Two randomized crossover multicenter studies investigating gastrointestinal symptoms after bread consumption in individuals with noncoeliac wheat sensitivity: do wheat species and fermentation type matter?

BACKGROUND: Many individuals reduce their bread intake because they believe wheat causes their gastrointestinal (GI) symptoms. Different wheat species and processing methods may affect these responses. OBJECTIVES: We investigated the effects of 6 different bread types (prepared from 3 wheat species and 2 fermentation conditions) on GI symptoms in individuals with self-reported noncoeliac wheat sensitivity (NCWS). METHODS: Two parallel, randomized, double-blind, crossover, multicenter studies were conducted. NCWS individuals, in whom coeliac disease and wheat allergy were ruled out, received 5 slices of yeast fermented (YF) (study A, n = 20) or sourdough fermented (SF) (study B, n = 20) bread made of bread wheat, spelt, or emmer in a randomized order on 3 separate test days. Each test day was preceded by a run-in period of 3 d of a symptom-free diet and separated by a wash-out period of ≥7 d. GI symptoms were evaluated by change in symptom score (test day minus average of the 3-d run-in period) on a 0-100 mm visual analogue scale (ΔVAS), comparing medians using the Friedman test. Responders were defined as an increase in ΔVAS of ≥15 mm for overall GI symptoms, abdominal discomfort, abdominal pain, bloating, and/or flatulence. RESULTS: GI symptoms did not differ significantly between breads of different grains [YF bread wheat median ΔVAS 10.4 mm (IQR 0.0-17.8 mm), spelt 4.9 mm (-7.6 to 9.4 mm), emmer 11.0 mm (0.0-21.3 mm), P = 0.267; SF bread wheat 10.5 mm (-3.1 to 31.5 mm), spelt 11.3 mm (0.0-15.3 mm), emmer 4.0 mm (-2.9 to 9.3 mm), P = 0.144]. The number of responders was also comparable for both YF (6 to wheat, 5 to spelt, and 7 to emmer, P = 0.761) and SF breads (9 to wheat, 7 to spelt, and 8 to emmer, P = 0.761). CONCLUSIONS: The majority of NCWS individuals experienced some GI symptoms for ≥1 of the breads, but on a group level, no differences were found between different grains for either YF or SF breads. CLINICAL TRIAL REGISTRY: clinicaltrials.gov, NCT04084470 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT04084470).

The effect of expectancy versus actual gluten intake on gastrointestinal and extra-intestinal symptoms in non-coeliac gluten sensitivity: a randomised, double-blind, placebo-controlled, international, multicentre study.

