Abstract Research has described the perceived social restrictions that people who suffer from celiacdisease can experience, but never investigated their actual amount of social contacts as compared to a healthy population. Therefore, we focus on the question whether people who suffer from celiacdisease or non-celiacglutensensitivity have less informal social capital (e.g. contacts with friends and family) than a healthy population and, if so, which health related factors can explain these differences in social capital. With the aid of the Dutch Celiac Association, we recently gathered high quality data. Results show that people who are diagnosed with celiacdisease or NCGS indeed have less informal social capital than a healthy control group. This can be explained partly because the former more often suffer from depression, poor subjective health and another chronic condition. Moreover, it appears that demographic factors, such as gender, age, having children and marital status, reduce the initial relationship completely. These demographic factors thus play a more important role. As yet, these findings may help healthcare professionals to interpret social consequences of celiacdisease and non-celiacglutensensitivity in a broader sense. Keywords : health related explanations, differences, informal social capital, celiacdisease, non-celiacgluten
Americans are becoming increasingly aware of what they are consuming through their diets. Recently, a large number of people have been removing gluten from their diet in an attempt to alleviate a wide variety of intolerance or allergy-like symptoms (Reilly, 2016). However, not all of these consumers are making educated choices when it comes to removing dietary gluten. One study found that many people who were opting for gluten-free alternative foods were buying these products because they thought it would be healthier, improve overall digestive health, aid in weight loss, or, least likely, they had a glutensensitivity (Gaesser & Siddhartha, 2012; Reilly, 2016). However, this careless adoption of the gluten free diet (GFD) is irresponsible due to the nutritional deficiencies that can accompany the diet. Gluten has been condemned as evil by many who are not educated in the characteristics of the molecule. Gluten itself is not unhealthy, toxic, or bad for those who do not have Celiacdisease (CD) or non-celiacglutensensitivity (NCGS) (Reilly, 2016). Gluten is a general name for a class of alcohol-soluble proteins present in wheat, barley, and rye (Biesiekierski, 2017). This class of proteins contains gliadin and glutenin, which are both characterized by high levels of glutamine and proline amino acids. Although this renders the protein difficult to digest, adverse immune reactions because of this are only observed in patients with CD and NCGS (Biesiekierski, 2017).
Dietary gluten present in wheat, rye and barley induces several gastrointestinal disorders, including celiacdisease and non-celiacglutensensitivity (NCGS). Celiacdisease is an immune-based enter- opathy triggered by ingestion of gluten in genetically susceptible individuals resulting from the interaction between genetic and environmental factors. Although gluten has been recognized as the main environmental trigger of the disease, a speci ﬁc role for the in- testinal microbiota in celiacdisease development has been suggested. NCGS individuals develop adverse reactions after the exposure to gluten. Due to the similarities in clinical outcomes and the absence of diagnostic biomarkers, it is challenging to differentiate NCGS from celiacdisease. The aetiology of NCGS remains unknown, although the involvement of innate immune mechanisms has been suggested. Since the inﬂuence of intestinal microbiota on immune cell ho- meostasis and on education of both innate and adaptive immune system is well known, the role of host-microbe interactions in the non-celiacglutensensitivity have been hypothesized.
• A lady who was claiming to be completely gluten-free but still suffered from all her symptoms. After some time, it was discovered that she was eating the communion wafer at church every Sunday. Once she stopped, then her symptoms improved.
studied forms of gluten-related disorders characterized by an evident immune mechanism (autoimmune in celiacdisease and IgE-mediated in wheat allergy), a new entity has been included, apparently not driven by an aberrant immune response: the non-celiacglutensensitivity (NCGS). NCGS is characterized by a heterogeneous clinical picture with intestinal and extraintestinal symptoms arising after gluten ingestion and rapidly improving after its withdrawal from the diet. The pathogenesis of NCGS is largely unknown, but a mixture of factors such as the stimulation of the innate immune system, the direct cytotoxic effects of gluten, and probably the synergy with other wheat molecules, are clues for the complicated puzzle. In addition, the diagnostic procedures still remain problematic due to the absence of efficient diagnostic markers; thus, diagnosis is based upon the symptomatic response to a gluten-free diet and the recurrence of symptoms after gluten reintroduction with the possibility of an important involvement of a placebo effect. The temporary with- drawal of gluten seems a reasonable therapy, but the timing of gluten reintroduction and the correct patient management approach are have not yet been determined.
