Wheat-based foods and non celiac gluten/wheat sensitivity: is drastic processing the main key issue?

Accepted Manuscript

Wheat-based foods and non celiac gluten/wheat sensitivity: is drastic processingthe main key issue?

Anthony Fardet

PII: S0306-9877(15)00340-0DOI: http://dx.doi.org/10.1016/j.mehy.2015.09.007Reference: YMEHY 8042

To appear in: Medical Hypotheses

Received Date: 17 May 2015Accepted Date: 4 September 2015

Please cite this article as: A. Fardet, Wheat-based foods and non celiac gluten/wheat sensitivity: is drastic processingthe main key issue?, Medical Hypotheses (2015), doi: http://dx.doi.org/10.1016/j.mehy.2015.09.007

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Wheat-based foods and non celiac gluten/wheat sensitivity: is drastic processing the

main key issue?

Anthony FARDET

INRA, UMR 1019, UNH, CRNH Auvergne, F-63000 CLERMONT-FERRAND & Clermont

Université, Université d'Auvergne, Unité de Nutrition Humaine, BP 10448, F-63000

CLERMONT-FERRAND, France

Tel. +33 (0)4 73 62 47 04; Fax: +33 (0)4 73 62 47 55; e-mail address:

[email protected]

Abbreviations

FODMAPs, fermentable, oligo-, di-, monosaccharides, and polyols

NCWGS, non-coeliac wheat/gluten sensitivity

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Abstract

While gluten and wheat must be absolutely avoided in coeliac disease and allergy,

respectively, nutritional recommendations are largely more confused about non-coeliac

wheat/gluten sensitivity (NCWGS). Today, some even recommend avoiding all cereal-based

foods. In this paper, the increased NCWGS prevalence is hypothesized to parallel the use of

more and more drastic processes applied to the original wheat grain. First, a parallel between

gluten-related disorders and wheat processing and consumption evolution is briefly proposed.

Notably, increased use of exogenous vital gluten is considered. Drastic processing in wheat

technology are mainly grain fractionation and refining followed by recombination and salt,

sugars and fats addition, being able to render ultra-processed cereal-based foods more prone

to trigger chronic low-grade inflammation. Concerning bread, intensive kneading and the

choice of wheat varieties with high baking quality may have rendered gluten less digestible,

moving digestion from pancreatic to intestinal proteases. The hypothesis of a gluten resistant

fraction reaching colon and interacting with microflora is also considered in relation with

increased inflammation. Besides, wheat flour refining removes fibre co-passenger which have

potential anti-inflammatory property able to protect digestive epithelium. Finally, some

research tracks are proposed, notably the comparison of NCWGS prevalence in populations

consuming ultra- versus minimally-processed cereal-based foods.

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Introduction: Position of the debate

Gluten is the protein fraction coming from Triticum species (wheat, rye and barley) or

from their crossbred varieties and of their derivatives, which is insoluble in water and in a

solution of 0.5M sodium chloride, and to which some people are intolerant.

Wheat/gluten-related disorders gather auto-immune diseases (coeliac disease, gluten

ataxia and dermatitis herpetiformis), allergies (respiratory allergy, food allergy, wheat-

dependent exercise-induced anaphylaxis, and atopic dermatitis and urticarial), and unknown

diseases like non-coeliac wheat/gluten sensitivity (NCWGS) [1].

The NCWGS is indeed not well-known and has poorly characterized symptoms, and

that are closed to those of celiac disease: digestive disorders coupled to headaches, muscle

and/or joint pains, depression… The diagnostic is most of the time made by elimination: this

is not an allergy and not a celiac disease. Today, some gastroenterologists propose to adopt a

gluten-free diet for three months then progressively reintroducing gluten to determine gluten

tolerance threshold, different for each patient.

While gluten and wheat must be absolutely avoided in coeliac disease and allergy,

respectively, nutritional recommendations are largely more confused about NCWGS. Indeed,

it seems that these symptoms would not be alleviated by only removing gluten from diet. As

stated by Catassi et al.: “Recent studies raised the possibility that, beside gluten [2] and wheat

amylase trypsin inhibitor [3], low-fermentable, poorly-absorbed, short-chain carbohydrates

[4] can contribute to symptoms (at least those related to irritable bowel syndrome)

experienced by NCWGS patients” (page 3841) [5].

