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Celiac disease (CeD) is an autoimmune disease with a strong association with human leukocyte antigen (HLA), characterized by the production of specific autoantibodies and immune-mediated enterocyte killing. CeD is a unique autoimmune condition, as it is the only one in which the environmental trigger is known: gluten, a storage protein present in wheat, barley, and rye. How and when the loss of tolerance of the intestinal mucosa to gluten occurs is still unknown. This event, through the activation of adaptive immune responses, enhances epithelial cell death, increases the permeability of the epithelial barrier, and induces secretion of pro-inflammatory cytokines, resulting in the transition from genetic predisposition to the actual onset of the disease. While the role of gastrointestinal infections as a possible trigger has been considered on the basis of a possible mechanism of antigen mimicry, a more likely alternative mechanism appears to involve a complex disruption of the gastrointestinal microbiota ecosystem triggered by infections, rather than the specific effect of a single pathogen on intestinal mucosal homeostasis. Several lines of evidence show the existence of intestinal dysbiosis that precedes the onset of CeD in genetically at-risk subjects, characterized by the loss of protective bacterial elements that both epigenetically and functionally can influence the response of the intestinal epithelium leading to the loss of gluten tolerance. We have conducted a literature review in order to summarize the current knowledge about the complex and in part still unraveled dysbiosis that precedes and accompanies CeD and present some exciting new data on how this dysbiosis might be prevented and/or counteracted. The literature search was conducted on PubMed.gov in the time frame 2010 to March 2024 utilizing the terms "celiac disease and microbiota", "celiac disease and microbiome", and "celiac disease and probiotics" and restricting the search to the following article types: Clinical Trials, Meta-Analysis, Review, and Systematic Review. A total of 364 papers were identified and reviewed. The main conclusions of this review can be outlined as follows: (1) quantitative and qualitative changes in gut microbiota have been clearly documented in CeD patients; (2) intestinal microbiota's extensive and variable interactions with enterocytes, viral and bacterial pathogens and even gluten combine to impact the inflammatory immune response to gluten and the loss of gluten tolerance, ultimately affecting the pathogenesis, progression, and clinical expression of CeD; (3) gluten-free diet fails to restore the eubiosis of the digestive tract in CeD patients, and also negatively affects microbial homeostasis; (4) new tools allowing targeted microbiota therapy, such as the use of probiotics (a good example being precision probiotics like the novel strain of B. vulgatus (20220303-A2) begin to show exciting potential applications.

Inflammatory bowel diseases (IBD) are chronic, incurable inflammatory condition of the gut. They comprise Crohn's disease and ulcerative colitis. Crohn's disease (CD) may affect any tract of the gastrointestinal (GI) tract and is a transmural inflammatory condition; ulcerative colitis (UC), on the other hand, is limited to the mucosal layer of the rectum and colon. Treatment options available for both IBD are notoriously loaded with potentially serious side effects and risks. Although the pathogenesis of IBD involves a complex interaction between genetic, environmental, microbial and immunological factors, there is evidence that the interplay between the microbiota and the GI mucosa has a preponderant role. It is therefore no surprise that in recent years, a growing interest for effective and safer alternatives has focused on the potential role of prebiotics and-especially-probiotics.The mechanisms of action underlying the potential benefits of probiotics in IBD have been largely and quite extensively investigated in vitro and in vivo experiments. In terms of clinical evidence, the results of trials in the induction of remission of active CD or the maintenance of its remission with probiotics have been so far largely disappointing, to the point that their use in this disease cannot be at present recommended.On the contrary, for the treatment as well as for maintenance therapy of UC, there is clinical evidence of efficacy for some specific strains or multi-strain preparations.It is evident that this is a rapidly evolving and promising field; more data are very likely to yield a better understanding on what strains and in what doses should be used in different specific clinical settings, as we expect new and exciting developments of precision and even personalized therapy by the fast-growing field of probiogenomics., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objectives: To gather the current evidence and to offer recommendations for follow-up and management., Methods: The Special Interest Group on Celiac Diseases of the European Society of Paediatric Gastroenterology Hepatology and Nutrition formulated ten questions considered to be essential for follow-up care. A literature search (January 2010-March 2020) was performed in PubMed or Medline. Relevant publications were identified and potentially eligible studies were assessed. Statements and recommendations were developed and discussed by all coauthors. Recommendations were voted upon: joint agreement was set as at least 85%., Results: Publications (n = 2775) were identified and 164 were included. Using evidence or expert opinion, 37 recommendations were formulated on: The need to perform follow-up, its frequency and what should be assessed, how to assess adherence to the gluten-free diet, when to expect catch-up growth, how to treat anemia, how to approach persistent high serum levels of antibodies against tissue-transglutaminase, the indication to perform biopsies, assessment of quality of life, management of children with unclear diagnosis for which a gluten-challenge is indicated, children with associated type 1 diabetes or IgA deficiency, cases of potential celiac disease, which professionals should perform follow-up, how to improve the communication to patients and their parents/caregivers and transition from pediatric to adult health care., Conclusions: We offer recommendations to improve follow-up of children and adolescents with celiac disease and highlight gaps that should be investigated to further improve management., Competing Interests: Mearin received receipt of grants/research supports from Research Grant Eurospital, ThermoFisher and BioHit and served as member of advisory board and consultancy and speaker from ThermoFisher. Agardh received receipt of grants/research supports from Novo Nordisk Foundation and served as member of advisory board from Takeda and ThermoFischer. Antunes received receipt of payment/honorarium for lectures from Danone, Catassi received receipt of payment/honorarium for consultation from Dr Schar Food. Dolinsek received receipt of payment/honorarium for lectures from Medis, Abbot, Merit. Guandalini served as member of advisory board from ExeGIPharma, Imaware. Koletzko received receipt of grants/research supports from Mead-Johnson, Biogaia; served as member of advisory board from Abbvie, Danone, Jannsen, Sanofi, Takeda; receipt of payment/honorarium for lectures from Danone, Mead-Johnson, Nestlé Nutrition, Pfizer, Takeda; receipt of payment/honorarium for consultation from Danone. Korponay-Szabó other support from patent on celiac disease rapid test licensed to Labsystems Oy, Vantaa, Finland. Kurppa received receipt of grants/research supports from Finnish Pediatric Foundation, Päivikki, and Sakari Sohlberg Foundation; served as member of advisory board from Finnish Coeliac Society; receipt of payment/honorarium for lectures from Thermo Fisher; and receipt of payment/honorarium for consultation from Takeda. Rodriguez-Herrera received other support from Patent and detecting gluten peptides in human fluids, March 29, 2019—Universidad de Sevilla. Shamir received receipt of grants/research supports from Helmsley Foundation; served as member of advisory board: Nestle Nutrition Institute, Teva; receipt of payment/honorarium for lectures from Abbott, Nutricia, Nestle Nutrition Institute; receipt of payment/honorarium for consultation from Abbott, Else, Nutricia, Nestle Nutrition Institute and Stock shareholder from NGS. Ciacci received receipt of honoraria or consultation fees from Takeda, GSK, Mediserve, Biogen Celltrion. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Intestinal microbiota play a role in the health and performance of athletes, and can be influenced by probiotics. Thus, in this study, we aimed to investigate the effect of the use of probiotics combined with chronic exercise on the thiol/disulfide homeostasis, a novel marker of oxidative stress., Methods: Male Wistar rats were randomly divided into four groups: control (Cn), exercise (Ex), probiotics (P), and probiotics + exercise (PEx). A capsule containing 6 × 10 8 CFU of L. rhamnosus , L. paracasei, L. acidophilus, and B. lactis was given daily for eight weeks to all the experimental animals. The total thiol (TT, μmol/L) and native thiol (NT, μmol/L) concentrations were measured to determine the oxidative stress parameters. The dynamic disulfide (DD, %), reduced thiol (RT, %), oxidized thiol (OT, %), and thiol oxidation reduction (TOR, %) ratios were analyzed., Results: The TT level was found to be significantly higher in the Ex group (p = 0.047, η 2 = 0.259). The DD level, a marker of oxidation, was significantly lower in the PEx group (p = 0.042, η 2 = 0.266); the highest value of this parameter was found in the Ex group. The use of probiotics alone had no effect on thiol/disulfide homeostasis., Conclusions: We showed, for the first time, that probiotics administered "with exercise" decreased dynamic disulfide and significantly reduced oxidative damage. Therefore, we speculate that the use of probiotics in sports involving intense exercise might be beneficial to reduce oxidative stress.

