoms are important: a. FODMAPs (fer‐ mentable oligo-, di- and monosaccharides and polyols) that include luminal distention; b. food chemicals (salicylates, amines) that potentially stimulates the enteric nervous system (ENS), and c. gluten that may trigger symptoms by as yet unknown mechanisms.

#### **a.** *Targeting luminal distention: The FODMAP approach*

Carbohydrates occur across a range of foods regularly consumed including grains such as wheat and rye, vegetables, fruit and legumes. Short-chain carbohydrates with chain lengths up to 10 sugars vary in their digestibility and subsequent absorption. Those that are poorly absorbed exert osmotic effects in the intestinal lumen increasing its water volume. They are also rapidly fermented by bacteria yielding consequent gas production. These two effects may underlie many of the gastrointestinal symptoms that follows their ingestion. Only monosac‐ charides (glucose, galactose) can be actively absorbed across the small intestinal epithelium. Di- and oligosaccharides must be hydrolyzed to their constituent hexoses for absorption to occur. All these molecules are plentiful in the diet and have been termed FODMAPs1

In general, the stronger the flavor of the food, the higher the chemical content will be. In clinical practice, food chemicals have received some attention in the pathogenesis and management

Food chemicals are major afferent stimuli to the enteric nervous system. In the presence of visceral hypersensitivity, normal physiological stimulation by such chemicals might result in exaggerated effector responses (luminal distention). [32] Plant chemicals are able to activate TRP channels. Chronic exposure to certain chemicals will lead to increased expression of TRP channels and this contributes to a higher sensitivity of the enteric nervous system, and thus to the development of functional gut symptoms. Withdrawing the offending chemicals from the diet may reverse the TRP channel overexpression with subsequent resolution of the gut

The only food chemicals that have been systematically studied with respect to gut symptoms are salicylates and related molecules such as non-steroid anti-inflammatory drugs. 2 to 4 % of patients with irritable bowel syndrome (IBS) or food allergies are salicylate-drug intolerant [29]. Examples of food sources containing high amounts of potentially bioactive chemicals are

**Salicylates Amines Glutamates**

Eggplant, olives

Brie , camembert, parmesan , tasty cheeses

tempeh

Surimi, soy sauce , miso,

Redcurrant Dried prunes, raisins,

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grapes, plum, sultanas

Brie , camembert , parmesan

protein

Canned baked beans in sauce , textured vegetable

of urticaria, headaches, asthma and anaphylactic reactions.

Avocado, berries , cherry, citrus , date, grape , kiwifruit, pineapple, plum ,

Mushrooms, sauerkraut, spinach, tomato, chicory, eggplant, onion, chili, ginger, herbs

Breakfast cereals , mueslis, dried fruit, honey, coconut,

strawberry

potato chips

nut pasta

seed pasta

sauce

Seeds Mustard seeds, sesame

Almond, hazelnut, marzipan , peanut butter ,

Milk with chocolate, strawberry or banana flavor , yoghurt

Bean mixes , broad beans , canned baked beans in

symptoms.

Fruits

Vegetables

Grains , cereals

Milk , milk products

Legumes

Nuts

summarized in Table 2.

FODMAPs are therefore poorly absorbed, highly osmotic and rapidly fermented by gastroin‐ testinal bacteria, leading to increased water and gas. The result is intestinal distention that also effects changes in motility, leading to symptoms of bloating and discomfort [26]. FOPMAPs induce functional symptoms in patients with IBS who have fructose malabsorption; reduction of dietary FODMAPs produces a durable symptomatic response [27, 28].


Some common food sources of FODMAPs are summarized in table 1:

#### **Table 1.**

#### **b.** *Targeting food chemicals*

Plants produce a wide variety of chemicals, some of which have survival function (the bad taste for protection, odors for reproduction), along with antibacterial or preservative proper‐ ties.

Potentially bioactive chemicals include salicylates (that have a protective role), amines and glutamates (that are products of protein breakdown), and common food additives such as benzoates, sulfites and, nitrates (as preservatives).

