text:
Open Access This article is
- freely available
- re-usable
Nutrients 2017, 9(11), 1268; https://doi.org/10.3390/nu9111268
The Overlapping Area of Non-Celiac Gluten Sensitivity (NCGS) and Wheat-Sensitive Irritable Bowel Syndrome (IBS): An Update
Department of Pediatrics, Marche Polytechnic University, 60121 Ancona, Italy
Department of Medicine, Columbia University Medical Center, New York, NY 10027, USA
Medical Department, Division of Gastroenterology, Infectiology and Rheumatology, Charité, Campus Benjamin Franklin, 12203 Berlin, Germany
Department of Gastroenterology and Liver Diseases, CHU, 38043 Grenoble, France
Celiac Center Amsterdam, Department of Gastroenterology, VU University Medical Center, 1117 Amsterdam, The Netherlands
Department of Internal Medicine, "Giovanni Paolo II" Hospital, Sciacca (AG) and University of Palermo, 92019 Sciacca, Italy
Paediatric Gastroenterology Unit, Sant Joan de Reus University Hospital. IISPV, 43003 Tarragona, Spain
Department of Internal and Experimental Medicine Magrassi-Lanzara, University of Campania Luigi Vanvitelli, 80131 Naples, Italy
Medical Clinic 1, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, 90133 Palermo, Italy
Center for the Prevention and Diagnosis of Celiac Disease, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
Center for Celiac Research and Treatment, Massachusetts General Hospital, Boston, MA 02114, USA
Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK
Academic Unit of Gastroenterology, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK
Gastroenterology Unit, Milton Keynes University Hospital, Milton Keynes MK6 5LD, UK
German Research Centre for Food Chemistry, Leibniz Institute, Lise-Meitner-Straße 34, D-85354 Freising, Germany
Institute of Translational Immunology, University Medical Center, Johannes Gutenberg University, 55131 Mainz, Germany
Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
Author to whom correspondence should be addressed.
Received: 12 October 2017 / Accepted: 17 November 2017 / Published: 21 November 2017
Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.
Keywords:gluten sensitivity; celiac disease; wheat allergy; gluten-related disorders; gluten-free diet; amylase-trypsin inhibitors (ATIs)
1. Introduction
Non-celiac gluten sensitivity (NCGS), sometimes referred as gluten sensitivity, gluten intolerance, or non-celiac wheat sensitivity, was already described in 1978 but did not receive much recognition from clinicians until the 21st century [1]. It is characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease (CD) or wheat allergy (WA). This is the original definition based on the Salerno Experts' Criteria [2]. However, our understanding has evolved since that time and we recognized that the spectrum of symptoms, which occur maybe due not just to the ingestion of gluten proteins but potentially other wheat-related components. In clinical practice, it is crucial to exclude CD in patients who present in this way. A recent PubMed search using the Medical Subject Headings (MeSH) index term of NCGS demonstrates 125 publications prior to 2000 but 490 since the start of the new millennium. Public and commercial interest in a gluten free diet (GFD) has galvanized the scientific community into undertaking research beyond the previously recognized gluten-related disorders such as celiac disease or dermatitis herpetiformis.
Irritable bowel syndrome (IBS) is a common intestinal disorder causing abdominal pain, bloating, gas, diarrhea and constipation. IBS-like complaints are often part of the NCGS clinical picture. Conversely, recent studies support the hypothesis that gluten and other wheat components may trigger IBS symptoms. Due to this overlap and lack of IBS/NCGS biomarkers, and there is a confusing situation for both the primary care physician and the general audience. This review article is aimed to present (1) an update on the complex relationship between NCGS and IBS and (2) the experts' opinion on this hot topic.
2. Methods
In order to provide consensus and promote collaborative research in this field, a group of 23 experts convened in Meran, Italy in December 2016. Each expert was assigned to separate work streams according to their areas of clinical and research experience. Work streams involved review of recent literature using PubMed and Embase Databases. The previous literature review occurred at the Salerno meeting in October 2014. For this reason, the new MeSH-based literature review encompassed all articles since that time but also key historical papers. Furthermore, experts in attendance were also asked to identify emerging studies (presented in abstract form). The experts were then divided into work streams, with sub-section presentations and break-out focus groups. Based on this current evidence, five areas were identified where significant progress within the medical literature has occurred: (1) Prevalence studies of NCGS; (2) Non-IgE wheat allergy; (3) Potentially harmful wheat components; (4) Pathogenetic mechanisms for IBS triggered by wheat; (5) Overlap between IBS-type symptoms and NCGS. This review provides the summary and consensus (undertaken using a Delphi method) from this International Workshop.
2.1. Prevalence of NCGS: Emerging Data and Ascertainment Pitfalls
We have previously categorized the spectrum of gluten-related disorders and provided a "road map" for clinicians seeking to manage their patients who have gluten-related symptoms [2,3,4]. Considering the uncertainty regarding the prevalence of NCGS, initial efforts at the Center for Celiac Research, University of Maryland (USA) were aimed at clarifying this with an original report of their experience with 5896 patients seen between 2004 and 2010 [3]. The criteria for NCGS were fulfilled by 347 patients suggesting a prevalence in their study population of 6% (1:17). The limitation to this important observation is that this is a tertiary center seeing patients within a fee-paying system. Due to a selection bias, this may not accurately reflect international prevalence figures for NCGS.
Since that time other international groups have tried to estimate the prevalence of NCGS (Table 1) [5,6,7,8,9,10,11,12,13,14]. Of these studies, three report data from the National Health and Nutrition Examination Survey (2009–2010), with the most recent study incorporating data from 2011 to 2012 [6,7,12]. The range when considering the general population and ensuring exclusion of CD, highlights a prevalence between 0.6% and 10.6%. The huge variability in prevalence figures is mainly explained by lack of diagnostic biomarker(s). In order to clarify the diagnosis of NCGS, at a previous consensus meeting the experts' group recommended a double-blind placebo controlled (DBPC) approach using 8 g of gluten [4]. Although a DBPC approach is the gold standard for a rigorous scientific identification of true cases, this is difficult to undertake in daily clinical practice. Patients frequently refuse to re-introduce gluten into their diet due to the immediate symptom burden which they perceive. This view is further reflected by the high levels of unsuccessful patient recruitment in studies to resolve these specific issues reported in the literature. There is still very limited data on the overlap between NCGS and IBS-type symptoms. The UK population survey undertaken in 1002 adults demonstrated that individuals with NCGS had an increased prevalence of fulfilling the Rome III criteria for irritable bowel syndrome in comparison with those without NCGS (20% vs. 3.89%, odds ratio 6.23, p < 0.0001) [8].
An emerging epidemiological issue is represented by self-reported NCGS, i.e., people excluding gluten-containing food without a medical diagnosis of a specific gluten-related disorder. Many individuals perceive the GFD as healthy life style practice. This group may be termed lifestyles, free from or clean eaters depending on which country they reside in. We propose to define them as people who avoid gluten [5,6,7,8,9,10,11,12,13,14]. These individuals are widely diffused in Western countries, with a prevalence of 6.2–13% [8,13].
They must be treated with great caution and if such patients present to clinicians it is imperative to first exclude celiac disease [2,3,4] or other causes not related to any specific trigger (placebo effect, implementation of a healthier diet, etc.). Such patients can be advised that simply by identifying gluten as a culprit for their symptoms, this gives them a risk ranging from 2% to 42% of having undiagnosed celiac disease (based on the current published literature) [8,15,16,17,18,19]. This extreme variation reflects an ascertainment bias related to the referral patterns of the centers that have published their data. Tertiary and quaternary centers may have a high prevalence of patients presenting with gluten-related symptoms who are subsequently recognized to have celiac disease.
2.2. Update on Non-IgE Mediated Wheat Allergy in NCGS
Wheat allergy is an adverse immune response which occurs reproducibly in affected individuals. The immune mechanism may be IgE or non-IgE mediated. Individuals may have a serological IgE response to wheat but this only demonstrates sensitization. To make a diagnosis of wheat allergy, patients must also describe reproducible symptoms and signs which occur quickly following wheat exposure. Typically, these symptoms may be gastrointestinal, respiratory, at skin level and in some rare cases anaphylaxis or angioedema [20,21]. Recent developments have occurred specifically in the field of adult non-IgE-mediated food allergy. Non-IgE-mediated food allergy is a condition well known by pediatricians who recognize at least three gastrointestinal clinical conditions: the food protein-induced enterocolitis syndrome, the food protein-induced proctocolitis, and the food protein-induced enteropathies [20]. In the pediatric population, this condition is mainly due to cow's milk protein hypersensitivity (CMPH) but also soya (most common triggers). Wheat is also involved in Food Protein Induced Enteropathy in children. It is difficult to diagnose as radioallergosorbent test or skin testing are neither specific nor sensitive. For this reason, a CMPH diagnosis must be posed exclusively on clinical basis by means of elimination diet and successive DBPC food challenge [22]. It is probable that in adults, the allergy-related gastro-intestinal symptoms are common and often underestimated [21] (confocal/review recent papers).
The hypothesis that NCGS could be a non-IgE-mediated wheat allergy is based on some clinical aspects (presence of a personal history of food allergy in the pediatric age, or of coexistent atopic diseases) [22], laboratory and histological data (positive serum anti-gliadin antibodies, positive cytofluorimetric assay revealing in vitro basophil activation by food antigens, and presence of eosinophils in the intestinal mucosa biopsies) [23,24,25] and by new and exciting endoscopic findings (see below) [26]. Further studies are required to explore the putative allergic mechanisms involved in the pathogenesis of NCGS. Recently immunological activation in the intestinal mucosa of the NCGS patients has been demonstrated. In fact, gastrointestinal food allergies are often mediated by IgE-independent mechanisms involving mast cells, eosinophils, and other immune cells [21]. An increase in mucosal lymphocytes has been reported in a consistent percentage of patients with NCGS diagnosed by DBPC challenge [25,27], and in general most of the studies on NCGS showed that about half of the patients have a raised IELs count >25 per 100 enterocytes [23,28,29]. Very recently, an increased infiltration of innate lymphocytes-1 cells, producing IFN-γ, in the rectal mucosa of NCGS patients has been reported; furthermore, this infiltration decreased after resuming a wheat-free diet [30]. Given these conflicting observations further work is required to clarify whether NCGS could have an association with either IgE or non IgE mediated wheat allergy.
There is a lack of consensus about intestinal permeability in NCGS. After a first report suggesting a reduced intestinal permeability [28], more recent studies have demonstrated an increased permeability in NCGS [31,32]. Uhde et al., in particular, were able to demonstrate a state of systemic immune activation, partly in response to translocated microbial components and possibly in conjunction with a compromised intestinal epithelium, which significantly improved on a wheat-free diet. Further studies are needed to decipher how wheat components can contribute to a compromised gut epithelial barrier and subsequent microbial translocation that result in systemic immune activation.
In this respect, the exciting findings by confocal endomicroscopy could be the keystone. Recently a novel strategy to identify IBS patients with food-related symptoms and specified sensitivities has been described [26]. Within five minutes after the administration of defined food suspensions to the duodenal mucosa of sensitive patients, confocal laser endomicroscopy demonstrated an increase in the number of intraepithelial lymphocytes, epithelial shedding and breaks followed by leaks with secretion of fluorescein into the lumen, and edema with increased inter-villous spaces. Characteristic mucosal changes after administration of a wheat suspension were seen in 13 (and after administration of milk, soy and yeast in another 9) of 36 IBS patients, and in all of the dietary elimination of the identified trigger, including wheat as prominent cause, resulted in a long-term improvement of symptoms. The 36% of wheat-sensitive IBS patients is in line with the proportions revealed in other studies [21,22], and suggests that this method may offer a remarkable sensitivity and specificity for NCGS. A German multi-center study (DRKS00010123) is currently recruiting patients to further validate these findings [33]. Finally, it is worth noting that endomicroscopy with several food challenges is a complex investigation requiring the patient's sedation.