BACKGROUND: Many individuals without coeliac disease or wheat allergy reduce their gluten intake because they believe that gluten causes their gastrointestinal symptoms. Symptoms could be affected by negative expectancy. Therefore, we aimed to investigate the effects of expectancy versus actual gluten intake on symptoms in people with non-coeliac gluten sensitivity (NCGS). METHODS: This randomised, double-blind, placebo-controlled, international, multicentre study was done at the University of Leeds (Leeds, UK), Maastricht University (Maastricht, the Netherlands), and Wageningen University and Research (Wageningen, the Netherlands). People aged 18-70 years with self-reported NCGS (ie, gastrointestinal symptoms within 8 h of gluten consumption) without coeliac disease and wheat allergy were recruited. Participants had to follow a gluten-free or gluten-restricted diet for at least 1 week before (and throughout) study participation and had to be asymptomatic or mildly symptomatic (overall gastrointestinal symptom score ≤30 mm on the Visual Analogue Scale [VAS]) while on the diet. Participants were randomly assigned (1:1:1:1; blocks of eight; stratified by site and gender) to one of four groups based on the expectation to consume gluten-containing (E+) or gluten-free (E-) oat bread for breakfast and lunch (two slices each) and actual intake of gluten-containing (G+) or gluten-free (G-) oat bread. Participants, investigators, and those assessing outcomes were masked to the actual gluten assignment, and participants were also masked to the expectancy part of the study. The primary outcome was overall gastrointestinal symptom score on the VAS, which was measured at and corrected for baseline (before breakfast) and hourly for 8 h, with lunch served after 4 h, and analysed per-protocol. Safety analysis included all participants incorporated in the per-protocol analysis. The study is registered at ClinicalTrials.gov, NCT05779358, and has ended. FINDINGS: Between Oct 19, 2018, and Feb 14, 2022, 165 people were screened and 84 were randomly assigned to E+G+ (n=21), E+G- (n=21), E-G+ (n=20), or E-G- (n=22). One person in the E+G+ group was excluded due to not following test day instructions, leaving 83 participants in the per-protocol analysis. Median age was 27·0 years (IQR 21·0-45·0), 71 (86%) of 83 people were women, and 12 (14%) were men. Mean overall gastrointestinal symptom score was significantly higher for E+G+ (16·6 mm [95% CI 13·1 to 20·0]) than for E-G+ (6·9 mm [3·5 to 10·4]; difference 9·6 mm [95% CI 3·0 to 16·2], p=0·0010) and E-G- (7·4 mm [4·2 to 10·7]; difference 9·1 mm [2·7 to 15·6], p=0·0016), but not for E+G- (11·7 mm [8·3 to 15·1]; difference 4·9 mm [-1·7 to 11·5], p=0·28). There was no difference between E+G- and E-G+ (difference 4·7 mm [-1·8 to 11·3], p=0·33), E+G- and E-G- (difference 4·2 mm [-2·2 to 10·7], p=0·47), and E-G+ and E-G- (difference -0·5 mm [-7·0 to 5·9], p=1·0). Adverse events were reported by two participants in the E+G- group (itching jaw [n=1]; feeling lightheaded and stomach rumbling [n=1]) and one participant in the E-G+ group (vomiting). INTERPRETATION: The combination of expectancy and actual gluten intake had the largest effect on gastrointestinal symptoms, reflecting a nocebo effect, although an additional effect of gluten cannot be ruled out. Our results necessitate further research into the possible involvement of the gut-brain interaction in NCGS. FUNDING: Government of the Netherlands Topsector Agri & Food Top Consortium for Knowledge and Innovation, AB Mauri Global Bakery Ingredients, Baking Industry Research Trust, Borgesius-Albert Heijn, CSM Innovation Centre, the International Maize and Wheat Improvement Center (CIMMYT), DSM Food Specialties, Fazer, Healthgrain Forum, the International Association for Cereal Science and Technology, the International Wheat Gluten Association, Lantmännen, Mondelez International, Nederlands Bakkerij Centrum, Nutrition & Santé, Puratos, Rademaker, Sonneveld Group, and Zeelandia HJ Doeleman.

Corrigendum: Diet associations in endometriosis: a critical narrative assessment with special reference to gluten.

[This corrects the article DOI: 10.3389/fnut.2023.1166929.].

Diet associations in endometriosis: a critical narrative assessment with special reference to gluten.

Endometriosis is characterized by the presence of endometrium-like tissue outside the uterus. The etiology remains largely unknown. Despite adequate treatment, patients can still experience symptoms or side effects resulting in therapy incompliance and in self-management strategies such as dietary measures is increasing. A gluten free diet is thought to be contributory in reducing endometriosis-related pain, thereby optimizing quality of life. However, data is conflicting and currently provides no evidence for causality. This narrative review aims to put the effect of dietary self-management strategies on endometriosis in a balanced perspective, especially the effect of gluten and a gluten free diet. Several studies have found a strong overlap in symptoms, metabolic and immune responses associated with endometriosis and those associated with celiac disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome and non-celiac wheat sensitivity. However, it remains unclear whether these diseases and/or disorders are causal to an increased risk of endometriosis. Some studies have found a positive effect on the risk of endometriosis, endometriosis-related symptoms and quality of life (QoL) when women either avoided certain nutrients or foods, or applied a specific nutrient supplementation. This includes the avoidance of red meat, an increasing intake of foods rich in anti-oxidants, omega-3, micronutrients and dietary fibers (e.g., fruit, vegetables) and the appliance of a gluten free diet. However, data from the available studies were generally graded of low quality and it was noted that placebo and/or nocebo effects influenced the reported positive effects. In addition, such effects were no longer seen when adjusting for confounders such as overweight, when a translation was made from in vitro to in vivo, or when the nutrients were not supplemented as isolated sources but as part of a mixed daily diet. Finally, some studies showed that long-term adherence to a gluten free diet is often associated with an impaired diet quality and nutrient intake, leading to negative health outcomes and reduced QoL. Concluding, scientific evidence on the efficacy of dietary interventions on well-defined clinical endpoints of endometriosis is lacking and recommending a gluten free diet to women solely diagnosed with endometriosis should therefore not be advised.

