Safety of occasional ingestion of gluten in patients with celiac disease: a real-life study.

BACKGROUND: Gluten-free diet (GFD) decreases the quality of life of celiac disease (CD) patients, who frequently ask to occasionally ingest gluten-containing food. We evaluated CD patients reporting voluntary and occasional transgressions to their GFD. METHODS: From October 2017 to September 2018, the patients reporting occasional and voluntary gluten ingestion (GFD-noncompliant) were prospectively enrolled. These patients underwent clinical examination, blood tests, duodenal biopsy, capsule enteroscopy (CE), and a validated food-frequency questionnaire (FFQ) assessing the frequency and quantity of gluten intake. Mortality was calculated and compared to the general population. A group of patients on strict GFD (GFD-adherent) acted as controls. RESULTS: One thousand three hundred seventy-eight CD patients were evaluated during the study period. One hundred nine (8%) reported occasional (weekly or monthly) voluntary ingestion of gluten. The mean gluten intake was 185.2 ± 336.9 g/year, and the duration of their incorrect GFD was 8.6 ± 6.9 years. Among the noncompliant patients, 57% did not present any histological alteration; furthermore, the Marsh score profile was not different between compliant and noncompliant patients. Seventy percent did not present any alteration at CE. Seventy-five percent of patients reported no gastrointestinal symptoms after gluten ingestion. Twenty-three percent of patients in the GFD-noncompliant group presented positive tTG-IgA. No association was found between gluten intake, clinical symptoms, and biomarkers. Mortality was not different between the groups and the general population. CONCLUSIONS: Our results are that in a real-life scenario, a group of CD patients on long-term gluten intake showed no significant clinical symptoms or small bowel damage, thus suggesting that a degree of tolerance towards gluten consumption can be reached.

How to manage celiac disease and gluten-free diet during the COVID-19 era: proposals from a tertiary referral center in a high-incidence scenario.

The outbreak of COVID-19 and SARS-CoV-2 infection is spreading worldwide as the first coronavirus pandemic. The clinical picture is variable but flu-like symptoms are common with bilateral interstitial pneumonia being the most frightening presentation. No specific therapies nor vaccine have been developed to date and the only way to limit the virus diffusion is by modifying one's lifestyle limiting social life and following strict hygienic precautions. No data is available on the risk of COVID-19 and its outcomes in celiac disease (CeD). The restrictions applied to counter COVID-19 can impact on CeD treatment and gluten-free dieting, the only available therapy for CeD. With the present manuscript, we aim to support gastroenterologists and nutritionists in the management of CeD patients in the new pandemic scenario, being conscious that availability and local situations are extremely various.

Celiac Disease 30 Years After Diagnosis: Struggling With Gluten-free Adherence or Gaining Gluten Tolerance?

OBJECTIVES: Studies investigating patients with coeliac disease (CD) on very long-term follow-up are limited. We aimed to evaluate the characteristics of patients with CD diagnosed more than 30 years ago. METHODS: Clinical, histologic, genetic, and demographic data of patients with CD diagnosis made before 1985 were collected and their standardised mortality ratio calculated. According to the gluten-free diet (GFD) status, CD patients were divided into 3 groups and a specific questionnaire on GFD awareness and gluten-free products was administered to patients and caregivers. RESULTS: A total of 337 CD patients were included in the study. The standardised mortality ratio was 0.37 (confidence interval 0.10 to 0.94) compared with a matched population. A total of 197 patients were grouped according to GFD compliance, with 35 CD patients reporting chronic voluntary gluten ingestion. No significant differences were found between groups regarding family history of CD, symptoms and histology at diagnosis, autoimmune disorders. Follow-up histology was performed in 63 patients. Twenty patients had normal histology on gluten-containing diet (GCD). Questionnaire scores were lower in patients on GCD. Caregivers scores were not correlated with patients' gluten consumption. CONCLUSIONS: Although poor adherence to GFD is the major predictor of persistence of mucosal lesions at follow-up histology, a proportion of patients did not show a relapse of villous atrophy in spite chronic voluntary gluten ingestion, nor increase in mortality. Moreover, GFD knowledge and adherence could be partly lost during the transition between childhood and adulthood.