In parallel to the increasing prevalence of people hypersensitive to gluten has raised a

recent debate about wheat and related disorders, and whose one of the main conclusion would

be that wheat protein would be responsible for wheat-related disorders and systemic low-

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grade inflammation [6]. As a consequence, wheat should be avoided from our diets and would

be responsible for, not only wheat/gluten-related disorders, but also for Western non

communicable diet-related chronic diseases raising prevalence, i.e., type 2 diabetes,

cardiovascular diseases and some cancers. This idea is based on the main argument that our

genetic background is not adapted to cereal products, especially wheat, that are quite recent

staple foods for humanity - being first cultivated with first settlements around 11,000 years

ago and concomitant with the Agricultural Revolution [7]. Our genetic background would be

more adapted to the Paleolithic diet - in contact of which we were for around 2 million years -

and that is characterized by wild animals, roots, tubers, berries and wild fruits, nuts and seeds,

and honey occasionally [7]. To summarize, according to these authors, one of the reason for

wheat/gluten-related disorders raising prevalence would be partly linked to the maladjustment

of our genetic background to wheat-based foods, and more generally cereal grains.

Such information - that cereal grains must be deleted from our diet - is importantly

relayed by various media, notably numerous internet websites, leading more and more people

to consume gluten-free cereal-based foods, even when they have no declared pathologies or

symptoms.

However, in a recent position paper, Kasarda convincingly demonstrates - in response

to the suggestion that an increase in the incidence of celiac disease might be attributable to an

increase in the gluten content of wheat resulting from wheat breeding - that the results do not

support the likelihood that wheat breeding has increased the protein content (proportional to

gluten content) of wheat in the United States [8]. Rather, the author interestingly hypothesized

that the increased use of vital gluten as a food additive in more and more products may be one

of the explanations, among others, for the increasing prevalence of gluten-related disorders. In

other words, he suggests that problem might be in processing rather that in the raw natural

and original wheat grain itself.

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In this position paper, it is therefore hypothesized that the increased NCWGS

prevalence may be linked to the use of more and more drastic technological processes applied

to the original wheat grain: in particular, high refining, leading to losses of antioxidants and

anti-inflammatory compounds, together with added potentially inflammatory ingredients such

as sugars and fats may contribute to chronic low-grade systemic inflammation. Besides, the

combination of both the use of more and more vital gluten in cereal-based foods and drastic

processes, that could render gluten less digestible, might also be partly responsible.

This leads to reformulate the question in a different way: has the evolution of gluten-

related disorders paralleled that of overall wheat-based food consumption or, more

specifically, that of „ultra-processed‟ wheat-based products? To address such an issue, it

would be interesting to assess what is the prevalence of gluten-related disorders in countries

where wheat is only minimally processed, e.g., pre-fermented, compared to countries in

which wheat is mainly highly refined and ultra-processed. Unfortunately, such data are

lacking.

Non-coeliac wheat/gluten sensitivity, wheat processing and consumption: is

there a parallel?

The evolution of non-coeliac wheat/gluten sensitivity

Non-coeliac wheat/gluten sensitivity has been first described in 1978 - therefore quite

recently - with a case report suffering from diarrhea and intermittent abdominal pain, without

abnormalities on biopsy and with improvement on a gluten-free diet [9]. If NCWGS has been

first attributed to gluten, fermentable, oligo-, di-, monosaccharides, and polyols (FODMAPs)

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are today involved as potential trigerring agents [4]. It is therefore still unclear whether gluten

or other factors are involved in NCWGS [10].

Besides celiac disease, NCWGS is today gaining more and more attention [11].

However, overall NCWGS prevalence is till unkonw because of self-diagnostic and starting

of a gluten-free diet without medical advice or consultation [5]. In the absence of a clear

diagnostic, NCWGS is negatively defined as a condition characterized by gastrointestinal or

extraintestinal symptoms that respond to gluten withdrawal without evidence for underlying

celiac disease or wheat allergy [11].

The evolution of wheat processing: Paleolithic versus Western diets or natural/minimally- vs

ultra-processed foods?

Following the first settlements by humanity around 11,000 years ago, new staple foods

began to be consumed, such as nonhuman milk and grain (i.e., legumes and cereals) products,

other cultivated plant foods, and domesticated meats; then very latter food isolated ingredients

such as fructose syrup, sucrose, plant oils, and alcoholic beverages [7]. In the same time, the

well-known Paleolithic diet began to be less predominant.