In recent years, a growing number of subjects worldwide have reported that ingestion of wheat and, to a lesser ex- tent, of other cereals such as barley, rye, and spelt cause them intestinal and extraintestinal symptoms without the diagnostic features of celiacdisease (CD) or wheat allergy (WA) . This self-reported wheat sensitivity has fueled the debate on the possible existence of a new syn- drome, which has been recently named as non-celiacglutensensitivity (NCGS) to differentiate it from CD [2-4]. Gluten, the main protein complex contained not only in wheat, but also in barley, rye, and spelt, has been identified as the possible trigger of this syndrome. The definition of NCGS has been questioned as possibly be- ing too restrictive . Indeed, it has been suggested that wheat proteins other than gluten, such as amylase trypsin inhibitors, can contribute to this disorder . In addition, recent studies have emphasized the possible role of fer- mentable oligosaccharides, monosaccharides and disac- charides and polyols (FODMAPs) in the development of this syndrome . Interestingly, together with milk, le- gumes, honey, some fruits (watermelon, cherry, mango, pear) and some vegetables (chicory, fennel, beetroot, and leek), the most common food sources of FODMAPs also include wheat and rye, the same grains and cereals that also contain gluten proteins . Despite awareness of these limitations, for the time being the acronym NCGS has been accepted by the scientific community, and it is commonly used to indicate this syndrome, as reported in the majority of published papers [2,3,9].
The authors found that incorporating a personal history of autoimmune illness, family history of celiacdisease and nutrient deficiencies could help in the diagnostic model particularly in subjects with negative serology. Subjects with negative serology on a gluten- containing diet, no risk factors and no symptoms of enteropathy are highly likely to have NCGS and do not require further testing. Conversely, in a subject with negative serology but with typical symptoms of malabsorption or risk factors for CD, a biopsy is indicated. In a subject with borderline serology on a gluten-containing diet, the next step is HLA typing to determine whether a biopsy is indicated. A subject with borderline serology and negative HLA typing is considered to have NCGS. HLA typing is also useful to evaluate subjects suspected of NCGS or CD who self- start a GFD without a prior check of celiac serologies on a gluten-containing diet. Due to the high negative predictive value of the genetic assay, a diagnosis of CD can be effectively excluded with a negative finding. If
Several components of wheat are potentially harmful for NCGS and IBS patients including gluten proteins, lipopolysaccharides, amylase/trypsin inhibitors (ATIs), wheat germ agglutinins (WGA) and fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) (Figure 1) [32,34–37]. Gluten proteins, the storage proteins of wheat, rye and barley, account for 70–80% of the total grain protein and are located exclusively in the starchy endosperm of the grains (Figure 2). The remaining proteins are albumins and globulins (20–30%) that have metabolic, protective or structural functions. Largely insoluble in water and salt solution, gluten can be subdivided into mostly monomeric prolamins (called gliadins in wheat) soluble in aqueous alcohols and polymeric glutelins (called glutenins in wheat) soluble only in the presence of reducing and disaggregating agents . Specific sequences from gluten, e.g., N-terminal peptides from α -gliadin, have been shown to induce an innate immune response in celiacdisease [39,40] and could also play a role in NCGS. In general, care is advised when using wheat or gluten for oral challenge, because all wheat is not the same and all gluten is not the same. The composition of the individual components and the overall protein contents can differ in a rather large range depending on wheat species, cultivar, growing conditions (e.g., soil, climate, fertilization) and processing, in the case of gluten and, especially, hydrolyzed gluten. Therefore, each material should be well characterized using proteomic methods and, if possible, standardized .
