Progression Of Celiac Disease Research Articles

Celiac Disease: The Importance of Studying the Duodenal Mucosa-Associated Microbiota.

There is increasing evidence indicating that changes in both the composition and functionality of the intestinal microbiome are closely associated with the development of several chronic inflammatory diseases, with celiac disease (CeD) being particularly noteworthy. Thanks to the advent of culture-independent methodologies, the ability to identify and quantify the diverse microbial communities residing within the human body has been significantly improved. However, in the context of CeD, a notable challenge lies in characterizing the specific microbiota present on the mucosal surfaces of the intestine, rather than relying solely on fecal samples, which may not fully represent the relevant microbial populations. Currently, our comprehension of the composition and functional importance of mucosa-associated microbiota (MAM) in CeD remains an ongoing field of research because the limited number of available studies have reported few and sometimes contradictory results. MAM plays a crucial role in the development and progression of CeD, potentially acting as both a trigger and modulator of the immune response within the intestinal mucosa, given its proximity to the epithelial cells and direct interaction. According to this background, this review aims to consolidate the existing literature specifically focused on MAM in CeD. By elucidating the complex interplay between the host immune system and the gut microbiota, we aim to pave the way for new interventions based on novel therapeutic targets and diagnostic biomarkers for MAM in CeD.

The modulation of macrophage subsets in celiac disease pathogenesis.

So far, limited studies have focused on the role of Macrophages (MQs) in the development or progression of celiac disease (CD). Researchers believe that increasing knowledge about the function of MQs in inflammatory disorders plays a critical role in finding a new treatment for these kinds of diseases. CD is a permanent autoimmune intestinal disorder triggered by gluten exposure in predisposed individuals. This disorder happens due to the loss of intestinal epithelial barrier integrity characterized by dysregulated innate and adaptive immune responses. MQs are known as key players of the innate immune system that link innate and adaptive immunity. MQs of human intestinal lamina propria participate in maintaining tissue homeostasis, and also intestinal inflammation development. Previous studies suggested that gliadin triggers a proinflammatory phenotype (M1 MQ) in human primary MQs. Moreover, M2-related immunosuppressive mediators are also present in CD. In fact, CD patients present an impaired transition from pro-inflammatory to anti-inflammatory responses due to inappropriate responses to gliadin peptides. The M1/M2 MQs polarization balancing regulators can be considered novel therapeutic targets for celiac disease.

The Progression of Celiac Disease, Diagnostic Modalities, and Treatment Options.

Celiac disease (CD) is an autoimmune disorder that affects genetically predisposed individuals who are sensitive to gluten and related proteins. It affects children and adults with increasing prevalence in the older age groups. Both adaptive and innate immune responses play role in CD pathogenesis which results in damage of lamina propria and deposition of intraepithelial lymphocytes. There are other proposed mechanisms of CD pathogenesis like gastrointestinal infections, intestinal microbiota, and early introduction of gluten. The diagnosis of CD is based on clinical symptoms and serological testing, though a majority of cases are asymptomatic, and small intestinal biopsies are required to confirm the diagnosis. Celiac disease is generally associated with other autoimmune diseases, and it is advisable to test these patients for diseases like type 1 diabetes mellitus, Addison’s disease, thyroid diseases, inflammatory bowel disease, and autoimmune hepatitis. The patient with a new diagnosis of CD requires close follow-up after starting treatment to see symptom improvement and check dietary compliance. A newly diagnosed patient is advised to follow with a dietitian to better understand the dietary restrictions as about 20% of patients stay symptomatic even after starting treatment due to noncompliance or poor understanding of diet restrictions. The most effective treatment for CD is a gluten-free diet, but work on non-dietary therapy is in process and few medications are in the clinical trial phase.

The Role of Early Programming and Early Nutrition on the Development and Progression of Celiac Disease: A Review.