All these new foods have therefore to be linked to the control of the food production at

a wider scale. The cultivated grains notably allowed populations to dramatically grow up

because grains are both energetic and nutrient-dense; a mix necessary for the growing of more

and more sedentary populations. In addition, it was a cheap source of diet: indeed, people at

this time have probably rapidly understood that with only one grain, it was quite easy to

obtain several-fold more grains!

First, these foods in relation with settlement were minimally processed. However, with

the occurrence of the nutritional transition and Industrial Revolution around one century ago,

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natural foods begins to be more and more processed [12]; and today, transformations are

become so drastic that ultra-processed products has become dominant in our diet. Globally,

ultra-processed foods are defined as products made of refined and isolated ingredients then

recombined with generally added salt, sugars and fats [13]. Some of these products (e.g.,

sodas) are also qualified by some authors as empty calories-containing foods [14,15].

As stated by the defenders of the Paleolithic diet, our genetic background is not really

adapted to these severe diet transformations that remain quite recent as regards with the origin

of humanity, i.e., more than 2,000,000 years ago. So, according to them, it is therefore not

surprising that we have developed in the same time more and more diet-related chronic

diseases. Notably, gluten-related disorders would be attributed to these changes: our organism

and digestive physiology is not adapted to cereal grains, specifically wheat-based foods [7].

In addition to refining, among drastic and less natural processes applied to wheat, one

can also cite higher kneading intensities for bread baking, the use of baking powder instead of

leaven, the increased use of extrusion-cooking at high temperature, the increased use of

additives (vital gluten, vitamin C…), and the addition of added fat, sugar and salt. For

example, Cabrera-Chavez et al. hypothesized that “traditional long fermentations in

sourdough systems have been almost totally replaced by the use of leavening agents in very

fast processes. These could result in gluten proteins remaining largely intact and their peptides

immunogenic for celiac disease sufferers [16]” (page 338) [17].

Otherwise, the use of transglutaminases for technological purposes in food processing

to cross-link proteins may also increase epitopes in gluten proteins - gluten peptides that

trigger celiac disease being preferred substrates for transglutaminases [17].

Finally, in its recent position paper, Kasarda interestingly approximatively calculated

that the intake of vital gluten (i.e., „exogenous‟ gluten used in many foods to confer properties

such as emulsification, cohesiveness, viscoelasticity, gelation and foaming) has tripled since

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1977, from 136 to 408 g/person/year [8]. He added that “This increase is of interest because it

is in the time frame that fits with the predictions of an increase in celiac disease” and “It may

be noted that whole wheat products, which are increasing in consumption for health reasons

(especially the higher fiber content), often have vital gluten added to them to compensate for

the negative effects of the ground whole grain on quality factors, such as loaf volume in

breadmaking” (page 1158) [8].

Cereal-based food consumption and disease risk

Cereals continue to be a major source of dietary energy supply around the world.

Thus, worldwide consumption of cereals rose from 128 to 147 kg/person/year between 1961

and 2009 [18]. One of the main tendencies is the shift towards the consumption of ultra-

processed products, especially refined cereals. For example, in Mexico, between 1988 and

1999, changes in food consumption concerns the development of the consumption of ultra-

processed foods and soft drinks as well as the decline of the traditional diet based on grains.

Consumption of fruits and vegetables fell sharply (-29%), as the consumption of cereals and

tortilla (divided by 2), while consumption of refined carbohydrates has increased (+ 6%) and

consumption of sodas increased sharply (+ 37%) [19,20]. And in India, almost 85% of the

food consumed are processed (cereal flour, bread, polished rice, and fermented milk) [21].

More generally, urbanisation processes bring rural migrants to cities where they tend to

abandon their traditional, rural diets rich in cereals, grains, and fibres.

This increased consumption of ultra-processed products, notably refined cereals, has

been demonstrated to be convincingly accompanied by an increased prevalence of diet-related

chronic disease [13,22-24]. From a nutritional perspective, it therefore seems that the real

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issue is not the cereals as such, or more generally the grain products, but rather the way they

have been transformed for the best or for the worst [25,26].

More generally, some authors today hypothesize that overall cereal-based foods are

implicated in systemic low-grad and chronic inflammation, further leading to more serious

chronic diseases [6]. Thus, in 2013, de Punder and Pruimboom discuss evidence from in vitro,

animal and human intervention studies that may support the fact that the consumption of

wheat, but also other cereal grains, can contribute to the manifestation of chronic

inflammation and autoimmune diseases by increasing intestinal permeability and initiating a

pro-inflammatory immune response [6].