<sup>1</sup> FODMAP is an acronym for different carbohydrates: F: fermentable; O: oligosaccharides (fructans , galacto-oligosac‐ charides); D: disaccharides (lactose); M: monosaccharides (fructose); A: and P: polyols (sorbitol , mannitol , xylitol , maltitol) [25].

In general, the stronger the flavor of the food, the higher the chemical content will be. In clinical practice, food chemicals have received some attention in the pathogenesis and management of urticaria, headaches, asthma and anaphylactic reactions.

Di- and oligosaccharides must be hydrolyzed to their constituent hexoses for absorption to

FODMAPs are therefore poorly absorbed, highly osmotic and rapidly fermented by gastroin‐ testinal bacteria, leading to increased water and gas. The result is intestinal distention that also effects changes in motility, leading to symptoms of bloating and discomfort [26]. FOPMAPs induce functional symptoms in patients with IBS who have fructose malabsorption; reduction

**Lactose Fructose Polyols**

Apple, apricot, pear, avocado, cherry, blackberries, plum, prune, nectarine

Cauliflower, mushroom, snow peas

xylitol, isomalt

Apple, cherry, mango, pear, Watermelon

Asparagus, artichokes, sugar snap peas

fructose corn syrup

occur. All these molecules are plentiful in the diet and have been termed FODMAPs1

custard, soft cheeses

Food additives Inulin Sorbitol, mannitol, maltitol,

Plants produce a wide variety of chemicals, some of which have survival function (the bad taste for protection, odors for reproduction), along with antibacterial or preservative proper‐

Potentially bioactive chemicals include salicylates (that have a protective role), amines and glutamates (that are products of protein breakdown), and common food additives such as

1 FODMAP is an acronym for different carbohydrates: F: fermentable; O: oligosaccharides (fructans , galacto-oligosac‐ charides); D: disaccharides (lactose); M: monosaccharides (fructose); A: and P: polyols (sorbitol , mannitol , xylitol ,

of dietary FODMAPs produces a durable symptomatic response [27, 28].

Some common food sources of FODMAPs are summarized in table 1:

**Oligosaccharides, fructans**

100 Dyspepsia - Advances in Understanding and Management

watermelon

Artichokes, beetroot, Brussels sprouts, chicory, garlic, onion, peas

Milk Milk, yoghurt, ice-cream,

benzoates, sulfites and, nitrates (as preservatives).

Other Chicory drinks Honey, high

Fruit Peach, persimmon,

Grains , cereals Wheat , rye, barley Nuts pistachios

Legumes Lentils, chickpeas

**b.** *Targeting food chemicals*

Vegetables

**Table 1.**

ties.

maltitol) [25].

Food chemicals are major afferent stimuli to the enteric nervous system. In the presence of visceral hypersensitivity, normal physiological stimulation by such chemicals might result in exaggerated effector responses (luminal distention). [32] Plant chemicals are able to activate TRP channels. Chronic exposure to certain chemicals will lead to increased expression of TRP channels and this contributes to a higher sensitivity of the enteric nervous system, and thus to the development of functional gut symptoms. Withdrawing the offending chemicals from the diet may reverse the TRP channel overexpression with subsequent resolution of the gut symptoms.

The only food chemicals that have been systematically studied with respect to gut symptoms are salicylates and related molecules such as non-steroid anti-inflammatory drugs. 2 to 4 % of patients with irritable bowel syndrome (IBS) or food allergies are salicylate-drug intolerant [29]. Examples of food sources containing high amounts of potentially bioactive chemicals are summarized in Table 2.



biopsy-proven celiac disease in individuals with dyspepsia may be as low as 1%, a value similar to that amongst individuals in the general population, or markedly higher at 6% to 9% [37]. Routine screening for celiac disease therefore seems useful through serological testing and with distal duodenal biopsy during upper gastrointestinal endoscopy done to investigate