Does sourdough bread provide clinically relevant health benefits?

During the last decade, scientific interest in and consumer attention to sourdough fermentation in bread making has increased. On the one hand, this technology may favorably impact product quality, including flavor and shelf-life of bakery products; on the other hand, some cereal components, especially in wheat and rye, which are known to cause adverse reactions in a small subset of the population, can be partially modified or degraded. The latter potentially reduces their harmful effects, but depends strongly on the composition of sourdough microbiota, processing conditions and the resulting acidification. Tolerability, nutritional composition, potential health effects and consumer acceptance of sourdough bread are often suggested to be superior compared to yeast-leavened bread. However, the advantages of sourdough fermentation claimed in many publications rely mostly on data from chemical and in vitro analyzes, which raises questions about the actual impact on human nutrition. This review focuses on grain components, which may cause adverse effects in humans and the effect of sourdough microbiota on their structure, quantity and biological properties. Furthermore, presumed benefits of secondary metabolites and reduction of contaminants are discussed. The benefits claimed deriving from in vitro and in vivo experiments will be evaluated across a broader spectrum in terms of clinically relevant effects on human health. Accordingly, this critical review aims to contribute to a better understanding of the extent to which sourdough bread may result in measurable health benefits in humans.

Comparative compositions of grain of tritordeum, durum wheat and bread wheat grown in multi-environment trials.

Three genotypes each of bread wheat, durum wheat and tritordeum were grown in randomized replicated field trials in Andalusia (Spain) for two years and wholemeal flours analysed for a range of components to identify differences in composition. The contents of all components that were determined varied widely between grain samples of the individual species and in most cases also overlapped between the three species. Nevertheless, statistically significant differences between the compositions of the three species were observed. Notably, tritordeum had significantly higher contents of protein, some minerals (magnesium and iron), total phenolics and methyl donors. Tritordeum also had higher levels of total amino acids (but not asparagine) and total sugars, including raffinose. By contrast, bread wheat and tritordeum had similar contents of the two major dietary fibre components in white flour, arabinoxylan and ß-glucan, with significantly lower contents in durum wheat.

Comparative Compositions of Grain of Bread Wheat, Emmer and Spelt Grown with Different Levels of Nitrogen Fertilisation.

Five cultivars of bread wheat and spelt and three of emmer were grown in replicate randomised field trials on two sites for two years with 100 and 200 kg nitrogen fertiliser per hectare, reflecting low input and intensive farming systems. Wholemeal flours were analysed for components that are suggested to contribute to a healthy diet. The ranges of all components overlapped between the three cereal types, reflecting the effects of both genotype and environment. Nevertheless, statistically significant differences in the contents of some components were observed. Notably, emmer and spelt had higher contents of protein, iron, zinc, magnesium, choline and glycine betaine, but also of asparagine (the precursor of acrylamide) and raffinose. By contrast, bread wheat had higher contents of the two major types of fibre, arabinoxylan (AX) and ß-glucan, than emmer and a higher AX content than spelt. Although such differences in composition may be suggested to result in effects on metabolic parameters and health when studied in isolation, the final effects will depend on the quantity consumed and the composition of the overall diet.

Do gluten peptides stimulate weight gain in humans?