2.3. Potentially Harmful Wheat Components
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) [32,34,35,36,37]. 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 [38]. Specific sequences from gluten, e.g., N-terminal peptides from α-gliadin, have been shown to induce an innate immune response in celiac disease [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 [41].
ATIs are a family of at least 11 structurally similar, small and compact mono-, di- or tetrameric wheat proteins, which serve as protective proteins in wheat and other cereals by inhibiting enzymes (amylase and trypsin-like activities) of wheat and some parasites. In the developing grain, ATIs are deposited together with gluten proteins in the endosperm and become associated with the starch granules [42]. Encoded mainly by the B and D genomes, ATIs are high in most modern hexaploid bread wheats, and low in spelt (old hexaploid), tetraploid (durum wheat, emmer) and diploid (einkorn) wheat species. They are also present in other gluten containing cereals such as barley and rye. Long known as major allergens in baker's asthma [43], ATIs were identified as triggers of innate immune activation in intestinal myeloid cells via stimulation of Toll-like receptor 4 (TLR4) [35]. Notably, nutritional ATIs enhance intestinal inflammation in models of inflammatory bowel disease in mice, and immune activation is higher in the mesenteric lymph nodes than in the intestinal mucosa [44].
Wheat germ agglutinins (WGA) are enriched in the germ of wheat grains with contents from 100 to 500 mg/kg, resulting in typical concentrations of approximately 4 mg/kg in white flour and approximately 30 mg/kg in whole grain flour [37]. Similar to ATIs, WGA are stable against heat and proteolysis and serve as protective proteins. As lectins, WGA are widely recognized as anti-nutrients in foods and bind to glycoproteins, such as human N-Acetylneuraminic acid, on the surface of cell membranes. WGA has been shown to induce the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-12 and IFN-γ) and impair the integrity of the intestinal epithelial layer [45]. However, in contrast to ATIs, no immune stimulatory activity was demonstrated for WGA in vivo.
The term FODMAPs comprises short chain oligosaccharides of fructose (fructans) and galactooligosaccharides (GOS, stachyose, raffinose), disaccharides (lactose), monosaccharides (fructose), and sugar alcohols (polyols), such as sorbitol, mannitol, xylitol and maltitol, that are resistant to digestion and absorption in the human small intestine with complete or partial fermentation in the large intestine. As such, FODMAPs are considered part of dietary fiber (Figure 2). Out of FODMAPs, wheat contains fructans that increase its tolerance to drought and cold. Typical quantities of fructans are 1.5% in white flour and 3.7% in bran [46] and they can be significantly degraded during yeast fermentation (>50%) and almost completely with fermentation [47]. Modern wheat breads contained 0.5–0.7% fructans (based on the product as consumed), spelt bread 0.2% and gluten-free bread 0.2% [48]. However, the fructan content of gluten-free products depends on the specific recipes and the generalized assumption that gluten-free products are always lower in FODMAPs compared to their wheat-containing counterparts is questionable, because e.g., corn flakes and rice bubbles each had 1.1% fructan [48], and another study did not find a significant difference between various wheat breads and gluten-free breads, because the average fructan content was approximately 1% in both [49].
2.4. Pathogenetic Mechanisms of IBS in Which Wheat can be the Trigger
Growing evidence indicates that the majority of IBS patients report a significant worsening of symptoms, e.g., abdominal pain, bloating and bowel habit abnormalities, after meals, while experiencing an improvement during fasting [50,51]. Furthermore, some IBS patients clearly identify foods that are thought to be more offending as they evoke more commonly the aforementioned digestive symptoms. Although the relationship between food ingestion and symptom generation in IBS patients has long been established, our understanding of dietary triggers and pathogenic mechanisms involved in IBS is still poorly defined [52]. Wheat is regarded as a possible culprit of symptom generation in some cases of IBS [53]. Wheat administered via endoscopic probe into the duodenal mucosa, was able to alter the integrity of the small intestinal mucosa as shown by epithelial leaks/gaps and widened intervillous spaces confocal detected by using laser endomicroscopy. Taken together both endomicroscopic features and histopathological abnormalities provide a morphological basis to the existence of (inflammatory) wheat sensitivity at least in a substantial subset of patients with IBS [26].
The insufficient degradation of gluten and certain other wheat proteins by small intestinal proteases leaves undigested peptides that can pass through a more permeable epithelial barrier (the so called "leaky gut"), reach the submucosa and activate the resident innate immune cells. Experimental data demonstrated that human leucocyte antigen DQ8 (HLA-DQ8) transgenic mice sensitized by gluten show an altered barrier function and enhanced muscle contractility (likely via an increased release of the excitatory transmitter acetylcholine from myenteric neurons), thereby mimicking mechanisms which are known to occur in patients with IBS. Both enhanced intestinal permeability and increased smooth muscle contractility reverted to normal after gluten withdrawal [54]. A recent clinical trial in patients with IBS with predominant diarrhea (IBS-D) confirmed the close relationship between wheat-containing food and a subgroup of IBS cases [55]. Withdrawal of wheat led to a significant improvement of intestinal symptoms together with a reduced small intestinal permeability, whereas wheat-containing food challenge was followed by the recurrence of symptoms and altered barrier function. These changes were linked to HLA-DQ2/8-positive cases. Markers of intestinal permeability such as small intestinal expression of myosin light chain kinase activity and enhanced colonocyte expression of claudin-15 significantly increased after the challenge and decreased following wheat withdrawal. Furthermore, in addition to gluten-derived peptides, both ATIs and WGA can trigger innate immune pathways.
ATIs elicit innate immune responses in vitro and in vivo, driving intestinal inflammation through the activation of TLR4, as exemplified by the worsening of intestinal inflammation in models of IBD [35,44]. In vitro WGA induces inflammatory response by immune cells leading to the release of IL-4 and IL-13 cytokines from human basophils, and can impair the integrity of intestinal barrier by increasing small intestinal permeability [37]. In addition to proteins, wheat contains fructans that also have a role in IBS symptoms. These are carbohydrates belonging to FODMAPs, which exert an important role in gut homeostasis by modulating the microbiota composition and short chain fatty acid synthesis. Fructans are also contained in fruits, vegetables and dairy products. In IBS, patient symptoms such as bloating, abdominal pain and altered bowel habit may have an association with enhanced bacterial colonic fermentation and gas production in the gut lumen. As a result, luminal distension occurs and through this an activation of enteric mechanoreceptors which generate IBS symptoms. However, it is worthy to mention that FODMAPs do not trigger extra-intestinal (e.g., neurological and fibromyalgia-like) manifestations commonly observed in NCGS, likely elicited by wheat proteins (i.e., gluten, ATIs and possibly WGA). Moreover, FODMAPs are generally considered beneficial by promoting intestinal (epithelial) integrity and health.
Regardless of the identification of the offending components, the scientific community agrees that the withdrawal of wheat from the diet can significantly improve symptoms in a subset of IBS patients, who can sometimes be diagnosed as NCGS. The group of IBS patients with gluten sensitivity gathers the vast majority of wheat sensitive patients, since only a minority of NCGS cases do not display a coexistent IBS [56]. The interplay between the various components of wheat, such as gluten, ATIs, WGA and FODMAPs, may elicit a wide array of both intestinal and extraintestinal symptoms in a subgroup of IBS patients by modulating intestinal permeability, microbiota composition, immune activation which, alone or more likely in combination, also affect the gut-brain axis activity thereby leading to symptom perception. Future research is awaited to decipher the complex interplay between food and digestive sensory-motor function in IBS and allied food-related disorders.
2.5. Overlap between IBS-Type Symptoms and NCGS
The prevalence of IBS globally has been estimated to be between 10% and 20% [57,58]. Approximately 50% of patients with gastrointestinal complaints seen in primary care have IBS-type symptoms [59]. Patients with IBS report a reduced quality of life and there is an associated economic and societal cost [60,61]. It is recommended that clinicians should make a positive diagnosis of IBS based on clinical features alone, currently using the Rome IV criteria [62]. The Rome IV criteria categorize IBS by the most predominant presenting symptom-diarrhea (IBS-D), constipation (IBS-C), mixed (IBS-M) or unspecified (IBS-U).
Patients have always reported that food plays an important role in their IBS-type symptoms with estimates of up to 80% of patients having postprandial symptomology, and up to 40% reporting specific "food intolerances" [63,64,65]. Historically, successful restrictive diets for IBS symptoms have been reported by specific research groups. This work has never been translated into daily clinical practice. However, over the last 10 years there has been renewed interest in the concept of dietary interventions for functional gastrointestinal disorders [66,67].
IBS dietary research has focused on the role of two common components of the western diet, specifically FODMAPs and gluten in relation to the induction of IBS symptoms (Figure 1). Initially a retrospective audit evaluated the effect of a low-fructose/fructan diet demonstrating symptomatic relief in 74% of participants with IBS symptoms [68]. Since then, several randomized control trials (RCTs) have demonstrated the efficacy of the low FODMAP diet (LFD) and probable mechanisms. A recent meta-analysis of six RCTs showed that a LFD lead to a 56% greater likelihood of decreasing IBS-SSS (symptom severity scores), however the analysis was limited by information on adherence figures and numerical quantities of FODMAPs ingested [69,70].
The LFD is a complex diet requiring delivery by an experienced dietitian to help ensure both success and overall nutritional adequacy [57,70,71]. The implementation of a low FODMAP diet, involves a strict reduction of all FODMAP groups for 4–8 weeks. This is then followed by a re-introduction of one FODMAP group per week, as tolerated by the patient. The drastic reduction of FODMAP intake could have negative physiological consequences on the colonocyte metabolism, the intestinal microbiota, and the nutritional status, which need further investigation. A significant reduction in iron and calcium intakes during a four-week trial (elimination phase of the LFD) has been reported [71,72,73]. Another potential problem is that the public may commence a LFD without an appropriate reintroduction phase under the guidance of a specialist dietitian. This is of concern considering that the LFD alters the colonic microbiota. A significant reduction in bifidobacteria after four weeks of a LFD has been observed [74]. A recent Australian trial showed that FODMAP restriction was associated with a higher fecal pH, significantly lower bacterial load and diversity, and a significant reduction in colonic bacterial groups with known health benefits when compared to the typical Australian diet [75]. Both studies suggest further trials are required to assess the long-term effects of FODMAP reduction on the microbiome and overall health.
Dietary adherence is another predictor of response in the LFD that warrants further investigation. Dietetic guidance and supportive written (or digital) information are essential. However, even with these aspects in place, the initial exclusion and reintroduction phases can be difficult to follow. Not all the LFD studies have reported a beneficial outcome for IBS patients and first line dietary advice has also been reported as of similar efficacy to FODMAP reduction [76,77,78,79].