Experimental and epidemiological evidence has shown that modifications of the intrauterine environment can have deleterious consequences for individuals, expressed as an increased risk of suffering non-communicable pathologies in adult life, which is known as the hypothesis of the early origin of diseases or fetal programming. On the other hand, changes in gene expression patterns through epigenetic modifications can be the basis for long-term maintenance of the effects of fetal programming. In this sense, epigenetics comprises the study of intrauterine disturbances, which develop diseases in the adult, including celiac disease (CD). In addition, early feeding practices could influence the risk of CD development, such as breastfeeding timing and duration and age of gluten introduction in the diet. Gluten acts as a trigger for CD in genetically predisposed subjects, although approximately 30% of the world population has HLA DQ2 or DQ8, the prevalence of the disease is only 1–3%. It is not known what factors act to modify the risk of disease in genetically at-risk subjects. Taking into account all these considerations, the aim of the current review is to elucidate the role of early programming and the effect of early nutrition on the development and progression of CD. It is logical that attention has been paid to gluten as a key element in preventing the disease. However, there is no strong evidence in favor of the protective factor of breastfeeding, timing of introduction of gluten during lactation, and the development of CD. Diet, genetic risk, microbiota, and environmental interaction are possible triggers of the change in tolerance to an immune response to gluten, but large-scale cohort studies are needed. Emerging scientific concepts, such as epigenetics, may help us establish the role of these factors.

Intestinal microbiota at functional intestinal disorders and celiac disease

Over the past decades, a large number of studies have been published to confirm the role of intestinal microbiota in the pathogenesis of functional intestinal disorders. The authors presented a review of the main mechanisms through which various microorganisms that colonize the digestive tract, have a beneficial effect on the human body. The results of experimental studies, that confirmed the ability of various bacteria to provoke the development of bacterial overgrowth syndrome, irritable bowel syndrome, functional constipation, have been presented. The data providing evidence of the intestinal microbiota role in the progression of celiac disease have been considered. The efficacy of various methods of restoration of intestinal eubiosis by non‑absorbable antibiotics (rifaximin), probiotics, fecal microbiota transplantation is analyzed. The data have been presented that confirm the expediency of rifaximin use in irritable bowel syndrome. In addition to the traditional bactericidal and bacteriostatic properties of many antibiotics, there is an evidence of additional eubiotic activity in rifaximin. The results of meta‑analyses studying the efficacy of various probiotics in the treatment of functional constipation are considered. The ambiguity of the evidence base with respect to the fecal microbiota transplantation for treatment of refractory irritable bowel syndrome is underlined. The expediency of inclusion of eubiotics in treatment of functional intestinal diseases is proved. Further research is needed to determine the prospects of treatment of intestinal dysbiosis in functional intestinal disorders with probiotics.

Progression of Celiac Disease in Children With Antibodies Against Tissue Transglutaminase and Normal Duodenal Architecture

Potential celiac disease is characterized by positive results from serologic tests for tissue transglutaminase antibodies (anti-TG2) but normal duodenal architecture (Marsh stages 0-1). There is controversy over the best way to manage these patients. We investigated risk factors associated with the development of villous atrophy in children with potential celiac disease. We performed a prospective study of 280 children (ages 2-18 years) in Italy with suspected celiac disease, followed for up to 12 years (range, 18-150 months; median 60 months). The subjects had 2 consecutive positive results from tests for anti-TG2, tested positive for the endomysial antibody (anti-EMA), had total serum levels of immunoglobulin A in the normal range, normal duodenal architecture (Marsh stages 0-1) in 5 biopsies, and HLA DQ2- or DQ8-positive haplotypes. The children underwent serologic tests and clinical analyses every 6 months and a small bowel biopsy was taken every 2 years. A total of 210 patients of the original cohort were assessed at the 9-year follow-up evaluation. We performed multivariate analyses of clinical, genetic, and histologic data to identify factors associated with progression to villous atrophy. During the follow-up period, 42 (15%) of 280 children developed villous atrophy, whereas 89 (32%) children no longer tested positive for anti-TG2 or anti-EMA. The cumulative incidence of progression to villous atrophy was 43% at 12 years. In multivariate analysis, the baseline factors most strongly associated with development of villous atrophy were numbers of γδ intraepithelial lymphocyte cells followed by age and homozygosity for the HLA DQB1*02. In discriminant analysis, these baseline factors identified 80% of the children who developed baseline atrophy. In a long-term study of 280 children with suspected celiac disease (based on anti-TG2 and anti-EMA) on gluten-containing diets, the cumulative incidence of progression to villous atrophy was 43% over a 12-year period. We identified factors that can be used to identify children at highest risk for villous atrophy. This approach might be used to determine whether children with suspected celiac disease should immediately start a gluten-free diet or be monitored on their regular diet.

