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The microbiota as a component of the celiac disease and non-celiac gluten sensitivity

Open AccessPublished:February 02, 2016DOI:https://doi.org/10.1016/j.yclnex.2016.01.002

      Summary

      Dietary gluten present in wheat, rye and barley induces several gastrointestinal disorders, including celiac disease and non-celiac gluten sensitivity (NCGS). Celiac disease is an immune-based enteropathy triggered by ingestion of gluten in genetically susceptible individuals resulting from the interaction between genetic and environmental factors. Although gluten has been recognized as the main environmental trigger of the disease, a specific role for the intestinal microbiota in celiac disease development has been suggested.
      NCGS individuals develop adverse reactions after the exposure to gluten. Due to the similarities in clinical outcomes and the absence of diagnostic biomarkers, it is challenging to differentiate NCGS from celiac disease. The aetiology of NCGS remains unknown, although the involvement of innate immune mechanisms has been suggested. Since the influence of intestinal microbiota on immune cell homeostasis and on education of both innate and adaptive immune system is well known, the role of host-microbe interactions in the non-celiac gluten sensitivity have been hypothesized.
      This review aims to summarize the current knowledge of the contribution of microbiota to the pathogenesis and/or onset of celiac disease. In addition, a brief overview of the possible role of the microbiota components on the NCGS is presented.

      Keywords

      1. Introduction

      Gluten-related disorders are the umbrella term for all conditions related to gluten ingestion, such as celiac disease and non-celiac gluten sensitivity (NCGS). The prevalence of these diseases has increased over the past 50 years, being an emerging health problem worldwide. Currently, celiac disease is considered the most common food intolerance, prevalence being approximately 1–2% of the population [
      • Ludvigsson J.F.
      • Leffler D.A.
      • Bai J.C.
      • Biagi F.
      • Fasano A.
      • Green P.H.
      • et al.
      The Oslo definitions for coeliac disease and related terms.
      ]. In contrast, the prevalence of NCGS has been estimated to be as high as 6% of the general population, depending on the population studied [
      • Sapone A.
      • Bai J.C.
      • Ciacci C.
      • Dolinsek J.
      • Green P.H.
      • Hadjivassiliou M.
      • et al.
      Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
      ]. The biological basis of gluten induced symptoms in the absence of celiac disease is unknown but it has been suggested to be related to immune responses to components of wheat apart from gluten, such as wheat amylase-trypsin inhibitors (ATIs) and fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) [
      • Sapone A.
      • Bai J.C.
      • Ciacci C.
      • Dolinsek J.
      • Green P.H.
      • Hadjivassiliou M.
      • et al.
      Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
      ,
      • 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.
      ].
      The main genetic component of celiac disease, HLA-DQ2/DQ8 heterodimers, is well-known. Although these HLA-DQ genes underlie the disorder, only a small percentage of carriers develop the disease and thus, other genetic and environmental factors must be involved in the onset of celiac disease. This review aims to summarize the current knowledge of the contribution of microbiota to pathogenesis and/or onset of CD. In addition, a brief overview of the possible role of the microbiota components on the development and/or onset of NCGS will be provided.

      2. Celiac disease

      Celiac disease is an immune-based enteropathy triggered by ingestion of wheat, rye and barley derived gluten in genetically susceptible individuals. Upon exposure to gluten, inflammatory cascade is induced in the small intestinal mucosa leading to villous atrophy, crypt hyperplasia and increased numbers of lymphocytes in the lamina propria. Disruption of intestinal villus structure leads to impaired epithelial barrier function resulting in nutrient malabsorption that may cause severe symptoms such as anaemia, osteoporosis and, in case of children, to growth retardation. The clinical picture of the celiac disease is highly variable and individual-specific. Classical symptoms of celiac disease include different gastrointestinal symptoms such as abdominal pain and diarrhoea. However, many CD patients are predominantly symptomatic, showing both gastrointestinal and extra-intestinal manifestations. In asymptomatic patients the diagnosis is often delayed and thus the small-bowel mucosal damage may be severe before the celiac disease is suspected. Therefore, early diagnosis of the disease is crucial for the prevention of persistent villous atrophy predisposing to severe complications. Celiac disease is a life-long disease that cannot be cured but the symptoms can disappear and small bowel mucosal damage, intestinal inflammation and epithelial integrity are improved by commitment to a life-long gluten-free diet.
      The main genetic predisposition to celiac disease are the human leucocyte antigen (HLA) DQ2 and DQ8 haplotypes. These HLA-DQ genes account for approximately 40% of the genetic risk of celiac disease [
      • Dubois P.C.
      • Trynka G.
      • Franke L.
      • Hunt K.A.
      • Romanos J.
      • Curtotti A.
      • et al.
      Multiple common variants for celiac disease influencing immune gene expression.
      ]. However, although these genes underlie the disorder, only a small percentage of carriers develop disease. In addition, the disease concordance in monozygotic twins has been reported to be only 85% [
      • Nisticò L.
      • Fagnani C.
      • Coto I.
      • Percopo S.
      • Cotichini R.
      • Limongelli M.G.
      • et al.
      Concordance, disease progression, and heritability of coeliac disease in italian twins.
      ]. Thus, other genetic and environmental factors must be involved in the onset of the disorder (Fig. 1). Recent genome wide association studies have reported additional 39 non-HLA regions associated with susceptibility to celiac disease development [
      • Dubois P.C.
      • Trynka G.
      • Franke L.
      • Hunt K.A.
      • Romanos J.
      • Curtotti A.
      • et al.
      Multiple common variants for celiac disease influencing immune gene expression.
      ]. Interestingly, most of these regions contain genes with immune related functions, several of which are also involved in shaping the intestinal microbiota. In addition, altered expression of non-specific celiac disease risk-genes affecting the host-microbe interactions has recently been reported. For instance, a decreased TOLLIP mRNA levels were observed in untreated celiac patients when compared to healthy controls [
      • Kalliomäki M.
      • Satokari R.
      • Lähteenoja H.
      • Vähämiko S.
      • Grönlund J.
      • Routi T.
      • et al.
      Expression of microbiota, toll-like receptors, and their regulators in the small intestinal mucosa in celiac disease.
      ]. TOLLIP is an intracellular protein that inhibits toll-like receptor signalling and failure to upregulate its transcription has been suggested to contribute to the chronic inflammation in celiac and inflammatory bowel disease patients [
      • Kalliomäki M.
      • Satokari R.
      • Lähteenoja H.
      • Vähämiko S.
      • Grönlund J.
      • Routi T.
      • et al.
      Expression of microbiota, toll-like receptors, and their regulators in the small intestinal mucosa in celiac disease.
      ,
      • Steenholdt C.
      • Andresen L.
      • Pedersen G.
      • Hansen A.
      • Brynskov J.
      Expression and function of toll-like receptor 8 and tollip in colonic epithelial cells from patients with inflammatory bowel disease.
      ]. These results suggest the potential role of disturbed host-microbe interaction in the pathogenesis of celiac disease.
      Figure thumbnail gr1
      Fig. 1Factors contributing to the onset of celiac disease. Both genetic and environmental factors contribute to the development of celiac disease. Of these, HLA-DQ2 and DQ8 as well as dietary gluten play a direct role in the disturbed immune homeostasis and the subsequent Th1-type immune response required for the disease onset. The other factors either directly or indirectly lead to the intestinal microbiota dysbiosis, which may also promote the development of celiac disease. HLA, human leucocyte antigen; PRRs, pattern recognition receptors.
      It is assumed that aberrant microbiota diversity and relative abundances of specific bacterial taxa lead to functional imbalance where the mutualistic relationship between the host and his microbes is disturbed. Deviations in the microbiota community structure has been associated with several local and systemic diseases, possibly contributing to the pathogenesis and/or clinical manifestation of these diseases [
      • Walker W.A.
      Initial intestinal colonization in the human infant and immune homeostasis.
      ]. A specific role for the intestinal microbiota in celiac disease development has been suggested, but the results remain contradictory [
      • Kalliomäki M.
      • Satokari R.
      • Lähteenoja H.
      • Vähämiko S.
      • Grönlund J.
      • Routi T.
      • et al.
      Expression of microbiota, toll-like receptors, and their regulators in the small intestinal mucosa in celiac disease.
      ,
      • De Palma G.
      • Nadal I.
      • Medina M.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • et al.
      Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children.
      ]. This inconsistency may possibly be explained by different techniques used, different sample types analysed (faecal material vs biopsies), patient's age range (infants, children or adults), small sample size and limited amount of studies performed.