Non-CeliacGlutenSensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiacdisease (CD) or wheat allergy (WA) [1,2]. The terminology “NCGS” is still a matter of debate. Although NCGS is triggered by gluten-containing cereals, the offending dietary protein has not been identified yet, and could include component/s that are different from gluten itself, e.g., the cereal protein amylase-trypsin inhibitors (ATIs) . Then the terminology “NCGS” could be changed into “NonCeliac Wheat Sensitivity” (NCWS) in the near future, although this would exclude other relevant cereals like barley and rye. The prevalence of NCGS is not clearly defined yet. Indirect evidence suggests that NCGS is more common than CD , the latter affecting around 1% of the general population . Treatment of NCGS is based on the celiac-type gluten-free diet (GFD) although it is unknown if long-term, strict avoidance of all gluten-related products is necessary. Since NCGS may be transient, gluten tolerance needs to be re-assessed in patients with NCGS .
In order to analyze the socialimplications of gluten free diets, we first need to understand what exactly gluten is and the types of restrictions that it puts on people. Gluten is a mixture of storage proteins present in the seeds of wheat, barley, and rye. The gluten provides nutrition for the seed to germinate. Gluten is responsible for the elastic and viscous consistency typical of many types of dough. On a biochemical level, this is “due to the formation of interchain disulfide bonds between gluten proteins and hydrogen bonds between glutamine residues that are abundantly present in all classes of gluten proteins” (Koning, 2015). This network forms a desirable texture across a wide range of food applications. Under normal circumstances, digestive enzymes break down long chains of proteins into smaller segments called peptides. The majority of these peptides can be broken down further, absorbed by the small intestine, and then transported around the body. However, in patients with celiacdisease, this does not occur; digestive enzymes cannot break down the long chains of gluten for these individuals. These undigested peptides trigger an immune response in the digestive tract (Healthcare Professional Resource for Gluten Related Disorders, 2017). The villi in the small intestine become damaged, preventing the proper absorption of vitamins and minerals (Moore, 2014). As of now, patients with celiacdisease have been told to eliminate gluten from their diet. Scientists are currently working on a pill to aid in the digestion of the gluten proteins while still being able to withstand the highly acidic
The current clinical consensus is that the diagnostic criteria on NCGS should include self-reported gluten intolerance, negative serology for CD (including immunoglobulin A (IgA) endomysial antibodies, IgA tissue transglutaminase antibodies, and IgG de-amidated gliadin peptide antibodies) and the absence of villous atrophy at duodenal histology (whilst on a gluten-containing diet) [ 1 , 3 , 11 ]. Similarly to CD and wheat allergy, the cornerstone of NCGS treatment is the withdrawal of gluten-containing foods. Although considered safe and effective, the lifelong elimination of gluten from the diet carries psychological and socialimplications. Patients with CD report about concerns related to the management of their social relationships and life routine [ 12 ]. Support and education are important to enable patients to adapt to their new diet [ 13 ]. However, given the uncertainty on the pathogenesis and trigger(s) of NCGS, it is not clear how strict such a new diet needs to be, how long its implementation and how to monitor the efficacy of the treatment other than by clinical response. Clinical experience suggests that patients affected by NCGS range from those who need to adhere to a strict GFD to those who can tolerate potential cross-contamination without any clinical consequences [ 14 ].
Glutensensitivity (GS) was originally described in the 1980s  and a recently “re-discovered” syndrome entity, characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiacdisease (CD) or wheat allergy (WA). Following the landmark work by Sapone and coworkers, describing the clinical and diagnostic features of GS in the year 2010 , a rapidly increasing number of papers have been published by many independent groups, confirming that GS should definitely be included in the spectrum of gluten-related disorders. However, many aspects of GS epidemiology, pathophysiology, clinical spectrum, and treatment are still unclear. Given the recent increase of the gluten-free market worldwide, partially sustained by individuals who claim a medical necessity to undertake a gluten-free diet (GFD), there is a need of “separating the wheat from the chaff” . This goal will be achieved by (a) proper scientific information, (b) shared definitions, and (c) prospective, multi-center studies addressing the many unsolved issues on GS. In order to develop a consensus on new nomenclature and classification of gluten-related disorders, a panel of experts first met in London, in February 2011. The panel proposed a series of definitions and developed a diagnostic algorithm that has been recently published .