There is overlap between NCGS and IBS-type symptoms [8,10]. The fundamental difference between NCGS and IBS is that patients with NCGS self-report symptoms when consuming gluten and have identified or perceive gluten as the culprit. Conversely IBS patients do not report gluten as a specific stimulus for their symptoms. However, previously published literature has demonstrated that wheat is a commonly reported "food intolerance" when IBS patients are specifically questioned [63,64,65]. There is now a body of literature supporting the role of a GFD as a specific dietary intervention in IBS (Table 2). The mechanism by which wheat or specific wheat components such as gluten or ATIs cause IBS-type symptoms is debated. Wheat (and even gluten) contains a number of compounds, apart from gluten, that could produce a symptomatic response; perhaps the most obvious of these are FODMAPS, specifically fructans (Figure 1 and Figure 2). One trial showed that individuals with self-reported NCGS (and IBS-type symptoms) already on a GFD further benefited when placed on a low FODMAP diet and found no specific or dose-dependent effect of gluten [80]. However, the participants reported very high visual analogue scale ratings for their symptoms at the start of the study when they were already on a GFD. This is unlikely to be representative of the NCGS population. Furthermore, this study's double-blind placebo-controlled crossover design, where all participants cycled through high-dose, low-dose or no gluten control diets could have produced an anticipatory nocebo response [81]. It is also interesting to note that all the participants returned to a GFD at the end of the trial as they "subjectively described feeling better" [82]. Research into the GFD in the treatment of IBS-D is summarized in Table 2.
Based on current evidence a gluten (and thus wheat) free diet also appears to be a potential dietary intervention for a subgroup of IBS patients and the term of gluten sensitive IBS has been coined. Like a LFD, a GFD has been shown to cause a reduction of lacto and bifidobacteria in the gut. There are also some studies suggesting lower intake of calcium, iron, folate and fiber, when compared to a gluten-containing diet [95,96,97,98]. There is clearly overlap between a GFD and a LFD. One of the key excluded components of a LFD is wheat; furthermore, patients on a long-term LFD (following the reintroduction phase) appear to view the reduced intake of wheat as essential to their maintained symptomatic response [99]. Thus, a GFD may be a more practical option for IBS patients, which does not impair their food-related quality of life to the same level as a LFD (Figure 3).
3. Conclusions
Since our initial consensus document of 2012 there has been a significant expansion of the published data in the field of gluten-related disorders. We now have an appreciation of two groups of patients who may benefit from a GFD, firstly those who present with self-reported gluten-related symptoms and may have NCGS and secondly those who present with IBS-type symptoms and could have gluten or wheat sensitive IBS. Clinicians involved in the management of IBS now have an exciting range of dietary interventions that may benefit their patients (Figure 3).
Author Contributions
All authors provided input on the content of the manuscript. All authors read and approved the final manuscript.
Conflicts of Interest
This paper was made possible by support from Schär Institute for traveling and lodging sponsorship for all co-authors to meet to discuss the object of this paper.
- Ellis, A.; Linaker, B.D. Non-coeliac gluten sensitivity? Lancet 1978, 1, 1358–1359. [Google Scholar] [CrossRef]
- Catassi, C.; Elli, L.; Bonaz, B.; Bouma, G.; Carroccio, A.; Castillejo, G.; Cellier, C.; Cristofori, F.; de Magistris, L.; Dolinsek, J.; et al. Diagnosis of non-celiac gluten sensitivity (NCGS): The salerno experts' criteria. Nutrients 2015, 7, 4966–4977. [Google Scholar] [CrossRef] [PubMed]
- Sapone, A.; Bai, J.C.; Ciacci, C.; Dolinsek, J.; Green, P.H.; Hadjivassiliou, M.; Kaukinen, K.; Rostami, K.; Sanders, D.S.; Schumann, M.; et al. Spectrum of gluten-related disorders: Consensus on new nomenclature and classification. BMC Med. 2012, 10, 13. [Google Scholar] [CrossRef] [PubMed]
- Catassi, C.; Bai, J.C.; Bonaz, B.; Bouma, G.; Calabro, A.; Carroccio, A.; Castillejo, G.; Ciacci, C.; Cristofori, F.; Dolinsek, J.; et al. Non-celiac gluten sensitivity: The new frontier of gluten related disorders. Nutrients 2013, 5, 3839–3853. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Tanpowpong, P.; Ingham, T.R.; Lampshire, P.K.; Kirchberg, F.F.; Epton, M.J.; Crane, J.; Camargo, C.A., Jr.; New Zealand Asthma and Allergy Cohort Study Group. Coeliac disease and gluten avoidance in New Zealand children. Arch. Dis. Child. 2012, 97, 12–16. [Google Scholar] [CrossRef] [PubMed]
- Rubio-Tapia, A.; Ludvigsson, J.F.; Brantner, T.L.; Murray, J.A.; Everhart, J.E. The prevalence of celiac disease in the United States. Am. J. Gastroenterol. 2012, 107, 1538–1544. [Google Scholar] [CrossRef] [PubMed]
- DiGiacomo, D.V.; Tennyson, C.A.; Green, P.H.; Demmer, R.T. Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: Results from the continuous national health and nutrition examination survey 2009–2010. Scand. J. Gastroenterol. 2013, 48, 921–925. [Google Scholar] [CrossRef] [PubMed]
- Aziz, I.; Lewis, N.R.; Hadjivassiliou, M.; Winfield, S.N.; Rugg, N.; Kelsall, A.; Newrick, L.; Sanders, D.S. A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care. Eur. J. Gastroenterol. Hepatol. 2014, 26, 33–39. [Google Scholar] [CrossRef] [PubMed]
- Lis, D.M.; Stellingwerff, T.; Shing, C.M.; Ahuja, K.D.; Fell, J.W. Exploring the popularity, experiences, and beliefs surrounding gluten-free diets in nonceliac athletes. Int. J. Sport Nutr. Exerc. Metab. 2015, 25, 37–45. [Google Scholar] [CrossRef] [PubMed]
- Volta, U.; Bardella, M.T.; Calabro, A.; Troncone, R.; Corazza, G.R.; The Study Group for Non-Celiac Gluten Sensitivity. An italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Med. 2014, 12, 85. [Google Scholar] [CrossRef] [PubMed]
- Golley, S.; Corsini, N.; Topping, D.; Morell, M.; Mohr, P. Motivations for avoiding wheat consumption in australia: Results from a population survey. Public Health Nutr. 2015, 18, 490–499. [Google Scholar] [CrossRef] [PubMed]
- Mardini, H.E.; Westgate, P.; Grigorian, A.Y. Racial differences in the prevalence of celiac disease in the us population: National health and nutrition examination survey (NHANES) 2009–2012. Dig. Dis. Sci. 2015, 60, 1738–1742. [Google Scholar] [CrossRef] [PubMed]
- Van Gils, T.; Nijeboer, P.; IJssennagger, C.E.; Sanders, D.S.; Mulder, C.J.; Bouma, G. Prevalence and characterization of self-reported gluten sensitivity in The Netherlands. Nutrients 2016, 8, 714. [Google Scholar] [CrossRef] [PubMed]
- Carroccio, A.; Giambalvo, O.; Blasca, F.; Iacobucci, R.; D'Alcamo, A.; Mansueto, P. Self-reported non-celiac wheat sensitivity in high school students: Demographic and clinical characteristics. Nutrients 2017, 9, 771. [Google Scholar] [CrossRef] [PubMed]
- Kaukinen, K.; Turjanmaa, K.; Maki, M.; Partanen, J.; Venalainen, R.; Reunala, T.; Collin, P. Intolerance to cereals is not specific for coeliac disease. Scand. J. Gastroenterol. 2000, 35, 942–946. [Google Scholar] [CrossRef] [PubMed]
- Kabbani, T.A.; Vanga, R.R.; Leffler, D.A.; Villafuerte-Galvez, J.; Pallav, K.; Hansen, J.; Mukherjee, R.; Dennis, M.; Kelly, C.P. Celiac disease or non-celiac gluten sensitivity? An approach to clinical differential diagnosis. Am. J. Gastroenterol. 2014, 109, 741–746. [Google Scholar] [CrossRef] [PubMed]
- Raju, S.A.; Mooney, P.D.; Aziz, I.; Kurien, M.; Sanders, D.S. Letter: Gluten challenge in the era of noncoeliac gluten sensitivity—A change in clinical practice? Aliment. Pharmacol. Ther. 2016, 43, 656. [Google Scholar] [CrossRef] [PubMed]
- Coburn, J.A.; Vande Voort, J.L.; Lahr, B.D.; Van Dyke, C.T.; Kroning, C.M.; Wu, T.T.; Gandhi, M.J.; Murray, J.A. Human leukocyte antigen genetics and clinical features of self-treated patients on a gluten-free diet. J. Clin. Gastroenterol. 2013, 47, 828–833. [Google Scholar] [CrossRef] [PubMed]
- Aziz, I.; Hadjivassiliou, M.; Sanders, D.S. Self-reported gluten sensitivity: An international concept in need of consensus? Am. J. Gastroenterol. 2014, 109, 1498–1499. [Google Scholar] [CrossRef] [PubMed]
- Turnbull, J.L.; Adams, H.N.; Gorard, D.A. Review article: The diagnosis and management of food allergy and food intolerances. Aliment. Pharmacol. Ther. 2015, 41, 3–25. [Google Scholar] [CrossRef] [PubMed]
- Bischoff, S.; Crowe, S.E. Gastrointestinal food allergy: New insights into pathophysiology and clinical perspectives. Gastroenterology 2005, 128, 1089–1113. [Google Scholar] [CrossRef] [PubMed]
- Carroccio, A.; Mansueto, P.; D'Alcamo, A.; Iacono, G. Non-celiac wheat sensitivity as an allergic condition: Personal experience and narrative review. Am. J. Gastroenterol. 2013, 108, 1845–1852. [Google Scholar] [CrossRef] [PubMed]
- Volta, U.; Tovoli, F.; Cicola, R.; Parisi, C.; Fabbri, A.; Piscaglia, M.; Fiorini, E.; Caio, G. Serological tests in gluten sensitivity (nonceliac gluten intolerance). J. Clin. Gastroenterol. 2012, 46, 680–685. [Google Scholar] [CrossRef] [PubMed]
- Carroccio, A.; Brusca, I.; Mansueto, P.; Pirrone, G.; Barrale, M.; Di Prima, L.; Ambrosiano, G.; Iacono, G.; Lospalluti, M.L.; La Chiusa, S.M.; et al. A cytologic assay for diagnosis of food hypersensitivity in patients with irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 2010, 8, 254–260. [Google Scholar] [CrossRef] [PubMed]
- Carroccio, A.; Mansueto, P.; Iacono, G.; Soresi, M.; D'Alcamo, A.; Cavataio, F.; Brusca, I.; Florena, A.M.; Ambrosiano, G.; Seidita, A.; et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: Exploring a new clinical entity. Am. J. Gastroenterol. 2012, 107, 1898–1906. [Google Scholar] [CrossRef] [PubMed]
- Fritscher-Ravens, A.; Schuppan, D.; Ellrichmann, M.; Schoch, S.; Rocken, C.; Brasch, J.; Bethge, J.; Bottner, M.; Klose, J.; Milla, P.J. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 2014, 147, 1012–1020. [Google Scholar] [CrossRef] [PubMed]
- Carroccio, A.; Soresi, M.; D'Alcamo, A.; Sciume, C.; Iacono, G.; Geraci, G.; Brusca, I.; Seidita, A.; Adragna, F.; Carta, M.; et al. Risk of low bone mineral density and low body mass index in patients with non-celiac wheat-sensitivity: A prospective observation study. BMC Med. 2014, 12, 230. [Google Scholar] [CrossRef] [PubMed]
- Sapone, A.; Lammers, K.M.; Casolaro, V.; Cammarota, M.; Giuliano, M.T.; De Rosa, M.; Stefanile, R.; Mazzarella, G.; Tolone, C.; Russo, M.I.; et al. Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: Celiac disease and gluten sensitivity. BMC Med. 2011, 9, 23. [Google Scholar] [CrossRef] [PubMed]
- Sapone, A.; Lammers, K.M.; Mazzarella, G.; Mikhailenko, I.; Carteni, M.; Casolaro, V.; Fasano, A. Differential mucosal il-17 expression in two gliadin-induced disorders: Gluten sensitivity and the autoimmune enteropathy celiac disease. Int. Arch. Allergy Immunol. 2010, 152, 75–80. [Google Scholar] [CrossRef] [PubMed]
- Di Liberto, D.; Mansueto, P.; D'Alcamo, A.; Lo Pizzo, M.; Lo Presti, E.; Geraci, G.; Fayer, F.; Guggino, G.; Iacono, G.; Dieli, F.; et al. Predominance of type 1 innate lymphoid cells in the rectal mucosa of patients with non-celiac wheat sensitivity: Reversal after a wheat-free diet. Clin. Transl. Gastroenterol. 2016, 7, e178. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Hollon, J.; Puppa, E.L.; Greenwald, B.; Goldberg, E.; Guerrerio, A.; Fasano, A. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Nutrients 2015, 7, 1565–1576. [Google Scholar] [CrossRef] [PubMed]
- Uhde, M.; Ajamian, M.; Caio, G.; De Giorgio, R.; Indart, A.; Green, P.H.; Verna, E.C.; Volta, U.; Alaedini, A. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut 2016, 65, 1930–1937. [Google Scholar] [CrossRef] [PubMed]
- Prospective, Double-Blind Diagnostic Study of Confocal Laser Endomicroscopy (CLE) for Wheat Sensitivity (WS) in Patients with Irritable Bowel Syndrome. German Clinical Trials Register. Available online: http://apps.who.int/trialsearch/trial2.Aspx?Trialid=drks00010123 (accessed on 18 August 2017).