      2.1 Microbiota in early life and risk of celiac disease

      The initial colonization process of the infant gastrointestinal tract forms the basis for the subsequent microbiota and immune response development, thus having a major influence on the later life health and predisposition to the development of several immune-mediated diseases. Life events occurring in early life and causing disturbances to the developing resident microbiota can lead to long-lasting dysbiosis with increased amounts or relative abundances of one or more disease associated bacterial species. Interestingly, a high frequency of infectious episodes as well as antibiotic treatments, known to affect the intestinal microbiota, have been associated with the onset of celiac disease in genetically susceptible infants [
      • Mårild K.
      • Ye W.
      • Lebwohl B.
      • Green P.H.
      • Blaser M.J.
      • Card T.
      • et al.
      Antibiotic exposure and the development of coeliac disease: a nationwide case-control study.
      ,
      • Mårild K.
      • Kahrs C.R.
      • Tapia G.
      • Stene L.C.
      • Stordal K.
      Infections and risk of celiac disease in childhood: a prospective nationwide cohort study.
      ].
      It has been suggested that despite the different life events, also a specific disease-biased host genotype may select for the first gut colonizers and thus contribute to the disease risk (Fig. 1). Several studies have reported the influence of genotype of infants at family risk for developing celiac disease (HLA-DQ2 vs non-HLA-DQ2/8 genotype) on the early life faecal microbiota composition [
      • Sánchez E.
      • De Palma G.
      • Capilla A.
      • Nova E.
      • Pozo T.
      • Castillejo G.
      • et al.
      Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by bacteroides species.
      ,
      • Palma G.D.
      • Capilla A.
      • Nova E.
      • Castillejo G.
      • Varea V.
      • Pozo T.
      • et al.
      Influence of milk-feeding type and genetic risk of developing coeliac disease on intestinal microbiota of infants: the PROFICEL study.
      ,
      • Olivares M.
      • Neef A.
      • Castillejo G.
      • Palma G.D.
      • Varea V.
      • Capilla A.
      • et al.
      The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease.
      ]. In a recent study, 1 month old infants with a high genetic risk for celiac disease were observed to have lower proportion of Actinobacteria and higher proportion of Firmicutes and Proteobacteria than infants with low genetic risk for disease development [
      • Olivares M.
      • Neef A.
      • Castillejo G.
      • Palma G.D.
      • Varea V.
      • Capilla A.
      • et al.
      The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease.
      ]. Moreover, HLA-DQ genotype seems to specifically influence the colonization process of Bacteroides species [
      • Sánchez E.
      • De Palma G.
      • Capilla A.
      • Nova E.
      • Pozo T.
      • Castillejo G.
      • et al.
      Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by bacteroides species.
      ]. In particular, an increased Bacteroides vulgatus prevalence was associated with the genotype of infants at high risk of celiac disease development, whereas increased Bacteroides uniformis prevalence was associated with a low genetic risk [
      • Sánchez E.
      • De Palma G.
      • Capilla A.
      • Nova E.
      • Pozo T.
      • Castillejo G.
      • et al.
      Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by bacteroides species.
      ]. Indeed, the most constant finding is the higher abundance of Bacteroides spp. in celiac disease patients [
      • De Palma G.
      • Nadal I.
      • Medina M.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • et al.
      Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children.
      ,
      • Collado M.C.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • Sanz Y.
      Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease.
      ], although a recent prospective study reported a complete lack of the members of phylum Bacteroidetes in celiac disease predisposed infants [
      • Sellitto M.
      • Bai G.
      • Serena G.
      • Fricke W.F.
      • Sturgeon C.
      • Gajer P.
      • et al.
      Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants.
      ]. In addition, Bacteroides fragilis has been associated with an increased risk for celiac disease development in genetically predisposed infants who were formula-fed [
      • Palma G.D.
      • Capilla A.
      • Nova E.
      • Castillejo G.
      • Varea V.
      • Pozo T.
      • et al.
      Influence of milk-feeding type and genetic risk of developing coeliac disease on intestinal microbiota of infants: the PROFICEL study.
      ]. Interestingly, polysaccharide A produced by B. fragilis has been shown to direct the immune system via its ability to direct the development of CD4+ T cells, thus inducing the differentiation of Th1-lineage [
      • Mazmanian S.K.
      • Liu C.H.
      • Tzianabos A.O.
      • Kasper D.L.
      An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.
      ]. Therefore, it seems likely that increased abundance of Bacteroides spp. contributes to the Th1 response found in the small intestinal mucosa of celiac disease patients [
      • Kalliomäki M.
      • Satokari R.
      • Lähteenoja H.
      • Vähämiko S.
      • Grönlund J.
      • Routi T.
      • et al.
      Expression of microbiota, toll-like receptors, and their regulators in the small intestinal mucosa in celiac disease.
      ,
      • Cheng J.
      • Kalliomäki M.
      • Heilig H.G.
      • Palva A.
      • Lähteenoja H.
      • de Vos W.M.
      • et al.
      Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease.
      ]. Furthermore, a study by Sanz et al. [
      • Sanz Y.
      • De Palma G.
      • Laparra M.
      Unraveling the ties between celiac disease and intestinal microbiota.