Purpose: To evaluate changes in peripapillary vascular blood flow indices (PVBFI) in patients with thyroid-associated ophthalmopathy (TAO) using OCT angiography (OCTA) technology., Methods: Patients with TAO and control subjects matched for age and sex were included in the study. Eye examination, Clinical Activity Score (CAS) evaluation and OCTA scan analysis (Topcon ImageNet 6; DRI OCT Triton, Topcon Corporation) were performed. In particular, PVBFI of the superficial capillary plexus (SCP), deep capillary plexus (DCP), outer retina (OR) and choriocapillaris (CC) layers were obtained by OCTA and extracted from 8-bit greyscale OCT images using the ImageJ software package., Results: Twenty-six patients with TAO (19 females, mean age 54.7 ± 5.2 and 7 males, mean age 51.4 ± 16.3) were compared with 26 healthy subjects (15 females, mean age 48.2 ± 14.1 and 11 males, mean age 53.1 ± 15.2). Both DCP-PVBF and CC-PVBFI were significantly reduced in TAO patients compared to control eyes (28.6 ± 2.1 vs. 29.7 ± 0.93, p = 0.002; 46.5 ± 1.72 vs. 47.2 ± 1.2, p = 0.019 respectively); on the other hand, no statistically significant differences were found in SCP-PVBFI and OR-PVBFI in TAO patients compared to healthy subjects (p > 0.05). Also, CC-PVBFI was associated with elevated values of CAS (p = 0.018) and ROC curve showed that patients with elevated CC-PVBFI were correlated with active TAO (CAS > 3) (p = 0.012)., Conclusions: TAO disease may be associated with changes in DCP-PVBFI and CC-PVBFI; also, CC-PVBFI seems to correlate with disease activity., (© 2022. The Author(s).)

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. Results: The median VH in NCGS was significantly shorter (600, IQR: 400−705) than controls (900, IQR: 667−1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390−620) vs. 427 µm (IQR: 348−569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

Assessment and management of pain are essential components of pediatric care. Pain in pediatric age is characterized by relevant health and socio-economic consequences due to parental concern, medicalization, and long-term physical and psychological impact in children. Pathophysiological mechanisms of nociception include several pathways in which also individual perception and gut-brain axis seem to be involved. In this narrative review, we analyze the rational and the current clinical findings of probiotic use in the management of functional gastrointestinal disorders (FGID) in pediatric age, with special focus on infantile colic, irritable bowel syndrome, constipation, and gastroesophageal reflux. Some specific probiotics showed a significant reduction in crying and fussing compared to placebo in breastfed infants with colic, although their exact mechanism of action in this disorder remains poorly understood. In irritable bowel syndrome, a limited number of studies showed that specific strains of probiotics can improve abdominal pain/discomfort and bloating/gassiness, although data are still scarce. As for constipation, whilst some strains appear to reduce the number of hard stools in constipated children, the evidence is not adequate to support the use of probiotics in the management of functional constipation. Similarly, although some probiotic strains could promote gastric emptying with a potential improvement of functional symptoms related to gastroesophageal reflux, current evidence is insufficient to provide any specific recommendation for the prevention or treatment of gastroesophageal reflux. In conclusion, probiotics have been proposed as part of management of pain in functional gastrointestinal disorders in pediatric age, but mechanisms are still poorly understood and evidence to guide clinical practice is currently inadequate., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Capozza, Laforgia, Rizzo, Salvatore, Guandalini and Baldassarre.)