Given the lack of consensus on the prevalence of true CD in schizophrenia, Samaroo et al.  tried to charac- terize the immune response to gluten in a subset of schizophrenic patients with elevated AGA titres. In this group, the elevation of AGA was not associated with increased prevalence of a-tTG, deamidated gliadin peptide (DGP) antibodies (another serological diagnostic marker of CD), or with celiac-related HLA genes. The authors con- cluded that these patients did not have celiacdisease, but that SCZ patients probably have different mechanisms evoking an immune response against gluten, independent of transglutaminase and HLADQ2 and/or DQ8 molecules. A longitudinal prospective study on antibody reactivity to gliadin, deamidated gliadin and tissue transglutaminase led to the same conclusions . Patients with recent-onset psychosis showed higher levels of IgG and IgA AGA than individuals with multi-episode schizophrenia and individ- uals without a psychiatric history. These results confirmed those of Samaroo et al. : the immunological pattern of schizophrenia diverged from that of celiacdisease, since increased IgA a-tTG and IgG DGP antibodies were absent except for a marginal elevation in IgA a-tTG titre measured in the recent-onset psychosis group. Again, disease-related differences in the prevalence of DQ2/DQ8 alleles associ- ated with CD were not found.
Most of the analysed studiers agree that NCGS would need to be diagnosed only after exclusion of celiacdisease and wheat allergy, and that a reliable serological marker is not available presently. The mechanisms causing symptoms in NCGS after gluten ingestion are largely unknown, but recent advances have begun to offer novel insights. The estimated prevalence of NCGS, at present, varies between 0.6 and 6%. There is an overlap between irritable bowel syndrome and NCGS with regard to the similarity of gastrointestinal symptoms. The histologic characteristics of NCGS are still under investigation, ranging from normal histology to slight increase in the number of T lymphocytes in the superficial epithelium of villi. Positive response to gluten free diet for a limited period (e.g., 6 weeks), followed by the reappearance of symptoms after gluten challenge appears, at this moment, to be the best approach for confirming diagnosis. The Salerno expert criteria may help to diagnose NCGS accurately in particular for research purposes but it has limited applicability in clinical practice.
The reported prevalence of positivity to antigliadin antibodies (AGA; IgG and IgA) without any confirm- ation of positivity to tTG or DGP antibodies in the blood of IBS patients has varied from 5 to 17 % [14, 44, 54] to as high as about 50 % [55, 56]. AGA positivity has been reported to have a good sensitivity, but a low specificity for CD , and the serum of 12–15 % of healthy sub- jects is positive for AGA [14, 44, 57, 58]. This raises an interesting question: why would a healthy subject have these antibodies to gliadin with no clinical implications? One could speculate that mucosal damage and failure of the mucosal barrier caused by acute or chronic alcohol consumption , or by a bout of gastroenteritis, would allow the immunogenic peptides resulting from the par- tial digestion of glutamines and gliadins to enter the lamina propria, where they could interact with immune cells, resulting in the production of AGA. Acute and chronic alcohol intake as well as gastroenteritis are not uncommon, and so this could explain both the high prevalence of AGA positivity in healthy subjects and the lack of clinical relevance of AGAs in both the healthy subjects and IBS patients.
derived from a single university clinic, this sample can- not be assumed as indicative of non-academic setting. Indeed, the sample was clinically referred and not intended to be representative of children with CD in the population. Second, symptoms scores were derived from assessment scales filled out by the parents and self- report questionnaires completed by the children them- selves, and a formal diagnosis of psychiatric disorders was not performed (although these rating scales have been shown to be valid instruments to identify children with psychiatric symptoms). Third, even though the social and cognitive relational skills of these patients were evaluated by professional child neuropsychiatrists, however, a complete cognitive evaluation with norma- tive scale was not assessed.