      ] reported a reduction in immunoglobulin A (IgA) -coated Bacteroides spp. in faeces of untreated and treated celiac patients when compared to healthy controls, suggesting that host defences against this bacterial groups may be reduced in celiac disease, thus allowing its increased colonization. Immunoglobulin A is the predominant antibody produced by at mucosal surfaces. Secretory IgA (sIgA) has diverse biological properties such as immune exclusion, immunomodulation and maintenance of the integrity of mucosal barriers. In addition, it provides the first line of defence against invading pathogens by targeting microbial antigens in the mucosal environment. However, the main role of sIgA seems to be the establishment and maintenance of homeostasis with the commensal microbiota [
      • Cong Y.
      • Feng T.
      • Fujihashi K.
      • Schoeb T.R.
      • Elson C.O.
      A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota.
      ]. It has been suggested that coating of commensal bacteria by sIgA may represent a mechanism by which this discrimination between abundant normal microbiota and rare pathogens are made [
      • Cong Y.
      • Feng T.
      • Fujihashi K.
      • Schoeb T.R.
      • Elson C.O.
      A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota.
      ]. Disrupted production of secretory IgA has been considered a risk factor for the development of gastrointestinal disorders such as celiac disease [
      • Wang N.
      • Truedsson L.
      • Elvin K.
      • Andersson B.A.
      • Rönnelid J.
      • Mincheva-Nilsson L.
      • et al.
      Serological assessment for celiac disease in IgA deficient adults.
      ]. IgA is also the most abundant antibody secreted into the breast-milk and the specificities of these sIgAs are shaped by maternal microbiota (reviewed in [
      • Kaetzel C.S.
      Cooperativity among secretory IgA, the polymeric immunoglobulin receptor, and the gut microbiota promotes host-microbial mutualism.
      ]). Breast milk sIgA provides the first source of antibody-mediated immune protection in the intestine of breast-fed neonate [
      • Rogier E.W.
      • Frantz A.L.
      • Bruno M.E.
      • Wedlund L.
      • Cohen D.A.
      • Stromberg A.J.
      • et al.
      Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression.
      ]. Transfer of these maternal sIgA to the infant promotes the establishment of regulatory immune system and supports the mutualistic relationship with the commensal microbiota [
      • Rogier E.W.
      • Frantz A.L.
      • Bruno M.E.
      • Wedlund L.
      • Cohen D.A.
      • Stromberg A.J.
      • et al.
      Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression.
      ]. In addition, the presence of commensal microbes is needed for the induction of the endogenous production of IgA, which is slowly started while the immune system develops [
      • Maynard C.L.
      • Elson C.O.
      • Hatton R.D.
      • Weaver C.T.
      Reciprocal interactions of the intestinal microbiota and immune system.
      ]. Thus, reduction in intestinal sIgA seems to contribute to microbiota dysbiosis and pro-inflammatory response [
      • Maynard C.L.
      • Elson C.O.
      • Hatton R.D.
      • Weaver C.T.
      Reciprocal interactions of the intestinal microbiota and immune system.
      ].
      Moreover, the reduction of total Gram-positive bacteria population, especially the abundance of Bifidobacterium spp. [
      • De Palma G.
      • Nadal I.
      • Medina M.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • et al.
      Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children.
      ,
      • Collado M.C.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • Sanz Y.
      Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease.
      ] and the increase in the proportions of Gram-negative bacteria such as Clostridium groups, Prevotella spp, and Escherichia coli [
      • Collado M.C.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • Sanz Y.
      Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease.
      ,
      • Cheng J.
      • Kalliomäki M.
      • Heilig H.G.
      • Palva A.
      • Lähteenoja H.
      • de Vos W.M.
      • et al.
      Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease.
      ] have been reported in paediatric celiac disease patients with an active disease. The reduced abundance of bifidobacteria may be of interest, since they have been suggested to alleviate gastrointestinal symptoms of adult celiac patients [
      • Smecuol E.
      • Hwang H.J.
      • Sugai E.
      • Corso L.
      • Cherñavsky A.C.
      • Bellavite F.P.
      • et al.
      Exploratory, randomized, double-blind, placebo-controlled study on the effects of bifidobacterium infantis natren life start strain super strain in active celiac disease.
      ] as well as to reduce abdominal pain in healthy individuals [
      • Jalanka-Tuovinen J.
      • Salonen A.
      • Nikkilä J.
      • Immonen O.
      • Kekkonen R.
      • Lahti L.
      • et al.
      Intestinal microbiota in healthy adults: temporal analysis reveals individual and common core and relation to intestinal symptoms.
      ]. Microbiota dysbiosis of paediatric celiac disease patients have been suggested to be characterized by an increased microbiota diversity [
      • Sanchez E.
      • Donat E.
      • Ribes-Koninckx C.
      • Fernandez-Murga M.L.
      • Sanz Y.
      Duodenal-mucosal bacteria associated with celiac disease in children.
      ], although contradictory finding has recently been reported in a study utilizing high-throughput microarray method [
      • Cheng J.
      • Kalliomäki M.
      • Heilig H.G.
      • Palva A.
      • Lähteenoja H.
      • de Vos W.M.
      • et al.
      Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease.
      ]. Further studies utilizing the high-throughput methods are needed to comprehensively evaluate the microbiota diversity and species richness associated with celiac disease.