Anti-sulfatide reactivity in patients with celiac disease.

OBJECTIVE: To explore a possible significance of the presence of anti-ganglioside and anti-sulfatide antibodies in sera of adult patients with celiac disease (CD) in different clinical scenario. METHODS: We selected 22 adult patients with newly diagnosed CD and 20 age-sex matched non-CD controls. Patients' serum was tested - before and after at least 6 months on a gluten-free diet (GFD) - for anti-GM1, GM2, GM3, GD1a, GD1b, GD3, GT1a, GT1b, GQ1b and sulfatide IgM, IgG and IgA auto-antibodies, by means of a dot blot technique and enzyme-linked immunosorbent assay (ELISA). RESULTS: We found the presence of auto-antibodies in untreated patients. In particular, anti-sulfatide IgG antibodies were present in 8 (36%) patients independently of the presence of neurological symptoms. Anti-sulfatide IgA antibodies were present in 3 (19%) patients. During GFD, anti-sulfatide IgG disappeared in all the patients, whereas IgA were observed in 2 patients. Anti-sulfatide, anti-GM1 and anti-GM2 IgM antibodies were also observed in 2 patients on a GFD. All the other auto-antibodies were absent and no demographic or clinical parameters were associated. Non-CD controls did not present any auto-antibody. CONCLUSIONS: We found anti-sulfatide IgG antibodies in CD patients on a gluten-containing diet. Anti-sulfatide IgA antibodies persisted during GFD together with the occurrence of other IgM auto-antibodies. These data suggest a possible link between gluten and IgG auto-antibodies.

Non Celiac Gluten Sensitivity.

PURPOSE OF REVIEW: A new syndrome responding to gluten-free diet and defined non-celiac gluten sensitivity entered the spectrum of gluten-related disorders, together with celiac disease and wheat allergy. However, its definition, prevalence, diagnosis, pathogenesis, treatment, and follow up are still controversial. The purpose of the review is to summarize the evidence and problems emerging from the current literature. RECENT FINDINGS: Direct implication of gluten in the onset of symptoms is often unproved as a low fermentable oligo-, di- and mono-saccharides and polyols diet or other components of cereals as wheat amylase trypsin inhibitor could be similarly involved. To date, no specific biomarkers or histological abnormalities confirm diagnosis, and only the self-reported response to gluten-free diet as well as a positive double blind placebo-gluten challenge characterizes these non-celiac, non-wheat allergic patients. Critical revision of published studies can offer practical indications in approaching this clinical topic and useful suggestions to standardize scientific researches.

Celiac Disease and Drug-Based Therapies: Inquiry into Patients Demands.

BACKGROUND/AIM: Medical research is looking for alternative drug-based options to the gluten-free diet (GFD) for celiac disease. We aimed at evaluating the need for alternative therapies perceived by celiac patients. METHODS: During the 2013 meeting of the Lombardy section of the Italian Celiac Patients Association, adult subjects were invited to fill in a questionnaire investigating their clinical profile in relation to compliance to the diet, quality of life (QOL) as well as their opinion on alternative therapies. RESULTS: Three hundred and seventy two patients (76 m, mean age 41.7 ± 13.9 years) completed the questionnaire. Patients reported a significant improvement in health status (HS) and QOL after the diet was started (p < 0.001). The GFD was accepted by 88% patients, but the need for alternative therapies was reported by 65%. Subjects expressing the need for a drug-based therapy showed a lower increase in QOL (p = 0.003) and HS (p = 0.005) on GFD. The preferred option for an alternative therapy was the use of enzymes (145 subjects), followed by a vaccine (111 subjects). CONCLUSION: The GFD is favorably accepted by most celiac patients. Nevertheless, a proportion of patients pronounce themselves in favor of the development of alternative drugs.