Mast cells are associated with the onset and progression of celiac disease

Celiac disease (CD) is an immune-mediated disorder characterized by an accumulation of immune cells in the duodenal mucosa as a consequence of both adaptive and innate immune responses to undigested gliadin peptides. Mast cells (MCs) are innate immune cells that are a major source of costimulatory signals and inflammatory mediators in the intestinal mucosa. Although MCs have previously been associated with CD, functional studies have never been performed. We aimed at evaluating the role of MCs in the pathogenesis of CD. Intestinal biopsy specimens of patients with CD were scored according to the Marsh classification and characterized for leukocyte infiltration and MC distribution. Moreover, MC reactivity to gliadin and its peptides was characterized by using invitro assays. Infiltrating MCs were associated with the severity of mucosal damage, and their numbers were increased in patients with higher Marsh scores. MCs were found to directly respond to nonimmunodominant gliadin fragments by releasing proinflammatory mediators. Immunohistochemical characterization of infiltrating MCs and the effects of gliadin peptides on intestinal MCs indicated an increase in proinflammatory MC function in advanced stages of the disease. This was also associated with increased neutrophil accumulation, the prevalence of M1 macrophages, and the severity of tissue damage. We provide a description of the progressive stages of CD, in which MCs are the hallmark of the inflammatory process. Thus the view of CD should be revised, and the contribution of MCs in the onset and progression of CD should be reconsidered in developing new therapeutic approaches.

Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease

The mechanisms of tissue destruction during progression of celiac disease are poorly defined. It is not clear how tissue stress and adaptive immunity contribute to the activation of intraepithelial cytotoxic T cells and the development of villous atrophy. We analyzed epithelial cells and intraepithelial cytotoxic T cells in family members of patients with celiac disease, who were without any signs of adaptive antigluten immunity, and in potential celiac disease patients, who have antibodies against tissue transglutaminase 2 in the absence of villous atrophy. We collected blood and intestinal biopsy specimens from 268 patients at tertiary medical centers in the United States and Italy from 2004 to 2012. All subjects had normal small intestinal histology. Study groups included healthy individuals with no family history of celiac disease or antibodies against tissue transglutaminase 2 (controls), healthy family members of patients with celiac disease, and potential celiac disease patients. Intraepithelial cytotoxic T cells were isolated and levels of inhibitory and activating natural killer (NK) cells were measured by flow cytometry. Levels of heat shock protein (HSP) and interleukin 15 were measured by immunohistochemistry, and ultrastructural alterations in intestinal epithelial cells (IECs) were assessed by electron microscopy. IECs from subjects with a family history of celiac disease, but not from subjects who already had immunity to gluten, expressed higher levels of HS27, HSP70, and interleukin-15 than controls; their IECs also had ultrastructural alterations. Intraepithelial cytotoxic T cells from relatives of patients with celiac disease expressed higher levels of activating NK receptors than cells from controls, although at lower levels than patients with active celiac disease, and without loss of inhibitory receptors for NK cells. Intraepithelial cytotoxic T cells from potential celiac disease patients failed to up-regulate activating NK receptors. A significant subset of healthy family members of patients with celiac disease with normal intestinal architecture had epithelial alterations, detectable by immunohistochemistry and electron microscopy. The adaptive immune response to gluten appears to act in synergy with epithelial stress to allow intraepithelial cytotoxic T cells to kill epithelial cells and induce villous atrophy in patients with active celiac disease.

Modulation of phenotypic and functional maturation of dendritic cells by intestinal bacteria and gliadin: relevance for celiac disease

DC maturation and functions are influenced by microbial and environmental stimuli, which could contribute to immune dysfunction. Here, we have investigated the role of enterobacteria (Escherichia coli CBL2 and Shigella CBD8) isolated from CD patients, bifidobacteria (Bifidobacterium longum CECT 7347 and Bifidobacterium bifidum CECT 7365), and gliadins on phenotypic and functional features of MDDCs and in coculture with Caco-2 cells. The ultimate goal of our study is to understand the roles played by specific components of the gut microbiota in CD. Enterobacteria induced marked alterations in MDDC morphology, inducing podosome dissolution and dendrites, and activated MDDC adhesion and spreading. Enterobacteria also induced inflammatory cytokine production (IFN-γ, TNF-α, and IL-12), partially resembling the gliadin-induced Th1-type cytokine profile. B. longum CECT 7347 and B. bifidum CECT 7365 induced minor MDDC morphological changes and activated adhesion and spreading and inflammatory cytokine production to a lesser extent compared with enterobacteria. B. longum CECT 7347 also induced lower CD86 and CD40 expression on MDDCs than the two enterobacteria. The aforementioned bifidobacterial strain also reduced gliadin-induced IFN-γ production and increased IL-10 secretion when both stimuli were combined. Similar trends were detected for MDDCs cocultured with Caco-2 cells. B. longum CECT 7347 reversed the gliadin-reduced ZO-1 expression in Caco-2 cells. Thus, our results suggest that specific components of the gut microbiota may influence phenotypic and functional maturation of DCs differently and their interactions with epithelial cells. This could ultimately define the role of DCs in CD progression.