      2.2 Microbiota in adult celiac disease patients

      Although the majority of studies evaluating the microbiota composition associated with celiac disease have been performed with paediatric patients, few studies have also assessed the microbiota in adult CD patients.
      Positive seroreactivity against different microbial antigens in celiac disease patients having established small-bowel mucosal damage with villous atrophy and crypt hyperplasia have been reported [
      • Viitasalo L.
      • Niemi L.
      • Ashorn M.
      • Ashorn S.
      • Braun J.
      • Huhtala H.
      • et al.
      Early microbial markers of celiac disease.
      ,
      • Ashorn S.
      • Välineva T.
      • Kaukinen K.
      • Ashorn M.
      • Braun J.
      • Raukola H.
      • et al.
      Serological responses to microbial antigens in celiac disease patients during a gluten-free diet.
      ]. These serological responses can be detected already in the early stages of the diseases [
      • Viitasalo L.
      • Niemi L.
      • Ashorn M.
      • Ashorn S.
      • Braun J.
      • Huhtala H.
      • et al.
      Early microbial markers of celiac disease.
      ], suggesting that immune responses to commensal microbiota are already present early in the disease stage and thus may have a role in the pathogenesis of the celiac disease and the development of mucosal damage.
      The role of intestinal microbiota on different clinical manifestations of the disease was demonstrated in a study by Wacklin et al. [
      • Wacklin P.
      • Kaukinen K.
      • Tuovinen E.
      • Collin P.
      • Lindfors K.
      • Partanen J.
      • et al.
      The duodenal microbiota composition of adult celiac disease patients is associated with the clinical manifestation of the disease.
      ], where the microbiota composition, structure and diversity were observed to differ depending on the manifestation of the disease, especially between intestinal symptoms (gastrointestinal symptoms or anaemia) and extra-intestinal symptoms (dermatitis herpetiformis). The patients with classical gastrointestinal symptoms had a higher amount of Proteobacteria than patients with other manifestation of the disease, whereas patients with anaemia had the lowest microbial richness and distinct clustering of duodenal microbiota profiles.
      After a gluten-free diet is initiated, healing of the intestinal mucosa usually starts. Mucosal healing is a gradual process and it has been estimated that the median time needed to achieve a normal villous height is 3.8 years [
      • Rubio-Tapia A.
      • Rahim M.W.
      • See J.A.
      • Lahr B.D.
      • Wu T.T.
      • Murray J.A.
      Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.
      ]. However, a significant fraction of celiac disease patients suffer from persistent symptoms despite an adherence to a gluten-free diet and normalized small bowel mucosa [
      • Midhagen G.
      • Hallert C.
      High rate of gastrointestinal symptoms in celiac patients living on a gluten-free diet: controlled study.
      ]. In some patients, symptoms can be explained by inadvertent gluten intake or the presence of additional gastrointestinal disease [
      • Nachman F.
      • del Campo M.P.
      • González A.
      • Corzo L.
      • Vázquez H.
      • Sfoggia C.
      • et al.
      Long-term deterioration of quality of life in adult patients with celiac disease is associated with treatment noncompliance.
      ]. In many cases the reason for persistent symptoms cannot be explained [
      • Midhagen G.
      • Hallert C.
      High rate of gastrointestinal symptoms in celiac patients living on a gluten-free diet: controlled study.
      ]. Microbiota dysbiosis observed in untreated celiac patients is not completely restored after adherence to a gluten-free diet, suggesting that some changes in microbiota are not secondary to the inflammatory milieu of the active phase of the disease but could play a primary role in predisposition to celiac disease development [
      • Collado M.C.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • Sanz Y.
      Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease.
      ,
      • Nadal I.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • Sanz Y.
      Imbalance in the composition of the duodenal microbiota of children with coeliac disease.
      ]. Treated celiac disease patients with persistent symptoms have been reported to have a microbiota dysbiosis, characterized by Proteobacteria-dominating duodenal microbiota and reduced microbial richness compared to treated patients without symptoms [
      • Wacklin P.
      • Laurikka P.
      • Lindfors K.
      • Collin P.
      • Salmi T.
      • Lähdeaho M.L.
      • et al.
      Altered duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet.
      ].
      It has been suggested that the IL17A producing cells play a major role in the pathogenesis of celiac disease, that both gluten and CD associated bacteria provoke an IL-17A response in the intestinal mucosa of CD patients and that the magnitude of the adverse IL-17A reaction to gluten is markedly influenced by the composition of the resident microbiota and the amount of CD associated bacteria present [
      • Sjöberg V.
      • Sandström O.
      • Hedberg M.
      • Hammarström S.
      • Hernell O.
      • Hammarström M.L.
      Intestinal T-cell responses in celiac disease - impact of celiac disease associated bacteria.
      ]. In their study, Sjöberg et al. [
      • Sjöberg V.
      • Sandström O.
      • Hedberg M.
      • Hammarström S.
      • Hernell O.
      • Hammarström M.L.
      Intestinal T-cell responses in celiac disease - impact of celiac disease associated bacteria.
      ] used a mixture of CD associated bacteria (five Prevotella, one Lachnoanaerobaculum and one Actinomyces isolate) and gluten to challenge the biopsies taken from untreated and treated CD patients and from clinical controls. At diagnosis, patients with CD were observed to have highly elevated levels of IL-17A mRNA in their jejunal mucosa. The levels returned to normal level on a gluten-free diet [
      • Sjöberg V.
      • Sandström O.
      • Hedberg M.
      • Hammarström S.
      • Hernell O.
      • Hammarström M.L.
      Intestinal T-cell responses in celiac disease - impact of celiac disease associated bacteria.
      ]. The celiac disease associated bacteria analysed in that study were capable of inducing an IL-17A response on their own, suggesting that this response seen in active celiac disease could be (in part) directed against the CD -associated bacteria. In addition, these bacteria determined the magnitude of the IL-17A response (either suppressing or enhancing) depending on whether the patient had a strong response to gluten digest alone or not. Interestingly, all patients that showed a suppressed IL-17A response were observed to be born during the Swedish celiac disease epidemic, whereas children born after the epidemic showed contradictive response.
      Homozygosity for non-functional fucosyltransferase 2 (FUT2) gene leads to the absence of ABH blood groups (FUT2 non-secretor status) in body fluids. Recently, FUT2 non-secretor status has been associated with the susceptibility to celiac disease in the Finnish population [
      • Parmar A.S.
      • Alakulppi N.
      • Paavola-Sakki P.
      • Kurppa K.
      • Halme L.
      • Färkkilä M.
      • et al.
      Association study of FUT2 (rs601338) with celiac disease and inflammatory bowel disease in the finnish population.
      ]. Moreover, FUT2 secretor status has been shown to be a major determinant for the gut microbiota richness and the composition of abundant microbiota in healthy individuals [
      • Wacklin P.
      • Tuimala J.
      • Nikkilä J.
      • Sebastian Tims
      • Mäkivuokko H.
      • Alakulppi N.
      • et al.
      Faecal microbiota composition in adults is associated with the FUT2 gene determining the secretor status.
      ,
      • Wacklin P.
      • Mäkivuokko H.
      • Alakulppi N.
      • Nikkilä J.
      • Tenkanen H.
      • Räbinä J.
      • et al.
      Secretor genotype (FUT2 gene) is strongly associated with the composition of bifidobacteria in the human intestine.
      ] as well as in Crohn's disease patients [
      • Rausch P.
      • Rehman A.
      • Künzel S.
      • Häsler R.
      • Ott S.J.
      • Schreiber S.
      • et al.
      Colonic mucosa-associated microbiota is influenced by an interaction of crohn disease and FUT2 (secretor) genotype.
      ]. Interestingly, recovery after the pathogenic infection was slower in FUT2 deficient mice when compared to FUT2 sufficient controls [
      • Pickard J.M.
      • Maurice C.F.
      • Kinnebrew M.A.
      • Abt M.C.
      • Schenten D.
      • Golovkina T.V.
      • et al.
      Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness.
      ]. These results suggest that fucosylation of intestinal epithelial cells may be a protective mechanism that maintains the host-microbial interactions, thus preventing the development of microbiota dysbiosis. For comprehensive conclusions considering the role of intestinal microbiota in adult celiac disease patients, further studies utilizing high-throughput analysis are needed.