To test the impact of celiac disease (CD) and depression symptoms on quality of life in adolescent patients., Methods: We conducted a prospective survey of 12- to 18-year-old celiac patients and their caregivers between January 2015 and November 2016. Enrolled parents and youth completed standard measures of adjustment to celiac disease, depression, and quality of life., Results: We enrolled 105 patients with CD and their parents. Both parents and youth reported high levels of depression symptoms. There were no associations between age, duration of CD, or following a gluten-free diet (GFD) and quality of life. No significant associations were found between adolescent perception of CD state and quality of life; parental report of adolescent's adjustment to CD; and youth report of quality of life were modestly associated (r = 0.19, P ≤ 0.05). Moderate associations were observed between adolescent reports of depression and quality of life (r = 0.59, P < 0.01) and between parental reports of adolescent depression and quality of life (r = 0.41, P  = 0.01). Only depressive symptoms by youth and parent report, however, and not adjustment to celiac, explained unique variance in quality of life., Conclusion: Adolescents with CD report levels of depression comparable to those reported by adolescents seeking mental health services. Length of time living with CD, or on GFD, age at diagnosis and perception of disease state do not appear to contribute to depression. High rates of depression may impact CD prognosis, therefore, screening for depression in adolescents with CD appears critical. Identification and intervention of depression may lead to improved adherence to the GFD during emerging adulthood., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

An expanding gluten-free marketplace has left children with celiac disease and their families with a host of new dietary options. The quality of these foods is inconsistent and processed items may be high in caloric content while lacking nutritional value. Assessing the dietary preferences of a cohort of children with celiac disease via cross-sectional survey, we find that these processed food items have become a staple of the gluten-free diet, and in many cases, these foods are consumed to the exclusion of healthy alternatives. Furthermore, children with celiac disease and their families become less interested in dietary education over time, indicating that the greatest opportunity for imparting a healthy diet may occur at the time of diagnosis.

The effects of gluten free diet (GFD) on body mass index (BMI) and growth parameters in pediatric patients with celiac disease (CD) and their dependence on different socio-cultural environments are poorly known. We conducted an international retrospective study on celiac patients diagnosed at the University of Verona, Italy, and at the University of Chicago, Chicago, IL, USA, as underweight. A total of 140 celiac children and 140 controls (mean age 8.4 years) were enrolled in Chicago; 125 celiac children and 125 controls (mean age 7.3 years, NS) in Verona. At time of diagnosis, Italian celiac children had a weight slightly lower ( p = 0.060) and a BMI z-score significantly ( p < 0.001) lower than their American counterparts. On GFD, Italian celiac children showed an increased prevalence of both underweight (19%) as well as overweight (9%), while American children showed a decrease prevalence of overweight/obese. We concluded that while the GFD had a similar impact on growth of celiac children in both countries, the BMI z-score rose more in American than in Italian celiac children. Additionally, in Italy, there was an alarming increase in the proportion of celiac children becoming underweight. We speculate that lifestyle and cultural differences may explain the observed variations., Competing Interests: The authors declare no conflict of interest.

Background: Rome IV criteria for functional gastrointestinal disorders state that children suspected of having Irritable Bowel Syndrome (IBS) with Constipation (IBS-C) should be preliminarily treated for constipation. We aimed at verifying if functional constipation may indeed lead to an erroneous diagnosis of IBS with diarrhea (IBS-D) or IBS with mixed pattern of diarrhea and constipation (IBS-M)., Methods: We prospectively enrolled in an unblinded fashion 10 and 16 consecutive children referred to our center who met Rome IV criteria for a diagnosis of IBS-D and IBS-M, respectively. Patients who fulfilled criteria for suspect "occult constipation" were then given a bowel cleaning regimen with Polyethylene glycol 3350, re-evaluated at 2 months and followed up for at least 6 months. Sixteen additional patients with IBS with Constipation (IBS-C) referred in the same period served as control. The endpoints were: 1) a decrease of more than 50% in abdominal pain intensity and frequency scores; and 2) for patients with IBS-D and IBS-M: resolution of diarrhea., Results: The endpoints were met by 8 (80%) and 14 (87%) of the patients with IBS-D and IBS-M, respectively, with decrease of abdominal pain and resolution of "diarrhea". The response was not significantly different from that observed in 15 (93%) of the IBS-C control group., Conclusion: Acknowledging the limitations of the small number of patients and of the uncontrolled nature of the study, we suggest that a possibly large number of patients labeled as IBS-D or IBS-M may actually simply present functional constipation and should be managed as such.

Celiac disease is a common inflammatory disease triggered by dietary gluten in genetically susceptible individuals. The strongest and best-characterized genetic susceptibilities in celiac disease are class II human leukocyte antigen (HLA) genes known as HLA-DQ2 and DQ8. HLA genetic testing is available through a number of commercial and academic laboratories and is used in the evaluation of celiac disease and to identify at-risk family members. Importantly, HLA genetic testing has a high negative predictive value for celiac disease, but a low positive predictive value. Therefore, for a practicing clinician, it is important to understand when to order HLA genetic testing, what test to order, and how to interpret the result. This review provides a practical primer on HLA genetics in celiac disease.