a well-recognized autoimmune disease, whereas NCGS is likely a gluten hypersensitivity without an established in- volvement of autoimmunity [2,5]. The persistence of AGA IgG in a large proportion of CD patients following GFD can be regarded as an expression of the immunological memory of the autoimmune disorder, whereas the gluten withdrawal in NCGS switches off the immune process and this effect is supposed to lead to the rapid disappear- ance of AGA . In contrast with AGA IgG, AGA IgA disappearance can be viewed as the result of a strict GFD as well as of a good clinical response in both NCGS and CD patients. Indeed, these antibodies disappeared in all the NCGS patients with a strict adherence to GFD and a good clinical response, remaining positive only in one patient with admitted low dietary compliance and mild clinical response to the diet. Similarly, the finding of AGA IgA in the celiac group on GFD was closely related to the low compliance with the diet and the mild clinical res- ponse to the dietary treatment. Our study focused on a specific subset of NCGS patients, i.e. those with AGA IgG positivity and whether GFD may have an effect on NCGS- related symptoms in the "antibody-negative" subset of gluten sensitive patients remains unknown. It is tentative to speculate that even in AGA-negative NCGS patients gluten withdrawal can improve the symptom profile. Clearly, further studies testing this hypothesis are eagerly awaited. The fluctuation of AGA with dietary changes (i.e. gluten withdrawal and re-challenge) in NCGS patients remains another very interesting aspect. In a recent double blind, placebo controlled study, Biesiekierski et al. have shown that NCGS patients in gluten-withdrawal for 6 weeks and re-challenged with high dose of gluten (16 g/day for one week) had an increase of AGA IgG and IgA in 8% and 21% of cases, respectively . These are lower proportions of NCGS patients compared to those detected in patients during a gluten containing diet. Thus, the data provided by Biesiekierski et al. appear quite different from our results, indicating about 50% of NCGS patients with positive AGA IgG. A possible explanation for such discrepancy may be the very short period (one week) of gluten challenge used by Biesiekierski et al. . Probably, this short-time gluten exposure in NCGS patients was not enough to evoke the reactivation of the adaptive immunity to produce AGA in response to gliadin. This exciting possibility should deserve further study.
in CD patients or even DC. Increased intestinal perme- ability is thought to be an early biological change that precedes the onset of several autoimmune diseases [32-34]. Loss of intestinal barrier function brings with it a continuous aberrant passage of antigens across the intestinal epithelium. This may cause a switch from tol- erance to immunity, hence representing an increased risk for autoimmune and allergic diseases in individuals whose other genetic determinants, MHC and non-MHC, give rise to inappropriate antigen processing and presen- tation. In the intestinal epithelium, paracellular perme- ability is regulated by intercellular TJ proteins. As recently shown, CLDNs are integral TJ components that are critical for maintaining cell-cell adhesion in epithe- lial monolayers [35-37]. The overall balance of CLDN species expressed in a particular cell type help to define the characteristics of its TJ. For instance, CLDN1 and CLDN4 are postulated to decrease, whereas CLDN2 is postulated to increase TJ-dependent permeability . In line with this notion, and with the appreciation of reduced small intestinal permeability in GS patients, we have shown here that the GS mucosa expresses signifi- cantly higher levels of transcripts for CLDN4 relative to CD or DC. In contrast, other CLDN genes and other genes associated with TJ function measured in this study did not appear to be expressed differently in the GS or CD mucosa compared to controls. Together, these findings suggest that the distinct clinical and sero- logical features between GS and CD patients are
period that is necessary for the histo- logic recovery correlates with the time needed for normalization of the CD an- tibodies. In our series, only 16 of the 129 children (12%) had a second bi- opsy after a mean time of 1.5 years (SD ⫾ 0.4 years) on a gluten-free diet, and 15 of them had normalization of the small bowel mucosa and were sero- negative at the moment of the control biopsy. The CD-speciﬁc antibodies de- crease and histologic recovery corre- lated well in these children, except for 1 child who had still small bowel lesions (M3B) after a 1.6-year gluten-free diet, despite having negative antibodies after 9 months on the diet. As described in the child’s patient ﬁle, he had a poor compli- ance with the diet.
Gluten is also found in oats, however many studies sug- gested that the ingestion of oats is safe for most patients [70-74]. This data was in line with recent studies, which failed to identify the toxic amino acid sequences in oats (see below) . Despite these observations, the inges- tion of oats can not be endorsed, since commercial oats are often contaminated with wheat or rye. In addition, the oats-containing gluten-free diet caused in some individu- als more intestinal symptoms than the traditional diet. Rarely, mucosal integrity was disturbed and more inflam- mation was evident in the group on oats diet. Neverthe- less, oats may provide an alternative in the gluten-free diet; at the same time, patients should be aware that the intestinal symptoms may worsen [76,77]. Antibodies to oat prolamines were more frequently found higher in children with CD ; however, the significance of this finding is not clear.