Concerning the role of the Western diet or lifestyle in chronic inflammation, another

hypothesis has been advanced to explain autoimmune disease [27]. It is based on the

assumption that insufficient intake of healthy foodstuffs adversely affects the production of

bacterial metabolites, these latter being involved in controlling various immune pathways

[27].

Yet, most recent comprehensive reviews report beneficial effect of whole-grain cereals

in epidemiological studies as compared to refined cereals [28]. Notably, based on a reviewing

of all meta-analyses and systematic reviews about food groups versus chronic diseases

association, we recently showed that highest whole-grain cereal consumption is either

protective or not associated with diet-related chronic disease risk, and may significantly

reduce type 2 diabetes, CVD and cancer risks by maximum of 27, 29 and 59%, respectively

[29]. On the contrary, highest refined cereal consumption is either not associated or

deleterious toward diet-related chronic disease risk risk, with maximum of +40% increased

risk for type 2 diabetes vs white rice [29]. Again - unless positive associations between

whole-grain cereals and chronic diseases risk have not been published for an unknown reason

- it seems that such results strongly prove that the problem would not be with cereals as such,

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but rather with the intensity of transformations. For example, while high level of white rice

consumption may increase type 2 diabetes risk, high level of brown rice significantly

decreases it [30].

The hypothesis of increased NCWGS prevalence due to ultra-processing:

some possible explanations

At this point, a question arises: do the increase in diet-related chronic diseases due to a

maladaptation of our genome or may it be attributed to too drastic food transformation that

notably occurred during this last century in our Western countries? In other words, the

question is whether increased chronic disease prevalence including gluten-related disorders is

due to original foods as such (e.g., cow milk, grains, and livestock meat) or to the way we

have transformed them? For example, is milk to be blamed or its transformation in numerous

derived products? The same question is true for minimally-processed versus ultra-processed

grains, normal processed meat versus highly transformed meat (e.g., delicatessen, etc.), or -

more generally - recombined foods from culinary ingredients versus whole complex and

natural foods?

Therefore, the apparent toxicity of wheat-based foods, especially in NCWGS, would

not be due to wheat as such but to the nature of the applied technological processes (our

summarized hypothesis is presented in Figure 1). In this section, the hypothesis that cereal

grains denaturation by drastic processing has rendered gluten unhealthy, toxic and/or not

easily digestible is discussed.

Previous arguments

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The impact of wheat processing methods on wheat sensitivity (including celiac

disease, wheat allergy, NCWGS, fructose malabsorption, and irritable bowel syndrome) has

been recently reviewed [31]. Authors recalled that “modern processing can differ from

traditional methods by (1) using ungerminated grain, (2) replacing long and diverse

fermentation with fast-acting baker‟s yeast (Saccharomyces cerevisiae), (3) using nonacidic

dough, (4) adding extracted wheat proteins and inulin to food products, and (5) focusing on

refined white flour” (page 293-294) [31].

Briefly, traditional methods such as malting, germination, fermentation and acidic

conditions may lead to fewer immunoreactive peptides (translated into lower celiac disease

epitope expression), to hydrolysis of reactive proteins, and to degradation of prolamins via

activation of protease activites from microorganisms or from cereal grains [31]. Then, authors

discussed the potential role of modern industrial processing such as the addition of more and

more vital gluten to processed foods. Then, as they wrote: “Neither vital wheat gluten nor

isolated wheat proteins contain most endogenous wheat enzymes that assist in the degradation

of persistent prolamins. Isolated wheat proteins might also produce de novo allergens” (page

295) [31]. The authors further emphasized that, because most endopeptidase activity was

found in the bran rather than the endosperm, the amount of reactive glutens may change with

the level of flour refinement.

This leads the authors to recommend consuming more germinated grains, and to a

lesser extent fermented products. Deservedly, authors emphasized that “No epidemiological

studies have evaluated the impact of wheat processing on the prevalence in wheat sensitivity

over the last fifty years”, adding that “Nevertheless, increases in disease diagnoses correlate

with food industry uses of compounds that can trigger sensitivity, such as gluten, inulin, and

high fructose corn syrup” (page 296) [31].

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As suggested by Kucek et al., a way to address the role of more or less transformed

cereal products in NCWGS is to search for studies investigating the association between

refined cereal intake and NCWGS prevalence. To say it differently, are there higher

percentages of declared NCWGS subjects in population consuming more refined cereals than

in populations consuming more whole-grain or minimally-processed cereals, e.g., pre-

fermented grains or wholemeal breads? Unfortunately, there is no study having addressed this

issue in human populations.