Objective: The coexistence of celiac disease (CeD) and eosinophilic esophagitis (EoE) in pediatric patients has been increasingly recognized. In the current study, we have aimed to assess the outcomes of therapeutic dietary interventions in a cohort of pediatric patients with CeD and EoE., Methods: Pediatric patient records obtained from the University of Chicago Celiac Center Database from August 2008 to July 2013 were reviewed. Information was collected on patients with concomitant CeD and EoE regarding age, sex, dates of diagnoses, presenting symptoms, length of symptoms before diagnosis, familial and personal atopic history, dietary therapy, and esophageal histologic response to dietary therapy., Results: A total of 350 records of patients with CeD were reviewed. Twenty-two (6.3%) had a confirmed diagnosis of CeD and EoE, 17 had repeat biopsies. Four of 17 (23.5%) had resolution of esophageal eosinophilia on an exclusive gluten-free diet, 10 of 17 (59%) required additional eliminations to show histologic resolution, 1 of 17 (6%) had not reached histological remission, and 2 of 17 (12%) were lost to follow-up. Success rates of single food reintroductions were: soy 5 of 5 (100%), eggs 3 of 5 (60%), dairy 3 of 7 (43%), nuts 2 of 4 (50%), and fish 2 of 4 (50%)., Conclusions: To our knowledge, this is the largest pediatric study to assess the histologic outcome of EoE-associated esophageal eosinophilia in response to dietary management of pediatric patients with concomitant CeD and EoE. We demonstrate that soy is well tolerated in this cohort, and suggest that reintroducing this food first, or trialing a soy-inclusive elimination diet is a viable strategy.

Background An automated multiplex platform using capillary blood can promote greater throughput and more comprehensive studies in celiac disease (CD). Diagnostic accuracy should be improved using likelihood ratios for the post-test probability of ruling-in disease. Methods The Ig&#95;plex™ Celiac Disease Panel on the sqidlite™ automated platform measured IgA and IgG antibodies to tTG and DGP in n = 224 CD serum or plasma samples. Diagnostic accuracy metrics were applied to the combined multiplex test results for several CD populations and compared to conventional single antibody ELISA tests. Results With multiple positive antibody results, the post-test probability for ruling-in untreated and treated CD increased to over 90%. The number of samples positive for more than one antibody also increased in untreated CD to ≥90%. Measurement of all four CD antibodies generate cut-off dependent accuracy profiles that can monitor response to treatment with the gluten-free diet (GFD). Higher positive tTG and DGP antibodies are seen more frequently in confirmed CD without (81%-94%) than with GFD treatment (44%-64%). In CD lacking biopsy confirmation, overall agreement of plasma to serum was ≥98% for all antibodies, and 100% for venous to capillary plasma. Conclusions The Ig&#95;plex Celiac Disease Panel increases the likelihood of confirming CD based on the post-test probability of disease results for multi-reactive markers. Specific positivity profiles and cut-off intervals can be used to monitor GFD treatment and likely disease progression. Using serum, venous and capillary plasma yield comparable and accurate results.

Objective: The aim of the study was to determine the effects of the gluten-free diet (GFD) on body mass indexes (BMIs) in children with celiac disease at University of Chicago before and after 2011, when processed gluten-free foods became readily available on the market., Methods: We conducted a retrospective chart review of children seen at University of Chicago Celiac Center from January 2002 to May 2016. BMI was recorded upon GFD initiation in addition to at least 1 other timepoint: 6 months, 1 year, 2 years, 3 years, and 4+ years. We compared the rate of BMI increase in children who were diagnosed before versus after 2011., Results: A total of 147 children (66% girls) with biopsy-confirmed celiac disease were included in the study. The mean BMI at diagnosis was 17.8 (standard deviation 3.9) for those diagnosed before 2011 and 17.1 (standard deviation 2.7) for those diagnosed after 2011. Based on a mixed-effects random-intercept random-slope regression model, there was no evidence for significant difference in BMI change over time between the 2 groups (P value = 0.36). BMI values overall were noted to increase after starting the GFD, even at the first appointment. Serologies were monitored after patients started the GFD and approached normal values, allowing us to conclude that patients were adherent to the GFD., Conclusions: Although overall we observed no significant changes in BMI before and after 2011, we did notice that in adolescent celiac patients there was a trend toward a higher postdiagnosis BMI in the years after 2011. We speculate that teenagers may be especially vulnerable to choosing quick and easy processed gluten-free options over more healthy, natural alternatives leading to a rise in their BMIs after the 2011 surge in production of processed gluten-free foods on the market. Therefore, special attention must be paid to this population to insure ongoing healthy food choices even after many years on the GFD.

Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4 + /Vδ1 + intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4 + /Vδ1 + IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1 + IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4 + /Vδ1 + subset among TCRγδ + IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ + IEL compartment in CeD. VIDEO ABSTRACT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

While considerable progress has been made in the treatment of inflammatory bowel diseases (IBD), alternative options are constantly sought by adult patients as well as frustrated parents of young patients. These include dietary modifications, food supplements, and, more recently, probiotics.Their potential use is based on the demonstrated role of the altered mucosal immune response to bacterial agents that eventually leads to the chronic intestinal inflammation that characterized IBD. In fact, probiotics might conceivably be beneficial due to multiple mechanisms: stimulation of anti-inflammatory cytokines, inhibition of inflammatory cytokines, strengthening of intestinal barrier, and antagonistic action on pathogens. Such mechanisms have been largely extensively investigated in animal models both in vitro and in vivo.Despite such premise, a relatively scarce number of clinical trials are available, and of them only a handful in pediatric age. Overall, available evidence is very disappointing in the treatment of Crohn's disease (CD), where no recommendation for probiotic use can be made. In ulcerative colitis (UC), on the other hand, there is clinical evidence of efficacy for some specific strains and especially for multi-strain preparations.In summary, more data are needed very likely to yield a better understanding on what strains and in what doses should be used in different specific clinical settings.

