Treatment

The currently accepted treatment to EoE is similar to other atopic diseases and is based on corticosteroid use and allergen avoidance. To treat EoE, steroid treatment for an IgEmediated food allergy is one convenient approach. Three accepted nutritional strategies can also be used to treat this disease: (1) an elemental diet in which only essential formulas are ingested; (2) avoidance of specific antigens according to allergy testing results and/or diet history; and (3) empiric food elimination of the most common food antigens [187,188]. The adaptation of an EG diet through empiric dietary elimination therapy, consisting of exclusion of common food triggers established for EoE, and very restrictive therapies, consisting of amino acid-based formula ingestion with a few foods, has been tried by pediatric and adult patients, and found to be effective in the majority of pediatric patients [189]. Nevertheless, diet alone is infrequently an effective therapy due to the severity of the symptoms and steroids are necessary to rapidly reduce them. For this reason, the majority of patients are primarily treated with systemic steroids (0.5–1 mg/kg/day for 5–14 days) followed by a gradual decrease over 2–4 weeks [168].

#### *3.4. Non-Celiac Wheat/Gluten Sensitivity*

Non-celiac wheat/gluten sensitivity (NCWGS) makes people experience symptoms similar to CD and WA. However, patients with NCWGS do not have specific IgE against wheat proteins or IgA anti-TG2 autoantibodies. The symptoms develop in a few hours or days after wheat/gluten consumption and include abdominal distension, abdominal pain, diarrhea, gas, among others. Patients also experience extraintestinal symptoms, including headache, fatigue, pain in muscles and joints, and eczema [190]. Recent studies have given rise to the idea that other wheat components, such as oligosaccharides like fructans [191],

α-amylase/trypsin inhibitors [192], and wheat-germ agglutinin [193], may contribute to the development of NCWGS.

The pathogenic mechanisms of NCWGS are far from understood. Preliminary data indicate that activation of innate immunity triggers NCWGS without the involvement of adaptive immunity, which would be a crucial factor in CD development [194–196]. The increased expression of toll-like-receptors (TLRs), a protein class that plays a vital role in innate immunity, in the small intestine is the evidence supporting the hypothesis of the activation of innate immunity in NCWGS. TLR2, TLR1, and TLR4 have been identified in the intestinal mucosa and some cells of the lamina propria of patients with NCWGS [194]. There is diverging information on intestinal permeability in NCWGS. A study conducted in 2011 determined the gu<sup>t</sup> permeability of NCWGS and CD patients using the urine lactulose/mannitol test. The small intestines of NCWGS patients were significantly less permeable than those of CD patients and controls. Moreover, duodenal biopsies of NCWGS patients found higher expression of claudin-4 mRNA, a marker of reduced permeability [194]. By comparison, another study reported a subgroup of HLA-DQ2/DQ8+ patients with diarrhea-predominant irritable bowel syndrome following a gluten challenge that had increased intestinal permeability [197]. Moreover, Hollon et al. (2015), in an ex vivo study, evaluated alterations in transepithelial electrical resistance (TEER) of tissue biopsies from NCWGS patients, active CD patients, CD patients in remission and controls subjected to pepsin-trypsin digested gliadin. This study has shown that exposure to gliadin increases intestinal permeability and decreases TEER in all patient groups compared to controls [198]. This discrepancy suggests that further studies are required to define the small intestine's permeability in NCWGS and improve our overall knowledge about it.

### 3.4.1. Diagnosis

Currently, the lack of diagnostic biomarkers for NCWGS means that diagnosis depends on a clinical symptoms evaluation and elimination of CD and WA. According to the Salerno Experts' criteria, first, patients have to adhere to a wheat/gluten exclusion or wheat/glutenreduced diet in order to reduce the symptoms. Then, to confirm the diagnosis, a doubleblind, placebo-controlled gluten challenge must be performed to determine if symptoms were indeed related to wheat/gluten ingestion [199,200]. About half of patients with NCWGS present the first generation antibody to gliadin (AGA) which is considered the only serological marker [199,201,202]. Nevertheless, testing for the presence of AGA is not a specific analysis to diagnose NCWGS. Still, for the moment, its positivity, particularly at a high titer, in suspected NCWGS patients can support the diagnosis [203].

Not long ago, Kabbani et al. reported a diagnostic algorithm based on the specific combination of the presence or absence of several histological, serological, and clinical markers to identify NCWGS and distinguish it from CD. The authors concluded that patients with negative celiac serologies (no IgA/IgG deaminated gliadin peptide or IgA tTG antibody) on a regular diet are improbable to have CD. Those with negative serology who also do not have a clinical indication of malabsorption and CD risk factors are likely to have NCWGS and may not necessitate additional examination. Those with ambiguous serology should be subjected to an HLA typing to establish the requirement for biopsy [204].