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B. *Gluten (wheat) sensitivity*. Gluten may also induce other pathological conditions, such as a wheat allergy. Wheat allergy is an immunoglobulin IgE–mediated disease and thus com‐ pletely unrelated to celiac disease. [33] Recent attention however has been given to another entity: gluten or wheat sensitivity (also termed non-celiac gluten sensitivity). This disorder misses one or more of the key criteria: enteropathy and the presence of specific autoantibod‐ ies that define celiac disease (CD). The current working definition of non-celiac gluten sensi‐ tivity is the occurrence of irritable bowel syndrome (IBS)-like symptoms after ingesting gluten, and improvement after gluten withdrawal from the diet. Celiac disease must be ex‐ cluded by negative celiac serology or a normal intestinal architecture, while wheat allergy should be negated by a negative IgE-mediated allergy test to wheat. Non-celiac gluten sensi‐ tivity (NCGS) thus encompasses a collection of medical conditions in which gluten leads to an adverse food reaction, clinically similar to some features of celiac disease, but celiac test‐ ing is negative or inconclusive [38, 39]. Such non-celiac IBS patients, in whom celiac disease

The key question is the mechanism by which gluten induces symptoms. Gluten may mediate cholinergic activation, leading to increased smooth muscle contractility and indirectly have effects on luminal water content. Another explanation might be the release of neutrally active peptides from the gluten digestion that might potentially gain access to enteric nerve endings. Gluten ingestion can precipitate duodenal tissue eosinophilia in those with wheat sensitivity [39]. Although there is no well-established mechanism for NCGS, the gluten-free diet has

Because of the many patients with functional dyspepsia and its serious impairment to their quality of life, this entity represents an important clinical challenge. Pharmacologic therapies are limited, leaving patients and physicians to often use dietary strategies in managing FD.

Unfortunately most of the available information concerning the role of diet and food intake in FD patients is inconclusive. Several studies fortunately have shown clear differences between FD patients and healthy persons in the ability to tolerate certain types of foods including

FD patients often maintain regular consumption of several foods despite these being impli‐ cated with the dyspepsia. Why these patients do not avoid the majority of food components, which they link to dyspepsia, remains unclear. Possible reasons might be ignorance of this association, a lack of alternatives to replace food items, or cultural habits such as the use of

is excluded, will improve on a gluten-free diet [30].

gained substantial popularity with the general public.

fermentable carbohydrates (FODMAPs).

**7. Dietary management strategies in functional dyspepsia**

dyspepsia.

**Table 2.** Examples of food sources with very high amounts of salicylates, amines and glutamates (reference: http:// www.allergy.net.eu)

#### **c.** *Targeting gluten: A suspected molecule without a known mechanism*

A. *Celiac disease* in recent years has undergone a profound revision. Celiac disease (CD) is now considered to be a systemic immune-mediated disorder elicited by gluten. The common denominator for all patients with CD is the presence of a combination of gluten-dependent clinical manifestations, specific autoantibodies (anti–tissue transglutaminase, anti-endomysial antibodies plus serum IgA) and different degrees of enteropathy, ranging from lymphocytic infiltration of the epithelium to complete villous atrophy. [33, 34] Nevertheless, CD remains underdiagnosed in all age groups. The advent of serological testing has improved the detection of celiac disease but typical endoscopic findings for villous atrophy such as scalloping of folds, a mosaic pattern, or decreased folds are often not evident in less severe cases. Magnification tools like confocal endomicroscopy or "water immersion" techniques help characterize the abnormal duodenal mucosa and target biopsying. In many patients, particular adults, the disease features atypical symptoms or is completely silent, the so-called "celiac iceberg". Upper abdominal symptoms, such as abdominal pain and dyspepsia, are a common primary complaint in CD [36]. 30 to 40 % of celiac patients have dyspeptic symptoms. From a different perspective, diagnostic testing for celiac disease in individuals with dyspepsia has some advocates, because of a trend to a greater prevalence [35]. Nevertheless, the prevalence of biopsy-proven celiac disease in individuals with dyspepsia may be as low as 1%, a value similar to that amongst individuals in the general population, or markedly higher at 6% to 9% [37]. Routine screening for celiac disease therefore seems useful through serological testing and with distal duodenal biopsy during upper gastrointestinal endoscopy done to investigate dyspepsia.