Observations from animal and in vitro laboratory research, and anecdotal evidence, have led to the suggestion that gluten consumption stimulates weight gain by the presence of peptides expressing opioid activity. Another proposed mechanism is that gluten peptides decrease resting energy expenditure resulting in a positive energy balance. In order to induce such effects in vivo, intact food peptides must be absorbed in sufficient quantities, remain intact in the blood for sufficient time to have long-lasting biological activity and bind to receptors involved in appetite, satiety and energy regulation. However, although peptides from food may pass from the intestine into the blood in extremely low quantities, they are generally rapidly degraded by plasma and vasculum-bound aminopeptidases, resulting in very short half-lives and loss of bioactivity. At present, gluten peptide sequences that influence regulators of energy metabolism have not been identified. Furthermore, data on the quantitative absorption of gluten peptides in the blood stream, their stability and lasting bioactivity are also lacking. Therefore, there is no evidence for proposed effects on driving appetite by the brain, nor on energy expenditure and weight gain. Furthermore, the level of overweight observed in various countries appears to be independent of the level of wheat consumption, and abundant observational evidence in humans shows that the levels of gluten consumption are neither related to daily calorie intake nor to BMI. This narrative review therefore discusses the proposed effects of gluten on bodyweight (BW) and putative biological mechanisms in the light of the current evidence.

Do ancient wheats contain less gluten than modern bread wheat, in favour of better health?

Popular media messaging has led to increased public perception that gluten-containing foods are bad for health. In parallel, 'ancient grains' have been promoted with claims that they contain less gluten. There appears to be no clear definition of 'ancient grains' but the term usually includes einkorn, emmer, spelt and Khorasan wheat. Gluten is present in all wheat grains and all can induce coeliac disease (CD) in genetically susceptible individuals. Analyses of 'ancient' and 'modern' wheats show that the protein content of modern bread wheat (Triticum aestivum) has decreased over time while the starch content increased. In addition, it was shown that, compared to bread wheat, ancient wheats contain more protein and gluten and greater contents of many CD-active epitopes. Consequently, no single wheat type can be recommended as better for reducing the risks of or mitigating the severity of CD. An estimated 10% of the population of Western countries suffers from gastrointestinal symptoms that lack a clear organic cause and is often referred to as irritable bowel syndrome (IBS). Many of these patients consider themselves gluten sensitive, but in most cases this is not confirmed when tested in a medical setting. Instead, it may be caused by gas formation due to fermentation of fructans present in wheat or, in some patients, effects of non-gluten proteins. A significant overlap of symptoms with those of CD, IBS and inflammatory bowel disease makes a medical diagnosis a priority. This critical narrative review examines the suggestion that 'ancient' wheat types are preferred for health and better tolerance.

Wheat amylase/trypsin inhibitors (ATIs): occurrence, function and health aspects.

Amylase/trypsin inhibitors (ATIs) are widely consumed in cereal-based foods and have been implicated in adverse reactions to wheat exposure, such as respiratory and food allergy, and intestinal responses associated with coeliac disease and non-coeliac wheat sensitivity. ATIs occur in multiple isoforms which differ in the amounts present in different types of wheat (including ancient and modern ones). Measuring ATIs and their isoforms is an analytical challenge as is their isolation for use in studies addressing their potential effects on the human body. ATI isoforms differ in their spectrum of bioactive effects in the human gastrointestinal (GI), which may include enzyme inhibition, inflammation and immune responses and of which much is not known. Similarly, although modifications during food processing (exposure to heat, moisture, salt, acid, fermentation) may affect their structure and activity as shown in vitro, it is important to relate these changes to effects that may present in the GI tract. Finally, much of our knowledge of their potential biological effects is based on studies in vitro and in animal models. Validation by human studies using processed foods as commonly consumed is warranted. We conclude that more detailed understanding of these factors may allow the effects of ATIs on human health to be better understood and when possible, to be ameliorated, for example by innovative food processing. We therefore review in short our current knowledge of these proteins, focusing on features which relate to their biological activity and identifying gaps in our knowledge and research priorities.

Comparative compositions of metabolites and dietary fibre components in doughs and breads produced from bread wheat, emmer and spelt and using yeast and sourdough processes.

Wholemeal flours from blends of bread wheat, emmer and spelt were processed into bread using yeast-based and sourdough fermentation. The bread wheat flour contained significantly higher concentrations of total dietary fibre and fructans than the spelt and emmer flours, the latter having the lowest contents. Breadmaking using sourdough and yeast systems resulted in changes in composition from flour to dough to bread including increases in organic acids and mannitol in the sourdough system and increases in amino acids and sugars (released by hydrolysis of proteins and starch, respectively) in both processing systems. The concentrations of fructans and raffinose (the major endogenous FODMAPs) were reduced by yeast and sourdough fermentation, with yeast having the greater effect. Both systems resulted in greater increases in sugars and glycerol in emmer than in bread wheat and spelt, but the significance of these differences for human health has not been established.