Food allergies are on the rise, for reasons that are not fully understood. However, there is a tendency to overestimate their frequency, mostly based on parents' reports or on the assumption that a positive skin or blood IgE test implies the existence of clinically relevant allergy. It is imperative to base food allergy diagnosis on well-defined criteria, avoiding "alternative" tests that are available to the general public. Non-celiac gluten sensitivity is a misnomer and should be abandoned in favor of non-celiac wheat intolerance, an entity suffering from lack of biomarkers and still not convincingly described in children., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Small intestinal biopsy interpretation has been the cornerstone for the diagnosis of celiac disease for over 50 years. Despite the existence of sensitive and specific serological tests, duodenal mucosal biopsies continue to be obtained in the vast majority of patients in whom a diagnosis of celiac disease is being considered. The accurate evaluation of these biopsies requires coordination and information sharing between the gastroenterologist, laboratory, and pathologist in order to optimize tissue sampling, preparation and interpretation. This document, a collaboration between the Rodger C. Haggitt Gastrointestinal Pathology Society and the North American Association for the Study of Celiac Disease, is intended to provide clinicians and pathologists with a summary of best practices in the use of endoscopy and biopsy for patients with suspected celiac disease. The authors present a comprehensive and critical appraisal of the literature with respect to the topics of endoscopic findings, best methods for the obtaining biopsies, completing the pathology form and pathologic assessment, including evaluating intraepithelial lymphocytes and villous architecture. A discussion of conditions with overlapping pathologic findings in duodenal mucosal biopsies is presented. In order to provide additional guidance for challenging situations, the authors include an appendix containing practical suggestions. This review may be utilized in interdisciplinary discussions to optimize care for patients with possible celiac disease.

The aim of this literature review is to discuss the extra-intestinal manifestations of celiac disease within the pediatric celiac population.

This chapter is based on the memories of those who shaped the relationship between the European and the North American Societies for Pediatric Gastroenterology, Hepatology and Nutrition. The first joint meeting of the 2 Societies took place in Paris in 1978, followed by 1 in New York in 1985, 1 in Amsterdam in 1990, 1 in Houston in 1994, and the last one in Toulouse in 1998. The formation of the Federation of the International Societies for Pediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN) preceded the First World Congress of all Societies, which took place in Boston in 2000. The success of this meeting was followed by world congresses in Paris in 2004, Iguassu in 2008, Taiwan in 2012, and Montreal in 2016. NASPGHAN and ESPGHAN jointly took on the direction of the Journal of Pediatric Gastroenterology and Nutrition in 1991. Communication between the 2 Societies is extremely active, with members participating in many joint projects.

Objective: The aim of the study was to evaluate the efficacy of the gluten-free diet (GFD) on gastrointestinal (GI) and extra-intestinal (EI) symptom resolution and identify predictors for persistence of symptoms in all celiac patients at the University of Chicago., Methods: We conducted a retrospective chart review from 2002 to 2015. GI symptoms included abdominal pain, bloating, constipation, diarrhea, failure to thrive/weight loss, nausea, reflux, and vomiting. EI symptoms included abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgia, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility., Results: A total of 554 patients (227 children) with celiac disease (CeD) were included. Abdominal pain, diarrhea and failure to thrive were the most common GI symptoms in children whereas diarrhea, bloating, and abdominal pain were most common in adults. Short stature, fatigue, and headache were the most common EI symptoms in children whereas iron deficiency anemia, fatigue, and headache/psychiatric disorders were most common in adults. Children had significantly higher rates of EI and GI symptom resolution as compared to adults, with greater rates of improvements in GI versus EI symptoms at more than 24 months. Long duration of symptoms, female sex, and non-adherence to a GFD were the most important significant predictors of failure to clinically improve., Conclusions: On a strict GFD, children report greater rates of both GI and EI symptom resolution as compared to adults with greater rates of improvement in GI over EI symptoms. Early recognition of CeD and close attention to diet adherence may help in symptom resolution.

Objective: The aim of the study was to evaluate the effectiveness of the gluten-free diet (GFD) on extraintestinal symptoms in pediatric and adult celiac populations at the University of Chicago., Methods: We conducted a retrospective chart review of the University of Chicago Celiac Center clinic charts from January 2002 to October 2014. Demographics, serologic testing, intestinal biopsies, and extraintestinal symptoms at presentation, 12, 24, and >24 months were recorded. Extraintestinal symptoms included abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgias, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility., Results: A total of 737 patients with biopsy-confirmed celiac disease or skin biopsy-confirmed dermatitis herpetiformis were included. Patients lost to follow-up, or with insufficient data were excluded leaving 328 patients (157 pediatrics younger than 18 years). For pediatrics, the female to male ratio was 2:1 and the mean age at diagnosis was 8.9 years. For adults, 4:1 and 40.6 years old. Extraintestinal symptom rates were similar in children (60%) and adults (62%). Short stature (33%), fatigue (28%), and headache (20%) were most common in children. Iron deficiency anemia (48%), fatigue (37%), and headache/psychiatric disorders (24%) were common in adults. Children had faster/higher rates of symptom resolution compared with adults. Twenty-eight percent of children with unresolved short stature on a GFD were found to have other comorbidities., Conclusions: Children and adults with celiac disease have similar rates of extraintestinal manifestations. In children short stature, fatigue, and headache were most common, whereas anemia, fatigue, and headache/psychiatric disorders were most common in adults. Children on a strict GFD showed faster and higher rates of symptom resolution as compared to adults. Unresponsive children with short stature must be assessed for comorbidities.

Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (T H 1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pT reg ) conversion and promoting T H 1 immunity to dietary antigen. Initiation of T H 1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pT reg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD., (Copyright © 2017, American Association for the Advancement of Science.)