Histological evaluation of duodenal biopsies from coeliac patients: the need for different grading criteria during follow-up.

BACKGROUND: Coeliac disease is characterised by villous atrophy, which usually normalises after gluten withdrawal. Sometimes the revaluation of duodenal histology is required during follow-up, even if the methodology for comparing duodenal histology before and after introducing a gluten-free diet is not yet established. Our aim was to evaluate a novel criterion to compare duodenal histology in coeliac disease before and after gluten withdrawal. METHODS: Duodenal biopsies from coeliac patients were retrospectively reviewed to compare duodenal histology at diagnosis and after at least one year on a gluten-free diet. Two different methods were used: the first was represented by the classical Marsh-Oberhuber score, the second compared the areas covered by each Marsh-Oberhuber grade and expressed as percentages, the final grade being calculated from the analysis of ten power fields per duodenal biopsy. RESULTS: Sixty-nine patients (17 males 52 females, age at diagnosis 36 ± 15 years) who underwent duodenal biopsies, were considered. According to the classical Marsh-Oberhuber scale, 32 patients did not present atrophy during follow-up while 37 showed duodenal atrophy, among whom 26 improved the grade of severity and 11 retained the same one. Of these latter, according to the second method, eight patients were considered improved, two showed a worsened duodenal damage and only one remained unchanged; the evaluation changed in 91 % of cases. CONCLUSIONS: The proposed semi-quantitative approach (i.e. the second method) for the evaluation of histology at follow-up provides additional information about the progression/regression of the mucosal damage.

Gluten-free diet or alternative therapy: a survey on what parents of celiac children want.

OBJECTIVES: Celiac disease (CD) is treated by life-long gluten-free diet (GFD). Novel therapies are under development. Willingness of CD children's parents to alternative therapies and GFD impact were evaluated. METHODS: Parents of celiac children on GFD were investigated on need and preference for novel CD therapies, children's enrolment in trials, compliance to and personal judgment on GFD, health status (HS) and quality of life (QoL). RESULTS: About 59.5% surveyed parents expressed the need for alternative therapies with a preference for vaccine-based strategy (39.9%). About 37.7% would accept enrollment in an ad hoc trial, 20.3% would agree to endoscopy during the trial. GFD compliance was 97.4% and well accepted by 93.8%. HS and QoL significantly improved during GFD (p < 0.001). CONCLUSIONS: The introduction of novel therapies for CD is desirable for over half of parents, with preference for vaccines. Parents frown upon enrolment in new clinical trials and the subsequent need for additional endoscopy.

miRNAs affect the expression of innate and adaptive immunity proteins in celiac disease.

OBJECTIVES: microRNAs (miRNAs) are short RNAs that regulate gene expression in various processes, including immune response. Altered immune response is a pivotal event in the pathogenesis of celiac disease (CD), and miRNAs could have a role in modulating both innate and adaptive response to gluten in celiac patients. METHODS: We compared miRNA profiles in duodenal biopsies of controls and CD patients by miRNA array. Differentially expressed miRNAs were validated in controls, Marsh 3A-B, and Marsh 3C patients by quantitative PCR (qPCR). Target gene expression was assessed by qPCR, western blotting, and immunohistochemistry, and the effect of gliadin was evaluated by in vitro stimulation experiments on duodenal biopsies. RESULTS: Seven miRNAs were identified as significantly downregulated in the duodenum of adult CD patients as compared with controls. qPCR validated the decreased expression of miR-192-5p, miR-31-5p, miR-338-3p, and miR-197, in particular in patients with more severe histological lesions (Marsh 3C). In silico analysis of possible miRNA targets identified several genes involved in innate and adaptive immunity. Among these, chemokine C-X-C motif ligand 2 (CXCL2) and NOD2 showed significantly increased mRNA and protein level in Marsh 3C patients and a significant inverse correlation with the regulatory miR-192-5p. In addition, forkhead box P3 (FOXP3), Run-related transcription factor 1, and interleukin-18 (targets of miR-31-5p, miR-338-3p, and miR-197, respectively) showed upregulation in CD patients. Furthermore, alterations in CXCL2 and NOD2, FOXP3, miR-192-5p, and miR-31-5p expression were triggered by gliadin exposure in CD patients. CONCLUSIONS: miRNA expression is significantly altered in duodenal mucosa of CD patients, and this alteration can increase the expression of molecules involved in immune response.