A recent discovery has given hope to future NCWGS diagnoses. This study developed by Barbaro et al. verified that NCWGS and CD patients had significantly increased levels of zonulin compared with asymptomatic controls and diarrhea-predominant irritable bowel syndrome (IBS-D) patients. They came to the conclusion that zonulin can be considered a diagnostic biomarker in NCWGS and combined with demographic and clinical data, differentiates NCWGS from IBS-D with high efficiency. Moreover, wheat withdrawal was associated with reducing zonulin levels only in NCWGS carrying HLA genotype [205]. However, further studies are necessary since the number of patients examined was low.

### 3.4.2. Treatment

The guidelines to treat NCWGS patients are not established yet. The specialists advise these patients to adjust their dietary preferences and begin a GFD [203]. In some cases, any progress after GFD is only partial. In these situations, a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet together with gluten removal can enhance the clinical condition considerably [206].

Significant research efforts are being made to manage NCWGS. For example, multiple studies have concentrated on analyzing the toxicity of different varieties of wheat. Intriguingly, Triticum monococcum ssp. monococcum, an ancient diploid wheat, does not activate distinct immune cells involved in gluten-related disorders as much [207]. While clinical studies have shown that CD patients cannot consume these varieties, it has been indicated that they would be safe for patients with NCWGS [208]. Innovative hybridized cereals such as tritordeum have also been shown to be an alternative for NCWGS patients due to their low gliadin content [209]. CRISPR/Cas9 technology has been used to produce wheat with less α-gliadin, translating into an 85% reduction in immunoreactivity [210]. Nevertheless, it should be mentioned that most of this research is designed to tackle gluten proteins, particularly gliadins, and their post-ingestion downstream effects in CD. In NCWGS, the environmental culprit is ye<sup>t</sup> to be well defined.

### **4. Gluten-Related Misconceptions**

GFDs are commonly recognized as the treatment for CD and other gluten-related disorders (GRD), as mentioned above. However, nowadays, the number of people without any GRD who adopt a GFD is rising [211]. The prevalence of adherence to a GFD in the overall adult population can reach 7% in a few countries [212,213]. As of 7th December 2020, a Google search for "gluten-free diet" generated over 4.5 million results. The general population's principal reason for purchasing gluten-free foods is that they are supposed to be healthier than their gluten-containing equivalents [214]. Recommendations from a multitude of books, celebrities, and other media have unquestionably supported the increased consciousness of the potential health benefits of gluten avoidance, such as weight loss [215].

There are three significant misconceptions by the general population leading them to follow a GFD. (1) A gluten-free diet is a healthier option. (2) Eating gluten-free will help them lose weight. (3) The wheat we consume today contains more gluten than older varieties.

Considering the first misconception, claims of the potential benefits of following a GFD include increased energy, better sleep, clearer skin, faster weight loss, and improved medical conditions such as autism and rheumatoid arthritis [214]. Evidence of the health benefits of a GFD for GRD patients is incontrovertible. However, no published experimental evidence supports similar claims for the overall population [216]. On the contrary, an issue associated with unnecessary gluten avoidance is the reduced consumption of whole grains, foregoing the likely benefit of lowering cardiovascular risk. The GFD promotion between people without CD must not be encouraged [217].

Regarding the second misconception, some studies of CD patients report a change in weight as an effect of following a GFD. In a survey of 369 adult patients with CD who followed a GFD for an average of 2.8 years, 22 of the 81 (27%) who were at first overweight increased weight [218]. In another study of 371 adults with CD who adhere to a GFD for two years, 55 of the 67 (82%) initially overweight patients earned weight [219]. Other researchers have reported that between 149 children with CD adhering to a GFD for at least 12 months, the percentage of overweight people almost duplicated (11% to 21%) [220]. These studies sugges<sup>t</sup> that body weight may increase for a considerable portion of overweight celiac patients while on a GFD. However, it has not been established if people without CD or gluten sensitivity would gain weight if they followed a GFD. In this respect, it is essential to note that gluten-free does not imply fat-free or calorie-free, and some gluten-free products contain more calories and sugar than corresponding glutencontaining foods [214]. Indeed, a study carried out in 2018 analyzed the most recent surveys on the nutritional quality of gluten-free products and concluded that the key inadequacies of currently available GF products are a low protein content and a high fat and salt content compared with their gluten-containing counterparts. However, they also verified more acceptable levels of fiber and sugar than in the past [221]. In this way, we can affirm that gluten-free products are not adequated to people wishing to lose weight.