      2.3 Effect of gluten-free diet on microbiota

      Currently, the only effective treatment available for celiac disease is a life-long adherence to a gluten-free diet. Although the diet is effective and safe, it also creates social and economic burdens to the patients and some reports have shown that intestinal microbiota is also affected [
      • Collado M.C.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • Sanz Y.
      Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease.
      ,
      • 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.
      ,
      • Di Cagno R.
      • De Angelis M.
      • De Pasquale I.
      • Ndagijimana M.
      • Vernocchi P.
      • Ricciuti P.
      • et al.
      Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization.
      ]. Microbiota deviations observed in untreated celiac disease patients were only partly restored after long-term treatment with gluten-free diet. In young children (6–12 years of age), who had followed gluten-free diet for two years, a higher diversity and a complete rearrangement in Eubacterium species community as well as changed metabolomics profiles were observed [
      • Di Cagno R.
      • De Angelis M.
      • De Pasquale I.
      • Ndagijimana M.
      • Vernocchi P.
      • Ricciuti P.
      • et al.
      Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization.
      ]. In contrast, the abundances of E. coli and Staphylococcus were observed to normalize after dietary treatment [
      • Collado M.C.
      • Donat E.
      • Ribes-Koninckx C.
      • Calabuig M.
      • Sanz Y.
      Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease.
      ]. Another study reported slightly different microbiota shifts, including decreased abundance of bifidobacteria, lactobacilli, Clostridium lituseburense and Faecalibacterium prausnitzii, whereas proportions of E. coli and Enterobacteriaceae increased [
      • 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.
      ]. Majority of these microbiota changes are most likely caused by a dietary effect, since transition to a gluten-free diet is associated with a reduced intake of complex polysaccharides. Although a long-term change in dietary habits is required to provoke major shifts in intestinal microbiota composition, changes in daily carbohydrate intake may affect specific groups of bacteria over a short period of time. For example, consumption of inulin or resistant starch increases the levels of Bifidobacterium spp. and Faecalibacterium prausnitzii or Ruminococcus bromii and Eubacterium rectale, respectively [
      • Walker W.A.
      Initial intestinal colonization in the human infant and immune homeostasis.
      ]. These non-digestible carbohydrates are fermented in the colon by its microbiota to yield energy for microbial growth and end products such as short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate. SCFAs have a profound impact on gut health as an energy source, an inflammation modulator, a vasodilator and part of gut motility and wound healing. In addition, they are energy substrates for the colonic epithelium (butyrate) and peripheral tissues (acetate and propionate). The patterns of intestinal fermentation and consequently the types and amounts of SCFAs produced are determined by how much carbohydrate is consumed and the composition of intestinal microbiota [
      • Tremaroli V.
      • Backhed F.
      Functional interactions between the gut microbiota and host metabolism.
      ]. Further studies are needed to shed light into the role of these host-microbiome interactions in the pathogenesis of celiac disease and other immune-mediated diseases.