- Pinto-Sanchez, M.I.; Verdu, E.F. Non-coeliac gluten sensitivity: Are we closer to separating the wheat from the chaff? Gut 2016, 65, 1921–1922. [Google Scholar] [CrossRef] [PubMed]
- Junker, Y.; Zeissig, S.; Kim, S.J.; Barisani, D.; Wieser, H.; Leffler, D.A.; Zevallos, V.; Libermann, T.A.; Dillon, S.; Freitag, T.L.; et al. Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. J. Exp. Med. 2012, 209, 2395–2408. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Gibson, P.R.; Varney, J.; Malakar, S.; Muir, J.G. Food components and irritable bowel syndrome. Gastroenterology 2015, 148, 1158–1174. [Google Scholar] [CrossRef] [PubMed]
- De Punder, K.; Pruimboom, L. The dietary intake of wheat and other cereal grains and their role in inflammation. Nutrients 2013, 5, 771–787. [Google Scholar] [CrossRef] [PubMed]
- Scherf, K.A.; Koehler, P.; Wieser, H. Gluten and wheat sensitivities—An overview. J. Cereal Sci. 2016, 67, 2–11. [Google Scholar] [CrossRef]
- Maiuri, L.; Ciacci, C.; Ricciardelli, I.; Vacca, L.; Raia, V.; Auricchio, S.; Picard, J.; Osman, M.; Quaratino, S.; Londei, M. Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease. Lancet 2003, 362, 30–37. [Google Scholar] [CrossRef]
- Frossi, B.; Tripodo, C.; Guarnotta, C.; Carroccio, A.; De Carli, M.; De Carli, S.; Marino, M.; Calabro, A.; Pucillo, C.E. Mast cells are associated with the onset and progression of celiac disease. J. Allergy Clin. Immunol. 2017, 139, 1266–1274. [Google Scholar] [CrossRef] [PubMed]
- Hajas, L.; Scherf, K.A.; Torok, K.; Bugyi, Z.; Schall, E.; Poms, R.E.; Koehler, P.; Tomoskozi, S. Variation in Protein Composition among Wheat (Triticum aestivum L.) Cultivars to Identify Cultivars Suitable as Reference Material for Wheat Gluten Analysis. Food Chem. 2017. [Google Scholar] [CrossRef]
- Tatham, A.S.; Shewry, P.R. Allergens to wheat and related cereals. Clin. Exp. Allergy 2008, 38, 1712–1726. [Google Scholar] [PubMed]
- Gomez, L.; Martin, E.; Hernandez, D.; Sanchez-Monge, R.; Barber, D.; del Pozo, V.; de Andres, B.; Armentia, A.; Lahoz, C.; Salcedo, G.; et al. Members of the alpha-amylase inhibitors family from wheat endosperm are major allergens associated with baker's asthma. FEBS Lett. 1990, 261, 85–88. [Google Scholar] [CrossRef]
- Zevallos, V.F.; Raker, V.; Tenzer, S.; Jimenez-Calvente, C.; Ashfaq-Khan, M.; Russel, N.; Pickert, G.; Schild, H.; Steinbrink, K.; Schuppan, D. Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells. Gastroenterology 2017, 152, 1100–1113. [Google Scholar] [CrossRef] [PubMed]
- Dalla Pellegrina, C.; Perbellini, O.; Scupoli, M.T.; Tomelleri, C.; Zanetti, C.; Zoccatelli, G.; Fusi, M.; Peruffo, A.; Rizzi, C.; Chignola, R. Effects of wheat germ agglutinin on human gastrointestinal epithelium: Insights from an experimental model of immune/epithelial cell interaction. Toxicol. Appl. Pharmacol. 2009, 237, 146–153. [Google Scholar] [CrossRef] [PubMed]
- Haska, L.; Nyman, M.; Andersson, R. Distribution and characterisation of fructan in wheat milling fractions. J. Cereal Sci. 2008, 48, 768–774. [Google Scholar] [CrossRef]
- Brouns, F.; Delzenne, N.; Gibson, G. The dietary fibers-FODMAPs controversy. Cereal Foods World 2017, 62, 768–774. [Google Scholar] [CrossRef]
- Biesiekierski, J.R.; Rosella, O.; Rose, R.; Liels, K.; Barrett, J.S.; Shepherd, S.J.; Gibson, P.R.; Muir, J.G. Quantification of fructans, galacto-oligosacharides and other short-chain carbohydrates in processed grains and cereals. J. Hum. Nutr. Diet. 2011, 24, 154–176. [Google Scholar] [CrossRef] [PubMed]
- Whelan, K.; Abrahmsohn, O.; David, G.J.; Staudacher, H.; Irving, P.; Lomer, M.C.; Ellis, P.R. Fructan content of commonly consumed wheat, rye and gluten-free breads. Int. J. Food Sci. Nutr. 2011, 62, 498–503. [Google Scholar] [CrossRef] [PubMed]
- Chey, W.D. Food: The main course to wellness and illness in patients with irritable bowel syndrome. Am. J. Gastroenterol. 2016, 111, 366–371. [Google Scholar] [CrossRef] [PubMed]
- Volta, U.; Pinto-Sanchez, M.I.; Boschetti, E.; Caio, G.; De Giorgio, R.; Verdu, E.F. Dietary triggers in irritable bowel syndrome: Is there a role for gluten? J. Neurogastroenterol. Motil. 2016, 22, 547–557. [Google Scholar] [CrossRef] [PubMed]
- Hayes, P.A.; Fraher, M.H.; Quigley, E.M. Irritable bowel syndrome: The role of food in pathogenesis and management. Gastroenterol. Hepatol. 2014, 10, 164–174. [Google Scholar]
- De Giorgio, R.; Volta, U.; Gibson, P.R. Sensitivity to wheat, gluten and FODMAPs in IBS: Facts or fiction? Gut 2016, 65, 169–178. [Google Scholar] [CrossRef] [PubMed]
- Natividad, J.M.; Huang, X.; Slack, E.; Jury, J.; Sanz, Y.; David, C.; Denou, E.; Yang, P.; Murray, J.; McCoy, K.D.; et al. Host responses to intestinal microbial antigens in gluten-sensitive mice. PLoS ONE 2009, 4, e6472. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Wu, R.L.; Vazquez-Roque, M.I.; Carlson, P.; Burton, D.; Grover, M.; Camilleri, M.; Turner, J.R. Gluten-induced symptoms in diarrhea-predominant irritable bowel syndrome are associated with increased myosin light chain kinase activity and claudin-15 expression. Lab. Investig. 2017, 97, 14–23. [Google Scholar] [CrossRef] [PubMed]
- Volta, U.; Caio, G.; Karunaratne, T.B.; Alaedini, A.; De Giorgio, R. Non-coeliac gluten/wheat sensitivity: Advances in knowledge and relevant questions. Expert Rev. Gastroenterol. Hepatol. 2017, 11, 9–18. [Google Scholar] [CrossRef] [PubMed]
- Dalrymple, J.; Bullock, I. Diagnosis and management of irritable bowel syndrome in adults in primary care: Summary of nice guidance. BMJ 2015, 350, h1216. [Google Scholar] [CrossRef] [PubMed]
- Lovell, R.M.; Ford, A.C. Global prevalence of and risk factors for irritable bowel syndrome: A meta-analysis. Clin. Gastroenterol. Hepatol. 2012, 10, 712–721. [Google Scholar] [CrossRef] [PubMed]
- Canavan, C.; West, J.; Card, T. The epidemiology of irritable bowel syndrome. Clin. Epidemiol. 2014, 6, 71–80. [Google Scholar] [PubMed]
- Whitehead, W.E.; Palsson, O.; Jones, K.R. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: What are the causes and implications? Gastroenterology 2002, 122, 1140–1156. [Google Scholar] [CrossRef] [PubMed]
- Akehurst, R.L.; Brazier, J.E.; Mathers, N.; O'Keefe, C.; Kaltenthaler, E.; Morgan, A.; Platts, M.; Walters, S.J. Health-related quality of life and cost impact of irritable bowel syndrome in a UK primary care setting. Pharmacoeconomics 2002, 20, 455–462. [Google Scholar] [CrossRef] [PubMed]
- Drossman, D.A. Functional gastrointestinal disorders: History, pathophysiology, clinical features and Rome IV. Gastroenterology 2016, 150, 1262–1279. [Google Scholar] [CrossRef] [PubMed]
- Morcos, A.; Dinan, T.; Quigley, E.M. Irritable bowel syndrome: Role of food in pathogenesis and management. J. Dig. Dis. 2009, 10, 237–246. [Google Scholar] [CrossRef] [PubMed]
- Bohn, L.; Storsrud, S.; Tornblom, H.; Bengtsson, U.; Simren, M. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am. J. Gastroenterol. 2013, 108, 634–641. [Google Scholar] [CrossRef] [PubMed][Green Version]
- McKenzie, Y.A.; Thompson, J.; Gulia, P.; Lomer, M.C. British dietetic association systematic review of systematic reviews and evidence-based practice guidelines for the use of probiotics in the management of irritable bowel syndrome in adults (2016 update). J. Hum. Nutr. Diet. 2016, 29, 576–592. [Google Scholar] [CrossRef] [PubMed]
- Jones, V.A.; McLaughlan, P.; Shorthouse, M.; Workman, E.; Hunter, J.O. Food intolerance: A major factor in the pathogenesis of irritable bowel syndrome. Lancet 1982, 2, 1115–1117. [Google Scholar] [CrossRef]
- King, T.S.; Elia, M.; Hunter, J.O. Abnormal colonic fermentation in irritable bowel syndrome. Lancet 1998, 352, 1187–1189. [Google Scholar] [CrossRef]
- Shepherd, S.J.; Gibson, P.R. Fructose malabsorption and symptoms of irritable bowel syndrome: Guidelines for effective dietary management. J. Am. Diet. Assoc. 2006, 106, 1631–1639. [Google Scholar] [CrossRef] [PubMed]
- Marsh, A.; Eslick, E.M.; Eslick, G.D. Does a diet low in FODMAPs reduce symptoms associated with functional gastrointestinal disorders? A comprehensive systematic review and meta-analysis. Eur. J. Nutr. 2016, 55, 897–906. [Google Scholar] [CrossRef] [PubMed]
- Francis, C.Y.; Morris, J.; Whorwell, P.J. The irritable bowel severity scoring system: A simple method of monitoring irritable bowel syndrome and its progress. Aliment. Pharmacol. Ther. 1997, 11, 395–402. [Google Scholar] [CrossRef] [PubMed]