Epidemiology of celiac disease: What are the prevalence, incidence, and progression of celiac disease?

Celiac disease (CD) is a chronic systemic autoimmune disorder induced by gluten proteins present in wheat, barley, and rye. Contrary to common belief, gluten enteropathy is a systemic disease rather than merely an ailment of the alimentary tract. Genetically susceptible persons develop autoimmune injury to the gut, skin, liver, joints, uterus, brain, heart, and other organs (Figure 1). The classical definition of CD included gastrointestinal manifestations (chronic diarrhea, failure to grow, weight loss, vomiting, abdominal pain, bloating, distention, and constipation), confirmed by a small bowel biopsy (SBB) with findings of villous atrophy, crypt hyperplasia, and normalization of the villous architecture in response to a gluten-free diet. 1,2 Previously, CD was thought to be a disease primarily of infancy; however, with the widespread delay in introduction of wheat into the infant diet, the clinical manifestations have become more subtle, and diagnosis is now typically made in older children and adults. 3‐5 SBB is poorly accepted by a majority of patients with mild or no symptoms, and the pathologic examination of biopsy material is suboptimal in most settings. The use of SBB as a “gold standard” for diagnosis has significant limitations. It is occasionally false-negative because of patchy mucosal changes. Villous atrophy is often most severe in the proximal jejunum, typically not reached by endoscopic biopsy. This has led some to propose a new definition of CD, based on the presence of serum IgA autoantibodies to tissue transglutaminase (IgA TG) and HLA-DQB1*0201 or *0302 alelles. 6 These markers are increasingly used in screening for CD, but their true sensitivity and specificity are debatable. Although efforts to standardize IgA TG assays have been undertaken, 7,8 previous reports have likely overestimated the sensitivity and underestimated the specificity because of verification bias 9 caused by the lack of SBB studies in patients negative on TG screening.

Gliadin as stimulator adaptive and innate immune responses in celiac disease.

Celiac disease (CD) has been considered as the typical model of disease in which the adaptive branch (T cells) of the immune system produces the whole pathogenic picture (1). The strict genetic association between HLA DQ2/8 alleles and CD (2), the recent and elegant studies which have unveiled the molecular mechanisms that control posttranslational modification of gliadin immunodominant epitopes have strengthen this view (1). Thought T cells are the key elements in the induction and progression of celiac disease, their activation must be preceded by an engagement/activation of the innate immune system. The role of resident professional antigen presenting cells is indeed essential for antigen recognition and T cell activation in CD. This function is operated by tissue myeloid derived cells (usually Dendritic Cells) which process antigen and deliver the appropriate co-stimulatory signal to T cells. In the case of gliadin in CD, another fundamental posttranslational modification is required as discussed above, which is operated by tTG. Interestingly, this enzyme is highly expressed upon maturation of Dendritic Cells (3), further stressing the potential close interaction between adaptive and innate immune systems in the induction of celiac disease. It is therefore natural to expect that the innate branch of the immune system must be involved, at least in the initial phases of celiac disease. It can be expected that this essential phase of the immune response, leading to gliadin specific T cell activation, might be supported by simultaneous and unrelated infections which could provide the required ‘non specific’ but essential cofactors for the induction of gliadin specific T cell activation. This is more than a theoretical option and epidemiologic data lends a hand to support this scenario (4).Despite all the unequivocal results on gliadin recognition by T cells and their critical activation for disease progression, there is increasing evidence that gluten/gliadin can induce specific mucosal changes which are apparently not driven by the activation of the adaptive immune system (5). This non T cell targeted activation might represent an important co-factor in the pathogenesis of celiac disease and we have proposed that a mucosal activation of the adaptive immune system might occur upon encounter of gliadin in the small intestine of celiac patients (5). The clarification of this unforeseen activation of the non adaptive branch of the immune system might hold clues to comprehend not only key steps in the pathogenesis of celiac disease, but also open unexpected scenarios in the whole area of mucosal functional homeostasis. In the context of the presentation it will be discussed how an activation of the innate immune system might occur and might influence CD progression.