The third misconception that wheat breeding has led to the production of wheat varieties containing higher levels of gluten originated from successful books like "Wheat Belly" by William Davis and "Grain Brain" by David Perlmutter [222]. However, the level of gluten in wheat has actually remained unchanged over the years. A 2013 study reported that gluten levels in numerous varieties, on average, have slightly changed since the 1920s, and although there was actually an increase in CD in the second half of the century, the breeding of wheat for higher gluten content does not sugges<sup>t</sup> to be the reason for that [223]. In 2010, van den Broeck, when studying old and modern wheat varieties toxicity, suggested that breeding practices may have influenced the increased CD prevalence. However, some evidence has shown that modern wheat is not more toxic for celiac patients and that breeding does not seem to be related to a higher prevalence of CD [224]. On the other hand, as nitrogen (N) fertilization of cereal crops has increased, another hypothesis has emerged. Intensified fertilization with N may increase the allergenic proteins content of wheat, which may be related to the increase in CD pathology. The study that put forward this hypothesis concluded, after a literature meta-analysis, that wheat grown under higher N availability in the soil produces not only higher yield but also grains and flour with higher concentrations of gliadin in all genotypes [225]. However, further experimental studies need to be done, and if this hypothesis stands, we will have an important lead to follow to prevent and control the spread of CD.

### **5. Conclusions**

Wheat is the widest cultivated crop on Earth and has been consumed for 10,000 years by humans from its most primitive form to the current species. Wheat is a nutritious cereal, rich in dietary fiber. The nutritional recommendations of many countries emphasize cereals as the basis of a balanced diet. This is particularly true in low and medium-income countries where grain-based food is the main source of energy, carbohydrates, fibers, proteins, B vitamins, and minerals essential for human survival. The exclusive properties of dough made from wheat flour derive from the gluten protein complex and allow it to be processed into bread, pasta and noodles, and other diverse forms of food feeding most of the world population.

Considering the predominance of wheat, the challenge of the increasing incidence of wheat/gluten-related disorders like CD and NCWGS must be addressed now. Patients with CD should strictly follow GFD since they must avoid foods containing gluten, patients with a WA should prevent contact with any form of wheat, and NCWGS patients should follow a wheat/gluten exclusion diet as well. In some cases, adherence to a low FODMAP diet and gluten removal can drastically improve the clinical outlook. There have been many research advances in improving CD and WA diagnosis, but the same does not happen at NCWGS. Thus, first, we have to comprehend the fundamental mechanism behind the NCWGS pathogenicity to establish more sensitive diagnostic markers and therapeutics then.

Only a tiny percentage of the worldwide population is affected by these wheat/glutenrelated disorders. Opting or promoting a GFD to improve well-being unwarranted by any medical suggestion is an unhealthy alternative since the consumption of wheat is more beneficial than its non-consumption. Thus, to answer the question "How healthy is to eat wheat?" and the take-home message is that wheat is an excellent food for people without any associated medical conditions because it is a very nutritious cereal, rich in macro and micronutrients that only beneficiate our health. The problem is that people are removing wheat from the diet without any medical indication or health/nutritional condition with a

proven relationship and consequently are not consuming the necessary nutrients. This is a mistake that results from a growing number of misconceptions related to this cereal that should be avoided and clarified as they end up harming these people's health. Here we have presented the medical conditions and the nutritional benefits of consuming wheat, so readers can access unbiased information that clearly shows the best and the worst of this cereal in terms of nutrition and health.

**Author Contributions:** Conceptualization, M.R.; investigation, M.R. and C.S.; data curation, C.S.; writing—original draft preparation, C.S.; writing—review and editing, C.S., M.R., T.d.S. and G.I.; project administration, G.I.; funding acquisition, G.I., P.P. and A.S.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was funded by the R&D Project GLUTEN2TARGET-Optimizing natural low toxicity of wheat for celiac patients through a nano/microparticles detoxifying approach, reference POCI-01-0145-FEDER-029068 and PTDC/BAA-AGR/29068/2017, financed by the European Regional Development Fund (ERDF) through COMPETE 2020-Operational Program for Competitiveness and Internationalization (POCI) and by Foundation for Science and Technology (FCT).

**Acknowledgments:** The authors acknowledge the supported by the Associate Laboratory for Green Chemistry-LAQV, which is financed by FCT under the Partnership Agreement UIDB/50006/2020.

**Conflicts of Interest:** The authors declare no conflict of interest.