Wheat ATIs: Characteristics and Role in Human Disease.

Amylase/trypsin-inhibitors (ATIs) comprise about 2-4% of the total wheat grain proteins and may contribute to natural defense against pests and pathogens. However, they are currently among the most widely studied wheat components because of their proposed role in adverse reactions to wheat consumption in humans. ATIs have long been known to contribute to IgE-mediated allergy (notably Bakers' asthma), but interest has increased since 2012 when they were shown to be able to trigger the innate immune system, with attention focused on their role in coeliac disease which affects about 1% of the population and, more recently, in non-coeliac wheat sensitivity which may affect up to 10% of the population. This has led to studies of their structure, inhibitory properties, genetics, control of expression, behavior during processing, effects on human adverse reactions to wheat and, most recently, strategies to modify their expression in the plant using gene editing. We therefore present an integrated account of this range of research, identifying inconsistencies, and gaps in our knowledge and identifying future research needs. Note  This paper is the outcome of an invited international ATI expert meeting held in Amsterdam, February 3-5 2020.

Phytic Acid and Whole Grains for Health Controversy.

Phytate (PA) serves as a phosphate storage molecule in cereals and other plant foods. In food and in the human body, PA has a high affinity to chelate Zn2+ and Fe2+, Mg2+, Ca2+, K+, Mn2+ and Cu2+. As a consequence, minerals chelated in PA are not bio-available, which is a concern for public health in conditions of poor food availability and low mineral intakes, ultimately leading to an impaired micronutrient status, growth, development and increased mortality. For low-income countries this has resulted in communications on how to reduce the content of PA in food, by appropriate at home food processing. However, claims that a reduction in PA in food by processing per definition leads to a measurable improvement in mineral status and that the consumption of grains rich in PA impairs mineral status requires nuance. Frequently observed decreases of PA and increases in soluble minerals in in vitro food digestion (increased bio-accessibility) are used to promote food benefits. However, these do not necessarily translate into an increased bioavailability and mineral status in vivo. In vitro essays have limitations, such as the absence of blood flow, hormonal responses, neural regulation, gut epithelium associated factors and the presence of microbiota, which mutually influence the in vivo effects and should be considered. In Western countries, increased consumption of whole grain foods is associated with improved health outcomes, which does not justify advice to refrain from grain-based foods because they contain PA. The present commentary aims to clarify these seemingly controversial aspects.

Saccharide Characteristics and Their Potential Health Effects in Perspective.

To understand the effects of saccharides on our metabolism and health, we need a clear understanding of what they are, how they differ, and why some types are deemed "less healthy" and others "better for health." There are various ways to look at this topic. Firstly, saccharides can be classified according to their degree of polymerization (DP). This classification is useful when qualitative or quantitative analysis and calculation of intakes are required or for food-labeling definitions. However, it does not account for the fact that saccharides with a similar DP can differ in molecular composition, which will influence digestion, absorption, and metabolism. Secondly, another approach widely used in the biomedical and nutritional sciences is therefore a physiological classification, which addresses the rate and degree of digestibility and absorption, the glycemic response, and the metabolic fate. The individual health status also plays a role in this respect. An active, lean person will have a metabolic response that differs from an inactive person with overweight and insulin resistance. However, this approach will not give a complete answer either because the characteristics of the matrix/meal in which these carbohydrates (CHOs) are present will also influence the responses of our body. Thirdly, one can also rank CHOs by comparing their functional/technological properties, such as relative sweetness, viscosity, and solubility. Understanding CHO characteristics and related physiological responses will help understand health and disease implications. Therefore, a brief outline of different carbohydrate classifications is presented. This outline will be placed in the context of potential overall effects after consumption. The answer to the question whether we should we eat less of certain sugars depends on the angle from which you look at this matter; for example, do you address this question from a single molecular characteristic point of view or from a meal quality perspective? Looking at one particular CHO characteristic will almost always lead to a different conclusion (e.g., the labeling of fructose as toxic) than evaluating from a "total perspective" (fructose has adverse effects in certain conditions). Examples are given to help understand this matter for the benefit of justified dietary/food-based recommendations.

