Food intolerances are affecting increasingly more people. However, the way they manifest and the wide range of associated non-immunological mechanisms are so heterogeneous that there is no clear consensus on their mechanisms (from pharmacological to non-specific gastrointestinal functioning), diagnosis and management.

A recent narrative review in Nutrients updates scientific evidence on common food intolerances that result in gastrointestinal and extra-intestinal symptoms.

Food intolerances are considered adverse food reactions, which do not have an immune basis and which are initiated by a food or food component at a dose that is normally tolerated. They can either be based on a sensitivity to specific food components or have a genetic background.

FODMAP (referring to fermentable oligosaccharides, disaccharides, monosaccharides and polyols) sensitivity

Within non-immunological food sensitivities, FODMAP sensitivity may emerge from increased osmotic activity of poorly absorbed carbohydrates in the small intestine and their subsequent fermentation by colonic bacteria, which leads to abdominal distension accompanied by visceral hypersensitivity. Food nutrients involved in functional gastrointestinal symptoms include fructose, lactose (in the presence of lactase deficiency), polyols, fructans, and galacto-oligosaccharides. FODMAP-related intolerances are diagnosed in the context of IBS based on Rome IV criteria and an initial lactose breath test to rule out lactose intolerance.

Randomized controlled trials have shown the efficacy of the low-FODMAP diet as a second-line treatment for ameliorating gastrointestinal symptoms in sensitive individuals (e.g. IBS patients) varying between 50% and 80%. When this diet is properly implemented with suitable alternatives included-preferably under the supervision of a registered dietitian-, nutritional adequacy is largely maintained.

In addition, the long-term consequences of the low-FODMAP diet on the gut microbiota have yet to be observed. A preliminary study showed that after 4 weeks, this diet may decrease Bifidobacteria and increase Bilophila wadsworthia while perpetuating IBS symptoms after the discontinuation of treatment.

Non-celiac gluten/wheat sensitivity (NCG/WS)

In some individuals, gluten/wheat intake is associated with functional gastrointestinal and systemic manifestations. Other proteins found in wheat (i.e. alpha-amylase/trypsin inhibitors and agglutinin) may be involved in food intolerances due to wheat.

The overlap between IBS and gluten-related disorders, together with placebo and nocebo responses and the difficulty with ensuring that celiac disease is ruled out, makes accurately diagnosing and managing wheat-related intolerances a challenge. Furthermore, the response to a gluten-free diet and subsequent reaction to re-challenge with gluten compared with placebo is not always possible to assess. Restricting fructans (a component from the carbohydrate fraction of wheat) in the context of a low-FODMAP diet is suggested as a first step in patients with NCG/WS, while further clinical trials are needed to clarify which diet they should follow.

Histamine intolerance

Histamine found in canned foods, ready meals and products that have been stored for a long time has been reported to cause unspecific gastrointestinal and extra-intestinal symptoms during and after meals.

Histamine intolerance results from a slow histamine degradation by amine oxidases, especially in cases of high intakes of histamine with diet. Currently, there is no definitive diagnostic tool for histamine intolerance. A short-term dietary histamine restriction is recommended as a first line of treatment, which may be complemented by the ingestion of the enzyme DAO or use of antihistamines as a measure to help relieve symptoms.

Non-immunological adverse reactions to natural and added food additives and chemicals

Although different bioactive food additives and preservatives found naturally or artificially added to foods have been thought to induce a wide range of symptoms—from gastrointestinal symptoms to atopic dermatitis—there is a shortage of controlled trials that have studied the health benefits of diets low in food chemical content (namely, the low chemical diet).

The particular adverse reaction to salicylates from aspirin and other non-steroidal anti-inflammatory drugs has been found to be involved in gastrointestinal symptoms in those with asthma. However, in the general population, there is a lack of reproducible and well designed clinical trials of chemicals found in lower doses in dietary sources. As such, as with non-celiac gluten/wheat sensitivity, understanding the mechanisms, diagnosis and management is difficult. The potential negative consequences for nutritional adequacy that come from using the low chemical diet in clinical practice should also be acknowledged, especially in children.

Sucrase and isomaltase deficiency

Genetic variants may also play a role in food intolerances. That is the case with sucrase-isomaltase deficiency that results in reduced tolerance to sugars and starch. As a result of neither being digested nor absorbed in the small intestine, the disaccharides sucrose and maltose act as FODMAPs in the lumen, retaining water. They can also be fermented by the gut microbiota in the colon, resulting in functional gut symptoms.

The gold standard for diagnosis includes duodenal or jejunal biopsies, with diagnostic challenges and responses to enzyme replacement therapy. Hydrogen breath testing for carbohydrate intolerances are not recommended due to their lack of reproducibility.

Dietary treatment includes restriction of sugars and starch, followed by gradual re-introduction to assess tolerance. This may be complemented by enzyme replacement therapy with sacrosidase.

On the whole, the lack of reliable diagnostic biomarkers for common food intolerances results in an inability to accurately diagnose and manage them. Identifying non-invasive biomarkers to predict response to dietary therapies is a hot area of research in the field that will help with tailoring the best diet for food intolerances based on dietary and clinical data, but also on genetic background and microbiome data.

In addition, the efficacy of a specific diet for tackling food intolerances cannot always be assessed due to inherent limitations of dietary clinical trials (e.g., a lack of food compositional data for histamine and food chemicals and difficult to randomize participants in each dietary intervention group). Other factors that should be considered are the information source patients use for following dietary advice, the level of dietary restriction necessary to achieve symptom resolution, and the long-term effects and safety of restriction diets commonly used for food intolerances.

Last but not least, it is important to ensure appropriate education provided by dietitians at an individualized level in order to guarantee adherence to initial restrictive diets and long-term dietary patterns, without compromising nutritional status and health outcomes. Patients tend to manage food intolerances themselves, which may lead to long-term perpetuation of restrictive diets without taking into account whether the individual has become tolerant to food triggers.

This review article belongs to the special issue “Food and Diet for Gut Function and Dysfunction” in the peer reviewed open access journal Nutrients. This issue was instigated by the European Society of Neurogastroenterology and Motility, guest edited by Profs Fernando Azpiroz and Paul Enck, and made possible through an unrestricted educational grant from Danone.



Tuck CJ, Biesiekierski JR, Schmid-Grendelmeier P, Pohl D. Food intolerances. Nutrients. 2019; 11(7). doi: 10.3390/nu11071684.