- Staudacher, H.M.; Lomer, M.C.E.; Whelan, K.; Irving, P. Pth-064 implementation of the low-fermentable oligo-, di-, mono-saccharides and polyols diet in the UK: How easy is it and does it work? Abstract pth-064. Gut 2010, 59. [Google Scholar] [CrossRef]
- Staudacher, H.; Ross, F.S.; Briscoe, Z.M.; Irving, P.M.; Whelan, K.; Lomer, M.C. Ptu-183 advice from a dietitian regarding the low FODMAP diet broadly maintains nutrient intake and does not alter fibre intake. Gut 2015, 64. [Google Scholar] [CrossRef]
- Rao, S.S.; Yu, S.; Fedewa, A. Systematic review: Dietary fibre and FODMAP-restricted diet in the management of constipation and irritable bowel syndrome. Aliment. Pharmacol. Ther. 2015, 41, 1256–1270. [Google Scholar] [CrossRef] [PubMed]
- Staudacher, H.M.; Lomer, M.C.; Anderson, J.L.; Barrett, J.S.; Muir, J.G.; Irving, P.M.; Whelan, K. Fermentable carbohydrate restriction reduces luminal bifidobacteria and gastrointestinal symptoms in patients with irritable bowel syndrome. J. Nutr. 2012, 142, 1510–1518. [Google Scholar] [CrossRef] [PubMed]
- Halmos, E.P.; Christophersen, C.T.; Bird, A.R.; Shepherd, S.J.; Gibson, P.R.; Muir, J.G. Diets that differ in their FODMAP content alter the colonic luminal microenvironment. Gut 2015, 64, 93–100. [Google Scholar] [CrossRef] [PubMed]
- Bohn, L.; Storsrud, S.; Liljebo, T.; Collin, L.; Lindfors, P.; Tornblom, H.; Simren, M. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: A randomized controlled trial. Gastroenterology 2015, 149, 1399–1407. [Google Scholar] [CrossRef] [PubMed]
- Whigham, L.; Joyce, T.; Harper, G.; Irving, P.M.; Staudacher, H.M.; Whelan, K.; Lomer, M.C. Clinical effectiveness and economic costs of group versus one-to-one education for short-chain fermentable carbohydrate restriction (low FODMAP diet) in the management of irritable bowel syndrome. J. Hum. Nutr. Diet. 2015, 28, 687–696. [Google Scholar] [CrossRef] [PubMed]
- Chey, W.D.; Whelan, K. Dietary guidelines for irritable bowel syndrome are important for gastroenterologists, dietitians and people with irritable bowel syndrome. J. Hum. Nutr. Diet. 2016, 29, 547–548. [Google Scholar] [CrossRef] [PubMed]
- Eswaran, S.L.; Chey, W.D.; Han-Markey, T.; Ball, S.; Jackson, K. A randomized controlled trial comparing the low FODMAP diet vs. Modified nice guidelines in US adults with IBS-D. Am. J. Gastroenterol. 2016, 111, 1824–1832. [Google Scholar] [CrossRef] [PubMed]
- Biesiekierski, J.R.; Peters, S.L.; Newnham, E.D.; Rosella, O.; Muir, J.G.; Gibson, P.R. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology 2013, 145, 320–328. [Google Scholar] [CrossRef] [PubMed]
- Aziz, I.; Hadjivassiliou, M.; Sanders, D.S. The spectrum of noncoeliac gluten sensitivity. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 516–526. [Google Scholar] [CrossRef] [PubMed]
- Peters, S.L.; Biesiekierski, J.R.; Yelland, G.W.; Muir, J.G.; Gibson, P.R. Randomised clinical trial: Gluten may cause depression in subjects with non-coeliac gluten sensitivity—An exploratory clinical study. Aliment. Pharmacol. Ther. 2014, 39, 1104–1112. [Google Scholar] [CrossRef] [PubMed]
- Wahnschaffe, U.; Ullrich, R.; Riecken, E.O.; Schulzke, J.D. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 2001, 121, 1329–1338. [Google Scholar] [CrossRef] [PubMed]
- Wahnschaffe, U.; Schulzke, J.D.; Zeitz, M.; Ullrich, R. Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 2007, 5, 844–850. [Google Scholar] [CrossRef] [PubMed]
- Biesiekierski, J.R.; Newnham, E.D.; Irving, P.M.; Barrett, J.S.; Haines, M.; Doecke, J.D.; Shepherd, S.J.; Muir, J.G.; Gibson, P.R. Gluten causes gastrointestinal symptoms in subjects without celiac disease: A double-blind randomized placebo-controlled trial. Am. J. Gastroenterol. 2011, 106, 508–514. [Google Scholar] [CrossRef] [PubMed]
- Vazquez-Roque, M.I.; Camilleri, M.; Smyrk, T.; Murray, J.A.; O'Neill, J.; Carlson, P.; Lamsam, J.; Eckert, D.; Janzow, D.; Burton, D.; et al. Association of hla-dq gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303, G1262–G1269. [Google Scholar] [CrossRef] [PubMed]
- Vazquez-Roque, M.I.; Camilleri, M.; Smyrk, T.; Murray, J.A.; Marietta, E.; O'Neill, J.; Carlson, P.; Lamsam, J.; Janzow, D.; Eckert, D.; et al. A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: Effects on bowel frequency and intestinal function. Gastroenterology 2013, 144, 903–911. [Google Scholar] [CrossRef] [PubMed]
- Aziz, I.; Trott, N.; Briggs, R.; North, J.R.; Hadjivassiliou, M.; Sanders, D.S. Efficacy of a gluten-free diet in subjects with irritable bowel syndrome-diarrhea unaware of their HLA-DQ2/8 genotype. Clin. Gastroenterol. Hepatol. 2016, 14, 696–703. [Google Scholar] [CrossRef] [PubMed]
- Di Sabatino, A.; Volta, U.; Salvatore, C.; Biancheri, P.; Caio, G.; De Giorgio, R.; Di Stefano, M.; Corazza, G.R. Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: A randomized, double-blind, placebo-controlled, cross-over trial. Clin. Gastroenterol. Hepatol. 2015, 13, 1604–1612. [Google Scholar] [CrossRef] [PubMed]
- Shahbazkhani, B.; Sadeghi, A.; Malekzadeh, R.; Khatavi, F.; Etemadi, M.; Kalantri, E.; Rostami-Nejad, M.; Rostami, K. Non-celiac gluten sensitivity has narrowed the spectrum of irritable bowel syndrome: A double-blind randomized placebo-controlled trial. Nutrients 2015, 7, 4542–4554. [Google Scholar] [CrossRef] [PubMed]
- Zanini, B.; Basche, R.; Ferraresi, A.; Ricci, C.; Lanzarotto, F.; Marullo, M.; Villanacci, V.; Hidalgo, A.; Lanzini, A. Randomised clinical study: Gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non-coeliac gluten sensitivity. Aliment. Pharmacol. Ther. 2015, 42, 968–976. [Google Scholar] [CrossRef] [PubMed]
- Zanwar, V.G.; Pawar, S.V.; Gambhire, P.A.; Jain, S.S.; Surude, R.G.; Shah, V.B.; Contractor, Q.Q.; Rathi, P.M. Symptomatic improvement with gluten restriction in irritable bowel syndrome: A prospective, randomized, double blinded placebo controlled trial. Intest. Res. 2016, 14, 343–350. [Google Scholar] [CrossRef] [PubMed]
- Elli, L.; Tomba, C.; Branchi, F.; Roncoroni, L.; Lombardo, V.; Bardella, M.T.; Ferretti, F.; Conte, D.; Valiante, F.; Fini, L.; et al. Evidence for the presence of non-celiac gluten sensitivity in patients with functional gastrointestinal symptoms: Results from a multicenter randomized double-blind placebo-controlled gluten challenge. Nutrients 2016, 8, 84. [Google Scholar] [CrossRef] [PubMed]
- Barmeyer, C.; Schumann, M.; Meyer, T.; Zielinski, C.; Zuberbier, T.; Siegmund, B.; Schulzke, J.D.; Daum, S.; Ullrich, R. Long-term response to gluten-free diet as evidence for non-celiac wheat sensitivity in one third of patients with diarrhea-dominant and mixed-type irritable bowel syndrome. Int. J. Colorectal Dis. 2017, 32, 29–39. [Google Scholar] [CrossRef] [PubMed]
- De Palma, G.; Nadal, I.; Collado, M.C.; Sanz, Y. Effects of a gluten-free diet on gut microbiota and immune function in healthy adult human subjects. Br. J. Nutr. 2009, 102, 1154–1160. [Google Scholar] [CrossRef] [PubMed]
- Nistal, E.; Caminero, A.; Vivas, S.; Ruiz de Morales, J.M.; Saenz de Miera, L.E.; Rodriguez-Aparicio, L.B.; Casqueiro, J. Differences in faecal bacteria populations and faecal bacteria metabolism in healthy adults and celiac disease patients. Biochimie 2012, 94, 1724–1729. [Google Scholar] [CrossRef] [PubMed]
- Wild, D.; Robins, G.G.; Burley, V.J.; Howdle, P.D. Evidence of high sugar intake, and low fibre and mineral intake, in the gluten-free diet. Aliment. Pharmacol. Ther. 2010, 32, 573–581. [Google Scholar] [CrossRef] [PubMed]
- Kinsey, L.; Burden, S.T.; Bannerman, E. A dietary survey to determine if patients with coeliac disease are meeting current healthy eating guidelines and how their diet compares to that of the british general population. Eur. J. Clin. Nutr. 2008, 62, 1333–1342. [Google Scholar] [CrossRef] [PubMed]
- Martin, L.; Van Vuuren, C.; Seamark, L.; Williams, M.; Staudacher, H.; Irving, P.M.; Whelan, K.; Lomer, M.C. Long-term effectiveness of short chain fermentable carbohydrate (FODMAP) restriction in patients with IBS. In Proceedings of the 2nd Digestive Disorders Federation Conference, London, UK, 22–25 June 2015. [Google Scholar]
Figure 1. Potential triggers in wheat that may account for both intestinal and extra-intestinal symptoms.