      3. Non-celiac gluten sensitivity

      The prevalence of NCGS patients is an emerging health problem and it has been estimated to account over 6% of the general population, depending on the population studied [
      • Sapone A.
      • Bai J.C.
      • Ciacci C.
      • Dolinsek J.
      • Green P.H.
      • Hadjivassiliou M.
      • et al.
      Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
      ]. However, the real prevalence of NCGS remains obscure. Currently the risk factors for NCGS have not been established, although the disorder has a tendency to be associated with female gender and young or middle age [
      • Volta U.
      • Bardella M.T.
      • Calabro A.
      • Troncone R.
      • Corazza G.R.
      Study Group for Non-Celiac Gluten Sensitivity
      An italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity.
      ]. Non-celiac gluten –sensitive individuals develop adverse reactions such as gastrointestinal and extra-intestinal symptoms after exposure to gluten [
      • Sapone A.
      • Lammers K.M.
      • Casolaro V.
      • Cammarota M.
      • Giuliano M.T.
      • De Rosa M.
      • et al.
      Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.
      ]. Typical gastrointestinal symptoms include abdominal pain, bloating and altered bowel habit, the most often reported extra-intestinal symptoms being fatigue, headache, joint or bone pain, mood disorders and skin manifestations [
      • Sapone A.
      • Bai J.C.
      • Ciacci C.
      • Dolinsek J.
      • Green P.H.
      • Hadjivassiliou M.
      • et al.
      Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
      ,
      • Volta U.
      • Bardella M.T.
      • Calabro A.
      • Troncone R.
      • Corazza G.R.
      Study Group for Non-Celiac Gluten Sensitivity
      An italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity.
      ]. Due to the similarities in clinical outcomes and the absence of diagnostic biomarkers, it is challenging to differentiate NCGS from other gluten related disorders. Typically the diagnosis of NCGS is made after the exclusion of celiac disease and wheat allergy by means of negative celiac serology, negative histological findings and negative testing for specific immunoglobulin E (IgE). The diagnosis is further confirmed by a positive oral gluten challenge after exclusion of gluten from the diet for few weeks. The gluten challenge should be implemented in a blinded fashion in order to avoid a possible placebo effect commonly seen in the dietary interventions [
      • Sapone A.
      • Bai J.C.
      • Ciacci C.
      • Dolinsek J.
      • Green P.H.
      • Hadjivassiliou M.
      • et al.
      Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
      ]. However, this approach lacks specificity and is difficult to carry out in clinical practise. In addition, the exclusion of irritable bowel syndrome (IBS) should be considered during the diagnostic process, since gluten may exacerbate the symptoms in these patients [
      • Vazquez-Roque M.I.
      • Camilleri M.
      • Smyrk T.
      • Murray J.A.
      • Marietta E.
      • O'Neill J.
      • et al.
      A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
      ]. In contrast, grain-free diet or diet low in FODMAPs have been shown to alleviate the symptoms in some IBS patients [
      • Shahbazkhani B.
      • Sadeghi A.
      • Malekzadeh R.
      • Khatavi F.
      • Etemadi M.
      • Kalantri E.
      • et al.
      Non-celiac gluten sensitivity has narrowed the spectrum of irritable bowel syndrome: a double-blind randomized placebo-controlled trial.
      ].
      Although the aetiology of NCGS is unknown, it has been hypothesized that NCGS involves innate immune mechanisms without any implication of adaptive immune response [
      • Brottveit M.
      • Beitnes A.C.
      • Tollefsen S.
      • Bratlie J.E.
      • Jahnsen F.L.
      • Johansen F.E.
      • et al.
      Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity.
      ]. This is in contrast to celiac disease where overexpression of adaptive immunity markers is detected. Previously it has been shown that NCGS patients have normal intestinal permeability, normal expression of tight junction proteins claudin-1 and ZO-1 and significantly higher expression of claudin-4 when compared to celiac disease patients [
      • Sapone A.
      • Lammers K.M.
      • Casolaro V.
      • Cammarota M.
      • Giuliano M.T.
      • De Rosa M.
      • et al.
      Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.
      ]. The upregulation of claudin-4 coincided with the increased expression of toll-like receptor (TLR) proteins TLR1, TLR2 and TLR4 and decreased amount of regulatory T cells when compared to celiac disease patients [
      • Sapone A.
      • Lammers K.M.
      • Casolaro V.
      • Cammarota M.
      • Giuliano M.T.
      • De Rosa M.
      • et al.
      Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.
      ]. Toll-like receptors are molecular pattern recognition receptors often residing in the epithelial cell surface that recognize microbe-associated molecular patterns (MAMPs). The dynamic host-microbe interaction mediated by these receptors is crucial for the maintenance of intestinal homeostasis. Moreover, intestinal microbes have been shown to decrease the intestinal permeability by upregulating the expression of tight junction proteins [
      • Ma X.
      • Fan P.X.
      • Li L.S.
      • Qiao S.Y.
      • Zhang G.L.
      • Li D.F.
      Butyrate promotes the recovering of intestinal wound healing through its positive effect on the tight junctions.
      ]. Since intestinal microbiota has an essential role in regulating the antigen milieu of enterocytes, it may contribute to the pathogenesis or onset of non-celiac gluten sensitivity. However, its role in the NCGS has not yet been studied.

      4. Conclusion

      Several studies have demonstrated an altered intestinal microbiota composition in celiac disease patients. However, there is still no consensus yet regarding the special microbial species affecting positively or negatively to the disease process. In addition, human studies tend to be correlative and thus evidence supporting the causality between specific bacteria and the pathogenesis of certain diseases are difficult to obtain. Majority of the studies reporting association of microbiota with celiac disease have been carried out with paediatric patients, whose microbiota is still developing and prone to the compositional fluctuation due to the influence of a variety of environmental factors. Thus, studies considering the mature, established microbiota of adult patients are warranted. Moreover, studies including larger sample sizes and utilizing the newest state-of-the-art methods are needed to comprehensively analyse the role of the intestinal microbiota and its metabolites in both celiac disease and NCGS.

      Conflict of interest

      None.

      Acknowledgements

      The Academy of Finland Research Council for Health ( 25012812321 and 250129238 ), the Competitive State Research Financing of the Expert Responsibility Areas of Tampere University Hospital (Grants 9P060 , 9R018 , 9S020 , 9R034 ), the Sigrid Juselius Foundation and the Päivikki and Sakari Sohlberg Foundation are acknowledged for the financial support.