In addition to the arguments supplied by Kucek et al., other potential explanations are

now proposed to explain the apparently increasing prevalence of NCWGS:

Reducing anti-inflammatory fiber co-passengers?

The concept of fibre co-passengers has been quite recently developped [32]. It

hypothesizes that the slow and continuous release in the gut of the dietary fibre-bound

antioxidants may determine health benefits, notably a protection against constant colonic

mucosal attacks by free radicals produced by microflora. Otherwise, fibre co-passengers have

also anti-inflammatory activity, notably ferulic acid [33].

In refined wheat-based products, anti-inflammatory fibre co-passengers are mainly

removed. Therefore, the repetitive consumption of refined wheat-based foods - generally

added with fats and sugars -, such as in the Western diet, provide both increased inflammatory

food factors and reduced anti-inflammatory food compounds. When chronically consumed

upon a long time, this may participate in a reduced ability of the mucosa to defend itself

against inflammation, and may participate in higher gluten sensitivity, when gluten comes

from highly refined and ultra-processed wheat-based foods.

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A less and less digestible gluten network?

Hypersensitivity to gluten may depend on its molecular nature (which varies according

to the species or varieties of cereals), the food that is vector (bread, pasta) and ultimately its

degradation by proteolytic enzymes before the step of intestinal digestion.

The nature of gluten in modern wheat varieties has changed to increase the baking

quality of the dough, and some glutenin fractions now have very high molecular weights.

These glutenin molecules currently allow obtaining - by kneading - a highly polymerized and

very resistant network, even if the presence of gliadins allows improving extensibility [34].

From a physiological standpoint, the compact and hydrophobic structure of gluten

prolamin, and its high levels in proline and glutamine, makes gluten very resistant to

pancreatic digestion [35], and the alterations associated with gluten kneading could

exacerbate this resistance. So, this is well intestinal enzymes which must finish the „job‟ of

hydrolysis into peptides and amino acids and it is this movement of the pancreatic digest to

the intestinal wall which appears problematic [36].

Therefore, triggering hypersensitivity to wheat gluten could be related to the poor

pancreatic digestibility of all gluten proteins following the selection of wheat and

technological treatments applied to the flour. We can make the assumption that there would

be fewer problems of intolerance to gluten at large if its pancreatic hydrolysis was sufficiently

rapid and complete [8, 36].

The hypothesis of a less digestible gluten network may be illustrated by comparing

bread and pasta: Unlike cooking pasta in boiling water, bread baking in oven, especially if it

is not very hydrated, is not perhaps the best way to facilitate the protein digestibility. The

bread could even induce and stabilize the formation of protein aggregates, thereby increasing

the resistance of potential allergens wheat flour to proteolytic digestion, if one refers to in

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vitro studies [37, 38]. However, we lack of comparative studies on the digestibility of gluten

polymers of different size and comparative digestibility of protein from bread and pasta.

The usual bread kneading promotes the creation of intramolecular bonds, which would

increase the difficulty of pancreatic enzymes to split the gluten, causing the intestinal wall to

take a tough relay. The addition of vitamin C in the current bread and development of

oxidation during mixing and the frequent addition of vital gluten only accentuate this process,

creating a more tenacious gluten network [38]. Theoretically, during bread fermentation,

proteases of the dough may start to hydrolyze the gluten, but this cutting work requires a

considerable drop in pH, which is not found with regular yeast fermentation.

In white bread, pancreatic and intestinal digestion of starch seem very fast, whereas

that of gluten seem much slower. Note that in the pasta, dietary proteins are able to protect the

grain starch, despite the technological processing. Gluten durum wheat is low in high-

molecular-weight glutenin, those involved in the formation of the viscoelastic network of

bread made with wheat flour. Kneading the semolina in the first stage of pasta manufacture

thus only partially modifies the physicochemical properties of proteins, in contrast to what is

observed for the baker's dough. Gluten pasta continues to enshrine the starch grain, which

slows the action of pancreatic amylase and finally obtained a good glycemic index [39].

Although data are lacking, digestive tolerance to gluten might pose fewer problems for pasta

than for bread.

Concerning bread, several studies show that proteolysis is an interesting way to

produce bread or develop new cereal products for the gluten intolerant [16,40,41]. Leaven,

with its flora of lactic acid bacteria is also involved in the destruction of FODMAPs, these

fermentable carbohydrates poorly tolerated in some people with irritable bowel syndrome.