Use of nutritional information: analysing clusters of consumers who intend to eat healthily.

Consumers intending to eat healthily should consult available information on the energy, salt, sugar and saturated fat content of foods. Some consumers, however, do this more than others do. The objective of this research was to identify distinct subgroups within the group of consumers who intend to eat healthily, segmented according to the timing and frequency of their use of information about energy, salt, sugar and saturated fat. Furthermore, we analysed whether consulting this information actually led to healthier food choices. Data on use of specific nutritional information in a computerised task in which participants made multiple dichotomous food choices (e.g. high-fat v. low-fat cheese) were recorded from 240 participants using process tracing software. Participants could view nutritional information by hovering the mouse over specific areas of the screen. We found three clusters of participants based on use of information about energy, salt, sugar and saturated fat: low, medium and high information users. There was a between-clusters difference in how often the healthy option was chosen (88·95 % with high information v. 67·17 % with low information usage). Presence in the medium and high information clusters was partially predicted by perceived self-efficacy in making healthy choices. It appears that some consumers are very confident of their ability to make healthy choices, which is a reason for making less use of nutritional information prior to making food choices and may result in unhealthy choices. Our findings improve understanding of the conditions needed to develop effective interventions targeted at health-conscious consumers.

Correction to: Overweight and diabetes prevention: is a low-carbohydrate-high-fat diet recommendable?

In the original publication, the disclosure of potential conflicts of interest statement was not correct.

Adverse Reactions to Wheat or Wheat Components.

Wheat is an important staple food globally, providing a significant contribution to daily energy, fiber, and micronutrient intake. Observational evidence for health impacts of consuming more whole grains, among which wheat is a major contributor, points to significant risk reduction for diabetes, cardiovascular disease, and colon cancer. However, specific wheat components may also elicit adverse physical reactions in susceptible individuals such as celiac disease (CD) and wheat allergy (WA). Recently, broad coverage in the popular and social media has suggested that wheat consumption leads to a wide range of adverse health effects. This has motivated many consumers to avoid or reduce their consumption of foods that contain wheat/gluten, despite the absence of diagnosed CD or WA, raising questions about underlying mechanisms and possible nocebo effects. However, recent studies did show that some individuals may suffer from adverse reactions in absence of CD and WA. This condition is called non-celiac gluten sensitivity (NCGS) or non-celiac wheat sensitivity (NCWS). In addition to gluten, wheat and derived products contain many other components which may trigger symptoms, including inhibitors of α-amylase and trypsin (ATIs), lectins, and rapidly fermentable carbohydrates (FODMAPs). Furthermore, the way in which foods are being processed, such as the use of yeast or sourdough fermentation, fermentation time and baking conditions, may also affect the presence and bioactivity of these components. The present review systematically describes the characteristics of wheat-related intolerances, including their etiology, prevalence, the components responsible, diagnosis, and strategies to reduce adverse reactions.

Wheat Seed Proteins: Factors Influencing Their Content, Composition, and Technological Properties, and Strategies to Reduce Adverse Reactions.

Wheat is the primary source of nutrition for many, especially those living in developing countries, and wheat proteins are among the most widely consumed dietary proteins in the world. However, concerns about disorders related to the consumption of wheat and/or wheat gluten proteins have increased sharply in the last 20 years. This review focuses on wheat gluten proteins and amylase trypsin inhibitors, which are considered to be responsible for eliciting most of the intestinal and extraintestinal symptoms experienced by susceptible individuals. Although several approaches have been proposed to reduce the exposure to gluten or immunogenic peptides resulting from its digestion, none have proven sufficiently effective for general use in coeliac-safe diets. Potential approaches to manipulate the content, composition, and technological properties of wheat proteins are therefore discussed, as well as the effects of using gluten isolates in various food systems. Finally, some aspects of the use of gluten-free commodities are discussed.