An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity.

BACKGROUND: Non-celiac gluten sensitivity (NCGS) is still an undefined syndrome with several unsettled issues despite the increasing awareness of its existence. We carried out a prospective survey on NCGS in Italian centers for the diagnosis of gluten-related disorders, with the aim of defining the clinical picture of this new syndrome and to establish roughly its prevalence compared with celiac disease. METHODS: From November 2012 to October 2013, 38 Italian centers (27 adult gastroenterology, 5 internal medicine, 4 pediatrics, and 2 allergy) participated in this prospective survey. A questionnaire was used in order to allow uniform and accurate collection of clinical, biochemical, and instrumental data. RESULTS: In total, 486 patients with suspected NCGS were identified in this 1-year period. The female/male ratio was 5.4 to 1, and the mean age was 38 years (range 3-81). The clinical picture was characterized by combined gastrointestinal (abdominal pain, bloating, diarrhea and/or constipation, nausea, epigastric pain, gastroesophageal reflux, aphthous stomatitis) and systemic manifestations (tiredness, headache, fibromyalgia-like joint/muscle pain, leg or arm numbness, 'foggy mind,' dermatitis or skin rash, depression, anxiety, and anemia). In the large majority of patients, the time lapse between gluten ingestion and the appearance of symptoms varied from a few hours to 1 day. The most frequent associated disorders were irritable bowel syndrome (47%), food intolerance (35%) and IgE-mediated allergy (22%). An associated autoimmune disease was detected in 14% of cases. Regarding family history, 18% of our patients had a relative with celiac disease, but no correlation was found between NCGS and positivity for HLA-DQ2/-DQ8. IgG anti-gliadin antibodies were detected in 25% of the patients tested. Only a proportion of patients underwent duodenal biopsy; for those that did, the biopsies showed normal intestinal mucosa (69%) or mild increase in intraepithelial lymphocytes (31%). The ratio between suspected NCGS and new CD diagnoses, assessed in 28 of the participating centers, was 1.15 to 1. CONCLUSIONS: This prospective survey shows that NCGS has a strong correlation with female gender and adult age. Based on our results, the prevalence of NCGS seems to be only slightly higher than that of celiac disease.

microRNA profiles in coeliac patients distinguish different clinical phenotypes and are modulated by gliadin peptides in primary duodenal fibroblasts.

CD (coeliac disease) is a frequent autoimmune disorder of the small bowel, which is characterized by an immunological reaction against gluten and transglutaminase in genetically predisposed subjects. However, the molecular determinants underpinning CD pathogenesis are yet to be fully elucidated and little data are available about the involvement of miRNAs (microRNAs) in CD. In the present study, the duodenal mucosa miRNA expression was profiled in adult untreated CD presenting with a classic phenotype or iron-deficiency anaemia, treated patients with or without duodenal normalization, and non-CD subjects as controls. Deregulation of seven miRNAs (miR-31-5p, miR-192-3p, miR-194-5p, miR-551a, miR-551b-5p, miR-638 and miR-1290) was determined in a larger series of CD patients with different clinical phenotypes compared with non-CD subjects. These seven microRNAs were then analysed in duodenal fibroblasts obtained from CD patients and incubated with gliadin peptides (13- and 33-mer). The miRNA cluster miR-192/194, involved in matrix remodelling, was deregulated in CD according to the different clinical presentations, and miR-192-3p levels were modulated by gliadin peptides in vitro. In conclusion, the analysis of miRNAs deserves further consideration for its potential use in the treatment and management of CD.

Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection.

Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (Fst) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.

Extracellular matrix proteins and displacement of cultured fibroblasts from duodenal biopsies in celiac patients and controls.

BACKGROUND: Celiac disease (CD) is mainly characterised by villous atrophy and mucosal architectural rearrangement. The fibroblasts (FBs) are the most abundant mesenchymal cell type in the intestinal mucosa and are responsible for both the architectural arrangement of the villi and the formation of the extracellular matrix (ECM). This study aimed at the evaluation of both the intracellular distribution of different proteins involved in ECM and FBs characterisation, and the cellular displacement of primary FBs obtained from duodenal endoscopic biopsies of healthy subjects and celiac patients. METHODS: Primary healthy and celiac duodenal FBs were evaluated by means of immuno-fluorescence assay for collagen type I and IV, fibronectin, actin, alpha-Smooth Muscle Actin (alpha-SMA), Fibroblast Surface Protein (FSP) and transglutaminase type 2 (TG2). The geometric indexes of the fluorescence signals were investigated by image analysis software (Image J, NIH). Both morphology and kinetic were evaluated during a 72 hours time course movie. TG2 medium activity was evaluated by means of ELISA. RESULTS: All the cells examined were immunopositive for FSP, alpha-SMA, actin, collagen I, collagen IV and TG2. CD cells showed a signet collagen-I and collagen-IV pattern, as compared to the controls being characterised by a spindle geometry. Moreover, the collagen signals in CD FBs showed a significantly higher circularity index (major orthogonal diameter ratio) than the controls (p<0.0001), whereas the perimeter and area ratio were significantly lower (p<0.0001). The TG2 signal had a decreased area (p<0.05), but a two-fold increased medium activity. The time course highlighted a reduction of the displacement of CD FBs. CONCLUSIONS: The isolated primary CD FBs showed a different collagen and TG2 pattern of distribution associated with a different cellular displacement. The reasons for such CD cell peculiar characteristics are yet unknown but they might represent a factor in the progression of the intestinal damage.

Celiac disease: experience of general practitioners in Brianza Area- Monza- Milan-Italy.

Aim: The purpose of the study was to better investigate the degree of knowledge and the diagnostic approach concerning celiac disease and its extra-intestinal manifestations by general practitioners in Italy. Background: Celiac Disease is a common chronic disease, but often goes undiagnosed because of atypical symptoms or silent disease. Currently there are non-definitive data about the disease management approach concerning celiac disease by general practitioners. Methods: To better investigate the degree of knowledge and the diagnostic approach concerning celiac disease and its extra-intestinal manifestations, questionnaire was used to assess the daily practice of diagnosis, treatment, and follow-up of this condition by general practitioners in two densely populated area in Italy: Monza-Brianza Area and Milan City. The questionnaire was composed of 18 questions that explored 3 precise domains: diagnosis criteria, correct management of celiac disease and availability for training. The frequencies of the domains explored were analyzed, analyzes were carried out to identify differences between the groups of general practitioners interviewed. Results: Analysis of the questionnaires showed a degree of knowledge and preparation comparable to that of other countries, even though not sufficient to guarantee access to early diagnosis for all patients with celiac disease. The knowledge was not influenced by the years of experience or specific curriculum of health professionals. General practitioners under 40 were much more in favor of continuous training and were aware of its importance (OR=10.55; CI95%: 1.62-445.39), although this need was a high priority in the whole group interviewed (84.7%). Conclusion: Continuous specific training aimed at primary care physicians and general practitioners is the first tool to improve early diagnosis. A second opportunity is represented by the continuous dialogue between general practitioners and tertiary level hospitals and universities.

Immunological comorbity in coeliac disease: associations, risk factors and clinical implications.