Objective: To test the hypothesis that children with celiac disease (CD) on gluten-free diet are at increased risk of abdominal pain (AP) associated-functional gastrointestinal disorders (FGIDs)., Study Design: This was a multinational cross-sectional study performed from 2014 to 2015. Patients 4-18 years of age with CD on gluten-free diet for longer than 6 months were recruited from pediatric CD clinics in US and Italy. Control groups included siblings of children with CD (with normal tissue transglutaminase levels) and unrelated controls. Subjects or parents completed the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III., Results: Children (n = 289) were recruited (55% US, 45% Italy): 96 children with CD, 96 sibling controls, and 97 unrelated controls. Chronic AP was present in 30 (30.9%) subjects with CD, 22 (22.7%) sibling controls, and 21 (21.6%) unrelated controls (P = .26 patients with CD vs siblings; P = .18 patients with CD vs unrelated; P = .96 siblings vs unrelated). AP-FGIDs were present in 8 (8.2%) subjects with CD, 8 (8.2%) sibling controls, and 2 (2.1%) unrelated controls (P = 1.00 subjects with CD vs sibling controls; P = .06 subjects with CD vs unrelated controls; P = .06 sibling controls vs unrelated controls)., Conclusion: This multinational study evaluated the prevalence of chronic abdominal pain and AP-FGIDs in the pediatric population with CD. We found that subjects with CD and controls have a similar prevalence of chronic AP and AP-FGIDs. This suggests that not all types of gastrointestinal inflammation result in AP-FGIDs in children., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Enzymatic digestion, or hydrolysis, has been proposed for treating gluten-containing foods and beverages to make them safe for persons with celiac disease (CD). There are no validated testing methods that allow the quantitation of all the hydrolyzed or fermented gluten peptides in foods and beverages that might be harmful to CD patients, making it difficult to assess the safety of hydrolyzed products. This study examines an ELISA-based method to determine whether serum antibody binding of residual peptides in a fermented barley-based product is greater among active-CD patients than a normal control group, using commercial beers as a test case. Sera from 31 active-CD patients and 29 nonceliac control subjects were used to assess the binding of proteins from barley, rice, traditional beer, gluten-free beer, and enzymatically treated (gluten-removed) traditional beer. In the ELISA, none of the subjects' sera bound to proteins in the gluten-free beer. Eleven active-CD patient serum samples demonstrated immunoglobulin A (IgA) or immunoglobulin G (IgG) binding to a barley extract, compared to only one nonceliac control subject. Of the seven active-CD patients who had an IgA binding response to barley, four also responded to traditional beer, and two of these responded to the gluten-removed beer. None of the nonceliac control subjects' sera bound to all three beer samples. Binding of protein fragments in hydrolyzed or fermented foods and beverages by serum from active-CD patients, but not nonceliac control subjects, may indicate the presence of residual peptides that are celiac-specific.

Introduction: Small bowel villous atrophy can represent a diagnostic challenge for gastroenterologists and pathologists. In Western countries small bowel atrophy and mild non-atrophic alterations are frequently caused by celiac disease. However, other pathology can mimic celiac disease microscopically, widening the differential diagnosis. The several novelties on this topic and the introduction of the device-assisted enteroscopy in the diagnostic flowchart make an update of the literature necessary. Areas covered: In this review, a description of the different clinical scenarios when facing with small bowel mucosal damage, particularly small bowel atrophy, is described. The published literature on this subject has been summarized and reviewed. Expert commentary: When an intestinal mucosal alteration is histologically demonstrated, the pathology report forms part of a more complex workup including serological data, clinical presentation and clinical history. A multidisciplinary team, including pathologists and enteroscopy-devoted endoscopists, is frequently required to manage patients with small bowel alterations, especially in cases of severe malabsorption syndrome.

Since the first description of celiac disease (CeD) by Samuel Gee in 1888 and the later "miraculous discovery" that bread was responsible for this condition following World War II in Europe, there has been an exponential growth of knowledge regarding CeD. Just when we thought that we knew everything there was to know about it, the disease is, however, offering new challenges, with its presentation having significantly morphed over the years from cases of overt gastrointestinal symptoms, malnutrition, and atrophic villi on duodenal biopsies to that of largely extraintestinal, subtle, or mild symptoms. Along with these changes, unexpectedly a new parallel entity appeared a few years ago and is gaining ground: the so-called nonceliac gluten sensitivity, an improper name because it should actually be referred to as wheat intolerance syndrome given that the role of gluten in all such cases is far from demonstrated and the implication of an immune involvement suggested by the term "sensitivity" is still unfounded. Lastly, wheat can be an offender also through an immunoglobulin E-mediated allergy, whose presence must also be evaluated and ruled out in selected cases.The practicing physician is therefore now challenged with the task of discerning which patients need to be assessed for one or the other of these disorders, and how.This review aims at providing an updated, critical reassessment of these 2 entities.

Background: The only current treatment for celiac disease (CD) is a gluten-free diet (GFD). Novel therapies are in development to supplement or replace a GFD. Knowledge of patients' attitudes toward these therapies is limited. The aim of this study was to determine attitudes about novel therapies in securely diagnosed patients with CD on a GFD and to correlate factors associated with these attitudes., Methods: A survey was created with two scenarios: a novel therapy that protects against cross contamination while on a GFD and one that allows intentional gluten consumption. The survey also included the Celiac Dietary Adherence Test and the CD Quality of Life (QOL) surveys., Results: A total of 182/284 (64%) CD patients completed the survey. Significantly more respondents would take a novel therapy to protect against cross contamination compared with one that allows intentional gluten consumption (87% vs. 65%; P<0.001). This difference was significant among women but not men. In both scenarios, protection against bowel inflammation was significantly more important than symptom control, and side effects were more important than cost. For a novel therapy that would allow intentional gluten consumption, a one-time injection was preferred over a daily pill, and patients willing to take this therapy had significantly lower QOL scores., Conclusions: CD patients on a GFD are interested in novel therapies. There were notable differences in attitudes by gender and QOL. Considering patient preferences, drugs with daily or less frequent dosing that protect against bowel inflammation from gluten cross contamination would be best accepted.