      References

        • Ludvigsson J.F.
        • Leffler D.A.
        • Bai J.C.
        • Biagi F.
        • Fasano A.
        • Green P.H.
        • et al.
        The Oslo definitions for coeliac disease and related terms.
        Gut. 2013; 62: 43-52
        • Sapone A.
        • Bai J.C.
        • Ciacci C.
        • Dolinsek J.
        • Green P.H.
        • Hadjivassiliou M.
        • et al.
        Spectrum of gluten-related disorders: consensus on new nomenclature and classification.
        BMC Med. 2012; 10 (13–7015-10-13)
        • 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 (320–8.e1-3)
        • Dubois P.C.
        • Trynka G.
        • Franke L.
        • Hunt K.A.
        • Romanos J.
        • Curtotti A.
        • et al.
        Multiple common variants for celiac disease influencing immune gene expression.
        Nat Genet. 2010; 42: 295-302
        • Nisticò L.
        • Fagnani C.
        • Coto I.
        • Percopo S.
        • Cotichini R.
        • Limongelli M.G.
        • et al.
        Concordance, disease progression, and heritability of coeliac disease in italian twins.
        Gut. 2006; 55: 803-808
        • Kalliomäki M.
        • Satokari R.
        • Lähteenoja H.
        • Vähämiko S.
        • Grönlund J.
        • Routi T.
        • et al.
        Expression of microbiota, toll-like receptors, and their regulators in the small intestinal mucosa in celiac disease.
        J Pediatr Gastroenterol Nutr. 2012; 54: 727-732
        • Steenholdt C.
        • Andresen L.
        • Pedersen G.
        • Hansen A.
        • Brynskov J.
        Expression and function of toll-like receptor 8 and tollip in colonic epithelial cells from patients with inflammatory bowel disease.
        Scand J Gastroenterol. 2009; 44: 195-204
        • Walker W.A.
        Initial intestinal colonization in the human infant and immune homeostasis.
        Ann Nutr Metab. 2013; 63: 8-15
        • De Palma G.
        • Nadal I.
        • Medina M.
        • Donat E.
        • Ribes-Koninckx C.
        • Calabuig M.
        • et al.
        Intestinal dysbiosis and reduced immunoglobulin-coated bacteria associated with coeliac disease in children.
        BMC Microbiol. 2010; 10 (63–2180-10-63)
        • Mårild K.
        • Ye W.
        • Lebwohl B.
        • Green P.H.
        • Blaser M.J.
        • Card T.
        • et al.
        Antibiotic exposure and the development of coeliac disease: a nationwide case-control study.
        BMC Gastroenterol. 2013; 13 (109–230X-13-109)
        • Mårild K.
        • Kahrs C.R.
        • Tapia G.
        • Stene L.C.
        • Stordal K.
        Infections and risk of celiac disease in childhood: a prospective nationwide cohort study.
        Am J Gastroenterol. 2015; 110: 1475-1484
        • Sánchez E.
        • De Palma G.
        • Capilla A.
        • Nova E.
        • Pozo T.
        • Castillejo G.
        • et al.
        Influence of environmental and genetic factors linked to celiac disease risk on infant gut colonization by bacteroides species.
        Appl Environ Microbiol. 2011; 77: 5316-5323
        • Palma G.D.
        • Capilla A.
        • Nova E.
        • Castillejo G.
        • Varea V.
        • Pozo T.
        • et al.
        Influence of milk-feeding type and genetic risk of developing coeliac disease on intestinal microbiota of infants: the PROFICEL study.
        PLoS One. 2012; 7: e30791
        • Olivares M.
        • Neef A.
        • Castillejo G.
        • Palma G.D.
        • Varea V.
        • Capilla A.
        • et al.
        The HLA-DQ2 genotype selects for early intestinal microbiota composition in infants at high risk of developing coeliac disease.
        Gut. 2015; 64: 406-417
        • Collado M.C.
        • Donat E.
        • Ribes-Koninckx C.
        • Calabuig M.
        • Sanz Y.
        Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease.
        J Clin Pathol. 2009; 62: 264-269
        • Sellitto M.
        • Bai G.
        • Serena G.
        • Fricke W.F.
        • Sturgeon C.
        • Gajer P.
        • et al.
        Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants.
        PLoS One. 2012; 7: e33387
        • Mazmanian S.K.
        • Liu C.H.
        • Tzianabos A.O.
        • Kasper D.L.
        An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.
        Cell. 2005; 122: 107-118
        • Cheng J.
        • Kalliomäki M.
        • Heilig H.G.
        • Palva A.
        • Lähteenoja H.
        • de Vos W.M.
        • et al.
        Duodenal microbiota composition and mucosal homeostasis in pediatric celiac disease.
        BMC Gastroenterol. 2013; 13 (113–230X-13-113)
        • Sanz Y.
        • De Palma G.
        • Laparra M.
        Unraveling the ties between celiac disease and intestinal microbiota.
        Int Rev Immunol. 2011; 30: 207-218
        • Cong Y.
        • Feng T.
        • Fujihashi K.
        • Schoeb T.R.
        • Elson C.O.
        A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota.
        Proc Natl Acad Sci U S A. 2009; 106: 19256-19261
        • Wang N.
        • Truedsson L.
        • Elvin K.
        • Andersson B.A.
        • Rönnelid J.
        • Mincheva-Nilsson L.
        • et al.
        Serological assessment for celiac disease in IgA deficient adults.
        PLoS One. 2014; 9: e93180
        • Kaetzel C.S.
        Cooperativity among secretory IgA, the polymeric immunoglobulin receptor, and the gut microbiota promotes host-microbial mutualism.
        Immunol Lett. 2014; 162: 10-21
        • Rogier E.W.
        • Frantz A.L.
        • Bruno M.E.
        • Wedlund L.
        • Cohen D.A.
        • Stromberg A.J.
        • et al.
        Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression.
        Proc Natl Acad Sci U S A. 2014; 111: 3074-3079
        • Maynard C.L.
        • Elson C.O.
        • Hatton R.D.
        • Weaver C.T.
        Reciprocal interactions of the intestinal microbiota and immune system.
        Nature. 2012; 489: 231-241
        • Smecuol E.
        • Hwang H.J.
        • Sugai E.
        • Corso L.
        • Cherñavsky A.C.
        • Bellavite F.P.
        • et al.
        Exploratory, randomized, double-blind, placebo-controlled study on the effects of bifidobacterium infantis natren life start strain super strain in active celiac disease.
        J Clin Gastroenterol. 2013; 47: 139-147
        • Jalanka-Tuovinen J.