PURPOSE: Coeliac disease is frequently associated with other immunomediated diseases. Our aim was to identify immunological comorbidities and possible risk factors for their development in coeliac patients. METHODS: We recruited a cohort of 1,015 coeliac patients followed from 0 to 46 years in a single tertiary referral centre. Data were collected from the yearly scheduled clinical and serological evaluations. Possible risk factors such as demographic parameters, type of symptomatic presentation, gluten exposure, gluten-free diet compliance and family history were all evaluated. Subjects (848,606) from the regional health registry were investigated as controls. RESULTS: The prevalence of immunomediated diseases was higher in patients with coeliac disease compared to the registry population (23 % vs 0.4 %, p < 0.001). Diagnosis during paediatric age represented a risk factor for the presence of at least an immunomediated disease (hazard ratio = 1.62, 95 % confidence interval 1.15-2.29, p = 0.0061). Type of presentation and dietetic compliance did not represent risk factors. Long-standing gluten exposure reduced the risk of developing immunomediated diseases in coeliac subjects (hazard ratio for 1 year longer exposure 0.23, 95 % confidence interval 0.16-0.33, p < 0.0001). A familiar background characterized by the presence of immunological disorders was not a risk factor, although 419 (13 %) first degree relatives of coeliac patients out of 3,195 had an immunomediated disease. CONCLUSIONS: Our study suggests the need to investigate coeliac patients for other associated immunomediated diseases, independently of sex, gluten exposure and compliance to therapy; also subjects diagnosed in paediatric age should be carefully screened during follow up.

Transient elastography in patients with celiac disease: a noninvasive method to detect liver involvement associated with celiac disease.

BACKGROUND: Liver involvement in celiac disease (CD) is clinically relevant and could require specific treatment in addition to gluten-free diet (GFD). Transient elastography (TE), a noninvasive tool for assessing liver stiffness (LS), has widely been reported as an accurate surrogate marker of liver fibrosis. AIMS: To prospectively identify celiac patients with liver involvement by TE and to assess the effect of GFD. MATERIAL AND METHODS: Ninety-five histologically confirmed CD patients (24 newly diagnosed) were consecutively evaluated by TE and compared with 146 patients with chronic hepatitis C (HCV) and 54 healthy subjects. RESULTS: LS ranged between 2.8 and 6.7 kPa (median 4.9) in healthy subjects, defining 6.9 kPa as the upper reference limit (2 SD above the mean levels). TE was above 6.9 kPa in 10 (10.5%) CD patients. Median TE values resulted significantly higher in CD patients with hypertransaminasemia than those without [6.1 vs. 4.2 kPa (p < 0.01)]. Among the 24 newly diagnosed patients with CD, median TE values declined from 4.4 to 4 kPa, after 6 months of GFD, resulting below 6.9 kPa in 100% of the patients. CONCLUSIONS: A subset of CD patients with hypertransaminasemia showed liver involvement by TE. Accordingly, based on its accuracy in predicting liver fibrosis, TE could be used to identify those CD patients suitable for liver biopsy.

Beneficial effects of treatment with transglutaminase inhibitor cystamine on the severity of inflammation in a rat model of inflammatory bowel disease.

Inflammatory bowel disease (IBD) represents a socially and clinically relevant disorder, characterized by intestinal chronic inflammation. Cystamine (CysN) is a multipotent molecule with healthy effects and, moreover, it is an inhibitor of transglutaminases (TGs), including the TG type 2 (TG2), an enzyme with pleiotropic functions, involved in different pathways of inflammation and central in the pathogenesis of some human disorders as the IBD. Our aim was to evaluate the effect of CysN in an IBD rat model. A total of 30 rats were divided into 4 groups: controls without treatment (CTR; n=7); receiving the 2,4,6-trinitrobenzene sulfonic acid enema (TNBS group; n=8); treated with TNBS enema plus oral CysN (TNBS-CysN group; n=8); treated with CysN (CysN group; n=7). After killing, bowel inflammation was evaluated applying specific scores. TG activity, TG2 and isopeptide bond immunohistochemical expression, and tumor necrosis factor-α (TNF-α) were evaluated in the colonic tissue, such as interleukin-6 (IL-6) serological levels (ELISA). TG2 was also evaluated on the luminal side of the colon by immunoautoradiography. Colonic samples from IBD patients were compared with animal results. TNBS-CysN group developed a less severe colitis compared with the TNBS group (macroscopic score 0.43±0.78 vs 3.28±0.95, microscopic score 6.62±12.01 vs 19.25±6.04, P<0.05, respectively) associated with a decrease of TG activity, TG2 and isopeptide bond immunohistochemical expression, TNF-α and IL-6 levels. No statistically significant differences were found between CysN and CTR groups. The colonic immunolocalization of TG2 was comparable in humans affected by IBD and TNBS-administered animals. This is the first demonstration that treatment with a CysN has an anti-inflammatory effect, reducing severity of colitis in a rat model. CysN could be tested as a possible treatment or co-treatment in IBD therapeutic trials.