Background: Celiac disease (CeD) is an autoimmune disease triggered by gluten ingestion., Aim: We assessed total direct costs burden associated with CeD in patients with CeD versus patients without CeD using administrative claims data., Methods: Patients with CeD (cases) with ≥1 occurrences of CeD diagnosis were selected at a randomly chosen date (index date) from the OptumHealth Reporting and Insights database from 01/01/1998 through 03/31/2013. Cases were continuously enrolled throughout baseline (1 year before index date) and study (1 year after index date) periods. Cases were categorized as full remission and partial remission and matched 1:1 based on age, sex, region, index date, company, and employment status. Total all-cause and CeD-related costs were calculated., Results: A total of 12,187 cases were matched with an equal number of controls. Mean total all-cause costs were $12,217 in cases versus $4935 in controls (P < 0.0001). In full remission (N = 10,181 [83.5 %]) and partial remission (N = 2006 [16.5 %]) cases, mean total all-cause direct costs (cases versus controls) were $11,038 versus $4962 and $18,206 versus $4796, respectively. All-cause medical costs ($9839 for all cases, $8723 for full remission cases, $15,499 for partial remission cases) accounted for the majority of all-cause total costs and included outpatient costs ($6675; $6456; and $7785, respectively) and hospitalizations ($2776; $1963; and $6906, respectively). CeD-related medical costs were 13 and 27 % of all-cause medical costs for all cases and partial remission cases, respectively., Conclusions: Patients with CeD and partial remission of CeD incurred significantly higher (2.5 and 3.8 times) total all-cause costs compared with matched controls.

Although the need for effective long-term follow-up for patients with celiac disease (CD) has been recognized by many expert groups, published practice guidelines have not provided a clear approach for the optimal management of these patients. In an attempt to provide a thoughtful and practical approach for managing these patients, a group of experts in pediatric CD performed a critical review of the available literature in 6 categories associated with CD to develop a set of best practices by using evidence-based data and expert opinion. The 6 categories included the following: bone health, hematologic issues, endocrine problems, liver disease, nutritional issues, and testing. Evidence was assessed by using standardized criteria for evaluating the quality of the data, grade of evidence, and strength of conclusions. Over 600 publications were reviewed, and 172 were chosen for inclusion. The thorough review of the results demonstrated that the quality of the data available was often insufficient to provide unequivocal best practices. However, using the available data and the clinical experience of the panel, a practical framework for the management of children with CD was created. These recommendations were developed by our expert panel and do not necessarily reflect the policy of the American Academy of Pediatrics. The potential usefulness of these best practices is underscored by the fact that consensus, measured by the outcome of anonymous voting, was reached by the panel for 24 of the 25 questions. We hope that these best practices may be useful to the pediatric gastroenterology and larger general pediatric communities., (Copyright © 2016 by the American Academy of Pediatrics.)

Dietary exclusion of gluten-containing products has become increasingly popular in the general population, and currently ∼30% of people in the United States are limiting gluten ingestion. Although celiac disease (CD), wheat allergy (WA), and nonceliac gluten sensitivity (NCGS) constitute a spectrum of gluten-related disorders that require exclusion of gluten from the diet, together these account for a relatively small percentage of those following a gluten-free diet, and the vast majority has no medical necessity for doing so. Differentiating between CD, WA, and NCGS has important prognostic and therapeutic implications. Because of the protean manifestations of gluten-related disorders, it is not possible to differentiate between them on clinical grounds alone. This clinical report will compare and contrast the manifestations of gluten-related disorders, emphasize the importance of differentiating between these conditions, discuss initial and subsequent tests needed to confirm the diagnosis, and provide recommendations on treatment and follow-up for each condition.

Objective: To review the evidence for the association of breast feeding, breastfeeding duration or the timing of gluten introduction and the later development of celiac disease (CD)., Design: Systematic review., Methods: We searched MEDLINE, via PubMed, EMBASE and Web of Science, for studies published up to 31 August 2015 investigating the association of breastfeeding duration, breast feeding at the moment of gluten introduction or the timing of gluten introduction and the later development of CD. Prospective studies had to enrol infants/children at high risk of CD. For retrospective studies, participants had to be children or adults with CD. The paper quality was assessed by means of a GRADE score and the bias risk was assessed by the Newcastle-Ottawa Scale (for observational cohort studies) and Cochrane Collaboration's tool (for randomised trials)., Results: Out of 149 retrieved papers, 48 were considered in depth and 16 were included in this review (9 were prospective and 2 were interventional). We found that neither duration of breastfeeding nor breastfeeding at time of gluten introduction nor the delayed introduction of gluten during weaning were effective in preventing later development of CD., Conclusions: Currently, there is no evidence on the optimal breastfeeding duration or the effects of avoiding early (<4 months of age) or late (≥ 6 or even at 12 months) gluten introduction in children at risk of CD. Accordingly, no specific general recommendations about gluten introduction or optimal breastfeeding duration can be presently provided on evidence-based criteria in order to prevent CD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To assess the evidence regarding the effect of time of gluten introduction and breastfeeding on the risk of developing celiac disease (CD)., Study Design: We included randomized controlled trials and observational studies evaluating the proper timing for introducing gluten to the infant diet, the appropriate quantity of gluten consumption at weaning, and the effect of breastfeeding on CD risk. Studies were located through the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), EMBASE (Ovid), and System for Information on Grey Literature in Europe (SIGLE). Two independent authors collected the data., Results: A total of 1982 studies were identified, 15 of which were eligible for data extraction. A meta-analysis was performed on 2 randomized controlled trials, 10 cohort studies, and 1 case-control study. There was a 25% increase in CD risk with late (>6 months) vs recommended (4-6 months) gluten introduction (risk ratio [RR], 1.25; 95% CI, 1.08-1.45). There was no significant effect of breastfeeding vs no breastfeeding on CD risk (OR, 0.55; 95% CI, 0.28-1.10), with substantial heterogeneity (I(2) = 92%) among studies., Conclusion: There is currently no evidence to support that early introduction of gluten to the infant diet increases the risk of CD; however, late introduction of gluten may be associated with increased risk of CD. More studies are needed that control for potential confounders and that evaluate environmental factors in low-risk families., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This commentary by the leadership of the North American Society for the Study of Celiac Disease (NASSCD) concerns recent research findings regarding infant feeding practices. Celiac disease has increased markedly in recent decades, and seroprevalence studies indicate that this is a true rise, rather than one due to increased awareness and testing. Prior studies have suggested that infant feeding practices and timing of initial gluten exposure are central to the development of celiac disease. Two recent multicenter randomized trials tested strategies of early or delayed gluten introduction in infants, and neither strategy appeared to influence celiac disease risk. These studies also found that breastfeeding did not protect against the development of celiac disease. While disappointing, these results should spur the study of wider environmental risk factors beyond infant feeding, such as intrauterine and perinatal exposures as well as environmental influences later in life, including drug exposure, microbial infections, and the microbiome. Given that celiac disease can develop at any age, it is imperative to study these proposed triggers so as to elucidate the loss of tolerance to gluten and to develop future intervention strategies.