        • Salonen A.
        • Nikkilä J.
        • Immonen O.
        • Kekkonen R.
        • Lahti L.
        • et al.
        Intestinal microbiota in healthy adults: temporal analysis reveals individual and common core and relation to intestinal symptoms.
        PLoS One. 2011; 6: e23035
        • Sanchez E.
        • Donat E.
        • Ribes-Koninckx C.
        • Fernandez-Murga M.L.
        • Sanz Y.
        Duodenal-mucosal bacteria associated with celiac disease in children.
        Appl Environ Microbiol. 2013; 79: 5472-5479
        • Viitasalo L.
        • Niemi L.
        • Ashorn M.
        • Ashorn S.
        • Braun J.
        • Huhtala H.
        • et al.
        Early microbial markers of celiac disease.
        J Clin Gastroenterol. 2014; 48: 620-624
        • Ashorn S.
        • Välineva T.
        • Kaukinen K.
        • Ashorn M.
        • Braun J.
        • Raukola H.
        • et al.
        Serological responses to microbial antigens in celiac disease patients during a gluten-free diet.
        J Clin Immunol. 2009; 29: 190-195
        • Wacklin P.
        • Kaukinen K.
        • Tuovinen E.
        • Collin P.
        • Lindfors K.
        • Partanen J.
        • et al.
        The duodenal microbiota composition of adult celiac disease patients is associated with the clinical manifestation of the disease.
        Inflamm Bowel Dis. 2013; 19: 934-941
        • Rubio-Tapia A.
        • Rahim M.W.
        • See J.A.
        • Lahr B.D.
        • Wu T.T.
        • Murray J.A.
        Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet.
        Am J Gastroenterol. 2010; 105: 1412-1420
        • Midhagen G.
        • Hallert C.
        High rate of gastrointestinal symptoms in celiac patients living on a gluten-free diet: controlled study.
        Am J Gastroenterol. 2003; 98: 2023-2026
        • Nachman F.
        • del Campo M.P.
        • González A.
        • Corzo L.
        • Vázquez H.
        • Sfoggia C.
        • et al.
        Long-term deterioration of quality of life in adult patients with celiac disease is associated with treatment noncompliance.
        Dig Liver Dis. 2010; 42: 685-691
        • Nadal I.
        • Donat E.
        • Ribes-Koninckx C.
        • Calabuig M.
        • Sanz Y.
        Imbalance in the composition of the duodenal microbiota of children with coeliac disease.
        J Med Microbiol. 2007; 56: 1669-1674
        • Wacklin P.
        • Laurikka P.
        • Lindfors K.
        • Collin P.
        • Salmi T.
        • Lähdeaho M.L.
        • et al.
        Altered duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet.
        Am J Gastroenterol. 2014; 109: 1933-1941
        • Sjöberg V.
        • Sandström O.
        • Hedberg M.
        • Hammarström S.
        • Hernell O.
        • Hammarström M.L.
        Intestinal T-cell responses in celiac disease - impact of celiac disease associated bacteria.
        PLoS One. 2013; 8: e53414
        • Parmar A.S.
        • Alakulppi N.
        • Paavola-Sakki P.
        • Kurppa K.
        • Halme L.
        • Färkkilä M.
        • et al.
        Association study of FUT2 (rs601338) with celiac disease and inflammatory bowel disease in the finnish population.
        Tissue Antigens. 2012; 80: 488-493
        • Wacklin P.
        • Tuimala J.
        • Nikkilä J.
        • Sebastian Tims
        • Mäkivuokko H.
        • Alakulppi N.
        • et al.
        Faecal microbiota composition in adults is associated with the FUT2 gene determining the secretor status.
        PLoS One. 2014; 9: e94863
        • Wacklin P.
        • Mäkivuokko H.
        • Alakulppi N.
        • Nikkilä J.
        • Tenkanen H.
        • Räbinä J.
        • et al.
        Secretor genotype (FUT2 gene) is strongly associated with the composition of bifidobacteria in the human intestine.
        PLoS One. 2011; 6: e20113
        • Rausch P.
        • Rehman A.
        • Künzel S.
        • Häsler R.
        • Ott S.J.
        • Schreiber S.
        • et al.
        Colonic mucosa-associated microbiota is influenced by an interaction of crohn disease and FUT2 (secretor) genotype.
        Proc Natl Acad Sci U S A. 2011; 108: 19030-19035
        • Pickard J.M.
        • Maurice C.F.
        • Kinnebrew M.A.
        • Abt M.C.
        • Schenten D.
        • Golovkina T.V.
        • et al.
        Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness.
        Nature. 2014; 514: 638-641
        • 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
        • Di Cagno R.
        • De Angelis M.
        • De Pasquale I.
        • Ndagijimana M.
        • Vernocchi P.
        • Ricciuti P.
        • et al.
        Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization.
        BMC Microbiol. 2011; 11 (219–2180-11-219)
        • Tremaroli V.
        • Backhed F.
        Functional interactions between the gut microbiota and host metabolism.
        Nature. 2012; 489: 242-249
        • Volta U.
        • Bardella M.T.
        • Calabro A.
        • Troncone R.
        • Corazza G.R.
        • 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 (85–7015-12-85)
        • Sapone A.
        • Lammers K.M.
        • Casolaro V.
        • Cammarota M.
        • Giuliano M.T.
        • De Rosa M.
        • 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 (23–7015-9-23)
        • Vazquez-Roque M.I.
        • Camilleri M.
        • Smyrk T.
        • Murray J.A.
        • Marietta E.
        • O'Neill J.
        • 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.e3)
        • Shahbazkhani B.
        • Sadeghi A.
        • Malekzadeh R.
        • Khatavi F.
        • Etemadi M.
        • Kalantri E.
        • et al.
        Non-celiac gluten sensitivity has narrowed the spectrum of irritable bowel syndrome: a double-blind randomized placebo-controlled trial.
        Nutrients. 2015; 7: 4542-4554
        • Brottveit M.
        • Beitnes A.C.
        • Tollefsen S.
        • Bratlie J.E.
        • Jahnsen F.L.
        • Johansen F.E.
        • et al.
        Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity.
        Am J Gastroenterol. 2013; 108: 842-850
        • Ma X.
        • Fan P.X.
        • Li L.S.
        • Qiao S.Y.
        • Zhang G.L.
        • Li D.F.
        Butyrate promotes the recovering of intestinal wound healing through its positive effect on the tight junctions.
        J Anim Sci. 2012; 90: 266-268