Absence of mucosal inflammation in uncomplicated diverticular disease.

BACKGROUND: Uncomplicated diverticular disease is a common condition in patients older than 50 years. Symptoms are aspecific and overlapping with those of irritable bowel syndrome. Nowadays, patients are often treated with antinflammatory drugs (5-aminosalicilic acid). AIM: Our purpose was to evaluate the presence of inflammation in the colonic mucosa of patients with symptomatic uncomplicated diverticular disease compared with subjects without diverticula. METHODS: Endoscopic biopsies of colon from 10 patients with symptomatic uncomplicated diverticular disease and 10 from subjects without diverticula (controls) were taken. Specimens were homogenised and IL2, IL4, IL5, IL8, IL10, IL12p70, IL13, IFN gamma, TNF alfa (searchlight multiplex technique), TGF beta, transglutaminase type 2 and caspase 9 were measured. Histochemistry for transglutaminase type 2 and TUNEL were performed on the histological sections, in addition to morphologic evaluation, as markers of tissue remodelling and apoptosis. For statistical analysis Student's t test and Spearman correlation test were used. RESULTS: No histological differences were detected between the patients with an uncomplicated diverticular disease and controls. Mean values of mucosal cytokines and of the other tested parameters did not show statistically significant differences between patients with uncomplicated diverticular disease and controls. CONCLUSIONS: Even if based on a small number of patients, the study demonstrates the absence of inflammation in the mucosa of subjects affected by uncomplicated diverticular disease.

Analysis of HLA and non-HLA alleles can identify individuals at high risk for celiac disease.

BACKGROUND & AIMS: Celiac disease (CD) is a common chronic disorder of the small intestine, resulting from aberrant cellular responses to gluten peptides, and often remains undiagnosed. It is a complex genetic disorder, although 95% of the patients carry the risk heterodimer human leukocyte antigen (HLA)-DQ2. Genome-wide association studies on CD have identified 9 non-HLA loci that also contribute to CD risk, most of which are shared with other immune-related diseases. Our aim is to predict the genetic risk for CD using HLA and non-HLA risk alleles. METHODS: We selected 10 independent polymorphisms in 2,308 cases and 4,585 controls from Dutch, UK, and Irish populations and categorized the individuals into 3 risk groups, based on their HLA-DQ2 genotype. We used the summed number of non-HLA risk alleles per individual to analyze their cumulative effect on CD risk, adjusting for gender and population group in logistic regression analysis. We validated our findings in 436 Italian cases and 532 controls. RESULTS: CD cases carried more non-HLA risk alleles than controls: individuals carrying > or = 13 risk alleles had a higher CD risk (odds ratio, 6.2; 95% confidence interval, 4.1-9.3) compared with those carrying 0-5 risk alleles. Combining HLA and non-HLA risk genotypes in one model increases sensitivity by 6.2% compared with using only HLA for identification of high-risk individuals with slight decrease in specificity. CONCLUSIONS: We can use non-HLA risk factors for CD to improve identification of high-risk individuals. Our risk model is a first step toward better diagnosis and prognosis in high-risk families and population-based screening.