However, it is not certain that we should completely destroy FODMAPs, some having a

prebiotic effect.

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Vital exogenous gluten versus natural endogenous gluten?

Another previously evoked hypothesis for the increase in NCWGS prevalnce may be

found in the excessive use of vital gluten. Such isolated and transformed gluten has lost its

natural food environment generally accompanied with protective phytochemicals naturally

found in whole-grain wheat, e.g., anti-inflammatory compounds. Thus, the apparent

concomitant increase in prevalence of NCWGS in population and in vital gluten consumption

is probably an axis of research to investigate more [8].

Glyphosate content in wheat?

Another argument in favor of the role of wheat transformation or artificial

modification by humans is the potential role of glyphosate, the active ingredient found in the

herbicide Roundup®. Indeed, the increased glyphosate application to wheat from 1990 to

2010 has been observed to be concomitant with both the increased celiac disease incidence

and deaths due to intestinal infection [42].

Thus, although wheat is not specifically mentioned in this study, Krüger et al. showed

in 99 and 41 urine samples collected from humans with conventional or organic diet,

respectively, that glyphosate was significantly higher in urine of humans with conventional

feeding and reported that chronically ill humans showed significantly higher glyphosate

residues in urine than healthy population [43].

Howver, such a hypothesis should be still taken very cautiously due to the lack of

scientific evidence directly in relation with wheat-based food consumption in human

populations.

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Conclusion and perspectives

For a long time, gluten-related disorders were therefore confined solely to celiac

disease that requires the exclusion of all traces of gluten. The intestine of our contemporaries

became more fragile and many people suffer from NCWGS, avoiding eating foods that do not

suit them. The importance of more and more ultra-processed food consumption, the decline in

the consumption of fruit and vegetables, and food hygienism perhaps are not strangers to the

weakening of the intestinal sphere, but obviously this does not explain all.

What conclusions can we draw from this knowledge? First it is not necessary to

maintain this phobia of gluten that led to the development of alternative foods often of poor

quality. There are certainly food preparations that facilitate digestibility and tolerance to

gluten, so are leavened bread and probably pasta or other grain products (bulgour, couscous

...). This issue would deserve to be more studied and well popularized. Although there are

food solutions that appear to be satisfactory, the issue of gluten is far from resolved.

Geneticists ensure that the varieties of modern and ancient wheat all have the same frequency

of allergen epitopes, and this argument is largely taken up by the seed companies to justify the

right direction for their selection, while ignoring the change has gluten in the presence of high

molecular weight glutenin. Although the presence of allergens epitopes is not limited to

modern wheat, NCWGS could be caused by the difficulty of its overall digestion. Clearly we

need a new scientific light on this issue. Furthermore, analysis of the potential impact of

gluten in NCWGS is all the more complicated that wheat and bread may contain FODMAPs

involved in irritable bowel syndrome.

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Otherwise, there are numerous track searches to gain a more thorough insight in the

aetiology of NCWGS and in the way wheat-based foods may trigger it. Among them, the

study of the role played by vital gluten and by the comparison minimally- vs highly-processed

wheat-based food consumption in relation with NCWGS prevalence should be investigated

first.

Finally, if we argue that gluten is rendered more and more resistant to digestion in

humans by drastic processing and therefore that is exist, as for starch, a gluten resistant

fraction that arrives to the colon, another interesting track search would be the role played by

microflora within colon in response to resistant gluten. To say it differently, is NCWGS a

response mediated by the microflora?

Conflict of interest statement

No author has any conflict of interest for any financial and personal relationships with

other people or organizations that could inappropriately influence (bias) their work.

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Figure legends

Figure 1. New hypotheses for explaining non celiac/wheat gluten sensitivity: a focus on the

impact of wheat processing

Figure 1. Wheat grain

Fractionation Refining

Vital gluten

Starch

Bran Germ

Refined flour Fibre

More or less refined wheat flour

Loss of the food structure and gluten environment

Loss of anti-inflammatory/antioxidant phytochemicals and fibre co-passengers

Glyphosphate from herbicide?

Drastic hydrothermal treatments (±high pressure) as in extrusion cooking or puffing, added sugars/fats/salt/gluten/vitamin C, use of yeast,

intensive kneading...

Pro-inflammatory wheat-based products and digestion-resistant

gluten

Non celiac gluten/wheat

sensitivity

?