Probiotics are increasingly used for prevention and treatment of diarrhea more in children than in adults. Given the broad spectrum of diarrhea, this review focuses on the main etiologies: acute gastroenteritis, antibiotic-associated diarrhea (AAD), and necrotizing enterocolitis (NEC). For each, we reviewed randomized controlled trials, meta-analyses, and guidelines. For acute gastroenteritis we found 12 guidelines: 5 recommended probiotics and 7 did not. However, the guidelines containing positive recommendations provided proof of evidence from clinical trials and meta-analyses. Lactobacillus rhamnosus GG (LGG) and Saccharomyces boulardii had the most compelling evidence of efficacy as they reduced the duration of the disease by 1 day. For AAD 4 meta-analyses were found, reporting variable efficacy of probiotics in preventing diarrhea, based on the setting, patient's age, and antibiotics. The most effective strains were LGG and S. boulardii. For NEC, we found 3 randomized controlled trials, 5 meta-analyses, and 4 position papers. Probiotics reduced the risk of NEC enterocolitis and mortality in preterm babies. Guidelines did not support a routine use of probiotics and asked for further data for such sensitive implications. In conclusion, there is strong and solid proof of efficacy of probiotics as active treatment of gastroenteritis in addition to rehydration. There is solid evidence that probiotics have some efficacy in prevention of AAD, but the number needed to treat is an issue. For both etiologies LGG and S. boulardii have the strongest evidence. In NEC the indications are more debated, yet on the basis of available data and their implications, probiotics should be carefully considered.

Eicosanoids are inflammatory mediators that play a key but incompletely understood role in linking the innate and adaptive immune systems. Here, we show that cytotoxic effector T cells (CTLs) are capable of both producing and responding to cysteinyl leukotrienes (CystLTs), allowing for the killing of target cells in a T cell receptor-independent manner. This process is dependent on the natural killer receptor NKG2D and exposure to IL-15, a cytokine induced in distressed tissues. IL-15 and NKG2D signaling drives the up-regulation of key enzymes implicated in the synthesis of CystLTs, as well as the expression of CystLT receptors, suggesting a positive feedback loop. Finally, although the CystLT pathway has been previously linked to various allergic disorders, we provide unexpected evidence for its involvement in the pathogenesis of celiac disease (CD), a T helper 1 cell-mediated enteropathy induced by gluten. These findings provide new insights into the cytolytic signaling pathway of NKG2D and the pathogenesis of organ-specific immune disorders. Furthermore, they suggest that the blockade of CystLT receptors may represent a potent therapeutic target for CD or potentially other autoimmune disorders in which NKG2D has been implicated., (© 2015 Tang et al.)

Background & Aims: 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., Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Underlying pathophysiological mechanisms of irritable bowel syndrome (IBS), a common disorder characterized by abdominal pain associated to a change in stool consistency or frequency, include low-grade inflammation and intestinal microbiota changes. Few and disappointing data are available for prebiotics. A few controlled trials (RCTs) of probiotics are instead available with favourable effects, although most are limited by suboptimal design and small sample size. A recent report from the Rome foundation group included 32 RCTs of probiotics, most of which showed an overall modest improvement in symptoms, with the patients most benefitting from probiotics being those with predominant diarrhoea and those having a post-infectious IBS. A review focusing only on children with functional gastrointestinal disorders concluded that probiotics are more effective than placebo in the treatment of patients with abdominal pain-related functional gastrointestinal disorders, although no effect on constipation was evident. The role for probiotics in inflammatory bowel disease (IBD) appears logical: the endogenous intestinal microbiota plays a central role in their development, and various probiotics have been found effective in animal models of IBD. However, research in humans has been overall quite limited, and it would seem that after a phase of intense research in the first decade of this century, the pace has slowed down, with fewer clinical trials been published in the past 2-3 years. To summarize current evidence: no probiotic has proven successful in Crohn's disease. In ulcerative colitis, on the other hand, data are more promising, and a very recent meta-analysis, that included 23 randomized controlled trials, concluded that there is evidence of efficacy for the probiotic mixture VSL#3 in helping inducing and maintaining remission, as well as in maintaining remission in patients with pouchitis. It is fair to state that for both IBD and IBS, more well-designed, rigorous, randomized clinical trials must be performed.