|Year of Publication
|Sample Size
|Avoidance of Gluten-Based Products
|Known Previous Diagnosis of CD
|Tanpowpong et al. [5]
|New Zealand
|Children-general population
|5% (n = 48)
|1% (n = 9)
|Rubio-Tapia et al. [6]
|Age ≥ 6 years, National Health and Nutrition Examination Survey (NHANES) 2009–2010
|0.63% (n = 55)
|0.1% (n = 6)
|DiGiacomo et al. [7]
|Aziz et al. [8]
|Adults-general population
|3.7% (n = 37)
|0.8% (n = 8)
|Lis et al. [9]
|41.2% (n = 375)
|Volta et al. [10]
|Adult and pediatric GI clinic population
|391 (3.2%)
|Within same population 340 (2.8%) coeliac patients diagnosed
|Golley et al. [11]
|Adults-general population
|10.6% (n = 126)
|1.2% (n = 14)
|Mardini et al. [12]
|Age ≥ 6 years, NHANES
2009–2010 & 2011–2012 data combined
|0.9% (n = 142)
|0.1% (n = 21)
|Van Gils T et al. [13]
|The Netherlands
|Adults-general population
|6.2% (49/785)
|0.25% (2/785)
|Carroccio A et al. [14]
|Age 14–18
|2.9% (16/548)
|1.26% (7/555)
|Lead Author
|Wahnschaffe [83]
|102 IBS-D without CD
|Stool frequency significantly improved in patients HLA DQ2/DQ8 + ve
|Wahnschaffe [84]
|145 IBS-D without CD
|HLA-DQ2 predicted response to GFD
|Biesikierski [85]
|Significant reduction in symptoms in GFD group
|Carroccio [25]
|920 patients with IBS
|70 patients wheat-sensitive and 206 food sensitivities
|Vazquez-Roque [86]
|45 patients with IBS-D
|Increased intestinal permeability in patients receiving gluten
|Vazquez-Roque [87]
|45 patients with IBS-D
|Reduction in stool frequency in patients on GFD
|Biesikierski [80]
|37 NCGWS on GFD
|Patients responded to reduction in FODMAPs during run-in but no difference between GFD and gluten-containing arms
|Fritscher-Ravens [26]
|36 patients with food-sensitive IBS 13/36 GFD after positive wheat challenge in CLE
|All patients improved significantly on the GFD for at least one year
|Aziz [88]
|40 patients with IBS-D
|70% had reduced symptomology with GFD for 6 weeks
|Di Sabatino [89]
|59 self-reported NCGWS
|4 g of gluten per day for 1 week increased overall clinical symptoms compared with placebo in (p = 0.034)
|Shahbazkhani [90]
|72 patients with IBS (Based on Rome III criteria)
|Worsening of intestinal symptoms with gluten compared to placebo
|Zanini [91]
|35 NCGWS on a GFD
|Given either and containing or gluten-free flour. 34% symptomatic with gluten-containing flour, 49% symptomatic with gluten-free flour, 17% no response
|Zanwar [92]
|60 patients with IBS (Based on Rome III criteria)
|GFD for 4 weeks. Significant reduction in visual analogue scales (VAS) of symptomology
|Elli [93]
|140 patients enrolled
|14% of patients shown to have symptomatic response to gluten on repeat challenge
|Barmeyer [94]
|34 patients with IBS
|34% responded to a GFD and continued on a GFD at 1 year
© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).


text:
Click-through rate or CTR is a way of measuring the success of an online advertising campaign. A CTR is obtained by dividing the number of users who clicked on an ad on a link, banner, or email creative by the number of impressions. For example, if a banner ad was delivered 100 times and one person clicked on it, then the resulting CTR would be 1 percent. This metric is good for PPC, search, email and banner advertising to determining the success of creative and the appropriateness of the placement.
What are CTRs?
Did you find it helpful? Yes NoSend feedback
Sorry we couldn't be helpful. Help us improve this article with your feedback.

subset: commoncrawl


text:
Absolutely loving the concept of Bagsy, small but perfectly formed handbag sized beauty products. I don't know what it is about the concept but something just feels fresh and appealing about the range. It is in part thanks to the packaging which I love. The exterior packaging is gorgeous, featuring whimsical patterns and gorgeous shades, while the interior packaging is is clean, simple and appealing.
While the range is really appealing the products I received are a bit of a mixed bag(sy). (Sorry).
Lets start off with the Bagsy Ray of Sunshine Perfect Glow Bronzing Powder in Medium/Dark £12.00*
Seriously, how gorgeous is this product? This shimmer free bronzer comes in a mirrored compact with a little pouch to keep it safe in your handbag. The shade, Medium/Dark is a little too dark for me, but I do love a matte bronzer, I'm not really sure shimmery bronzers are much use except for maybe nights out and this has a gorgeous soft blendable texture, it's also available in Light/Medium. I would recommend this, even though the shade wasn't quite right for me. See swatch at the end of the post.
Next up, the Bagsy Wonder Wand, Concealing & Illuminating Duo £18*
I love this product in principle, its a great item for your handbag, offering a concealer and a highlighter in one. Unfortunately, the execution of this one isn't great. The highlighter is fabulous, its blends beautifully to offer a gorgeous glowy highlight, but the concealer lets it down. The Wonder Wand is only available in the colour way shown, and the concealer is dark, you'll see from the swatches at the end that actually the concealer is darker than the bronzer, which considering the bronzer I have is medium/dark is especially surprising. It's not like you can even just use the highlighter, and nor should you at £18, the product just wouldn't work if you only used one half of it. It's so dark I don't even have any friends or family I can pass this over too. Shame really, they need to either make this product lighter, or add different colour ways. See swatches at the end of the post.
Finally, Bagsy Wow Lips Full Colour Chubby Stick in Killer Heels, £12*Hands down my favourite product. Available in four shades these are gorgeous. Creamy, opaque, easy to apply and best of all this shade, Killer Heels is glorious.
Swatches Left to Right, Wow Lips Chubby Stick in Killer Heels, Ray of Sunshine Bronzing Powder in Medium/Dark, Wonder Wand Highlighter and Concealer.
See what I mean about that Concealer? Its so so dark. But that highlighter is beautiful!
Other products in the range include Matte Lip Colours (yes please!), Pretty Cheeks Velvet Blush (oh yes please!) as well as hand creams, make up bags and more. Honestly its a great range, very appealing, well to me at least.
Exclusively available at Feel Unique, you can find the whole range here.
*Products received free of charge for review purposes.
Ooh! Lovely product alert! No7 have just released two new Shimmer Palettes, just in time for Summer, available in Rose and Caramel. I believe I have Caramel but confusingly it has a Rose label!
So meet the No7 Shimmer Palette in Caramel (but it could be Rose!)*
The palette itself is a beautiful metallic rose gold, mine doesn't look it because its reflecting my textured ceiling and light fitting, but its really nice.
Inside are four gorgeous soft, stripes of shimmering colour.
The colours swatch beautifully, they are soft and they are indeed shimmery, but happily, glitter free. Below are all four shades swatched separately, followed by a larger swatch on the far right of the shades blended together.
This is a beautiful product for Summer and I actually love how this looks on my skin, it's radiant and glowing. I would also think you could use it on your eyes, picking out the shades you wish to use with a brush, and that makes this a nice versatile purchase too.
Both shades are £13.50 each from Boots and there's a three for two offer on at the time of writing, so go forth and shop!
*Product received free of charge for review purposes.
I've not tried any Vivo Cosmetics for ages now so it was a surprise when these two popped through my letter box the other day. Meet the Vivo Shimmer Block Blusher and Shimmer Block Bronzer.
Now the last time I dipped into the world of cheap shimmer bricks/blocks, they were very soft very pigmented and VERY metallic cheek making. Not a look I love especially so I approached these with trepidation.
I needn't have worried, these are shimmery and they are pigmented but I can report that in the case of the blusher this is a definite hit. Dare I say that they are a very similar texture to the Bobbi Brown Shimmer Bricks? Yes I do dare say it, because it's true. Only a hell of a lot cheaper. Try £3.99.
Now I've not swatched each stripe individually because, although pretty, no one actually picks out individual shades to wear do they? If I'm wrong and you'd love individual stripe swatches please let me know, I'd be happy to do them!
Instead, here's how the blusher looks on me.
The next picture really makes me laugh, my hair is insane and I've got cross eyes but hey, look at my rosy cheeks!
It's a really lovely blusher and I'd happily pay more than the £3.99 it costs. I have to confess I've not tried out the Bronzer and I'm not sure I will, I don't do shimmery bronzers at all, in fact I rarely do bronzers!
But there you have it. The blusher definitely gets my seal of approval and I'm sure the bronzer is probably up to the same standard!
Get them HERE
*Disclosure – PR Samples*
Clinique have everything you need to get Summer ready and today I'm going to run through few of them!
*Disclosure – All items received free of charge for review purposes*
So here we are with part two of my posts about Clarin's gloriously summery Summer collection, Splendours.
If you missed my first part featuring all the lip products, you can find it here. Today I'm gonig to show you the Eye Shadow Palette and the Bronzer.
Starting with the Splendours Summer Bronzing Palette, which is £30.
There are no words really. This bronzer is beautiful. It's not only got a beautiful case, but the powder itself is stunning. It goes without saying that texture wise this is so soft and entirely buildable (although never dark or orange). I am wearing it in the final picture of this post, but I never go heavy on bronzers, it's not my thing, so don't be surprised if you can't spot it, just know that I'm even whiter without it!
Then the final thing I have to show you from the collection, the Splendours Colour Quartet and Eyeliner Palette which is £31. Again, the case itself is a thing of beauty and as they always are, the products in their pans are so pretty too.
Classic Summer colours, warm, shimmery, rich and very beautiful.
The only disappointment for me is the eyeliner shade, on the right, which is patchy and I struggle to get it to show up, but that said, all of the shades can be used wet or dry and I think it'll spring to life with a damp brush, so I'm going to try that next. As with all the Clarins Eyeshadow palettes, the colours are pigmented but soft so you can build and build but they blend like a dream. Absolutely stunning.
See how the liner barely shows up. But I'm confident wet it will do a good job.
It's a lovely lovely Summer palette, up to the usual high Clarins standard.
Here's how I wore it, with the Crystal Smooth Lip Balm in Crystal Rose, and indeed the Bronzing Powder, but as I mentioned, I always go very lightly with bronzer, so don't be expecting a bronzed goddess!
All of the above are available from Clarins counters nationwide now or www.clarins.co.uk/
That is all there to the Clarins Splendours collection, but it's certainly not all Clarins have to offer this Summer so stay tuned!
*Disclosure – PR Sample*
So I tried out a couple of the new Liz Earle colour cosmetics a few months ago, namely a lip gloss and the concealer. Both products were really nice, but they didn't rock my world as I just didn't find them that exciting. Quality wise, they were great, but I did struggle to find things to say about them, not because there was anything wrong with them, there was nothing wrong with them, but they just weren't that exciting and I do like to get excited about make up.
I am pleased to say I now have something from the line to be excited about, namely the Healthy Glow Powder Blush in Nectar and the Natural Glow Bronzer. Both are extremely lovely indeed.
Love the simple presentation for a start.
Both products are excellent, but the blusher is really special indeed. Along with foundation and brow products, blushers are my favourite cosmetic obsession and this has sky rocketed to the top of my charts. The blusher is £16.50, so not especially cheap, but worth it. The Blusher is available in seven shades, and I don't think Nectar could be any more perfect. Such a healthy pop of peachy pink colour. It builds well, it blends well, it delivers heaps of colour and I should think would work on most skin tones. Truly a gorgeous product. There is a hint of shimmer, nothing obvious, more of a glow I think.
Then there's the Natural Glow Bronzer, again at £19.50 it's not cheap but it performs very well. Pigment is excellent but it applies sheerly enough to build it up where you want it, and the colour is perfect for my pale skin. There is shimmer this time, but it's barely there shimmer. You really have to look for it. Perfect. I don't like shimmery bronzers as a rule, except for evenings.
Swatches of joyousness.
And the products on my face. my current favourite look, defined brows, mascara and Liz Earle cheeks, usually some gloss but I forgot to put it on for these pictures.
Gorgeous stuff, makes me excited to try more of the range now!
Both items are available from the Liz Earle website now.
Well, you can see my original post on the YSL Summer Collection here. I received a few bits from the collection but also bought a few so thought I'd show you some swatches and how I put them all together in order to look like this.
I'm kidding of course, I bear absolutely no resemblance whatsoever to this stunning model but hopefully I can show you how a normal person can make some of the products work for them this Summer.