**Salicylates Amines Glutamates**

Beef : billong, jerky Chicken : pressed , seasoned , gravy

Almond oil , extra virgin olive oil , sesame oil

Beer , champagne , cider , tea , herbal tea , wine

Jam , fruit flavored sweets , yeast extract , fermented products , chicken salt , sauces ( tomato , soy , fish

and oyster)

Ham , bacon , anchovies, prawns tuna , fish : pickled ,

Almond oil , extra virgin olive oil , sesame oil

Beer , champagne , cider , tea , herbal tea , wine Chocolate drinks , cocoa

Jam , marmalade , yeast extract , vinegar , chocolate , sauces ,

salted, smoked

powder

**Table 2.** Examples of food sources with very high amounts of salicylates, amines and glutamates (reference: http://

A. *Celiac disease* in recent years has undergone a profound revision. Celiac disease (CD) is now considered to be a systemic immune-mediated disorder elicited by gluten. The common denominator for all patients with CD is the presence of a combination of gluten-dependent clinical manifestations, specific autoantibodies (anti–tissue transglutaminase, anti-endomysial antibodies plus serum IgA) and different degrees of enteropathy, ranging from lymphocytic infiltration of the epithelium to complete villous atrophy. [33, 34] Nevertheless, CD remains underdiagnosed in all age groups. The advent of serological testing has improved the detection of celiac disease but typical endoscopic findings for villous atrophy such as scalloping of folds, a mosaic pattern, or decreased folds are often not evident in less severe cases. Magnification tools like confocal endomicroscopy or "water immersion" techniques help characterize the abnormal duodenal mucosa and target biopsying. In many patients, particular adults, the disease features atypical symptoms or is completely silent, the so-called "celiac iceberg". Upper abdominal symptoms, such as abdominal pain and dyspepsia, are a common primary complaint in CD [36]. 30 to 40 % of celiac patients have dyspeptic symptoms. From a different perspective, diagnostic testing for celiac disease in individuals with dyspepsia has some advocates, because of a trend to a greater prevalence [35]. Nevertheless, the prevalence of

Beef : smoked , corned ,

Almond oil , extra virgin olive oil , sesame , avocado

Flavored mineral waters, spirits (except gin, tonic, whisky, vodka) , wine, fruit juices, ginger beer, beer , champagne , cider , herbal

Jam , marmalade , fruit flavored syrup , yeast extract , vinegar (cider , red

**c.** *Targeting gluten: A suspected molecule without a known mechanism*

and white wine) Honey , peppermints, tomato sauce , soy sauce

Chicken : nuggets , smoked Meat pastes , fish pastes ,

dried

102 Dyspepsia - Advances in Understanding and Management

salami

oil

tea , tea

Meat, fish , chicken

Fats and oils

Beverages

Other

www.allergy.net.eu)

B. *Gluten (wheat) sensitivity*. Gluten may also induce other pathological conditions, such as a wheat allergy. Wheat allergy is an immunoglobulin IgE–mediated disease and thus com‐ pletely unrelated to celiac disease. [33] Recent attention however has been given to another entity: gluten or wheat sensitivity (also termed non-celiac gluten sensitivity). This disorder misses one or more of the key criteria: enteropathy and the presence of specific autoantibod‐ ies that define celiac disease (CD). The current working definition of non-celiac gluten sensi‐ tivity is the occurrence of irritable bowel syndrome (IBS)-like symptoms after ingesting gluten, and improvement after gluten withdrawal from the diet. Celiac disease must be ex‐ cluded by negative celiac serology or a normal intestinal architecture, while wheat allergy should be negated by a negative IgE-mediated allergy test to wheat. Non-celiac gluten sensi‐ tivity (NCGS) thus encompasses a collection of medical conditions in which gluten leads to an adverse food reaction, clinically similar to some features of celiac disease, but celiac test‐ ing is negative or inconclusive [38, 39]. Such non-celiac IBS patients, in whom celiac disease is excluded, will improve on a gluten-free diet [30].

The key question is the mechanism by which gluten induces symptoms. Gluten may mediate cholinergic activation, leading to increased smooth muscle contractility and indirectly have effects on luminal water content. Another explanation might be the release of neutrally active peptides from the gluten digestion that might potentially gain access to enteric nerve endings. Gluten ingestion can precipitate duodenal tissue eosinophilia in those with wheat sensitivity [39]. Although there is no well-established mechanism for NCGS, the gluten-free diet has gained substantial popularity with the general public.