So starting with the Rouge Pur Couture in Rouge Madras (£23.50)*
A truly stunning colour with a gorgeous finish. I love YSL Lipsticks, I'm not sure anyone does them better and this is no exception, its moisturising, comfortable and long wearing. I wouldn't have picked this shade out of the four available in the collection but it would have been error not to have got it!
Then we have the Terre Saharienne Collector Limited Edition Powder in Tanned (£39.00)*
A lovely light bronzer. One of those that is so pretty to look at, it's hard to use. There are three shades, two of which are matte, the third and largest has a light shimmer, it really is subtle on the face though imparting a soft glow rather than shimmer or glitter. In fact I'd had this for a few days before I even noticed the shimmer. It is very lovely and works very well on my pale colouring. In any pictures of my face in this blog post I am wearing it. It's subtle and lovely.
Swatches of the Terre Saharienne and Rouge Pur Couture.
I bought a few of the eye products for myself. I couldn't resist. First of all I got the Pure Chromatics Quad in No 7. (£39)
These wet and dry shadows are beautiful shades for Summer, or perhaps even Autumn. I wasn't at all sure they would work for me, but with a light hand they seem to work just fine. I do just love the colours so much especially teamed with the following products.
Dessin Du Regard Waterproof Eyeliner in Azure Blue (£19)
O.M.G. What a liner, what a colour. Intensely pigmented, smudge proof and waterproof. Apply this first thing in the morning and will look freshly applied in the evening, it's stunning. Works on the waterline and lash line, although doesn't last quite as long on the waterline. Swatches below. I must say I also swatched the gold version in store which is AMAZING. If I would have had the money I'd have gone back for the gold liner and the Pure Chromatics Pallet No. 9.
Mascara Volume Effet Faux Cils Waterproof in Majorelle Blue (£23)
Eighties-tastic. I had an Avon mascara like this back in the 80's and I'm totally loving this one! It's vivid, it's blue, it makes my lashes look great and it wears all day with no smudging, even with my watery eyes (thanks a bunch hayfever!).
Swatches of the above eye products.
Please excuse the eyebrows, not managed to get an appointment for ages!
The final item I have to show you is Dore Orfevre La Laque Couture.*
A beautiful molten gold polish that wears extremely well and applies like a dream. I love gold polish…but not on me, so this is a colour I'd recommend to others but not necessarily wear myself…I don't know why, I've just never liked gold polish on me. It's completely non-streaky, it doesn't have a frost finish, it does however show up every flaw in your nail, so if you have ridges, fill them first!
So to finish here are just a few pictures of my complete face.
So I'm pretty happy because I love the colours so much, but the big problem is that when I went into the store I realised that I need the gold liner, the Pure Chromatics No8 palette, the golden gloss in No52 (Golden Pebble) and at least two more of the lipsticks. Alas, I've spent my Summer make up allowance so I'll have to hope that they're still around at some point in the future.
Anything take your fancy? I think that whats so fab about this collection is that there is something for everything from the shimmery, to the creamy, to the neutral to the vivid. Absolutely gorgeous and out now!
*Items marked with a * were provided to me free of charge for review purposes*
It does seem a bit daft to be doing this post when the weather is so diabolical but you know, not only are the products suitable for the hot sunny weather, but you could just use them to get you in the Summer mood when its wet outside.
Starting with this beauty. My new love.
Givenchy Prisme Again in Happy Sun. I was gifted this so I don't really know how much it costs, but its a beautiful product. Soft and buttery and sheer. Not a hint of orange, just healthy subtle bronze glow. I've been completely unable to find this online anywhere other than Ebay, the ones on Ebay aren't the Union Jack version but are also gorgeous… it does however go without saying to be wary and keep your wits about you so you don't end up with a fake. I'll be trying Givenchy more in future that's for sure. Perfect for us pale skinned ladies.
The next item is something I was sent a press release for the other day.
The Weleda Summer Travel Kit. I have never tried Weleda, I've not tried anything in the kit but I've heard nothing but good things about the range and whilst this kit isn't on my wishlist purely because I'm not going on holiday, if I was going on holiday I'd definitely buy this! Fir £29.99 this is all you need. Actually, I've just read in the press release it's suitable for a UK holiday and I don't need much of an excuse so maybe I will treat myself. So what we've got in there is a 20ml Citrus Creamy Body Wash, a 30ml Citrus Deodorant and 10ml of Citrus Refreshing Body Oil. Then there's 30ml of Combudoron Spray for the relief of insect bites, 25ml Melissa Comp Drops to elieve nausea, stomach upset and occasional diarrhoea, perfect for over indulgence, travel sickness or a minor tummy upset and finally there's 20ml of Rhiondoron Nasal Spray with Aloe Vera for clearing and moisturising the nasal passages, perfect for dry air and high pollen counts. It really does sound like a great kit.
So if you put that together with the next kit and aside from your facial skin care and make up you'll be all set for your holiday.
The label.m Mini Airliner*. The deal is that for £12.99 you can choose any 4 label.m favourites in mini sizes which all go into the zipped pouch. You choose one Cleanse product, one Condition product and any two Create and Complete products. my kit contains the Daily Moisturising Shampoo, the Daily Shine Conditioner, both absolutely lovely, the Sea Salt Spray for your beachy waves and the Dry Shampoo which does a great job! These kits are available at label.m salons globally and Toni & Guy Salons. You can find your nearest stockist on the label.m website.
Then there's my new favourite deodorant.
Dove Natural Touch Dead Sea Minerals*. I have the roll on which is £2.19 but there's also an aerosol which is £3.39 or £2.49 depending on which size you like. I didn't think I liked roll on deodorants and have used the stick type of deodorants for years and years… it was a surprise to find I liked this one. It has a very strong scent which is absolutely lovely, but it does fade which is good news for those who don't like their deodorants to be strongly scented. It keeps me dry all day and it smells nice. That's all I need from a deodorant and this fits the bill well!
My final suggestion is this beauty. The Melvita Gradual Self-Tanning Moisturising Gel-Cream* £20
If you don't like the sun's rays on your skin but don't like being a pale skinned beauty, but also don't want to do the full on fake tan thing in order to be a bronzed goddess, this could be the product for you. It creates a natural looking light tan which is relatively streak free, for some reason I seem to be able to get at least one streak with every tan product I try and this is no exception, but I must say to have only one little streak is virtually unheard of for me, I usually just end up one big streaky mess whereas this is pretty much great. it contains no DHA at all which is the usual active agent in tanners and instead contains Erythrulose which is derived from sugar cane. Thisdevelops over a few hours and one application works well enough all though I do need more to build up the colour. One application takes the tinge off my blueness. It's really moisturising but even better, although it claims to be vanilla scented, to me it smells just like fudge yoghurt! Nom!
So there we have it, my top picks for your holidays. Some of them I've tried, some of them I haven't some were PR samples and some weren't, all are fab…trust me when I say I've not included some items that definitely didn't make it to my top holiday picks list!
*Items marked with a * were provided to me free of charge as PR samples*
I was pleasantly surprised when this box of goodies arrived through my letter box a couple of weeks ago.
I had no idea where it came from but was in New Look packaging so guessed it was from there, a little look on the New Look site confirmed that the Gold by Giles range is indeed from New Look. I don't know how they got my details, but am very grateful. Also, if I agreed to review these products it's terribly embarrassing as I have no recollection whatsoever of doing so.
That's irrelevant anyway, what is relevant is that this is a box of make up received for review. Now I think I've swatched everything and have taken photographs of some of the item in use. This would have been a very huge post if I'd shown everything!
So anyway, Gold by Giles for New Look. The Giles in question is in fact Giles Deacon, the designer. He's pretty well known I think and I think putting his name to New Look cosmetics is a slightly odd combination because this make up is so incredibly cheap. Not that thats a bad thing as I think you'll see, but in some cases it's not a great thing either.
In terms of packaging, I like it, it looks great, it does however feel cheap. I don't mind that too much, I find the packaging to be completely in line with the pricing, it IS cheap, so of course the packaging is cheap. It looks nice though so thats fine by me.
Let's look at the brow and Eye Liner Set first. It's £2.99 for both products.
The black kohl liner has a smudger on one end, it's decently pigmented and nicely blendable without being too smeary, its decent enough and I've used it a few times actually, it really is quite a bargain I have to say.
It's the Brow Pencil I've used a lot though. I think it does a great job, the spoolie on the end is great and the colour is perfect. In any of the following pictures where you can see my brows, I'm wearing this pencil to fill in. Excellent. I can't decide whether I prefer pencil or powder at the moment and tend to mix and match but if I need a new pencil, I'll get this one.
Next, The Liquid Eyeliners in Turquoise, Gold and Black. £2.99 each.
These are great for the money, they don't last all day, but they don't transfer to my upper lid which is great, I love the turquoise shade especially. The brush is average, its not brilliant, it's just okay. Ignore the shoddy application of the gold there, that's me, not the product.
Next the Scandal Eye Shadow Quad £3.99
Love the colours in this palette I have to say, I wish I'd gone a little lighter on the blue-ish shade bottom left, but they are all fab. In terms of quality, these feel cheap, they feel exactly like the MUA eyeshadows, but they are very pigmented and actually wear very well indeed. They just have this sort of wet-ish texture about them. I've worn this a few times lately though and I'm a big fan of the colours.
Next up the cheek products…. The Metallic Blusher Set and the Bronzer. Both £2.99. Alas my bronzer arrive a bit damaged but not too badly.
I'm not sure what to say about these, they are super pigmented and VERY metallic, both of them, the bronzer is actually very gold and not all that bronze. Thats not a criticism, these are just for evening only I think.
Here's the blusher…
Gold. I don't know though, I kind of like it! Like I say though, evenings only!
Finally the lip products. I was sent the Red and Pink lipsticks, £2.99 each.
Love these, gorgeous colours, nice texture. Bargain price. Would totally be happy to buy them and may indeed check out the other shades.
Then there are Three Lip Gloss Tubes £1.99 each.
All nice, all pretty shades, the first in particular. It's an interesting method of dispensing too…you sort of pump product out onto the brush. They are all nice, nothing amazing but they are nice and as with the rest of the range an absolute bargain for the price!
Finally there are Three Lip Gloss Wands, £2.99 Each.
Love these, I don't know if they really differ formula wise from the the tubes, but I love them, the colours are beautiful, and they wear as well as any high end gloss I own.
All in all a very cheap but cheerful range. There are some absolute gems in there, like the Brow Pencil and the Lip Gloss Wands and if budget beauty is your thing, well worth checking out.
Available from www.newlook.com
*Disclosure – PR Samples*
The penultimate post in my short series dedicated to the beautiful Clarins Summer Collection. I've shown you the lip products and today its the turn of the Bronzing Duos.
As with everything Clarins, the packaging is beautiful, the compacts are a amber transparent, well plastic I suppose with a gold base. Beautiful, heavy and stylish, each comes with a brown velvet pouch (not shown).
The Bronzing Duo's come in three colourways, 1, 2 and 3.
These aim to give you a natural colour when blended and White tea extract and 100% mineral sunscreen help to protect your skin from pollution and UV and I'm told that the combination of mineral and soft-focus pigments are combined with pearls to optically minimise fine lines and imperfections as well as giving you a luminous glow.
I love Clarins powders and foundations. I've not found a brand that does them better. Something about the brands products suits me very well indeed so given the above descriptions I was pretty keen to give these a go.
Here they are swatched (on Chloe's arm) in the order shown above. The light shade, the dark shade and the two mixed. 1, 2 and 3.
I've tried all three on my face, and really 2 and 3 are a little too dark for me although I could probably get away with it if I'd had a bit of skin, but for now, number 1 suits me perfectly well.
In the following pictures I mostly have it on my cheeks as a blusher, to try and show you the colour, but this is not necessarily how I'd normally wear it as I'd normally wear it in addition to blusher.
A very beautiful bronzer indeed. This retails at £26 and actually, it does fall in with my expectations of a Clarins powder, butter soft, applies like a dream, doesn't look powdery, just feels gorgeous. Well worth it. I do recommend if you're looking a posh bronzer this Summer.
*Disclosure – PR Sample*


text:
Open Dojo Session - Rhodesian Regiment - Critique Using Fundamentals [Vintage]
In this class, John produces an excellent rendition of Rhodesian Regiment. How can this be improved? Let's carefully analyze each of the fundamentals to find out!
Date of Original Live Class: Thursday, February 7th, 2013 at 7:30am
Course Name: Open Dojo Session
Class Name: Rhodesian Regiment - Critique Using Fundamentals
Class Instructor: Andrew Douglas
Access This Class Recording:
This class link is restricted to those with a 'Basic' membership or above. Don't worry though - you can have access to this class in 3 minutes or less! Click here to purchase your membership now!
tags: Basic
You must be logged in to post a comment.


text:
Banana Ghost Pop Recipe For Healthy Halloween Treat
A Healthy Halloween Treat That's to Die For!
Scare away your sugar cravings with our new favorite Halloween treat: banana ghost pops. Coated in coconut, this variation of classic frozen banana will satisfy your taste buds and add some potassium to snack time. Watch this video to learn how to make your own ghostly treats.


text:
Medical Center Library
HOURS for January 27, 2020: 8:00am - Midnight
About Medical Center Library
Phone: (859) 323-5300
Fax: (859) 323-1040
E-Mail: firstname.lastname@example.com
Address: William R. Willard Medical Education Building 298
800 Rose St.
Lexington, KY
New PubMed Interface New!
EndNote for Health Sciences classes
LibKey PubMed: One Click Access to Articles
Legal Use of UK Libraries' Electronic Resources
EndNote X9 Available on UK Download Site
BROWZINE! Get Tables of Contents for New Journal Issues
See News & Events for other Medical Center Library news.
UK faculty, staff and students use their UK Wildcard as their library card. Persons not affiliated with UK may obtain a library card if they are 18 years of age and present a valid Kentucky driver's license or a valid non-driver ID. Faculty, staff, and students from reciprocal colleges and universities in Kentucky may obtain a UK library card with proper identification. Anyone with a UK library card may check out materials in the Medical Center Library or any UK campus library.
Use InfoKat Discovery Library Catalog (UK Libraries Holdings) to locate materials owned by the UK Libraries.
|Loan Period
|First floor
|7 days
|Remote Storage
28 days for UK Non-UK borrowers
42 days for UK Undergraduates
90 days for UK Graduate students
120 days for UK Faculty/Staff
|Reference Books
|First floor
|Special permission
|Permanent Reserve
|First floor
|2 hours
|Unbound Journals
|First floor
|2 hours
|Bound Journals
|Remote Storage
|4 days
|MCL pre-1987 Collection
|William T. Young Library
|UK Libraries Circulation Policy
|Rare Books
|Special Collections
|19th Century Collection
|William T. Young Library
|UK Libraries Circulation Policy
E-mail notices
The Medical Center Library sends library notices via e-mail.
If a book, journal, or audiovisual you need is checked out, you may place a hold on it so that when it is returned to the Medical Center Library it will be held at the User Services desk for you. You will be notified when it is available.
Contact Genia Kempster if you have questions about placing a hold on library materials or for any questions related to borrowing library materials.
If you have questions or comments about the University of Kentucky Medical Center Library, please contact us. If you would like to contact individual staff members, please use the Medical Center Library Faculty/Staff Directory.
Call: (859)323-5300
Fax: (859)323-1040
Email: email@example.com
Mailing Address:
800 Rose St.
Lexington, KY
EndNote for Health Sciences classesDecember 4, 2019
Check out the upcoming spring 2020 dates for EndNote for Health Sciences classes! All faculty, staff, and students are invited to view the class calendar and register for sessions of ...Read more ›


text:
Cooperstowners in Canada
Kevin Glew's Canadian Baseball History Blog
Skip to content
About Kevin Glew
Tag Archives:
Jackie Robinson Day
But What Do I Know? . . . Goose Gossage, Rob Butler, Dave Stieb
Post navigation
Privacy & Cookies: This site uses cookies. By continuing to use this website, you agree to their use.
To find out more, including how to control cookies, see here:
Cookie Policy


text:
Cosmic Supremacy (Windows)
Critic Score
100 point score based on reviews from various critics.
User Score
5 point score based on user ratings.
Not an American user?
DescriptionCosmic Supremacy is a free tick/turn-based massively multiplayer space strategy game with a 3D interface. It belongs to the category of the 4X strategy games, being inspired by Master of Orion, Civilization, and similar games. You need to explore the galaxy around you, colonize new planets, expand your empire, research new technologies, design your ships and build your fleets, and finally establish contact with other players, with whom you can sign military or trade treaties, or engage them in battle.
The gameplay is a mix between traditional multiplayer strategy games and persistent online games. A game in Cosmic Supremacy exists in its own completely separate galaxy. Every Galaxy has a definite start, and ends when there is an obvious winner. Galaxies usually last between 3 and 6 weeks, with ticks speed that usually ranges between 30 minutes and 2 hours. The game keeps on running, even while players are not online. To ease the management of the empire and reduce the time to spend online while still being competitive, players can assign programmable governors to their own planets, and admirals to their fleets, which will follow the orders given by players while they're not online.
Beside normal galaxies, there are also Speed Galaxies, with very short turns and that reach their conclusion usually in a couple of days, such weekends, and Team Galaxies, where players are assigned to two or more teams, and where communication and coordination of the strategies among players are obviously more important.
The game is played with a small downloadable client.
There are no Windows user screenshots for this game.
Promo Images
There are no promo images for this game
User Reviews
|One of the best 4x multiplayer games I've tried
|code120 (13)
Critic Reviews
There are no critic reviews for this game.
There are currently no topics for this game.
There is no trivia on file for this game.
code120 (13) added Cosmic Supremacy (Windows) on Jun 19, 2011
Game Creator:
Johannes Graf (Jogi[CS]), Peter Pisarik (SarikSan[CS])
Wolfgang Breyha (MASHtm)Internet Expert:
Wolfgang Breyha (MASHtm)Artist:
Andy Le Conte (Earendel)Game Design:
Andy Le Conte (Earendel)PHP Programming Suppot:
Manfred Blazek (aix)Additional Graphics:
Manfred Satzer (manni)Additional Game Design:
Helmut Hutterer (Tofukiller)Additional Programming:
Special Thanks to:
Arcady, Rismagi, Gedrin, uncountednose, DarkLStrike, JackJack, SHRIKEE, KillerSoft, Steve, F. Brebion (from Infinity), and all Cosmic Supremacy Players and Beta-Testers.And especially to:


text:
Atomic Clock Music Events Свежая информация Washer Repair на нашем сайте.
In C
Born in 1935, American composer Terry Riley launched what is now known as the Minimalist movement with his revolutionary classic In C in 1964. Any number of players perform a series of 53 musical fragments--repeating, looping, pausing, listening, and shifting registers at will to create a shifting, hypnotic musical tapestry. Refrigerator Repair home pro refrigeration and appliance Repair.
The players interact, listening to each other and finding inspiration for the way they will play in their own imaginations and the behaviors of the musicians around them. A constant pulse of high C's keeps the ensemble together.
In this unique performance, the audience shares in the interaction: musicians are distributed throughout the BMoCA galleries, and listeners are encouraged to explore this world of sound by walking through it, experiencing the different personalities and interactions--perhaps even inspiring them! A computer-controlled audio system distributes the electronic pulse, and mixes sound between the galleries.
Thursday, December 9, 2004, 8 pm
Boulder Museum of Contemporary Art
1750 13th Street
$12 general admission, $10 students/seniors, $8 BMoCA members
(303) 443-2122
Return to the main ACME page


text:
The Usefulness Of Doctrine (Part 3)
According to a 14 century idiom "the proof of the pudding is in the eating" makes reference to finding out if something is true by testing it. Timothy had been a keen observer of the effectual working of God in a few select lives. That in addition to his own, Paul, Lois, and Eunice were


text:
Basic GK Questions and Answers for Railways,IES,CRPF,BSF,Income Tax Exams
Question No:1
The main security guard of international trade is
Question No:2
National Rural Development Institute is located in
Question No:3
'Closed Economy' is that economy in which
Neither export nor import takes place
Question No:4
The most important factor in soil erosion is
Action of wind and water
Question No:5
The Almatti Dam is constructed on the river
Question No:6
Sand stone is metamorphosed into
Question No:7
Trans-Canadian Highway links
St. John City to Vancouver
Question No:8
The Lowest density in India is recorded in North-Eastern state of
Arunachal Pradesh
Question No:9
The cold current flowing along the Western Coast of South America from south to north is called
Peru current
Question No:10
Kishtwar town is situated on The Bank of The river
Question No:11
National Institute of Oceanography is located in
Question No:12
Lipulekh pass is situated in
Himachal Pradesh
Question No:13
Which State of India receives rain when The Summer Monsoon recedes?
Tamil Nadu
Question No:14
'Milk of Magnesia' is a suspension of
Magnesium Hydroxide
Question No:15
The part of the human brain that retains memory is the
Question No:16
The device to convert alternating current into direct current is
Question No:17
Which organ is affected in Pneumonia?
Question No:18
Formation of Red Blood Corpuscles (RBC) takes place in
Bone marrow
Question No:19
Isotopes are atoms of the element with
Same atomic number but different atomic weight
Question No:20
The commonly used safety fuse wire is made of
An alloy of tin and lead
Question No:21
Cathode rays when obstructed by metal cause emission of
Question No:22
Hydrogen bomb is based on the principle of
Nuclear fusion
Question No:23
Carbon credit' is a term associated with the
Protection of environment
Question No:24
Indian Institute of Sugarcane Research is located in
Question No:25
Central Rice Research Institute is located in
Question No:26
High rainfall, abundant sunshine, gently sloping land and well drained soil are the suitable conditions of the cultivation of
Question No:27
Ergot is the disease of
Question No:28
Mixed cropping is useful when
Crops with different nutritional requirement are grown
Question No:29
HB-4 is a high yielding variety of
Question No:30
Two rice crops are raised in a year from the same field in
Question No:31
COJ-64 and CO-7717 are early maturing varieties of
Question No:32
The second largest agro-based industry in India is
Sugar industry
Question No:33
Largest saffron growing state in India is
Jammu & Kashmir
Question No:34
Mahela Jayawardene is the legendary batsman of
Sri Lanka
Question No:35
Roger Federer is the star tennis player of
Question No:36
Hop man Cup is associated with which game?
Lawn Tennis
Question No:37
Maracana Stadium is located in
Rio de Janeiro (Brazil)
Question No:38
The terms LBW, Midfield and Slip are used in


text:
Sealed with Love Valentine Treat Box
It's really hard to believe, but today is February 1! It's especially hard to believe here in Texas since it's in the 70's outside. Not complaining though....
Since February is the month of Love, I thought I'd kick off the month by sharing with you a fun little Valentine treat box.
This adorable little box is one of our Clear Tiny Treat Boxes. I LOVE these boxes! They make it so quick and easy to create little party favors or treats to give out.
Here's a free tutorial of how to make this little box with all of the needed supplies and measurements. Enjoy!
Download Sealed with Love Treat Box